R a d io lo g y a n d O n c o lo g y I V o lu m e 5 9 I N u m b e r 1 I P a g e s 1 -1 5 2 I M a r c h 2 0 2 5 march 2025 vol.59 no.1 Radiol Oncol 2025; 59(1): A. March 2025 Vol. 59 No. 1 Pages 1-152 ISSN 1318-2099 UDC 616-006 CODEN: RONCEM eISSN: 1581-3207 Publisher Association of Radiology and Oncology Aims and Scope Radiology and Oncology (ISSN 1318-2099) is a multidisciplinary journal devoted to the publishing original and high-quality scientific papers and review articles, pertinent to oncologic imaging, interventional radiology, nuclear medicine, radiotherapy, clinical and experimental oncology, radiobiology, medical physics, and radiation protection. Papers on more general aspects of interest to the radiologists and oncologists are also published (no case reports). Editor-in-Chief Gregor Serša, Institute of Oncology Ljubljana, Department of Experimental Oncology, Ljubljana, Slovenia (Subject Area: Experimental Oncology) Executive Editor Viljem Kovač, Institute of Oncology Ljubljana, Outpatient Clinic, Ljubljana, Slovenia (Subject Areas: Clinical Oncology, Radiotherapy) Deputy Editors Božidar Casar, Institute of Oncology Ljubljana, Department for Dosimetry and Quality of Radiological Procedures, Ljubljana Slovenia (Subject Area: Medical Physics) Andrej Cör, Valdoltra Orthopaedic Hospital, Ankaran, Slovenia (Subject Areas: Clinical Oncology, Experimental Oncology) Maja Čemažar, Institute of Oncology Ljubljana, Department of Experimental Oncology, Ljubljana, Slovenia (Subject Area: Experimental Oncology) Blaž Grošelj, Institute of Oncology Ljubljana, Department of Radiation Oncology, Ljubljana, Slovenia (Subject Areas: Radiotherapy, Clinical Oncology) Igor Kocijančič, Medicointerna d.o.o., Ljubljana, Slovenia (Subject Areas: Radiology, Nuclear Medicine) Miha Oražem, Institute of Oncology Ljubljana, Department of Radiation Oncology, Ljubljana. (Subject Areas: Radiotherapy, Clinical Oncology) Primož Strojan, Institute of Oncology Ljubljana, Department of Radiation Oncology, Ljubljana, Slovenia (Subject Areas: Radiotherapy, Clinical Oncology) Katarina Šurlan Popovič, University Medical Center Ljubljana, Institute of Radiology, Ljubljana, Slovenia (Subject Areas: Radiology, Nuclear Medicine) Editorial Board Subject Areas: Radiology and Nuclear Medicine Sotirios Bisdas, University College London, Department of Neuroradiology, London, United Kingdom Boris Brkljačić, University Hospital “Dubrava”, Department of Diagnostic and Interventional Radiology, Zagreb, Croatia Iztok Caglič, Cambridge University Hospitals, NHS Foundation Trust, Cambridge, United Kingdom Gordana Ivanac, University Hospital Dubrava, Department of Diagnostic and Interventional Radiology, Zagreb, Croatia Luka Ležaić, University Medical Centre Ljubljana, Department for Nuclear Medicine, Ljubljana, Slovenia Maja Mušič Marolt, Institute of Oncology Ljubljana, Department of Radiology, Ljubljana, Slovenia Igor Serša, Institut Jožef Stefan, Ljubljana, Slovenia Jernej Vidmar, University Medical Center Ljubljana, Clinical Institute of Radiology, Ljubljana, Slovenia Žiga Snoj, University Medical Center Ljubljana, Institute of Radiology, Ljubljana, Slovenia Subject Areas: Clinical Oncology and Radiotherapy Serena Bonin, University of Trieste, Department of Medical Sciences, Cattinara Hospital, Surgical Pathology Blg, Molecular Biology Lab, Trieste, Italy Luca Campana, Manchester University NHS Foundation Trust, Department of Surgery, Manchester, United Kingdom Christian Dittrich, Kaiser Franz Josef - Spital, Vienna, Austria Eva Oldenburger, University Hospital Leuven, Department of Radiation Oncology, Leuven, Belgium Gaber Plavc, Institute of Oncology Ljubljana, Department of Radiation Oncology, Ljubljana, Slovenia Csaba Polgar, National Institute of Oncology, Budapest, Hungary Dirk Rades, University of Lubeck, Department of Radiation Oncology, Lubeck, Germany Ivica Ratoša, Institute of Oncology Ljubljana, Department of Radiation Oncology, Ljubljana, Slovenia Luis Souhami, McGill University, Montreal, Canada Borut Štabuc, University Medical Center Ljubljana, Division of Internal Medicine, Department of Gastroenterology, Ljubljana, Slovenia Subject Area: Experimental Oncology Jean-Michel Escoffre, University de Tours, Tours, France Mihaela Jurdana, University of Primorska, Faculty of Health Sciences, Izola, Slovenia Janko Kos, University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia Damijan Miklavčič, University of Ljubljana, Faculty of Electrical Engineering, Ljubljana, Slovenia Gabriele Grassi, Universita degli Studi di Trieste, Trieste, Italy Nina Petrović, Laboratory for Radiobiology and Molecular Genetics, Department of Health and Environment, "VINČA "Institute of Nuclear Sciences- National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia Kristijan Ramadan, The MRC Weatherall Institute for Molecular Medicine, University of Oxford, United Kingdom Subject Area: Medical Physics Robert Jeraj, University of Wisconsin, Carbone Cancer Center, Madison, Wisconsin, USA Mirjana Josipovic, University of Copenhagen, Faculty of Health, Department of Clinical Medicine, Copenhagen, Denmark Slaven Jurković, University of Rijeka, Department of Medical Physics and Biophysics, Rijeka, Croatia Häkan Nyström, Skandionkliniken, Uppsala, Sweden Ervin B. Podgoršak, McGill University, Medical Physics Unit, Montreal, Canada Matthew Podgorsak, Roswell Park Cancer Institute, Departments of Biophysics and Radiation Medicine, Buffalo, NY, USA Radiol Oncol 2025; 59(1): B. Editorial office Radiology and Oncology Zaloška cesta 2 P. O. Box 2217 SI-1000 Ljubljana Slovenia Phone: +386 1 5879 369 Phone/Fax: +386 1 5879 434 E-mail: gsersa@onko-i.si Copyright © Radiology and Oncology. All rights reserved. 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Indexed and abstracted by: • Baidu Scholar • Case • Chemical Abstracts Service (CAS) - CAplus • Chemical Abstracts Service (CAS) - SciFinder • CNKI Scholar (China National Knowledge Infrastructure) • CNPIEC - cnpLINKer • Dimensions • DOAJ (Directory of Open Access Journals) • EBSCO (relevant databases) • EBSCO Discovery Service • Embase • Genamics JournalSeek • Google Scholar • Japan Science and Technology Agency (JST) • J-Gate • Journal Citation Reports/Science Edition • JournalGuide • JournalTOCs • KESLI-NDSL (Korean National Discovery for Science Leaders) • Medline • Meta • Microsoft Academic • Naviga (Softweco) • Primo Central (ExLibris) • ProQuest (relevant databases) • Publons • PubMed • PubMed Central • PubsHub • QOAM (Quality Open Access Market) • ReadCube • Reaxys • SCImago (SJR) • SCOPUS • Sherpa/RoMEO • Summon (Serials Solutions/ProQuest) • TDNet • Ulrich's Periodicals Directory/ulrichsweb • WanFang Data • Web of Science - Current Contents/Clinical Medicine • Web of Science - Science Citation Index Expanded • WorldCat (OCLC) This journal is printed on acid- free paper On the web: ISSN 1581-3207 https://content.sciendo.com/raon http://www.radioloncol.com Radiol Oncol 2025; 59(1): C. review 1 Pulsed field ablation in medicine: irreversible electroporation and electropermeabilization theory and applications Edward J Jacobs, Boris Rubinsky, Rafael V Davalos 23 Recurrent respiratory papillomatosis: role of bevacizumab and HPV vaccination. A literature review with case presentations. Silvio Sporeni, Francesca Rifaldi, Irene Lanzetta, Ilaria Imarisio, Benedetta Montagna, Francesco Serra, Francesco Agustoni, Paolo Pedrazzoli, Marco Benazzo, Giulia Bertino 31 The financial toxicity of breast cancer: a systematic mapping of the literature and identification of research challenges Ivica Ratosa, Mojca Bavdaz, Petra Dosenovic Bonca, Helena Barbara Zobec Logar, Andraz Perhavec, Marjeta Skubic, Katja Vörös, Ana Mihor, Vesna Zadnik, Tjasa Redek nuclear medicine 43 Early-time-point 18F-FDG-PET/CT and other prognostic biomarkers of survival in metastatic melanoma patients receiving immunotherapy Nezka Hribernik, Katja Strasek, Andrej Studen, Katarina Zevnik, Katja Skalic, Robert Jeraj, Martina Rebersek radiology 54 Prevalence of diffuse idiopathic skeletal hyperostosis and association with coronary artery calcifications in Slovenia Vesna Lesjak, Timea Hebar, Maja Pirnat 63 Accuracy of transthoracic echocardiography in diagnosis of cardiac myxoma: single center experience Polona Kacar, Nejc Pavsic, Mojca Bervar, Zvezdana Dolenc Strazar, Katja Prokselj 69 Comparison of 2D and 3D radiomics features with conventional features based on contrast-enhanced CT images for preoperative prediction the risk of thymic epithelial tumors Yu-Hang Yuan, Hui Zhang, Wei-Ling Xu, Dong Dong, Pei-Hong Gao, Cai-Juan Zhang, Yan Guo, Ling-Ling Tong, Fang-Chao Gong 79 Cardiac MRI for differentiating chemotherapy-induced cardiotoxicity in sarcoma and breast cancer El-Sayed H Ibrahim, Lubna Chaudhary, Yee-Chung Cheng, Antonio Sosa, Dayeong An, John Charlson contents contents Radiol Oncol 2025; 59(1): D. 91 Innovative strategies for minimizing hematoma risk in MRI-guided breast biopsies Michael P Brönnimann, Matthew T McMurray, Johannes T Heverhagen, Andreas Christe, Corinne Wyss, Alan A Peters, Adrian T Huber, Florian Dammann, Verena C Obmann clinical oncology 100 Comparison of selective intra-arterial to standard intravenous administration in percutaneous electrochemotherapy (pECT) for liver tumors Tim Wilke, Erschad Hussain, Hannah Spallek, Francesca de Terlizzi, Lluis M Mir, Peter Bischoff, Andreas Schäfer, Elke Bartmuß, Matteo Cadossi, Alessandro Zanasi, Michael Pinkawa, Attila Kovács 110 Investigation of GSTP1 and PTEN gene polymorphisms and their association with susceptibility to colorectal cancer Durr-e-Shahwar, Hina Zubair, Muhammad Kashif Raza, Zahid Khan, Lamjed Mansour, Aktar Ali, Muhammad Imran 121 Management of adrenocortical carcinoma in Slovenia: a real-life analysis of histopathologic markers, treatment patterns, prognostic factors, and survival Urska Bokal, Jera Jeruc, Tomaz Kocjan, Metka Volavsek, Janja Jerebic, Matej Rakusa, Marina Mencinger 132 Effectiveness of tramadol or topic lidocaine compared to epidural or opioid analgesia on postoperative analgesia in laparoscopic colorectal tumor resection Alenka Spindler-Vesel, Matej Jenko, Ajsa Repar, Iztok Potocnik, Jasmina Markovic-Bozic 139 Interobserver and sequence variability in the delineation of pelvic organs at risk on magnetic resonance images Wanjia Zheng, Xin Yang, Zesen Cheng, Jinxing Lian, Enting Li, Shaoling Mo, Yimei Liu, Sijuan Huang 147 Bronchial bacterial colonization and the susceptibility of isolated bacteria in patients with lung malignancy Sabrina Petrovic, Bojana Beovic, Viktorija Tomic, Marko Bitenc, Mateja Marc Malovrh, Vladimir Dimitric, Dane Luznik, Martina Miklavcic, Tamara Bozic, Tina Gabrovec, Aleksander Sadikov, Ales Rozman I slovenian abstracts contents Radiol Oncol 2025; 59(1): 1-22. doi: 10.2478/raon-2025-0011 1 review Pulsed field ablation in medicine: irreversible electroporation and electropermeabilization theory and applications Edward J Jacobs1, Boris Rubinsky2, Rafael V Davalos1 1 Wallace H Coulter School of Biomedical Engineering, Georgia Institute of Technology & Emory Medical School, Atlanta, Georgia, USA 2 Department of Bioengineering and Department of Mechanical Engineering, University of California, Berkeley, Berkeley, California, USA Radiol Oncol 2025; 59(1): 1-22. Received 21 November 2024 Accepted 7 December 2024 Correspondence: Rafael Davalos, Ph.D., Wallace H. Coulter School of Biomedical Engineering, Georgia Institute of Technology & Emory Medical School, Atlanta, Georgia, USA. E-mail: Rafael.Davalos@bme.gatech.edu Disclosure: R.D. and B.R. have patents in the field of bioelectrics. This is an open access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/). Background. Focal ablation techniques are integral in the surgical intervention of diseased tissue, where it is neces- sary to minimize damage to the surrounding parenchyma and critical structures. Irreversible electroporation (IRE) and high-frequency IRE (H-FIRE), colloquially called pulsed-field ablation (PFA), utilize high-amplitude, low-energy pulsed electric fields (PEFs) to nonthermally ablate soft tissue. PEFs induce cell death through permeabilization of the cellular membrane, leading to loss of homeostasis. The unique nonthermal nature of PFA allows for selective cell death while minimally affecting surrounding proteinaceous structures, permitting treatment near sensitive anatomy where thermal ablation or surgical resection is contraindicated. Further, PFA is being used to treat tissue when tumor margins are not expected after surgical resection, termed margin accentuation. This review explores both the theoretical foundations of PFA, detailing how PEFs induce cell membrane destabilization and selective tissue ablation, the outcomes following treatment, and its clinical implications across oncology and cardiology. Conclusions. Clinical experience is still progressing, but reports have demonstrated that PFA reduces complications often seen with thermal ablation techniques. Mounting oncology data also support that PFA produces a robust im- mune response that may prevent local recurrences and attenuate metastatic disease. Despite promising outcomes, challenges such as optimizing field delivery and addressing variations in tissue response require further investigation. Future directions include refining PFA protocols and expanding its application to other therapeutic areas like benign tissue hyperplasia and chronic bronchitis. Key words: puled-field ablation; irreversible electroporation; pulsed electric fields; margin accentuation; oncology; atrial fibrillation Electropermeabilization theory Electropermeabilization is a biophysical phenom- enon in which exogenous electric fields (EFs) in- crease the permeability of the cellular membrane (Figure 1). The application of an electric potential across tissue generates an EF whose shape and magnitude depend on the local electrical tissue properties. The EF induces ion movement (i.e., cur- rent) within the tissue (Figure 2), and the subse- quent charge concentration around cells generates an electric potential across the cellular membrane. This transmembrane potential (TMP) permeabi- lizes the cellular membrane through phospholipid oxidation1-6, modulation of electrically-induced proteins7, and the generation of nano-scale pores Radiol Oncol 2025; 59(1): 1-22. Jacobs EJ et al. / Pulsed field ablation in medicine2 (electroporation).8 Standard electroporation theory and experiments suggest that pores are the domi- nant factor in mass transport across the membrane following electropermeabilization9 and that pore formation occurs when the induced TMP exceeds a critical threshold (~0.258 V).10 The magnitude of the induced TMP is dependent on the local ge- ometry of the membrane and directly related to cell size and shape.11,12 Once the exogenous EF is removed, the hydrophobic interactions, Van der Waals forces, and electrostatic interactions within the phospholipid bilayer may cause the pores to reseal within seconds to hours.13-15 The transitory formation of pores is called reversible electropora- tion (rEP) and has been used for decades to deliver chemotherapeutics (electrochemotherapy; ECT)16- 18, calcium (calcium electroporation; CaEP)19-25, ge- netic material (gene electrotherapy, GET)26,27, and otherwise impermeable substances28 into cells. With the application of higher magnitude and pro- tracted pulses, pore nucleation increases within the cellular membrane, and existing pores ex- pand, allowing for increased mass transport, con- sequently with the increased likelihood of losing homeostasis or causing cellular membrane hemor- rhage.7,29,30 Concomitant to pore formation, the applied EF generates reactive oxygen species (ROS) that can induce lipid oxidation within the membrane.1-6 Lipid oxidation increases the spacing between li- pids and decreases membrane thickness, leading to increases in membrane permeability and elec- trical conductivity.5,6,31 Since oxidative agents are slowly removed from the membrane32, these effects FIGURE 1. Conceptual schematic of the molecular mechanisms of electropermeabilization. (A) An intact cell membrane (B) in an exogenous electric field experiences an induced transmembrane potential. (C) Hydrophobic pores become energetically favorable as water infiltrates the bilayer. With the removal of the applied electric field, the hydrophobic pore reseals within nanoseconds. (D) If higher and longer external electric fields are applied, phospholipids invert to form small hydrophilic pores that allow the passage of ions and small molecules. Elastic forces within the membrane allow for these pores to reseal within nanoseconds to microseconds after the removal of the electric field. (E) With higher magnitude and longer duration electric fields, pores number may increase, and nucleated pores may expand or combine, allowing the transport of larger molecules and higher quantities across the membrane. Significant lipid oxidation is indicated to occur at high electric fields. (F) If excessive, the lipid bilayer may hemorrhage leading to lytic (necrotic) cell death. (G) After cessation of the applied electric field, the cell membrane may remain permeable due to the presence of lipid oxidation, which, in return, also allows for easier pore formation upon the introduction of another electric field. (H) As significant mass transport occurs over the cell membrane, the cell may lose homeostasis and die through regulated cell death, or (G) the cell may repair the permeable and damaged cell membrane to regain homeostasis. A B C DE F G H Radiol Oncol 2025; 59(1): 1-22. Jacobs EJ et al. / Pulsed field ablation in medicine 3 also persist after pores reseal.4,5 Further, subse- quent pore formation and increased oxidation may occur more easily at locations of previous oxida- tion33, and oxidative lipids may diffuse throughout the membrane between applied pulses.34 Excessive oxidation can occur using higher magnitude EFs, longer pulses, and more pulses2-4, leading to com- plete bilayer disruption and cell death.31 Further, PEFs can destabilize and fragment cy- toskeletal elements35, including actin filaments36-39, microtubules40,41, and intermediate filaments41-43, which collectively maintain cell shape, enable intracellular transport, and support membrane stability.44 The membrane and cytoskeleton are functionally and structurally linked, so disrup- tion can exacerbate membrane deformation and impair cellular mechanical properties, increasing the susceptibility of the membrane to subsequent pore formation and enhancing ion and molecule transport.39,45 Cytoskeletal disruption may also interfere with cellular signaling pathways reliant on cytoskeletal integrity, affecting processes such as cell adhesion, motility, and division36,42,45, with implications in blood vessel permeabilization.46-48 As with membrane oxidation, cytoskeletal damage can persist even after the EF is removed, leading to prolonged changes in cell structure and negatively impacting cell viability and function.49,50 Pulsed field ablation techniques in medicine Irreversible electroporation (IRE) was initially considered the upper limit of rEP and, as such, something to be avoided when post-treatment vi- ability is desired.11 With their seminal paper, R. Davalos, L. Mir, and B. Rubinsky mathematically described that EFs necessary to induce clinically relevant volumes of IRE did not simultaneously generate significant Joule heating and subsequent thermal damage.51 Edd et al. supported this hy- pothesis by generating contiguous ablations in rat livers at EFs indicated to not cause thermal dam- age.52 Following, Al-Sakere et al. reported the first successful use of IRE in oncology, achieving com- plete regression in 92% (12/13) of treated cutaneous mouse tumors using an optimized waveform (80 monophasic pulses of 100 µs at 0.3 Hz and 2500 V/cm), with a maximum measured temperature of 37.5°C.53 The results from these studies demon- strated the feasibility of increasing the number of pulses from conventional ECT (8 pulses) without inducing thermal damage and provided the foun- dation for parameters used in current IRE proto- cols. Shortly after, Bertacchini et al. developed the first IRE generator approved for clinical use.54 Since the introduction of IRE in the clinic in 2010, over 100 clinical trials have been registered world- wide (Figure 3), with hundreds of research articles published demonstrating safe and effective treat- ment of prostate55-64, pancreas65-74, liver75-84, and kidney85-97 tumors, but feasibility in many other solid tumors like lung98-99 and brain100 has been demonstrated. IRE as a clinical technique is described as a non-thermal focal ablation modality that employs high-magnitude (1–3 kV) and short (70–100 µs) monophasic pulses (Figure 4A) generated between conductive electrodes placed into or around the targeted tissue. In clinical practice, conventional FIGURE 2. Electric field and current through heterogeneous tissue. (A) Without electroporation, current (green arrows) passes around the cells (pink) through the extracellular space (blue). (B) Electroporation allows for current to pass through the cells, but it is still influenced by tissue heterogeneity. A B FIGURE 3. (A) cumulative registered patient and trial numbers for IRE and PFA on ClinicalTrials.gov. (B) Breakdown of trials and (C) patient populations by tissue type. Other contains renal, lung, stomach, esophageal, gallbladder, hilus pulmonis, extremity, lymph node, intestinal, rectal, laryngeal, head and neck, and breast cancers; benign prostate hyperplasia; chronic bronchitis; tonsillar hypertrophy. A B C Radiol Oncol 2025; 59(1): 1-22. Jacobs EJ et al. / Pulsed field ablation in medicine4 monophasic IRE pulses must be delivered using general anesthesia and prophylactic neuromuscu- lar blockers to reduce muscle contractions.53,101-103 Induced muscle contractions are undesirable in debilitated patients and can cause an involuntary shift in the electrode locations, leading to incom- plete ablation of the target region or puncture of neighboring critical structures (e.g., blood vessels, nerves). Early experience with IRE was also asso- ciated with incidence of cardiac dysrhythmia, so pulse delivery is now synchronized to the R-wave on electrocardiogram (ECG) recording with a 0.05 s delay to avoid interference with normal cardiac rhythm.104 IRE is still contraindicated in patients with cardiac arrhythmia, as pulses cannot be con- FIGURE 4. (A) Monophasic IRE waveform and (B) Biphasic H-FIRE waveform. (1) Magnitude (voltage or current), (2) pulse width, (3) interphase delay, (4) interpulse / intercycle delay, (5) burst repitition interval. FIGURE 5. Pulsed field ablation treatment planning pipeline. (A) Images of the region of interest are taken through CT, MRI, US, or other modalities. Typically, segmentation is performed to define individual tissue regions before computational modeling, as the dynamic electric field, temperature, and conductivity distributions are tissue dependent. Numerical modeling is performed with the intent to maximize targeted tissue coverage with a critical electric field while minimizing deleterious effects on nearby structures. Following, the protocol is implemented for the treatment of the target tissue. While computational modeling can inform treatments, the exact application of PFA can often differ from a priori computational modeling. Post-treatment imaging is frequently used to assess acute and long-term ablation success. (B) Tissue electroporation modeling is multifaceted and requires knowledge about multiple electroporation-dependent and electroporation-independent tissue properties. The local electric potential depends on the local electrical conductivity and temperature. The electrical conductivity also depends on the local temperature and the electric field, as pore formation due to the local electric field allows for current to flow through cells. Subsequently, temperature generation depends on the electric field magnitude and the local conductivity. Images in panel A were adapted from various sources for instructional purposes.100,235 A B A B Radiol Oncol 2025; 59(1): 1-22. Jacobs EJ et al. / Pulsed field ablation in medicine 5 sistently synchronized with the cardiac refractory period. To overcome these limitations, Arena et al. de- veloped High-Frequency IRE (H-FIRE)105, which utilizes a series of short (0.5–10 µs) biphasic pulses. The H-FIRE waveform is constructed of a positive pulse, interphase delay (d1), negative pulse, and interpulse delay (d2), repeated for several cycles to achieve an on-time comparable to IRE (Figure 4B). H-FIRE significantly reduces muscle contraction during treatment and obviates the use of neuro- muscular blockers or cardiac synchronization.106 Further, the shorter pulses are suggested to pro- vide more predictable ablations when the pulse width is below the cell membrane charging time of 1–2 µs.107-108 However, as a consequence of the reduced membrane charging, the EF threshold (EFT) required to induce electroporation increas- es as pulse width decreases, but thermal heat- ing remains relatively the same.109-110 H-FIRE has been used pre-clinically to treat breast111, liver106, brain112, lung113, and prostate114 cancer with mixed results. To date, H-FIRE has not demonstrated the same tumor ablation capability as IRE, but H-FIRE has been evaluated clinically in prostate cancer, of- fering a potential reduction in experienced compli- cations.115,116 Notwithstanding, H-FIRE has gained prodigious attention for the treatment of cardiac arrhythmias under the name PFA.117-129 Between the different groups, H-FIRE (i.e., PFA) is indicated to have been performed in over 100,000 patients as of September 2024, not without appropriate criti- cism of the lack of transparency for treatment de- tails. Since PFA primarily induces cell death through permeabilization of the cell membranes, the PEFs minimally affect proteinaceous structures. The nonthermal mechanism is paramount for the con- trol of diseased tissue near critical structures, such as bowels97, ducts130, mature blood vessels131,132, es- ophagus133, and nerves56,134,135, where surgical resec- tion and thermal ablation methods are contraindi- cated. Further, PFA is not influenced by the “heat sink” effect, where blood flow in adjacent vessels dissipates heat, reducing ablation effectiveness and potentially sparing targeted tissue. This al- lows PFA to completely treat tissue abutting blood vessels. Narayan et al. examined the patency of 158 vessels with a mean distance from the treatment lesions of 2.3 mm and noted abnormal changes in 4.4% (7/158) of vessels.132 Only 1.4% (2/158) were hemodynamically significant, with many vessels that experienced thrombosis post-treatment al- ready heavily involved before treatment. Tumors abutted 40 vessels and encased 10 vessels, but 96% (48/50) maintained patency despite being di- rectly within the ablation. Further, Li et al. found that neurovascular bundles are not destroyed even when directly treated with ablative PEFs.134 Subsequent studies have observed that there may be some degree of thermal damage to the tissue immediately near the treatment electrodes136-137, so careful planning and probe placement are still needed. Pretreatment planning Computational modeling is necessary for the suc- cessful delivery of PFA138, as the entire target tissue must be covered by a critical EF while minimizing collateral damage to nearby critical structures.139 Treatment planning includes (Figure 5): 1. Imaging of the treatment area and surrounding structures Before surgery, the location, size, and geometry of the tissue to be treated are determined with one or more imaging modalities, including contrast- enhanced computed tomography (Ce-CT), posi- tron emission tomography (PET), magnetic reso- nance imaging (MRI), and 3D-mapping biopsy for prostate cancer (PCa). Except for PCa, Ce-CT is the most used modality due to its availability, high resolution, and ability to rapidly create multi-pla- nar reconstructions of the tumor and surrounding structures.140 For cancer patients, tumor growth or shifting may cause differences between prior- and intra-procedural images, so Ce-CT also allows for rapid adjustments in the treatment planning and probe position.140-142 2. 3D reconstruction of the anatomy of the treatment area Multi-planar images are imported into a segmen- tation software (e.g., 3DSlicer) to separate the tu- mor, parenchyma, and nearby structures. The ge- ometries are then meshed for importing into finite element analysis software (e.g., COMSOLTM). 3. Define the electroporation-dependent material properties for the different tissues A priori information about the target tissue is need- ed for accurate treatment modeling. Both the EF Radiol Oncol 2025; 59(1): 1-22. Jacobs EJ et al. / Pulsed field ablation in medicine6 and temperature distributions strongly depend on the tissue-specific electrical properties143,144, which both differ between patients in healthy and ma- lignant tissues and change non-linearly from the electroporation process itself.145 Results in compu- tational modeling significantly differ when con- sidering electroporation effects146,147, but validated tissue properties are sparse within the literature. Conventional methods for tissue characteriza- tion use ex vivo tissue slices with fixed geometries to translate impedance at different applied EF magni- tudes to conductivity.146,148 Quantifications are often limited to healthy animal tissues due to their avail- ability and can misrepresent the targeted tissue, es- pecially when translating results to tumors. Tissue characterization using patient-derived xenografts is more representative149, but they can take weeks to grow, are not widely available during treatment planning, and do not replicate in situ conditions. Further, even within a specific tumor type, there can be a high degree of tumor tissue heterogene- ity between patients and even between tumors at different locations in the body. Translating experi- mentally found properties to an individual can be unreliable, so improved methods for patient-spe- cific tissue characterizations are greatly needed.147 In addition to simulating the EF and thermal distributions, it is necessary to know the EFT of the tissues being treated to quantify the lesion coverage. Values for the lethal EFT are variable within the literature due to the lack of validated and standardized protocols. Thresholds gathered in vitro using cuvette systems are typically higher than those gathered using 2D or 3D platforms, but in-situ data is the most translatable.150 Pulse widths from nanoseconds to milliseconds will generate ablations, but pulse width negatively correlates with EFTs.109,110,151,152 4. Incorporation of treatment probes within the model and numerical optimization Intrinsic tissue properties cannot often be changed; thus, treatment parameters (i.e., voltage, probe ge- ometry, and PFA waveform) must be adjusted to find solutions that solve the desired objective. The two main objectives that are usually investigated for PFA are (1) encompassing the target tissue with a lethal EF while (2) minimizing Joule heating and subsequent thermal damage to nearby critical structures. The number of probes depends on the ability to cover the tumor and margin with a lethal EF. For deep soft tissue neoplasms, typically 2 to 6 monopo- lar probes are inserted into or around the neoplasm. For lesions smaller than 2 cm, 3 probes are placed at the periphery of the tumor in a triangle; for le- sions between 2–3 cm, 4 probes are placed at the periphery in a square; for lesions larger than 3 cm, 4–6 probes are used, with 1–2 of the probes placed within the lesion and the rest at the periphery.153 The distance between electrode pairs should not ex- ceed 2.2 cm, but values have ranged from 0.7 to 2.9 cm in literature. The electrode exposure can vary from 0.5 to 3 cm, but 1.5 cm is the most common. The applied current scales linearly with electrode exposure, and too large of an exposure can trigger the overcurrent on electroporation generators at 50 A. Therefore, if the target is larger than the possi- ble electrode exposure, the deepest portion of the target should be treated first; then, the electrodes can be “pulled back” for subsequent treatments to ensure overlapping and cohesive ablations. Applied EFs or “voltage-to-distance ratios” (VDRs) typically range from 1200 V/cm to 2000 V/ cm for IRE and 2000 V/cm to 3000 V/cm for H-FIRE. Higher VDRs will generate larger ablations at the consequence of increased Joule heating, neuro- muscular excitation, and electrochemical effects. Probe positioning and treatment IRE has been successfully performed through in- traoperatively154, laparoscopy155, and percutane- ous156 insertion of treatment probes. For percutane- ous insertion, the probes must be carefully insert- ed under contrast-enhanced ultrasound (ce-US) or ce-CT guidance to prevent puncturing sensitive structures and maintain parallel insertion of the electrodes. Imaging is used to verify correct probe placement and measure the center-to-center probe separation to calculate the VDR. Probes should be placed parallel to each other with no more than 10-degree deviations to prevent irregular ablations and possible incomplete treatment. Despite the EF coverage ultimately dictating ablation size, clinicians have found that electrical currents between 20 and 40 A during IRE provide sufficient ablations. With the NanoKnife system, 10 pulses are initially delivered to assess the applied current between each electrode pair. Following, if the current is adequate, the rest of the treatment will be delivered. Otherwise, the clinicians will in- crease or decrease the VDR to achieve the desired current and then deliver the appropriate number Radiol Oncol 2025; 59(1): 1-22. Jacobs EJ et al. / Pulsed field ablation in medicine 7 of pulses. An applied potential is only generated between one electrode pair at a time, and the final train of pulses is typically either 70 or 90 pulses between each probe pair. In addition to cardiac arrhythmia, other abso- lute contraindications for PFA include the pres- ence of non-removable pacemakers or implantable cardioverter defibrillators, a history of epilepsy or seizures, a history of bleeding disorders, and the presence of anatomical obstacles blocking safe probe insertion. Post treatment imaging CT imaging is predominantly used after the procedure to determine treatment success and to evaluate disease recurrence or remission dur- ing follow-ups157, but ablations are also regularly visualized using PET140, MRI157, and US.137 Further, both IRE and H-FIRE produce ablations with sharper delineation than other ablation modali- ties.158 Histology of ablations demonstrates de- marcation between the ablated and live tissue on the order of 1–2 cells. Cell death and immune activation Given the complex and nuanced processes in- volved, the cell death mechanisms following IRE and H-FIRE are still under investigation. Researchers originally attributed necrosis due to FIGURE 6. Immune response following pulsed field ablation. The tumor microenvironment (TME) evolved through all stages of cancer progression and protects itself through reprogramming immune cells (T regulatory cells [T-reg], myeloid-derived suppressor cells [MDSCs], and tumor-associated macrophages [TAMs]), attracting stromal cells (endothelial cells and fibroblasts) that help deposit a dense extracellular matrix (ECM). This produces an immunosuppressive “cold” tumor that excludes normal immune cells from infiltrating. Pulsed-field ablation indiscriminately kills tumor cells, stromal cells, and immunosuppressive immune cells within the ablation and restructures the ECM. The removal of active immunosuppression, permeabilization of mature blood vessels, and release of Damage Associated Molecular patterns (DAMPs) by IRE entices innate immune cell infiltration. Tumor antigens are released by treated cells, which are either taken up by dendritic cells or drained directly into lymph nodes for antigen presentation. Tumor-specific T- and B-cells mature within the lymph nodes, then antigen-specific T- and B-cells leave the lymph node to potentially remove residual cancer or target distant metastatic disease. Radiol Oncol 2025; 59(1): 1-22. Jacobs EJ et al. / Pulsed field ablation in medicine8 disruption of the osmotic balance as the killing mechanism of electroporation. However, in the late 1990s, it was demonstrated that electropora- tion not only caused necrosis but also induced delayed cell death following chromosomal DNA fragmentation, which is an explicit indication of late apoptosis.159,160 There is a plethora of competing findings for cell death pathways and mechanisms following PFA, including immunogenic (e.g., necrosis, necropto- sis, and pyroptosis) and non-immunogenic (e.g., apoptosis) cell death.136,159-163 Each pathway has unique implications for treatment side effects, immune activation, and efficacy.164 Increasing evidence suggests that H-FIRE induces delayed, regulated cell death while IRE induces immedi- ate, lytic cell death.163,165,166 Further, it is suggested that higher EFs are more likely to induce necrosis through membrane hemorrhaging and thermal damage, while lower EFs may permit membrane recovery but induce regulated cell death follow- ing ROS generation, DNA damage, mitochondrial damage, ATP loss, osmotic imbalance, or calcium influx.29,136,165,166 While apoptosis is frequently high- lighted as a key form of cell death in PFA, immedi- ate cell death observed following IRE and H-FIRE often shows characteristics of necrosis. Thus, rath- er than a single pathway, it is likely a combination of overlapping death mechanisms that lead to the loss of cellular homeostasis. I. PFA reduces the anti-inflammatory cell populations within the tumor microenvironment In many solid tumors, multiple cell populations contribute to the immunosuppressive “cold” TME (Figure 6), including differentiated cancer cells, cancer stem cells, tumor-associated fibro- blasts (TAFs), and immunosuppressive immune cells (ISICs) (e.g., tumor-associated macrophag- es [TAMs], myeloid-derived suppressor cells [MDSCs], and regulatory T-cells [Treg]).167 Further, the epigenetic and cellular composition of tu- mors can vary between patients, between differ- ent tumors within a patient, and even at different locations within the same tumors168, making it challenging to provide single-target therapeutics. PFA acts indiscriminately on proliferating and non-proliferating cells169 within the critical EFT. Therefore, recalcitrant (e.g., cancer stem cells170,171) and immunosuppressive cells (TAMs, MDSCs, TAFs, and Tregs111,172,173) are removed in addition to bulk tumor cytoreduction. II. PFA effectively reverses the stroma- induced immunosuppression PFA ablation alters the physical properties of the TME through reduction of the extracellular ma- trix density and rigidity174,175 and increases tumor- associated blood vessel permeability.47,48,137,175,176 These both reduce tumor-associated hypoxia that impedes leukocyte function.175 Increases in micro- vascular density are indicated after treatment174,175, but this may be attributed to transient decreases in vascular junction integrity and subsequent in- creases in the expression of junction proteins to re- gain microvasculature function. The preservation of mature vasculature patency while increasing permeability allows for infiltration of leukocytes and transport of TAAs to tumor-draining lymph nodes238. These results are not replicated in other focal ablation therapies, indicating that IRE may uniquely modulate the TME. Regeneration of the ablation site by parenchymal cells is also indicated at 1–2 weeks post ablations177, but underlying tis- sue disease or chemoembolization may prevent the healing process.95 III. PFA induces a pro-inflammatory TME and activates the adaptive immune system In addition to reducing anti-inflammatory cell populations, PFA actively promotes an immune- supportive TME. Damage associated molecular patterns (DAMPs) are released by electroporated cells and recognized by the innate immune system for generating early inflammation.111,175 Tumor- associated antigens (TAAs) are also released and evaginated by dendritic cells and macrophages for antigen presentation.178 Unlike with thermal ab- lation modalities, DAMPs and TAAs released by electroporated cells are presumably not destroyed due to the lack of sufficient thermal heat to dena- ture proteins, potentially allowing for the priming of mature T-cells with receptors directed at the in- situ protein motif.179 Although PFA treatment success is not predi- cated by the induction of an anti-tumor immune response, both in vivo and clinical data suggest a correlation between immune activation and pro- gression-free survival (PFS) and overall survival (OS). He et al. demonstrated the disparity in patient OS when gating by immune activation; when sep- arating patients into high and low T-lymphocyte responses, there was 70–80% and 0% survival at 30 months post-IRE, respectively.74 Goboers et al. Radiol Oncol 2025; 59(1): 1-22. Jacobs EJ et al. / Pulsed field ablation in medicine 9 found that T-cell activation correlated with pre- treatment tumor sizes and suggested that antigen release may correlate with the extent of ablation.173 Larger ablation volumes would presumably induce more TAA and DAMP release while generating a larger variety of cell death mechanisms to create a robust immune response. They also found a de- crease in circulating dendritic cell populations in- dicative of activation-induced migration to lymph nodes and treated tissue, which was supported by the activated T-cells expressing specific receptors against prostate cancer-associated antigens. IV. PFA can be combined with immunotherapies To consistently generate persistent peripheral anti- tumor immune activation, current research aims to adjust pulsing waveforms to generate more inflammatory cell death modalities or combine treatment with adjuvant immunotherapies. The combination of IRE and immune checkpoint in- hibitors (ICIs), such as anti-CTLA4, anti-PDL1, and anti-PD1, have positive results in both mice and humans.172,175,178,180 He et al. presented promising re- sults when combining IRE with anti-PD1 in Stage III locally advanced pancreatic cancer, achiev- ing an overall survival of 44.3 months versus 23.4 months for IRE alone.180 Further, they did not ob- serve differences in adverse side effects between the two treatment groups, demonstrating that ICIs may offer a significant increase in IRE efficacy without additional side effects. Primary tumor ab- lation with IRE in a PCa mouse model, followed by anti-CTLA4 and anti-PD1 immune checkpoint inhibitors, induced a significant increase in both tissue-resident and circulating memory cytotoxic T-cells with T-cell receptors targeting PCa-specific antigen, SPAS-1.178 Subsequently, this work indicat- ed that a tumor vaccine effect was achieved by the tissue-resident and circulating memory cytotoxic CD8+ T-cells, limiting the reintroduction of new PCa. A recent direct comparison of IRE with cry- oablation (CA) and thermal ablation further dem- onstrated that anti-PD1 synergizes best with IRE, leading to longer tumor-free survival, increased infiltration of CD8+ T-cells, and protection against tumor reintroduction.181 Due to the modulation of the immunosuppressive TME, the efficacy of den- dritic cell vaccination is improved after IRE.182 Despite promising results, local and distant tumor recurrence still occurs. A potential reason for the eventual tumor recurrence is that major histocompatibility complex I (MHC I) downregu- lation occurs 30–100% in many cancer types, with pancreatic cancer having a suppression rate of 40–100%.183,184 IRE clearly benefits from an induced immune response, but without antigen presenta- tion for T-cell recognition, the local and metastatic micro-tumors are hidden from the heightened im- mune response and eventually repopulate local and distant sites. Lin et al. demonstrated the poten- tial for combining IRE with autologous γδ T-cells, which can recognize and lyse cancers in an MHC- unrestricted manner. Patient γδ T-cells were iso- lated from the blood, expanded, and then reintro- duced after IRE through at least 2 cycles.185 Patients with multiple infusions survived longer after treatment (17 months) than patients with a single infusion (13.5 months) or IRE alone (11 months). Further, IRE has been combined with natural kill- er (NK) cells186-189, which recognize cells that have downregulated MHC I receptors.190 Despite only evaluating the efficacy at 1-mo post-treatment, a randomized study of 92 LAPC patients found that the IRE-NK group achieved an overall response of 71.7% compared to IRE alone with 56.5%.188 Prostate (PCa) PCa is a leading cause of cancer-related deaths among men191, and the contemporary treatment for localized PCa is active surveillance, radical pros- tatectomy, and radiation therapy. Routine prostate examinations are becoming increasingly popu- lar, resulting in earlier detection of manageable small-volume neoplasms. While whole-gland ap- proaches have historically offered the best possible oncological outcome for local disease, low- to inter- mediate-risk patients may not benefit from radical treatments, as damage to the neurovascular bun- dle, external sphincter, bladder neck, urethra, and rectum are often associated with gastrourinary dysfunction which could include impotence, in- continence, pain, loss of rectal control, and loss of sensation. IRE offers a valuable treatment option for these patients, as the negative side effects can be circumvented while still achieving sufficient oncological outcomes. Further, IRE can be success- fully delivered to any region of the gland (apex, middle, or base) with similar disease control192, while other focal ablation therapies are known to be preferential for certain areas.193,194 The first evaluation of IRE in the prostate was performed by Onik et al. in 2007 in six healthy canine prostates.61 Histology revealed a fine de- marcation between the unaffected and necrotic Radiol Oncol 2025; 59(1): 1-22. Jacobs EJ et al. / Pulsed field ablation in medicine10 prostate tissue, spanning only a few cells. When directly including the urethra within the abla- tion, necrotic glandular tissue abutted urethral structures without necrosis within the sub-mu- cosa. Vessel patency was also preserved when deliberately treating the neurovascular bundle, though variable endothelial and fibrinoid necrosis was observed. The authors expressed that nerves within the neurovascular bundles did not appear to be affected, with no evidence of ganglion cell death. Following, Onik et al. performed the first human clinical trial for IRE, involving 16 patients with low- to moderate-risk prostate cancer in a se- ries of outpatient procedures.62 All patients were continent immediately after IRE, and all patients who were potent before the procedure were still potent after the procedure. Two patients who had bilateral areas treated required 6 months for a full return of potency. Color Doppler US showed intact flow within the neurovascular bundle immediate- ly after the procedure, and postoperative biopsies taken from the area of previously known cancer in 15 patients showed no evidence of cancer. A disadvantage of focal ablation therapies is the possible presence of multi-focal disease that is not initially diagnosed through imaging or biopsy. As PCa is frequently multi-focal, IRE application to multiple segments or the entire prostate gland can extend its coverage. A multi-center rand- omized clinical trial evaluated the control of focal and extended IRE in 106 low- to intermediate- risk patients.56 A similar total rate of recurrence was observed, but the extended ablation cohort experi- enced lower recurrence away from the lesion site. Guenter et al. also presented encouraging results from a large retrospective assessment of 429 pa- tients with low (n = 25), intermediate (n = 88), and high-risk (n = 312) prostate cancer.195 Patients were treated focally (n = 123), sub-whole-gland (n = 154), whole gland (n = 134), or for recurrent disease after previous treatment with other modalities (n = 63). During a maximum follow-up time of 72 months, 3 (12%), 18 (20.4%), and 26 (8.3%) recurrent can- cers were observed in the low-, intermediate-, and high-risk groups, respectively. Urinary continence was preserved in all patients. Ten patients devel- oped a temporary decrease in erectile function, with 4 patients experiencing a decrease longer than a year. Scheltema et al. recently released their longer-term (60 months) oncologic and functional evaluation following IRE as a primary treatment in 229 patients (International Society of Urologic Pathologists [ISUP] grade 1–4).196 The long-term follow-up confirmed earlier findings that IRE provides acceptable local and distant oncological control with lower loss of continence and potency than radical treatments. Radiotherapy is a well-established therapy for PCa; however, one in five patients recur with sig- nificant disease, forming a difficult-to-treat patient sub-population. Recently, IRE has been evaluated in patients with recurrent PCa, specifically follow- ing prostatectomy and radiotherapy.197-199 Mid-term oncological and safety results demonstrate that IRE can be delivered safely to ISUP 1–5 recurrent patients, with similar in-field oncologic responses to in situ treatment.197 Dong et al. were the first to demonstrate the feasibility of tumor ablation using H-FIRE in hu- mans.115 They treated 40 PCa patients using a 5 µs pulse width without ECG synchronization and with moderately lower muscle relaxants than con- ventional treatments. No muscle contractions or abnormalities were observed during H-FIRE deliv- ery, with all patients able to move ~10 hours after treatment. Lesions were clearly visible on MRI at 4 weeks post-treatment. At a median follow-up of 6 months, no major complications were experienced, with sexual function and urinary continence pre- served in all patients. A recent multi-center non- randomized prospective clinical study treated 109 patients with low (n = 27) and intermediate (n = 82) risk PCa using an unspecified H-FIRE waveform.116 One hundred patients underwent a 6-month biop- sy, with clinically significant prostate cancer in the treatment zone and out of the treatment zones for 1 and 5 patients, respectively. Urinary continence was maintained in 99.1% of patients, and emergent sexual dysfunction was experienced in 9% of pa- tients. Pancreas (PC) Pancreatic cancer is currently the 3rd deadliest malignancy and possesses an insidious progno- sis due to its surreptitious progression, with over 80% of patients unfortunately presenting stage III locally advanced pancreatic cancer (LAPC) or metastatic disease at diagnosis. Poor outcomes for LAPC are attributed to diffuse cancer infiltration, the sclerotic and immunosuppressive tumor mi- croenvironment, and significant involvement of sensitive structures. This precludes surgical resec- tion in > 80% of patients. The intervention of un- resectable PC consists of chemoradiation, which has not meaningfully increased survival, with a median overall survival of 9.3–11.8 months after Radiol Oncol 2025; 59(1): 1-22. Jacobs EJ et al. / Pulsed field ablation in medicine 11 diagnosis.200,201 IRE provides perhaps one of the largest benefits to patients with LAPC, and numer- ous clinical evaluations are published yearly, dem- onstrating its safety and efficacy. Further, multiple studies have evaluated IRE to treat margins after pancreatectomy in borderline resectable pancre- atic cancers (BRPCs), termed margin accentuation (MA), when negative margins are not expected. Martin et al. and Narayanan et al. published the first clinical series on the treatment of PC using IRE.156,202 Martin et al. treated 27 patients with IRE either in situ (n = 19) or for MA following surgical resection (n = 8). They achieved 100% ablation of the primary tumor evaluated at the 90-day follow-up. Nine patients experienced 18 complications, with most being potentially associated with the open surgery approach and 4 being possible device- related complications. In parallel, Narayanan et al. treated 11 patients with LAPC and 3 with metastat- ic disease using a percutaneous approach. Ten of the 11 LAPC patients were still alive at 14 months post-treatment, but the 3 metastatic patients did not benefit from IRE with a median overall surviv- al of 4 months. Contrast-enhanced CT immediately and 24 hours after treatment showed that vascular patency was preserved in all patients. Martin et al. subsequently treated 200 Stage III LAPC patients treated with either in situ (n = 150) or for MA fol- lowing surgical resection (n = 50).203 All patients had initially undergone induction chemotherapy, and 52% were additionally given chemoradiation therapy for a median of 6 months before IRE. At a median follow-up of 29 months, 58 patients de- veloped recurrences (6 local recurrences) with a median progression-free survival of 12.4 months. MA had a higher median overall survival than IRE alone (28.3 vs. 23.2 months). Twenty patients (40%) experienced 49 complications in the MA group, and 54 patients (36%) experienced 100 complica- tions in the in situ group, with the most common complications being gastrointestinal complaints. Ten severe complications were experienced after treatment. The same group published their results on another prospective multi-institutional assess- ment with 152 additional patients treated.67 In situ IRE was successfully delivered to all patients with tumors ranging from 1 to 5.4 cm in diameter with a median follow-up of 19 months. There were 9 local recurrences and 27 distant recurrences, re- sulting in a median progression-free survival of 22.8 months and a median overall survival of 30.7 months. Nineteen patients experienced severe adverse events, with the most common complica- tions being gastrointestinal or hepatic related. In both studies, the liver was the most common site of distant recurrence. Many clinical studies have evaluated IRE fol- lowing inductive chemotherapy. A randomized trial demonstrated the additive effect of IRE with or without chemotherapy.204 Specifically, combi- natorial treatment patients had higher OS (20.3 vs. 16.2 months). Similarly, the PANFIRE-2 trial found IRE following induction chemotherapy provided a benefit to OS (17 vs. 12.4 months).140 A recent pro- spective randomized clinical trial compared the safety and efficacy of IRE (n = 34) to MRI-guided stereotactic ablative body radiotherapy (SABR, n = 34) following induction FOLFIRINOX.205 There were no differences in OS (12.5 vs. 16.1 months), PFS (9.5 vs. 8.5 months), or number of complications. Distant tumor-free survival was higher following IRE (13.2 vs. 8.5 months), but this could be due to a higher percentage of patients receiving adjuvant therapy following IRE. He et al. analyzed the SEER and SYUCC databases to compare the efficacy and long-term safety of IRE (n = 206) following induc- tion chemotherapy against chemotherapy alone (n = 3444)206 and found that IRE following induction chemotherapy had a higher OS (18 vs. 8 months) and PFS (7.7 vs. 4.1 months). Recently, Suraju et al. compared resection (n = 40), MA (n = 13), in situ IRE (n = 14), and unresected (n = 35) in BRPC and LPAC patients who received neoadjuvant chemothera- py.236 Despite having a higher number of patients with LAPC in the MA group, they experienced a non-significantly higher OS and PFS compared to resectable patients; the median OS from diagnoses were 30 months for MA, 28 months for in situ IRE, 27 months for resection, and 14 months for the un- resected group. Neoadjuvant chemoradiation, IRE, and resection were independently associated with decreased risk of mortality, and IRE with an open approach had fewer severe complications than pancreatectomy. Liver Liver cancer is the fifth most fatal malignancy globally, with hepatocellular carcinoma (HCC) comprising over 80% of primary liver tumors.207 Additionally, the liver is a frequent site of metasta- sis, especially from colorectal cancer; at least 25% of colorectal cancer patients develop liver metasta- ses (CRLM), accounting for a substantial propor- tion of secondary liver tumors.208 Standard treat- ment approaches for HCC and CRLM, including chemoradiation and surgical resection, are often Radiol Oncol 2025; 59(1): 1-22. Jacobs EJ et al. / Pulsed field ablation in medicine12 limited, and up to 80% of patients are deemed inel- igible for resection due to tumor burden, anatomi- cal location, or proximity to critical structures. Following hepatectomy, critical structures like the single remaining portal vein, central bile duct, and one or two major hepatic veins limit further resec- tion, as removal or damage to these could compro- mise liver function. If further resection of these structures is not feasible, then focal ablation offers an effective treatment, but thermal ablation strate- gies are limited due to the associated “heat sink” effects and potential damage to critical structures. Thus, IRE has been an increasingly effective method for treating tumors near these struc- tures.155,209 Ma et al. demonstrated that percutane- ous IRE is a safe and effective treatment for HCC abutting the diaphragm.210 They successfully ab- lated 36/39 tumors with no major complications and achieved a median 20.4 months to local tumor progression. The COLDFIRE-I ablate and resect clinical trial demonstrated the feasibility and safe- ty of IRE to treat CRLM in 10 patients.211 The subse- quent COLDFIRE-II trial further demonstrated the efficacy and safety of IRE in 51 patients with a total of 76 CRLMs.237 The 1-year local-progression-free (LPF) rate was 68%, and following repeated pro- cedures in 8 patients, local control was achieved in 37/50 (74%) patients. The median overall sur- vival from treatment was 32 months. Fruhling et al. further demonstrate that IRE was a safe abla- tion modality in 149 patients with HCC (n = 53) and CRLM (n = 71) when other treatment options are unsuitable.212 At 12 months, they achieved lo- cal ablation success of 40.3% in HCC patients and 25.4% in CRLM patients. This translated to a me- dian OS of 35 months and 27 months for HCC and CRLM patients, respectively. Three patients expe- rienced severe complications, with one death due to thromboembolism. In a subsequent analysis of the patient population, they found that smaller de- creases in resistance and larger tumor sizes were associated with earlier recurrence in CRLM but not HCC patients.213 In an evaluation of IRE as a salvage treatment, Hitpass et al. demonstrated that IRE is a safe op- tion when resection and thermal ablation are un- suitable.84 All tumors were located adjacent to the sole remaining intrahepatic blood vessels and bile ducts, but IRE was successfully delivered with a 5 mm margin in 31/32 lesions across 23 patients, with one incomplete ablation. The local progres- sion-free rate was 64% and 57.4%, and the intra- hepatic progression-free rate was 36.4% and 19.5% at 12 and 36 months, respectively. Altogether, five patients were tumor-free at the last follow-up. No vessel injury or thrombosis was observed, and on- ly minor complications occurred, including mod- erate segmental cholestasis, which spontaneously resolved. Recently, Narayanan et al. confirmed that IRE is a safe and viable option for the treat- ment of unresectable CLRMs close to the portal and hepatic veins, inferior vena cava, bile duct, and gallbladder.214 They achieved a median OS of 40.4 months with only minor complications. In a recent randomized non-inferiority clinical trial, Zhang et al. compared IRE (n = 78) to radiofre- quency ablation (RFA) (n = 78) for the treatment of malignant liver tumors.215 They demonstrated that IRE was not inferior to RFA, with comparable tumor ablation rates (94.9% vs. 96%), similar com- plication rates, and similar 6-mo recurrence rates (13.3% vs. 19.7%) between IRE and RFA. In a di- rect comparison of IRE to RFA and MWA in a pro- pensity score-matched population of early HCC, Wada et al. found 2-year local tumor progressions of 0%, 45%, and 25% for IRE, RFA, and MWA, re- spectively.216 A majority of HCC develops in patients with un- derlying pathologies, and the possibility of dam- aging diseased hepatic parenchyma (e.g. Child- Pugh B/C) has the associated risk of severe liver failure and mortality.217 Bhutiani et al. compared the tolerability and efficacy of IRE and microwave ablation for treating HCC patients with moderate Child-Pugh B liver dysfunction.218 They found that both modalities had comparable success rates, but IRE was better tolerated with a significantly lower length of stay and 90-day readmission rate. Kidney Small renal cell carcinoma (RCC) has traditionally been treated with surgical resection, with radical nephrectomy being the most common treatment. IRE has yet to be fully established for the treatment of renal tumors, but it may be considered when surgical resection or thermal ablation is not an op- tion. Thomson et al. treated 7 patients with RCC using IRE.95 Transient hematuria was observed in two patients with treatments near the center of the kidney, which resolved in under 24 hours. Follow- up CT at 3 months confirmed successful ablations in 71.4% (5/7) of patients, with the other 2 receiving a second IRE procedure. The first large cohort of patients with renal tumors treated with IRE was reported by Trimmer et al., in which 20 patients with T1a renal carcinoma (n = 13), indeterminate Radiol Oncol 2025; 59(1): 1-22. Jacobs EJ et al. / Pulsed field ablation in medicine 13 masses (n = 5), or benign masses (n = 2) underwent CT-guided IRE.86 All ablations were initially tech- nically successful, as verified with ce-CT, but two patients required salvage therapy at 2 weeks due to incomplete ablation. All 15 patients imaged at 6 months had no evidence of recurrence, and only one patient was observed to experience recurrence at 1 year after IRE. Despite initial data supporting the feasibil- ity and safety of IRE, a few clinical studies have found suboptimal short- and mid-term disease control. Canvasser et al. found that the initial treat- ment was successful in 93% (39/42) of tumors, but the 2-year local-recurrence-free rate was 83%89, which is unfavorably compared to contemporary local-recurrence-free rates of >97% for partial ne- phrectomy of tumors < 3.0 cm. Further, the first prospective Phase II clinical trial (IRENE) found “complexities in the overall procedure”.92 All tu- mors were resected after treatment to assess the le- sion. Four patients had no residual tumor, while 3 had microscopic residual tumor due to incomplete ablation. Dai et al. found similar results in a retro- spective study of 47 patients with 48 tumors, with 45.8% (22/44) being biopsy-proven RCC.219 At a me- dian follow-up of 50.4 months, their 5-year local re- currence-free rate was 81.4% in biopsy-confirmed RCC patients and 81.0% in all patients. None of the studies observed major complica- tions, supporting the safe initial use of IRE for RCC. While the safety profile after IRE is compel- ling, if it is concluded that IRE does not present a significant advantage over conventional therapies, patient selection for IRE could include those with central renal tumors near blood vessels and col- lecting systems in which the nonthermal mode of ablation can be exploited. Min Wah et al. evaluated the safety and efficacy of CT-guided IRE in 26 pa- tients with 30 biopsy-proven RCCs near vital struc- tures of the kidney.96 Nearby structures included the colon (n = 11), ureter (n = 11), and renovascu- lar pedicles (n = 7). They specified that the initial technical success of 73.3% was due to an early operator’s learning curve, and 7/8 of the residual tumors were treated with CA to achieve a techni- cal success rate of 97%. They state that one patient was not retreated due to an unexpected stroke at 4 months post-IRE. The 2- and 3-year recurrence- free survival was 91% for both time points. Six patients experienced minor complications, and 1 patient experienced a major complication (Clavien- Dindo III), as the patient developed post-proximal ureteral stricture that required long-term retro- grade ureteric stenting. Lung Lung cancer is the deadliest and most prevalent cancer globally, with few curative treatment op- tions. Central tumors near the central bronchial structures and large blood vessels are especially challenging to treat with surgical resection and thermal ablation modalities. IRE can potentially spare critical structures, but current oncological outcomes are lacking. Thomson et al. treated 1 patient with 1 non- small-cell carcinoma and 3 patients with 5 colorec- tal lung metastases.95 None of these patients treat- ed with IRE had a satisfactory tumor response, and they all presented with progressive disease when assessed by the 3-mo time point. A biopsy from one of the patients showed coagulative ne- crosis in a portion of the tumor with viable can- cerous tissue at the margin of the treated lesion. All four patients experienced transient ventricu- lar arrhythmia, one patient presented transient supraventricular tachycardia, and one patient re- quired cardioversion as a response to atrial fibril- lation. Pneumothorax was observed in two out of the four patients which resolved spontaneously. Usman et al. reported on the use of IRE to treat two patients with lung neoplasms that had been previ- ously deemed unresectable.98 One of the patients presented with an increase of the right suprahilar mass with ce-CT, suggesting tumor growth report- ed 2 months after the procedure. Moderate paren- chymal hemorrhage was observed during the pro- cedure, and at the 9-month follow-up, it was sug- gested that the tumor had invaded the trachea. The cancer continued to progress, and the patient suc- cumbed to the disease within a year post-IRE. The other patient was reported to still be alive 2.5 years after the procedure, with no major complications described. The authors explain that challenges still remain with using IRE to treat lung tumor masses due to the heterogeneity, geometry, and low den- sity of lung tissue. It is clear that further research is needed to optimize IRE treatment of lung cancer through collaboration between engineers and cli- nicians. It can be argued that these studies were limited because the probes themselves were not designed for lung treatments, and thus, surgical probes need to be tailored for this particular ap- plication. Kodama et al. determined that electroporation applied through an endobronchial catheter is a feasible technique for the treatment of parabron- chial tumors in a pig lung tumor model.220 The ab- lations measured on gross pathology were signifi- Radiol Oncol 2025; 59(1): 1-22. Jacobs EJ et al. / Pulsed field ablation in medicine14 cantly smaller than the treatment-related changes measured on CT, contrasting observations in other organ systems. Using FEM, they predicted EFs suf- ficient to induce irreversible electroporation (500– 2000 V/cm) within a 1 cm circumference around the probe, which was reflected by extensive abla- tions seen in gross histology. However, large blood vessels and airways significantly affected the EF distribution, reducing the local EF in portions of the tumor below the lethal EFT. Lastly, they found that electroporation does not affect the patency of the treated bronchi. Cardiac Catheter-based PFA is emerging as a promising alternative to thermal techniques (RFA & CA) in treating cardiac arrhythmias due to the better safety profile and similar efficacy.221,222 The rapid success of PFA in the clinic has led many research groups and companies to develop their own probes and electroporation systems (Figure 8), often keep- ing technical details and treatment parameters se- cret. Direct electric currents were first used to treat cardiac arrhythmias in the 1980s; however, the continuous application of the EF caused electrical arcing, barotrauma, and proarrhythmic effects. Lavee et al. were the first to utilize IRE for atrial ablation in 5 pigs, which mitigated the previous complications experienced with direct current ap- plications124 and achieved sharp transmural with no evidence of thermal damage. Subsequently, preclinical and clinical studies have demonstrated that PFA selectively ablates cardiac tissue while minimally affecting peri-atrial tissue, such as the esophagus and phrenic nerve223, and lowers the risk of pulmonary vein stenosis compared to ther- mal ablation. Recently, the results from multiple large clinical trials have been released. The first and most studied PFA catheter is the multi-electrode pentaspline catheter.122 The Impulse, PEFCAT, PEFCAT2, and PersAFONE tri- als demonstrated the initial feasibility and safety of this catheter for treating paroxysmal and per- sistent AF in relatively small cohorts.224 Recently, the MANIFEST-PF117 and MANIFEST-17k225 clini- cal trials provide compelling safety and efficacy results in larger patient cohorts and across more centers. The MANIFEST-PF trial included 24 cent- ers and 1,758 patients to determine the acute ef- fectiveness and safety of PFA and found that PFA achieved complete acute pulmonary vein isolation in 99.9% of patients on immediate electroanatomi- cal mapping. The 1-year recurrence rates were 31% for the total cohort, 27% for paroxysmal AF, and 42% for persistent AF. The MANIFEST-17k trial evaluated the safety of PFA across at 106 centers across 20 countries in 17,642 patients with parox- ysmal (57.8%) and persistent (35.2%) AF. At a me- dian of 15 months follow-up, no esophageal dam- age, pulmonary vein stenosis, or persistent phren- ic nerve palsy were reported. Major complications were reported in 0.98% of patients, with the most common being pericardial tamponade (0.36%), vascular events (0.30%), stroke (0.12%), hemoly- sis-related acute renal failure (0.03%), and death (0.03%). Two of the deaths (0.01%) were procedure- related from irreversible neurological damage; post-procedural brain MRI was performed in 96 asymptomatic patients to determine the rate of silent cerebral lesions (SCLs), of which 9.4% of pa- tients showed abnormalities. Further, the recent ADVENT trial demonstrated the non-inferiority of PFA using the pentaspline catheter in a ran- domized, single-blind prospective comparison to conventional thermal ablation (RFA or CA) in 707 paroxysmal AF patients221,222 evaluating the safety and 1-year recurrence rates of pulsed-field ablation against thermal ablation (RFA or CA). Urbanek et al. found similar results in 400 patients and achieved similar 1-year success rates between CA and pentaspline PFA in both paroxysmal AF (83.1% CA vs. 80.3% PFA) and persistent AF (71% CA vs. 66.8% PFA).126 The PULSED AF pivotal trial evaluated the circular-lasso-type 9-electrode catheter in 150 paroxysmal and 150 symptomatic persistent AF patients.125 They achieved 100% acute pulmonary vein isolation rates for both groups, but at the 90- day follow-up, the recurrence rate was already 30.5% and 37.7% for the paroxysmal and persistent AF groups, respectively. The 1-year recurrence rates did not increase much from the 90-day rates, with 33.8% for the paroxysmal AF and 44.9% for the persistent AF patients. Two severe adverse effects occurred due to treatment (0.7%): one cer- ebrovascular accident occurred the same day as treatment and one pericardial effusion that re- quired draining. The SPHERE PER-AF trial is a randomized, 2-arm prospective study evaluating a large-tip catheter dual PFA and RFA ablation system against a control RFA system.226 They found that PFA had significantly lower energy application times, tran- spired ablation times, and skin-to-skin procedural times. At a 1-year follow-up, 73.8% and 65.8% of patients were arrhythmia-free for the large-tip Radiol Oncol 2025; 59(1): 1-22. Jacobs EJ et al. / Pulsed field ablation in medicine 15 catheter and control system, respectively, with no major complications observed in either group. The insPIRE and admIRE trials investigated the safety and efficacy of using a variable-loop circu- lar catheter (VLCC).227,228 The inspIRE trial inves- tigated the safety and efficacy of the VLCC in 226 patients with paroxysmal AF. The 12-month free- dom from symptomatic arrhythmia was 79%. Pre- and post-treatment MRI imaging detected SCLs in 4 of the first 6 patients. After adjusting treatment to include a 10-second pause between PFA applica- tions and strictly adhering to the anticoagulation regimen, SCLs were found in 4 of the remaining 33 patients. All the SCLs were asymptomatic and resolved spontaneously. The VLCC can be used for guidance, stimulation/recording of cardiac signals, and applying PFA, so the admIRE trial investigated the use of the VLCC for real-time non-fluoroscopic procedural guidance and lesion indexing in 277 patients with paroxysmal AF. They achieved 97.5% success on first-pass per vein isolation, with 100% of veins ultimately isolated. At 12 months, they found similar efficacy to patients treated without fluoroscopy (75% vs. 72.7%), demonstrating that treatments can be delivered without fluoroscopy, which can potentially speed up procedures, mini- mizing procedure-related complications and expo- sure to X-rays. Collectively, these results indicate that H-FIRE is a safe and effective method for pulmonary isola- tion, but high acute pulmonary isolation rates have not necessarily translated to long-term freedom from disease. Nevertheless, PFA has similar, if not slightly better, efficacy than thermal ablation, but currently, methods are still needed to generate deeper and wider transmural lesions to prevent recurrence. Multiple preclinical and early clinical evalu- ations have also demonstrated the feasibility of PFA for the treatment of ventricular arrhythmias (VAs).229-231 VAs pose a unique challenge due to the thickness of the tissue and frequent scar tis- sue, making it challenging to develop deep lesions. PFA is indicated to better penetrate through scar tissue231-233, allowing for treatment of tissue that other focal ablation therapies cannot reach and for redo ablations. Peich et al. evaluated focal PFA in 21 patients with ventricular premature complexes and 23 partients with scar-related ventricular tach- ycardia.234 Using the highest energy setting (25A), they achieve 81% and 52% success for the prema- ture complex and tachycardia patients, respective- ly, at a mean follow-up of 116 days. Concluding remarks It has almost been 300 years since the earliest re- cording of electrically mediated tissue damage by Jean-Antoine Nollet in 1754. He observed the for- mation of red spots, presumably due to IRE, fol- lowing the application of high voltages to human and animal skin. Only 20 years ago was IRE again described as a viable option for controlled tissue destruction. In such a short period, it has signifi- cantly impacted the treatment of soft tumors and cardiac tissue. However, there are still multiple ar- eas of improvement: (1) Factors influencing electroporation at the cel- lular and tissue level are still not fully understood, and there is still a large gap in knowledge on the precise mechanisms of cell death following differ- ent PFA procedures. PFA is unique compared to every other focal therapy, and understanding ge- netic and proteomic changes following treatment is paramount for developing synergistic therapies. (2) Accordingly, the dynamics of tumor micro- environmental changes following PFA have only recently started being investigated. (3) Electroporation-dependent tissue properties for many tissues and tumors are not available, and there are currently no guidelines on appropriate methods for gathering and validating data. This limits confidence in computational models for pre- dicting ablation outcomes before treatment. (4) Inserting and maintaining multiple probes is the most technically challenging and time-con- suming aspect of IRE treatments. Improved meth- ods for delivering PEFs will presumably help in- crease the adoption of PFA and decrease operating room times. (5) While ablations can be measured soon after treatment, there are no clinically ready methods for real-time ablation progression or temperature monitoring. The lack of real-time feedback can lead to unnecessary thermal damage and avoid- able complications. (6) Due to the multifaceted nature of PFA, op- timized waveforms for oncology and cardiology have yet to be developed. Therefore, it is important for industry, clini- cians, and researchers to work together to allow for independent analysis and validation of data. If clinicians are aware of the capabilities and limi- tations of PFA procedures, tissues that were once considered untreatable and unresectable may now find a legitimate contender with IRE. 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Irreversible electroporation of hepatocellular carcinoma and colorectal cancer liver metastases: a nationwide multicenter study with short- and long-term follow-up. EJSO 2023; 49: 107046. doi: 10.1016/j.ejso.2023.107046 213. Frühling P, Stillström D, Holmquist F, Nilsson A, Freedman J. Change in tis- sue resistance after irreversible electroporation in liver tumors as an indica- tor of treatment success - a multi-center analysis with long term follow-up. EJSO 2024; 50: 108508. doi: 10.1016/j.ejso.2024.108508 214. Narayanan G, Gentile NT, Eyshi J, Schiro BJ, Gandhi RT, Peña CS, et al. Irreversible electroporation in treating colorectal liver metastases in proximity to critical structures. J Vasc Interv Radiol 2024; 35: 1806-13. doi: 10.1016/j.jvir.2024.08.021 215. Zhang X, Zhang X, Ding X, Wang Z, Fan Y, Chen G, et al. Novel irrevers- ible electroporation ablation (Nano-knife) versus radiofrequency abla- tion for the treatment of solid liver tumors: a comparative, randomized, multicenter clinical study. Front Oncol 2022; 12: 945123. doi: 10.3389/ fonc.2022.945123 216. Wada T, Sugimoto K, Sakamaki K, Takahashi H, Kakegawa T, Tomita Y, et al. Comparisons of radiofrequency ablation, microwave ablation, and irreversible electroporation by using propensity score analysis for early stage hepatocellular carcinoma. Cancers 2023; 15: 732. doi: 10.3390/can- cers15030732 217. Schlageter M, Terracciano LM, D’Angelo S, Sorrentino P. Histopathology of hepatocellular carcinoma. World J Gastroenterol 2014; 20: 15955-64. doi: 10.3748/wjg.v20.i43.15955 218. Bhutiani N, Philips P, Scoggins CR, McMasters KM, Potts MH, Martin RCG. Evaluation of tolerability and efficacy of irreversible electroporation (IRE) in treatment of Child-Pugh B (7/8) hepatocellular carcinoma (HCC). HPB 2016; 18: 593-9. doi: 10.1016/j.hpb.2016.03.609 219. Dai JC, Morgan TN, Steinberg RL, Johnson BA, Garbens A, Cadeddu JA. Irreversible lectroporation for the treatment of small renal masses: 5-year outcomes. J Endourol 2021; 35: 1586-92. doi: 10.1089/end.2021.0115 Radiol Oncol 2025; 59(1): 1-22. Jacobs EJ et al. / Pulsed field ablation in medicine22 220. Kodama H, Vroomen LG, Ueshima E, Reilly J, Brandt W, Paluch LR, et al. Catheter-based endobronchial electroporation is feasible for the focal treatment of peribronchial tumors. J Thorac Cardiovasc Surg 2018; 155: 2150-9.e3. doi: 10.1016/j.jtcvs.2017.11.097 221. Reddy VY, Gerstenfeld EP, Natale A, Whang W, Cuoco FA, Patel C, et al. Pulsed field or conventional thermal ablation for paroxysmal atrial fibrilla- tion. N Engl J Med 2023; 389: 1660-71. doi: 10.1056/nejmoa2307291 222. Reddy VY, Mansour M, Calkins H, d’Avila A, Chinitz L, Woods C, et al. 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Bipolar electroporation across the interventricular septum: electrophysiological, imaging, and histopathological characteristics. JACC Clin Electrophysiol 2022; 8: 1106-18. doi: 10.1016/j.jacep.2022.06.002 230. Koruth JS, Kuroki K, Iwasawa J, Viswanathan R, Brose R, Buck ED, et al. Endocardial ventricular pulsed field ablation: a proof-of-concept preclinical evaluation. Europace 2020; 22: 434-9. doi: 10.1093/europace/euz341 231. Younis A, Buck E, Santangeli P, Tabaja C, Garrott K, Lehn L, et al. Efficacy of pulsed field vs radiofrequency for the reablation of chronic radiofre- quency ablation substrate. JACC Clin Electrophysiol 2024; 10: 222-34. doi: 10.1016/j.jacep.2023.09.015 232. Im S Il, Higuchi S, Lee A, Morrow B, Schenider K, Speltz M, et al. Pulsed field ablation of left ventricular myocardium in a swine infarct model. JACC Clin Electrophysiol 2022; 8: 722-31. doi: 10.1016/j.jacep.2022.03.007 233. Sandhu U, Alkukhun L, Kheiri B, Hodovan J, Chiang K, Splanger T, et al. 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A literature review with case presentations Silvio Sporeni1, Francesca Rifaldi1, Irene Lanzetta1, Ilaria Imarisio2, Benedetta Montagna2, Francesco Serra1,2, Francesco Agustoni1,2, Paolo Pedrazzoli1,2, Marco Benazzo3,4, Giulia Bertino3 1 Department of Internal Medicine and Medical Therapy, University of Pavia, Pavia, Italy 2 Department of Oncology, Hospital IRCCS Policlinico San Matteo Foundation, Pavia, Italy 3 Department of Otolaryngology, Hospital IRCCS Policlinico San Matteo Foundation, Pavia, Italy 4 Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy Radiol Oncol 2025; 59(1): 23-30. Received 3 November 2024 Accepted 26 November 2024 Correspondence to: Silvio Sporeni, M.D., Department of Internal Medicine and Medical Therapy, University of Pavia and Department of Oncology, IRCCS Policlinico San Matteo Foundation, Pavia, Italy. E-mail: silvio.sporeni01@universitadipavia.it and Francesco Agustoni, M.D., Department of Internal Medicine and Medical Therapy, University of Pavia and Department of Oncology, IRCCS Policlinico San Matteo Foundation, Pavia, Italy. E-mail: f.agustoni@smatteo.pv.it Disclosure: No potential conflicts of interest were disclosed. This is an open access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/). Background. Recurrent respiratory papillomatosis (RRP) is a condition caused by human papilloma virus (HPV) infec- tion. Curative treatments aren’t identifiable, and conservative surgery is often the best option to preserve respiratory functions. To date monoclonal antibodies are considered to be a treatment choice with both good efficacy and safety profile. Materials and methods. A web-based search of MEDLINE/PubMed library from 2000 to 2024 of English-language papers was performed to identify articles by using “respiratory or laryngeal papillomatosis” and “HPV respiratory infec- tion, papillomatosis treatment, papillomatosis vaccine immunization, papillomatosis systemic treatment”. Furthermore, a manual screening of references from original articles was done to identify additional studies. We selected 34 articles. Results. Since 2009, the systemic administration of Bevacizumab has been used to treat RRP not responding to surgical treatment. The efficacy of an anti-VEGF monoclonal antibody in RRP lesions can be related to their vascular nature. The major concern is the rebound papilloma growth within the cessation of treatment. An interesting solution could be the concomitant use of immunotherapy to both reduce the burden of residual disease and activate the immune system against the HPV-infected cells. Conclusions. Bevacizumab has a safe profile with a short-term local eradication of HPV. Further prospective research with long-term follow-up is needed to better define its safety and results against the disease recurrence. Considering the role of the anti-HPV vaccine, both, in the prophylaxis of the infection and in the adjuvant setting, the actual data underline the need for evaluation of its therapeutic efficacy for the management of RRP. Key words: oral cavity papillomatosis; respiratory recurrent papillomatosis; multimodal treatment; systemic therapy; vaccine immunization Introduction Recurrent respiratory papillomatosis (RRP) de- scribes a morbid benign condition caused by the infection of the upper aerodigestive tract operated by human papillomavirus (HPV), a non-encapsu- lated, double chain icosahedral structured virus composed of 72 capsomeres. Radiol Oncol 2025; 59(1): 23-30. Sporeni S et al. / Recurrent respiratory papillomatosis: A literature review24 There is currently no curative treatment for RRP. The primary approach consists in surgical excision to debulk the papilloma and ensure an adequate vocal outcome, as much as possible. HPV The term “Papillomatosis” collects a heterogene- ous group of non-oncological lesions that affect the mucosal tissue of the oral cavity and upper respiratory tract. The etiopathogenesis of this morbid condi- tion isn’t totally understood yet, although some potential risk factors were identified: mostly the same that could potentially lead to the develop of Squamocellular Carcinoma (SCC) and can be clas- sified in non-viral and viral risk factors. Excessive smoking, chronic alcoholism, poor oral hygiene, edentations and mucosal trauma inducted by in- correct prosthetic works are fundamental in pro- ducing a persistent inflammation and irritation.1 Nowadays, especially with the improvement of diagnostic molecular biology techniques, human papillomavirus (HPV) is identified as essential cause of papillomatous lesions.2 HPV is a non-enveloped double-stranded circular genome DNA virus classified into Papillomaviridae family, whose 200 different genotypes are known. Up to 90% of the infec- tions are related to genotypes 6 and 11, which are characterized by a weak potential of malignant transformation. The remaining 10% of infections are caused by genotypes 16, 18, 31 and 33, which are associated to a high carcinogenic power and can induce the development of malignancies such as squamous cell carcinoma of the oropharynx, cervix, vagina, uterus, anus and penis.3,4 The vi- ral infection is globally widespread, nevertheless with a geographical linked incidence variability. It’s higher in East African countries, due to the underdeveloped economic system and the inef- ficacy of the medical system in promoting the vaccination program, while the rate in West Asia is the lowest. The transmission can be sexual or non-sexual and, in 1% of general population, HPV 6 and 11 can be “commensal” of the oral cavity, especially in the larynx.5 The virus infiltrates the mucosal basal membrane and the profound cell layer, through epithelial discontinuation, where is able to multiply; all the process is mainly driven by genes E6 and E7, key regulators of cell cycle progression.6 In order to sustain its proliferation, HPV main- tains itself inside the host cell, fusing its genes with the host cell genome: this phenomenon is probably responsible for a persistent viral infection defined as Recurrent Respiratory Papillomatosis (RRP).7 Recurrent Respiratory Papillomatosis (RRP) Is a rare pathological condition that usually pri- mary affects the upper aerodigestive tract.8 Three peaks of onset are recognized at ages 7, 35, and 64.9 The juvenile form (JoRRP) is more aggressive, and it’s estimated to affect 4.3 per 100000 children, otherwise the adult form (AoRRP) involves 1.8 per 100000.5,10 It’s known a geographical as previously said, even if, interestingly, the incidence of RRP is similar in both developed and developing coun- tries.11 Diagnosis Starting from the larynx, the infection can spread to extra laryngeal structures such as trachea, oro- pharynx, nasopharynx, nose, oral cavity, and rare- ly the lung. The involvement of these anatomical structure explains the most frequent symptoms onset: hoarseness, typical of young age, and dys- phonia, common in the adults’ forms. Dyspnoea, chronic cough, recurrent respiratory infections, pneumonia, acute respiratory distress, dysphagia are usually result of an upper airway involve- ment.12 Clinical pattern is the first thing to consider, then a tissue biopsy must be performed, leaded with flexible fiberoptic laryngoscopy or direct la- ryngoscopy. While bronchoscopy is considered the most accurate technique for diagnosis of lesions in the central airways.13 Histologically, RRP is composed by papil- lomatous structures made of abnormal squamous epithelium, where keratinization and basal cell hyperplasia are in excess, with exophytic projec- tions overlying supporting fibrovascular cores. Epithelial atypia is usually absent, although these benign lesions can undergo malignant transforma- tion. Pathological changes include atypia, focal ne- crosis, foci of keratinization and sheets of polygo- nal tumoral cells.5 Radiological diagnostic strategies include x- rays, particularly indicated for RPP with lung in- volvements; CT scan, that allow to find the pres- ence of focal or diffused airway narrowing on the mucosal surface; MRI, that can detect the presence of lesions in the larynx, tracheobronchial and pul- monary regions. Radiological assessments are nec- Radiol Oncol 2025; 59(1): 23-30. Sporeni S et al. / Recurrent respiratory papillomatosis: A literature review 25 essary to determine the correct staging and, conse- quently, the correct treatment option.13,14 Treatment Currently, there is no curative treatment for RRP. However, the primary approach is surgical excision. The aim of the surgical strategy is to debulk the pap- illomatous lesions at the same time preserving the integrity of the underlying anatomical structures and maintain the airway patency. The excision mo- dalities are multiple and surgeon-dependent; the focus is to prevent damage of surrounding tissue. Recurrences are common, and repeated surgery is often necessary to preserve good respiratory and phonatory quality. For these reasons, double-stage procedures or subtotal resections are preferred, re- ducing the risks of webbing and scarring.15 Different surgical techniques have evolved in the management of RRP, moving from cold instru- ments and microdebriders to different types of lasers, mainly: ablative/cutting lasers or photoan- giolytic lasers.15 On the other hand, this strategy can increase the risk of local damage and complications such as laryngeal stenosis, reduction of the respiratory space, formation of tracheoesophageal fistulas and increase expression of HPV dormant in nearby cells.16 Adjuvant treatment In about 1 out of 5 patients, the disease cannot be controlled by surgery alone and adjuvant treat- ments are needed. The adjuvant therapy should be considered if palliative surgery is needed more than 4 times a year, in case of rapid recurrence of papillomatous lesions with the risk of airway ob- struction and in case of disease spread to the dis- tal respiratory tree. The main purpose of adjuvant treatments is to remodulate the action of the im- mune system against the effective agent to inhibit the replication of the virus. Several adjuvant therapies have been adminis- tered, with a little consensus on which treatments are most effective and the timing of their admin- istration. Antiviral agents such as interferon-alpha and cidofovir were commonly considered the first line treatment. The mechanism of action is pre- dominantly inhibition of viral nucleic acid syn- thesis. But the results were heterogeneous and, in some cases, burdened by considerable side effects including neurological disorders, leukopenia and thrombocytopenia.15,17 To date, in locally advanced disease or meta- static forms, other therapeutic options taken into account are antiangiogenic monoclonal anti- bodies, approved as single agent or in combina- tion with chemotherapy, and targeted therapies. Bevacizumab, a recombinant human monoclonal antibody that acts selectively, binding the circulat- ing vascular endothelial growth factor VEGF-A18, is one of the agents that have been investigated in these settings. Interferon In the 1980s interferon-alpha was one of the first adjuvant treatments adopted for the treatment of RRP and it was used either intralesional or intra- muscular. It is a cytokine that binds to specific cell receptors and modifies the immune response with an anti-proliferative and anti-viral effect.19 Its use was progressively abandoned due to the severe side effects, mainly hepatotoxicity. Antiviral agents (acyclovir, ribavirin, cidofovir) The efficacy of Acyclovir and Ribavirin was tested in the 1990s by Bergler et al. and in a few case series and seemed to be linked to the presence of viral co-infections (Herpes Syimplex, Cytomegalovirus, or Epstein-Barr virus).20 These clinical studies were insufficient to conclude a beneficial effect of these drugs. Cidofovir on the other hand is a cytosine nu- cleotide analogue and its introduction resulted in a great improvement in the control of the disease. Once converted in its active form, it is incorporated into DNA and exerts its toxicity in the Papilloma and Herpesviridae families. It can be administered intravenously or intralesional. Unfortunately, sys- temic treatment has been associated with neutro- penia and nephrotoxicity.21 The intralesional off- label use has been adopted for the treatment of genital HPV or RRP, but there are no clear proto- cols for dose, concentration, and frequency.22 Even if many studies have reported signifi- cant response rates with almost no side effects in January 2011, a communication provided by the manufacturer of cidofovir addressed very serious side effects concerning its off-label use: reporting nephrotoxicity, neutropenia, oncogenicity and even some fatalities. In 2012 followed a study in- volving 16 different hospitals in 11 different coun- tries worldwide which submitted 635 RRP pa- tients, of whom 275 were treated with intralesional Radiol Oncol 2025; 59(1): 23-30. Sporeni S et al. / Recurrent respiratory papillomatosis: A literature review26 cidofovir, with no clinical evidence for long-term nephrotoxicity, neutropenia, or malignancies.19 Nevertheless, drug import is now allowed only for authorised clinical trials. Bevacizumab Bevacizumab is a recombinant monoclonal hu- manised antibody that blocks angiogenesis by in- hibiting human vascular endothelial growth fac- tor A (VEGF-A) and by preventing the activation of its receptor (VEGF-R).18 A retrospective study conducted by Rahbar et al. demonstrated the role of VEGF-A in the pathogenesis of RRP.23 The squa- mous epithelium of papilloma presented a strong expression of VEGF-A mRNA, and VEGFR-1 and VEGFR-2 were strongly expressed in papilloma’s blood vessels endothelial cells. From these obser- vations Bevacizumab was considered as a treat- ment. The predominant effect of Bevacizumab in RRP is modulation of vasculature and not the induction of apoptosis, stronger effects are seen coupling the use of this drug with photoangiolytic lasers.23 Bevacizumab can be administered both intrave- nously and intralesionaly, where the intravenous use is indicated for patients with non-accessible le- sions, at the dose of 5-15 mg/kg every 2-3 weeks in adults and 5-10 mg/kg every 2-4 weeks in chil- dren.24,25 Intralesional use instead has an approved dose of 7.5-12.5 mg at 25 mg/ml.26 Studies have not yet shown statistically sig- nificant differences between the use of intral- esional Cidofovir and Bevacizumab, however Bevacizumab shows a higher rate of partial remis- sions and fewer adverse events.27 Other adjuvant treatments Other compounds have been proposed, such as celecoxib, indole-3-carbinol, anti-reflux drugs, PD- 1 inhibitors, and gefitinib. Unfortunately, no clini- cal trials are yet available to assess the actual ef- ficacy of these adjuvant treatments.15 Vaccination Recent research has shown that the HPV vac- cine plays a significant role in not only prevent- ing the transmission of RRP but also in aiding the eradication of the disease in an adjuvant context. Currently, two safe and highly immunogenic vac- cines are available that effectively stimulate both humoral and cellular immunity: Gardasil, a quad- rivalent vaccine containing recombinant HPV proteins targeting genotypes 6, 11, 16, and 18, which aims to prevent cervical and anal cancers28, and Gardasil 9, which offers protection against ad- ditional HPV genotypes 31, 33, 45, 52, and 58, and is recommended for individuals aged 9 to 45. Now there are interesting clinical trials on- going like the INO-3107 (NCT04398433), a DNA immunotherapy designed to elicit targeted T-cell responses against human papillomavirus (HPV) types 6 and 11, in adult patients with recurrent respiratory papillomatosis. Which shows prom- ising results with a tolerable and beneficial ef- fect.29 FIGURE 1. Inspection of the oral cavity and fiberoptic images of patient 1, a 44 yar-old woman, after systemic treatment. (A) Picture of tongue fissurization and oral cavity of the patient. (B) Oropharyngeal overview of the patient, with no sign of papillomatosis A B Radiol Oncol 2025; 59(1): 23-30. Sporeni S et al. / Recurrent respiratory papillomatosis: A literature review 27 Presentation of successful treatment cases We present two cases of RRP successfully treated with surgery, adjuvant systemic Bevacizumab and HPV vaccination. Patient 1 A 44-year-old woman, with a previous his- tory of uterus conizations for LSIL (Low grade Squamous Intraepithelial Lesion) / CIN1 (Cervical Intraepithelial Neoplasia) lesions, underwent an ENT evaluation after the onset of widespread pap- illomatous lesions located on the tip, base and mar- gins of the tongue and on the median raphe of the upper lip. An excisional biopsy and scraping of the oral cavity were performed. The histological exami- nation of the squamous papillomatous lesions re- ported the positivity for Human Papillomavirus of genotype 6. Surgery was evaluated as the best first line treatment option, therefore a bilateral laser vapori- zation of most of the visible papillomatous lesions on the tip, margins, ventral face, dorsal face and base of the tongue was performed. Since this surgical treatment resulted in an in- complete removal of the widespread papillomato- sis, the case was discussed by our tumor board, and we decided to proceed with systemic adjuvant therapy with Bevacizumab at the dose of 10 mg/kg every three weeks, repeated for six cycles. At our first oncological evaluation, before the beginning of treatment, the patient was in good clinical conditions, with an ECOG PS equal to 0 and no pathological signs at the physical exami- nation. The inspection of the oral cavity showed papillomatous lesions of the tongue without any symptoms referred. For each infusion, 470 mg of Bevacizumab were administered. Due to the patient’s previous his- tory of serious allergic reactions both after the ad- ministration of the anti-SARS-COV2 vaccine and amoxicillin, an appropriate premedication of hy- drocortisone 250 mg and chlorphenamine 10 mg was administered at every cycle. Following the first Bevacizumab infusion the patient reported pain in the right cubital fossa and low-grade ede- ma of the ipsilateral hand with symmetrical isos- phygmic peripheral pulses. Deep vein thrombosis was suspected; but the venous doppler ultrasound scan of the arms resulted negative. The edema then resolved spontaneously. Furthermore, after the third infusion, an isolated case of proteinuria G1 was detected at urine analysis. The treatment was overall well tolerated with no clinically sig- nificant side effects reported. After the treatment completion, at the first on- cological re-evaluation the patient complained of sore throat and foreign body sensation. At the oral cavity examination, diffuse papillomatous lesions in the left edge, lingual base and right labial fornix were observed, although decreased in number and locations; hypertrophy of the right tonsil was also noticed. New biopsies and scraping of the oral cav- FIGURE 2. Inspection of the oral cavity and fiberoptic images of patient 2, a 58 years-old male, after systemic treatment. (A) Oropharyngeal overview at slightly different angles of the patient (B), with no sign of papillomatosis. A B Radiol Oncol 2025; 59(1): 23-30. Sporeni S et al. / Recurrent respiratory papillomatosis: A literature review28 ity were performed. On the right anterior lingual margin and on the left posterior lingual margin, squamous papillomas with diffuse superficial ero- sion were diagnosed. The Innogenetics tests per- formed on the scrapings of the oropharynx result- ed as negative, both for the identification of HPV DNA and HPV genotypes. The patient performed a facial MRI, which re- ported the absence of signal alterations affecting the lingual body or suspicious DWI signal abnor- malities; only some immunoreactive lymph nodes at the IIa level of the right neck were highlighted (the largest one of 11 x 7 mm of diameter). Three months after the completion of treatment with Bevacizumab, the patient underwent the anti- HPV vaccination for therapeutic purposes and two doses of Gardasil 9 were administered without re- markable side effects. The patient will undergo an annual ENT follow- up. Patient 2 A 58-year-old male, with no significant pathologi- cal anamnesis (GERD, disc herniation), underwent ENT evaluation due to breathing difficulty and hoarseness; turbinates’ hypertrophy and vegeta- tive exophytic neoformation on the left epiglottis were diagnosed, so the specialist recommended the turbinates’ reduction with radiofrequency and the neoformation’s removal. The patient under- went both procedures, and the histological exami- nation came back positive for HPV-related squa- mous cells laryngeal papillomatosis, p16-, low risk strains (genotyping not executable). Three months later, a new episode of dysphonia occurred; again, ENT evaluation was requested, and the reappear- ance of papillomatous lesions was diagnosed. The patient then underwent a second exeresis (CO2 la- ser mediated) of a right arrhythmenoideal neofor- mation and a left anterior commissural lesion. To histological examination: HPV-related squamous cells papillomatosis; HPV-DNA positive for low- risk strains. Two months later, at ENT follow-up re-evaluation, the patient was diagnosed with a re- currence of the disease (appearance of: four laryn- geal papillomatosis lesions, one infrahyoid lesion, one right false vocal cord lesion, one left true vocal cord lesion conditioning phonatory difficulty). He then underwent HPV-vaccination (3 inoculations) and surgical exeresis of the above-mentioned le- sions, again with histological positivity for HPV. Because of the evidence of a new recurrence of disease on the left vocal cord one month later, the patient was candidate to systemic treatment with intravenous Bevacizumab, at the dose of 10 mg/ kg q21 for 6 cycles, after which an instrumental restaging with CT scan will be carried out. The treatment was overall well tolerated; drug-induced hypertension (maximum values of 140/90 mmHg) responsive to low dose antihypertensive, and oc- casional itching well responsive to low doses of antihistamines were observed. Due to the appearance of leukoplakia e aph- thous stomatitis of the oral cavity, the patient un- derwent local ozone therapy treatment sessions with clinical benefit. The CT scan performed at the end of the treat- ment administration reported the complete resolu- tion of the two lesions on the left vocal cord previ- ously described and the total absence of new ones. The patient will undergo an annual ENT follow- up. Discussion In 2009 Nagel et al. described a case of pulmonary and tracheal RRP requiring laser-debridement 4 times a year over a 10-year period.30 The pa- tient had a significant regression of the disease following the first systemic administration of Bevacizumab. In 2017, after many years of clinical experimentation with a nationwide survey, Best et al. concluded that systemic Bevacizumab at a dose of 5–10 mg/kg every 2–4 weeks showed significant positive outcome in patients with advanced, treat- ment-resistant papillomatosis.31 The reason behind these results is that RRP lesions possess a vascu- lar nature, therefore drugs designed to disrupt blood vessels’ density or formation are effective in hindering papillomatous lesions’ progression. Bevacizumab, being an anti-VEGF monoclonal an- tibody, administered both locally (intralesional in- jection) or systemically (intravenous injection) has shown excellent results.32 The major concern about the use of an antiangi- ogenic therapy is the rebound papilloma’s growth within the cessation of the treatment, since VEGF- blockade alone does not intrinsically activate im- munity against HPV. Moreover, Bevacizumab has a known side effect profile (renal insufficiency), and prospective studies are needed to determine optimal long-term dosing schedules aimed at keeping enough drug in the system to suppress papilloma’s growth while reducing the risk of ad- verse events. An interesting solution could be the concomitant use of immunotherapy, to both reduce Radiol Oncol 2025; 59(1): 23-30. Sporeni S et al. / Recurrent respiratory papillomatosis: A literature review 29 the burden of the residual disease and activate the immune system against the HPV infected cells. These aspects certainly deserve further studies. Promising data concern the possible use of HPV vaccine in the adjuvant treatment of RRP, despite the primary purpose of vaccination is to prevent future HPV infection. In their study, Young et al. showed a clinical benefit of HPV vaccination in RRP patients: eight patients experienced complete remission, and five patients experienced partial re- mission.28 Also, Yiu et al. demonstrated an increase in the time interval between repeated surgeries in vaccinated patients.33 The mechanism that un- derlies the vaccine’s potential therapeutic efficacy against HPV is still unknown. Therefore, two strategies against RRP should be considered: firstly, the vaccine reduces the risk of infection and consequently the incidence of HPV- related pathologies; secondly, patients who tested anti-HPV positive at baseline could develop a booster response to vaccination that prevents the infection from recurring.34 For these reasons HPV vaccination is the most promising development in the treatment of RRP.15 Despite the encouraging literature on adjuvant HPV vaccination for secondary prevention in RRP, this strategy has not yet been accepted widely in treating the RRP population: the inconsistent find- ings data from published reports underline the need for evaluation of therapeutic efficacy of cur- rently available HPV vaccines for the management of RRP. Conclusions RRP is a chronic disease currently difficult to treat due to the unpredictability of its recurrences and aggressive nature. The cases we reported are an example of the efficacy of systemic Bevacizumab at the dose of 10 mg/kg as a first line adjuvant therapy. As previously published clinical cases and series suggest, this treatment has shown a safe profile with overall good results, with the short- term local eradication of HPV. Further randomized prospective research with long-term follow-up is needed to better define the safety of this agent and the results against the disease’s recurrence. We also discussed the effectiveness of anti-HPV vaccination, not only as a prophylaxis of the infec- tion but also as adjuvant treatment in preventing or delaying the recurrence of the disease, a role that needs to be demonstrated with further stud- ies. References 1. Andrei EC, Baniță IM, Munteanu MC, Busuioc CJ, Mateescu GO, Mălin RD, et al. Oral papillomatosis: its relation with human papilloma virus infection and local immunity - an update. Medicina (Kaunas) 2022; 58: 1103. doi: 10.3390/medicina58081103 2. Betz SJ. 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Torres-Canchala L, Cleves-Luna D, Arias-Valderrama O, Candelo E, Guerra MA, Pachajoa H, et al. Systemic bevacizumab for recurrent respiratory papillomatosis: a scoping review from 2009 to 2022. Child 2022; 10: 54. doi: 10.3390/children10010054 17. Derkay CS, Wikner EE, Pransky S, Best SR, Zur K, Sidell DR, et al. Systemic use of bevacizumab for recurrent respiratory papillomatosis: who, what, where, when, and why? Laryngoscope 2023; 133: 2-3. doi: 10.1002/lary.30180 18. Pogoda L, Ziylan F, Smeeing DPJ, Dikkers FG, Rinkel RNPM. Bevacizumab as treatment option for recurrent respiratory papillomatosis: a system- atic review. Eur Arch Otorhinolaryngol 2022; 279: 4229-40. doi: 10.1007/ s00405-022-07388-6 19. Gerein V, Rastorguev E, Gerein J, Jecker P, Pfister H. Use of interferon-alpha in recurrent respiratory papillomatosis: 20-year follow-up. Ann Otol Rhinol Laryngol 2005; 114: 463-71. doi: 10.1177/000348940511400608 Radiol Oncol 2025; 59(1): 23-30. Sporeni S et al. / Recurrent respiratory papillomatosis: A literature review30 20. Bergler WF, Götte K. Current advances in the basic research and clinical management of juvenile-onset recurrent respiratory papillomatosis. Eur Arch Otorhinolaryngol 2000; 257: 263-9. doi: 10.1007/s004050050236 21. Patel A, Orban N. Infantile recurrent respiratory papillomatosis: review of adjuvant therapies. J Laryngol Otol 2021; 135: 958-63. doi: 10.1017/ S0022215121002322 22. Tjon Pian GiREA, Dietz A, Djukic V, Eckel HE, Friedrich G, Golusinski W, et al. Treatment of recurrent respiratory papillomatosis and adverse reactions fol- lowing off-label use of cidofovir (Vistide®). Eur Arch Otorhinolaryngol 2012; 269: 361-2. doi: 10.1007/s00405-011-1804-7 23. Rahbar R, Vargas SO, Folkman J, McGill TJ, Healy GB, Tan X, et al. Role of vascular endothelial growth factor-A in recurrent respirato- ry papillomatosis. Ann Otol Rhinol Laryngol 2005; 114: 289-95. doi: 10.1177/000348940511400407 24. Mohr M, Schliemann C, Biermann C, Schmidt LH, Kessler T, Schmidt J, et al. Rapid response to systemic bevacizumab therapy in recurrent respiratory papillomatosis. Oncol Lett 2014; 8: 1912-8 doi: 10.3892/ol.2014.2486 25. Ryan MA, Leu GR, Upchurch PA, Tunkel DE, Walsh JM, Boss EF, et al. Systemic bevacizumab (Avastin) for juvenile-onset recurrent respiratory papillomatosis: a systematic review. Laryngoscope 2021; 131: 1138-46. doi: 10.1002/lary.29084 26. Zeitels SM, Barbu AM, Landau-Zemer T, Lopez-Guerra G, Burns JA, Friedman AD, et al. Local injection of bevacizumab (Avastin) and angiolytic KTP laser treatment of recurrent respiratory papillomatosis of the vocal folds: a prospective study. Ann Otol Rhinol Laryngol 2011; 120: 627-34. doi: 10.1177/000348941112001001. 27. Zagzoog FH, Mogharbel AM, Alqutub A, Bukhari M, Almohizea MI. Intralesional cidofovir vs. bevacizumab for recurrent respiratory pap- illomatosis: a systematic review and indirect meta-analysis. Eur Arch Otorhinolaryngol 2024; 281: 601-27. doi: 10.1007/s00405-023-08279-0 28. Young DL, Moore MM, Halstead LA. The use of the quadrivalent human papillomavirus vaccine (gardasil) as adjuvant therapy in the treatment of recurrent respiratory papilloma. J. Voice 2015; 29: 223-9. doi: 10.1016/j. jvoice.2014.08.003 29. Mau T, Amin MR, Belafsky PC, Best SR, Friedman AD, Klein AM, et al. Interim results of a phase 1/2 open-label study of INO-3107 for HPV-6 and/or HPV- 11-associated recurrent respiratory papillomatosis. Laryngoscope 2023; 133: 3087-93. doi: 10.1002/lary.30749 30. Nagel S, Busch C, Blankenburg T, Schütte W. [Treatment of respiratory papillomatosis − a case report on systemic treatment with bevacizumab]. [German]. Pneumologie 2009; 63: 387-9. doi: 10.1055/s-0029-1214714 31. Best S R, Mohr M, Zur K. B. Systemic bevacizumab for recurrent respiratory papillomatosis: a national survey. Laryngoscope 2017; 127: 2225-9. doi: 10.1002/lary.26662 32. Allen CT. Biologics for the treatment of recurrent respiratory papillomatosis. Otolaryngol Clin North Am 2012; 54: 769-77. doi: 10.1016/j.otc.2021.05.002 33. Yiu Y, Fayson S, Smith H, Matrka L. Implementation of routine HPV vaccina- tion in the management of recurrent respiratory papillomatosis. Ann Otol Rhinol Laryngol 2019; 128: 309-15. doi: 10.1177/0003489418821695 34. Chirilǎ M, Bolboacǎ SD. Clinical efficiency of quadrivalent HPV (types 6/11/16/18) vaccine in patients with recurrent respiratory papillomatosis. Eur Arch Otorhinolaryngol 2014; 271: 1135-42. doi: 10.1007/s00405-013- 2755-y Radiol Oncol 2025; 59(1): 31-42. doi: 10.2478/raon-2025-0002 31 review The financial toxicity of breast cancer: a systematic mapping of the literature and identification of research challenges Ivica Ratosa1,2, Mojca Bavdaz3, Petra Dosenovic Bonca3, Helena Barbara Zobec Logar1,2, Andraz Perhavec2,4, Marjeta Skubic2, Katja Vörös2, Ana Mihor5, Vesna Zadnik2,5,6, Tjasa Redek3 1 Division of Radiotherapy, Institute of Oncology Ljubljana, Ljubljana, Slovenia 2 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 3 School of Economics and Business, University of Ljubljana, Slovenia 4 Sector for Oncology Epidemiology and Cancer Registry, Institute of Oncology Ljubljana, Ljubljana, Slovenia 5 Sector for Oncology Epidemiology and Cancer Registry, Institute of Oncology Ljubljana, Ljubljana, Slovenia 6 Faculty of Health Sciences, University of Primorska, Izola, Slovenia Radiol Oncol 2025; 59(1): 31-42. Received 3 April 2024 Accepted 16 August 2024 Correspondence to: Assist. Prof. Ivica Ratoša, M.D., Ph.D., Division of Radiotherapy, Institute of Oncology Ljubljana, Ljubljana, Slovenia. E-mail: iratosa@onko-i.si Disclosure: No potential conflicts of interest were disclosed. This is an open access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/). Background. Breast cancer is one of the most common cancers, increasingly prevalent also among working-age populations. Regardless of age, breast cancer has significant direct and indirect costs on the individuals, families and society. The aim of the research was to provide a comprehensive bibliometric analysis of the financial toxicity of breast cancer, to identify research voids and future research challenges. Materials and methods. The systematic mapping of literature relied on a multi-method approach, combining bibliometric methods with a standard review/discussion of most important contributions. The analysis employed Bibliometrics in R and VosViewer. Results. The results highlighted the key authors, journals and research topics in the investigation of the financial toxic- ity of cancer and stressed the concentration of work around several authors and journals. Conclusions. The results also revealed a lack of a comprehensive approach in the study of financial toxicity, as the literature often focuses on one or few selected aspects of financial toxicity. In addition, geographic coverage is un- even and differences in the healthcare systems represent a challenge to straightforward comparisons. Key words: breast cancer; financial toxicity; bibliometric analysis Introduction Cancer care is not only a medical challenge, but also a complex socio-economic issue. The term fi- nancial toxicity has gained prominence in recent years to describe the adverse financial effects ex- perienced by cancer patients as they navigate di- agnosis, treatment, and survivorship.1 Financial toxicity in cancer care is prevalent and causes significant financial loss, psychological distress, and maladaptive coping strategies, requiring mul- tilevel, coordinated efforts among stakeholders.2 Patients with breast cancer frequently experience financial toxicity as a result of extended and multi- modal treatment; in low- and middle-income coun- tries, this was reported to affect 78.8% of patients, while in high-income countries, it affected 35.3% of patients.3 Systematic reviews of the literature Radiol Oncol 2025; 59(1): 31-42. Ratosa I et al. / Financial toxicity of breast cancer: bibliometric analysis32 have shown that patients with cancer from various income-group countries experience a significant financial burden during their treatment4, and de- spite publicly funded universal public healthcare, financial toxicity remains a concern for patients with cancer and their families.5 However, patients with cancer in countries with more market-driven health care face more financial toxicity since they have to co-pay for medical services and medicines, even if they have insurance. This is one of the rea- sons why the prevalence of financial toxicity is higher in the US compared to nations with univer- sal health care (22–27%).5,6 Although financial tox- icity levels vary by country, the data indicate that financial protection is inadequate in many coun- tries and highlight the need for targeted interven- tions to alleviate financial strain among affected individuals.5 Generally, women fare worse finan- cially than men after cancer treatment.7 Various factors contribute to the development and exacerbation of financial toxicity among pa- tients with breast cancer. Socioeconomic factors, such as income level, employment status, and education, play a significant role in determining an individual’s vulnerability to financial strain. Additionally, clinical factors, such as disease stage, further compound the financial burden experi- enced by patients. Geospatial differences also ex- ist, with certain counties exhibiting higher risk profiles for financial toxicity due to disparities in healthcare infrastructure and access to supportive resources.7-9 In a single-institution cross-sectional survey of adult female patients with breast cancer who underwent lumpectomy or mastectomy, lower fi- nancial distress was associated with factors such as having supplemental insurance, higher house- hold income, and a higher credit score, while work reduction, increased out-of-pocket spending, ad- vanced tumour stage, and being employed at di- agnosis were associated with increased distress.10 For survivors of breast and gynaecologic cancer, greater financial toxicity is associated with greater distress and a lower quality of life.11 As the incidence and prevalence of breast can- cer continues to rise worldwide12, understanding its impact on financial toxicity in Europe is essen- tial for guiding policy interventions and improv- ing patient outcomes. In light of these challenges, there is a growing recognition of the need to ad- dress financial toxicity as an integral component of comprehensive cancer care. In recent years, the utilization of visualization analysis has surged as a prominent approach for scrutinizing vast biblio- metric datasets and results of scientific contribu- tions. This methodology employs specialized soft- ware to conduct correlations within data, translat- ing findings into visual representations that facili- tate a more intuitive comprehension of pertinent information. By doing so, it facilitates the detection of underlying patterns concealed within extensive datasets, streamlining the assimilation of valuable insights.13 While existing literature has compre- hensively summarized various aspects of finan- cial toxicity3,5,13, there remains a notable need for bibliometric and visual studies examining the cur- rent landscape of financial toxicity in patients with breast cancer. Therefore, the aim of present study was to gain insights into the current literature and trends on financial toxicity in patients with breast cancer using bibliometrics and visualization anal- ysis to identify key journals, countries, research- ers, institutions, and collaborations among them to identify research voids and future research chal- lenges and discuss most important contributions. Materials and methods Research goals This paper relies on a multi-method approach to identify research challenges in the field of the fi- nancial toxicity of breast cancer, primarily rely- ing on bibliometric analysis with text mining to provide a solid base for a classic problem-based literature review. The research goal of the biblio- metric analysis of the research done within the field of financial toxicity of breast cancer focuses on identifying key challenges and research gaps in understanding the causal relationships between breast cancer, its treatment and direct and indirect financial burden. To do so, the following research questions were addressed: 1. What was the evolution of research in this topic and its dynamics throughout time? 2. Which were the important journals and influ- ential authors who have contributed to the un- derstanding of financial toxicity in cancer, as well as what was the influence of collaboration between authors and countries? 3. Which were the main topics that were investi- gated in relation to the financial toxicity of can- cer? and 4. Which are the current gaps in the literature? 5. While the first two research questions are pre- dominantly explored using bibliometric analy- sis, the last two are explored using a multi-meth- od approach: the bibliometric analysis is used Radiol Oncol 2025; 59(1): 31-42. Ratosa I et al. / Financial toxicity of breast cancer: bibliometric analysis 33 to provide the general guidelines for further re- search using content analysis and extended by a standard review of key contributions. Methodology Scopus was used as a base for the bibliometric analysis due to its wide coverage in the field of medicine (including Medline) as well as wider cov- erage of publication types than Web of Science.* Initially, 252 papers were obtained from the Scopus database on February 4th 2024, using the search focusing on a wider span of relevant key- words in paper titles (see Figure 1). The final data- base was prepared based on content analysis of the paper titles and abstracts to limit the analysis only to those relevant for the study. The final set of stud- ied papers comprised 165 papers (151 articles, 5 notes, 5 reviews, one conference paper, one editori- al, one letter, one survey), published in 97 different sources between 1995 and 2024. The papers were prepared by in total 926 authors, with an average of 6.76 authors per paper and only 9 papers being single authored. The content was summarized in 293 different keywords and 1065 key-words plus. The research, presented in the investigated papers, relied on a broad set of knowledge, the total num- ber of cited references was 5323. The investigated body of literature already made a significant im- pact in the field, since the studied papers were on average cited close to 23 times. Figure 1 summa- rizes the research approach summary. Methodologically, the paper combines two ap- proaches: (1) bibliometric analysis, serving as a base for a 2 more detailed review of the key lit- FIGURE 1. Step-by-step research approach summary (based on ref.16). * For example, in December 2023 Scopus included more than 29200 active serial publications, more than 330 thousand books and 23.4 million open access items from more than 7000 publishers. In total, the data comprised the work of almost 20 million authors, and almost 100 thousand affiliations.14 Scopus also includes data from MEDLINE and EMBASE.15 The wider and highly topic-relevant coverage were the main reasons why Scopus was chosen over Web of Science.16 Radiol Oncol 2025; 59(1): 31-42. Ratosa I et al. / Financial toxicity of breast cancer: bibliometric analysis34 erature, identified by the bibliometric analysis. The bibliometric analysis relies on the established bibliometric approaches.17-20 The analysis provides first the dynamics of the field development, in- cluding key authors, outlets, citation and collabo- ration. Co-citation and collaboration analyses were used to further explore the relationships between papers, clusters of papers with common topics or origin and also to identify the teams of authors, collaborations that contributed most to the devel- opment of the field. The more general thematic analysis was conducted in Bibliometrix pack- age in R online environment (R-Studio 0.98.1091 software).21 It was used to extract key topics us- ing keywords and also identify the topics using keyword co-occurrences. Namely, key-words are according to the literature the first and most gen- eral summary of the main topics in the text.22-25 To further investigate the evolution of themes in the field, a conceptual structure was created using the Multiple Correspondence Analysis (MCA), an exploratory multivariate technique that identifies themes based on distances.18 Content analysis rely- ing on keywords was conducted also in R.26 The research also utilized VOSviewer (version 1.6.20) for visualization.27 Results The interest in the topic of financial toxicity of can- cer in the literature (focusing on Scopus) has been growing since the 1990s, with the number of pa- pers increasing fast in particular after 2010. In 2021, 31 papers, dealing with the topic of financial toxic- ity of breast cancer were published. The published papers were on average cited more than 20 times over the observed period. In some years, though, the number of citations in the investigated body of the literature on average exceeded 160 in 2004, 137 in 2002 and 100 citations in 2007, when also some of the more cited papers were published.28,29 But, even if the total number of citable years is considered, the investigated body of literature on average still received several citations, apart from the papers published in 2024 (Figure 2). The outlets, that published most papers on the topic, are the following: Supportive Care in Cancer, with 20 papers studying financial toxicity of cancer, followed by Cancer (10 papers), Breast Cancer Research and Treatment (6), Journal of Cancer Survivorship (6), Psycho-oncology (5). Bradford law states that there are only a few very productive publications, and a much larger number of those of low(er) relevance. The so-called Zone 1 or core journals are those most often cited in the litera- ture for a specific field and thus most important. Mathematically, the rank is inverse with a propor- tion of the articles in the journal using a logarith- mic scale.30 The Bradford law analysis of the investigated body of literature suggests that the most impor- tant sources are indeed Supportive Care in Cancer, Cancer, Breast Cancer Research and Treatment, Journal of Cancer Survivorship, Psycho-oncology, but also Journal of Clinical Oncology, Clinical Breast Cancer FIGURE 2. Published number of papers by year (left axis) and mean citations per paper and mean citations per citable year (right axis). FIGURE 3. Bradford law with Zone 1 journals. Radiol Oncol 2025; 59(1): 31-42. Ratosa I et al. / Financial toxicity of breast cancer: bibliometric analysis 35 and JCO Oncology Practice, which all are in Zone 1 (or most important journals) (Figure 3). Hawley31-33, Offodile10,34,35, Wheeler36-38, Bradley29,39,40 and Jagsi31,32,41 are some of the most important authors, authoring or co-authoring at least 6 published articles or 3.6% or more of the in- vestigated body of literature (Table 1, for each au- thor the citations in the brackets in the text refer to the 3 most cited papers). Lotka Law42, which investigates the concen- tration (or distribution of papers by authorship) also highlights that 3 authors (Hawley, Offodile, Wheeler), who in total represent 0.3% of all au- thors, have contributed a significant proportion of the studied papers, while on the other hand 87% of authors have only contributed one paper. H index43, measuring authors’ local impact, shows that Hawley, Jagsi, Wheeler and Offodile have the highest H-index of 6, indicating that each has at least 6 papers, each cited at least 6 times. Authors are international, coming from a num- ber of different countries, most often collaborating with the US (25 papers), UK (13), Switzerland (7), Australia (6). While authors are from a number of different institutions, the most common affili- ations are: University of Michigan, University of Texas (MD Anderson Cancer Center), University of California, University of North Carolina, Shiraz University of Medical Sciences, Johns Hopkins University, University of Maryland and Harvard Medical School, each with at least 13 mentions with Michigan in total with 38. USA dominates also among the cited references, with in total 2565 cited papers, followed by Australia with 233, Canada with 180 papers and UK with 145 cited papers in the list of references. Further investiga- tion of the collaboration between groups of au- thors shows that there are five strong groups of authors, who collaborate frequently. Among those are: (1) Wheeler, Spencer, Blinder, Reeder-Hayes, Swanberg and Vanderpool, (2) Hawley, Bradley, Jagsi, Katz, Hamilton, Abrahamse, Griggs, Janz, Kurian, Wallner, Blinder, and (3) Offodile, Asaad, TABLE 1. A list of authors with at least 4 published papers in the investigated set of literature Authors Articles Articles Fractionalized* No of documents (in % of all) HAWLEY ST31-33 7 0.919 4.2 OFFODILE AC10,34,35 7 0.774 4.2 WHEELER SB36-38 7 0.868 4.2 BRADLEY CJ29,39,40 6 1.569 3.6 JAGSI R31,32,41 6 0.701 3.6 ASAAD M10,34,35 5 0.549 3 BOUKOVALAS S10,34,35 5 0.549 3 KATZ SJ31-33 5 0.576 3 AZUERO A46 4 0.522 2.4 CHAN A64–67 4 0.342 2.4 COOPER B64–67 4 0.342 2.4 GORDON L45 4 0.501 2.4 HAMILTON AS31,32 4 0.476 2.4 KOCZWARA B64–67 4 0.342 2.4 MIASKOWSKI C64–67 4 0.342 2.4 * Fractionalized authorship to papers assesses individual productivity taking into account co- authorships, assuming equal distribution of contributions across all authors TABLE 2. A list of 10 most cited papers in the investigated set of literature (only the first author is listed in case of multiple authors)* Paper DOI/PMID Totalcitations TC per year Normalized TC Jagsi et al., 2014, J Clin Oncol31 10.1200/JCO.2013.53.0956 206 18.73 4.73 Arozullah et al., 2004, J Support Oncol28 PMID: 15328826 161 7.67 1.00 Bradley et al., 2002, J Health Econ29 10.1016/S0167-6296(02)00059-0 137 5.96 1.00 Bradley et al., 2007, Cancer Invest39 10.1080/07357900601130664 117 6.50 1.12 Lauzier et al., 2008, J Natl Cancer Inst44 10.1093/jnci/djn028 111 6.53 1.51 Jagsi et al., 2018, Cancer32 10.1002/cncr.31532 104 14.86 2.82 Meneses et al., 2012, Gynecol Oncol46 10.1016/j.ygyno.2011.11.038 94 7.23 2.40 Gordon L et al, 2007, Psycho-Oncology45 10.1002/pon.1182 92 5.11 0.88 Greenup et al, 2019, J Oncol Pract37 10.1200/JOP.18.00796 81 13.50 4.12 Wheeler et al., 2018, J Clin Oncol36 10.1200/JCO.2017.77.6310 81 11.57 2.20 * TC per year = total citations per year; Normalized TC = Normalized total citations Radiol Oncol 2025; 59(1): 31-42. Ratosa I et al. / Financial toxicity of breast cancer: bibliometric analysis36 Boukovalas, Greenup, Lin, Bailey, and Butler, to list just the first three groups of authors. The investigation of the financial toxicity of breast cancer was highly influenced by a smaller set of highly cited papers (Table 2). Below, a summary of the most cited is provided. Jagsi and co-authors31 published in 2014 the most cited paper with in total 206 citations. They used a longitudinal approach to study the long-term fi- nancial burden of breast cancer that showed that a quarter of women suffered financial decline due to breast cancer, and that the minorities were more vulnerable to the effects. Arozullah et al.28 showed that the financial burden of cancer in the US accounted for at least 26% of monthly income to as much as 98%, depending on income group, and that the insurance policies covered on aver- age only around 3% of out-of-pocket expenditures of the studied women, providing valuable policy input that affordable compensation plans should be available in particular to those in low income brackets. Bradley et al.29 in 2007 investigated the relationship between breast cancer survival, work and earnings in the US and found that while breast cancer does have a negative impact on employment, the responses of women are heter- ogenous and that the survivors who do work in fact worked and earned more than those in the control group. In 2002, Bradley et al.39 showed in a US-based longitudinal study that the greatest impact on labour supply was present in the first six months after diagnosis, while between 12 and 18 months after diagnosis many already returned to work. Among the papers with more than 100 citations is also the work of Lauzier et al.44 who showed that in Canada on average around a quar- ter of projected annual wage was lost due to breast cancer, more among those with lower education, those with lower social support, receiving chemo- therapy, self-employed and short work-experi- ence, to list just those with highest significance. A longitudinal study in Australia showed that economic costs continue to affect women even 1.5 years after surgery, where income loss and the costs of health service were the most important sources of economic burden, which is higher for women with positive lymph nodes.45 Related to the longer-term analysis of financial toxicity of cancer, a follow-up study of 132 survivors showed that the impacts in the longer term are signifi- cant in the financial sense (e.g. increased insur- ance premiums) and otherwise (lower motivation, productivity, quality of work, impact on absence from work), stressing the extended impact of can- cer burden on post-treatment period in the US.46 Wheeler et al.36 discuss the racial differences in breast cancer financial toxicity in the US and find that the impact of race was significant for job loss, transportation barriers, income loss, and overall financial impact. Jagsi et al.32 investigated the role of clinicians’ engagement in the patient care also from the perspective of financial toxicity of can- cer, not just health aspects of the disease in the US. Between 15−30% of patients, depending on ethnicity, expressed desire to discuss also finan- cial burden of cancer, however, depending on the topic, between 50 and 70% of those longing to talk also about the financial aspect, did not report or receive such support. Financial toxicity impacts also the decision for the type of breast cancer sur- gery. For example, more than a quarter of studied women in the US reported that costs were consid- ered when deciding about preservation and ap- pearance.37 Bilateral mastectomy was associated with higher debt, very high financial burden and changed employment.37These findings, which re- fer to the most cited papers, mainly refer to the US, which has a specific health insurance system. Although the investigated literature focuses on the financial toxicity of breast cancer, the literature deals with a wide array of subtopics. The simplest content analysis is done using keywords, as they are used to efficiently summarize the text.47 Most common author-used keywords by frequency are the following: breast cancer and financial toxicity, return to work, quality of life, survivorship, cost of illness, costs, metastatic breast cancer, oncology, cancer survivors/survivorship, chemotherapy, fi- nancial burden, lymphedema, fatigue, healthcare costs, treatment, financial stress, occupation, reha- bilitation, social support, unemployment, work. Thematic map, investigating the relationships between the words, prepared in Bibliometrix, allows the division of the topic also into basic themes, motor themes, niche themes and emerg- ing/declining themes, which are investigated us- ing keywords for each theme (100 words were in- cluded, minimum cluster frequency 5, Walktrap clustering algorithm). Table 3 summarizes the main topics and provides selected references for each of the identified topics. The motor themes are three (T1–T3, Table 3). The first motor topic is related to the individual and the consequences of the disease for the indi- vidual, in particular in relation to employment and financial toxicity. This topic deals with can- cer survivorship, employment and the return to work, occupational differences, related disability Radiol Oncol 2025; 59(1): 31-42. Ratosa I et al. / Financial toxicity of breast cancer: bibliometric analysis 37 and the consequences of treatment (chemother- apy, fatigue, burnout) as well as mental health aspects of the disease. In terms of financial toxic- ity, a number of aspects are investigated, besides employment also unemployment, social support, rehabilitation, return to work, occupations, needs assessment (which can also be related to return to work), socio-economic status, sick-leave, career change, fatigue, job loss, quality of life, and oth- er.29,33,39 The second motor topic is related to meta- static breast cancer, its prevalence, the impact on healthcare use, utilization and costs. This topic is more closely related to the wider healthcare aspect of cancer-related cost.48,49 The third motor topic was dealing with COVID-19 and breast cancer.50,51 The COVID-19 is on the margin between a niche and a motor theme, indicating a fast development of a narrow theme, which focuses on the impact of cancer during COVID-19, to job-loss and men- tal health. The access to healthcare was also high- lighted. The topic of financial toxicity of cancer (T1, Table 3) is also close to the border between ba- sic and motor themes, while the broader economic burden is a major motor theme. General economic burden, cost of illness and cancer is a basic theme. The key words stress the cost-effectiveness, re- source utilization, healthcare use and healthcare costs, screening. The topic also highlights differ- ences between diagnoses (e.g. metastatic, hormone positive, premenopausal). A close link between the motor theme (T1) and basic theme is for example productivity loss, which highlights the aggregate effects of the impact of the disease on the indi- viduals’ labour market outcome.52-54 Niche themes revolve around reasonable accommodations and sick-leave, highlighting also the importance of as- sessment and planning.55,56 Emerging or declining themes revolve around coping strategies, health- care costs as well as regional and ethnic differ- ences.57,58 An investigation into the evolution of the themes between 1995 and 2024 shows that before 2010, the number and diversity of the topics in the literature was significantly narrower, focusing primarily on (1) employment (hours worked, labour market effects, disability, earnings), (2) process of treat- ment and return to work (oncology, breast neo- plasms, chemotherapy, rehabilitation, occupation, return to work), (3) process of the return to work (assessment and planning, reasonable accommo- dations, job retention), (4) healthcare system and costs (prevalence, direct and indirect costs, cost of illness, administrative claims) and (5) selected demographic aspects. After 2010, the number of topics significantly increased, predominantly due to further disaggregation of selected aspects. In addition to the aforementioned key aspects, which were driving the literature before 2010, several ad- ditional aspects emerge: (1) financial toxicity in relation to coping strategies, social supports, com- munity programs, (2) metastatic cancer is studied in relation to cancer distress, costs, role of screen- ing, (3) healthcare costs and use are studied in rela- tion to cost drivers and adverse events, while also (4) covid-19 emerges as a topic, both in relation to financial toxicity as well as anxiety, and cognition. TABLE 3. Thematic map of (financial) toxicity of breast cancer with most common author keywords for each of the themes and selected references Key term(s) Other key terms* Selected papers (No. of reference) Motor themes T1: Breast cancer (neoplasms), employment, financial toxicity Quality of life, return to work, (cancer) survivor(ship), treatment, financial burden / stress, fatigue, chemotherapy, mental health, caregivers, social support, disability, occupation, burnout complaints 29, 33, 39 T2: Metastatic breast cancer Prevalence, healthcare use, healthcare utilization, healthcare costs, advanced breast cancer, adverse effects, administrative claims, breast cancer costs 48, 49 T3: COVID-19 Depression, job loss, access to healthcare, breast cancer survivors, cognition, anxiety, autonomy 50, 51 Basic themes T1 Economic burden Cost(s), oncology, lymphedema, rehabilitation, breast neoplasm, cost-effectiveness, recurrence, screening, cost of illness, cancer, resource utilization, healthcare use 52-54 Emerging or declining themes T1: Coping strategies Breast cancer, healthcare, costs, regional, ethnic differences 55, 56 Niche themes T1: Reasonable accommodations Sick leave, assessment and planning 57, 58 * Other key terms (T) selected based on centrality and repetition (overlap with other similar key terms within same topic). Radiol Oncol 2025; 59(1): 31-42. Ratosa I et al. / Financial toxicity of breast cancer: bibliometric analysis38 Discussion Discussion of bibliometric analysis: a review of most important findings According to the results of the bibliometric analy- sis, the literature on the financial toxicity of breast cancer is marked with a significant concentration in terms of relevant research journals (Supportive Care in Cancer, Cancer, Breast Cancer Research and Treatment, Journal of Cancer Survivorship), au- thors (Hawley31-33, Offodile10,34,35, Wheeler36-38, Bradley29,39,40 and Jagsi31,32,41) as well as concentration of topics, with the two most important and widest being the (1) individual-level investigation of finan- cial toxicity of cancer in relation to earnings, em- ployment and other related topics and (2) a more aggregated health-care and social system perspec- tive related to cancer treatment and its costs. However, the financial toxicity of cancer is a much wider concept, encompassing (i) direct or active financial spending, (ii) passive financial re- sources’ spending, (iii) psychosocial impacts, (iv) the need for external support, (v) coping with care and (vi) changes in lifestyle.47 The direct payments TABLE 4. A systematization of (financial) toxicity of breast cancer at the level of the individual (left column) and research gap (right column) Type of financial burden/burden Coverage in the literature and research gap 1. Medical costs Weaker coverage, survey based, depends on social security system, more relevant for private-insurance based system (e.g. US)Treatment expenses Hospitalization costs 2. Non-medical costs Weaker coverage, survey based, depends on social security system, more relevant for private-insurance based system (e.g. US) Travel expenses Accommodation costs Other 3. Out-of-pocket costs Weak coverage, survey basedDeductibles and co-payments Prescription drug costs* 4. Loss of income Well-documented employment impacts, income impacts, less focus on occupational change Changed work hours Job loss Change in occupation Loss/change in income 5. Insurance-related costs Weak coverage, depends on social security system, but has broader relevance for other non-medical insurances (life, travel, etc.) 6. Impact on finances and assets: Weak coverage Debt accumulation Asset depletion 7. Psychosocial impact: Well-documented, focus on stress, anxiety, less focus on quality of life as a wholeStress and anxiety Quality of life 8. Long-term financial consequences Increasing interest on recurrence, screeningSurvivorship costs Cancer recurrence 9. Geographical coverage Vast body of evidence for the US, poorer coverage for EU/European contextUS Europe * Can differ between countries depending on health-care system Radiol Oncol 2025; 59(1): 31-42. Ratosa I et al. / Financial toxicity of breast cancer: bibliometric analysis 39 include medical (potential treatment expenses, hospitalization expenses, depending on social se- curity system), non-medical costs (travel, accom- modation, other travel related costs), out-of-pocket costs (medications, deductibles and co-payments, depending on social system).59,60 Second, the indi- vidual suffers loss of income due to reduced work- ing hours or even job-loss61, domestic finances and assets can be affected due to the use of savings62, and individuals can suffer insurance-related costs (increased premiums).63 In the short and in the long-term, the disease can bear significant costs due to stress and anxiety, while the quality of life can also suffer. In the long term, primarily the so- called survivorship costs, related to on-going care or long-term effects of cancer and potential recur- rence are important. The investigated body of literature, which ex- amines financial toxicity of breast cancer, focuses most on the employment, job, and income related consequences (Table 4). These are also the consequences that can more easily and reliably be measured, either via surveys or registry-data, both cross-sectional and longitu- dinal, focusing also on the differences conditional on the demographic characteristics of patients. The literature also demonstrates a lot of focus on phycological impacts on the individual, which can have longer-term effects on both health as well as financial stress. The aggregated perspective on the health-care system is also at the forefront of research. On the other hand, the reviewed body of literature on financial toxicity of breast cancer displayed little interest in the non-medical costs, insurance related costs, impact on debt accumu- lation and depletion of savings. However, cross- country differences are notable, depending not only on the health-care system, but also on the income (development) level of the countries.4,68 In particular, when comparing developed economies, the evidence is widely focused on the experiences of the US patients, there is significantly less evi- dence for European context.69-72 The studies show a significant level of financial burden of cancer in both US and EU, however, in the US the pri- vate insurance, varying insurance coverage and reimbursement policies referring to cancer care, including diagnostics, treatments (chemotherapy and radiation), medications and also supportive care medications cause substantial out-of-pocket expenses for patients.60 In Europe, where health- care systems are predominantly publicly funded and universal, breast cancer patients generally face lower out-of-pocket costs for medical services. However, disparities in access to innovative treat- ments and supportive care services may still exist across different European countries, contribut- ing to variations in financial toxicity among pa- tients4,73,74, which highlights also the need for using an adjusted methodology.75 Limitations and future research orientation This analysis contributes to the literature in sev- eral aspects. First, it studies the body of literature on the financial toxicity of breast cancer in Scopus. A comparable analysis using Web of Science76 is narrower due to the coverage as well as due to its focus on solely bibliometric issues. This paper re- lies on a multi-method approach to provide a more comprehensive overview – first, it highlights in a systematic manner the most notable authors and papers as well as stresses the concentration of au- thors, journals and topics in the literature. Second, the paper shows that the majority of the literature focuses on selected aspects of financial toxicity of cancer. Thereby, it identified a research gap that can propel future development of the study area. The analysis can in the future also be extended and improved to overcome some of the limitations of the existing analysis. First of all, a more detailed analysis into each of the key topics would allow identification of main linkages between the varia- bles of interest within a specific topic. An in-depth investigation of each of these variables would al- low identification of possible causal mechanisms in the existing literature that explain the channels through which cancer is related to financial toxic- ity in both short and long term. It is also impor- tant to highlight the methodological downsides of bibliometric analysis77, which is in fact quantita- tive, although it often seeks to provide qualitative conclusions. Furthermore, the body of literature is focusing on different health-care systems, reveal- ing also the differences in the financial toxicity. Future research should adequately address these differences in empirical assessment75, in particular when comparing different countries. This could also imply that data gathered based on established international methodology (questionnaires such as Comprehensive Score for financial Toxicity - Functional Assessment of Chronic Illness Therapy (COST-FACIT)78 should be used with care and questionnaires should be extended to capture na- tional specifics. Radiol Oncol 2025; 59(1): 31-42. Ratosa I et al. / Financial toxicity of breast cancer: bibliometric analysis40 Conclusions The financial toxicity of breast cancer represents a burden that encompasses a wide range of effects, from the direct to the indirect financial costs as well as wider socio-economic impacts on patients. This paper provides a systematic mapping of the literature, relying on the bibliometric analysis that shows that despite the relatively wide coverage, there are still significant research gaps in the liter- ature. The literature often concentrates on specific aspects of financial toxicity, is often focusing on one country and thereby also one specific health- care system, or is not addressing the broader, more holistic aspects of the problem. In particular, the literature is focusing on the aspects that are easier to measure or capture, while a more holistic ap- proach would require both a broader as well more often also a longitudinal approach. Such an ap- proach would also allow better informed policy- making to alleviate the short- and long-term ef- fects of the financial toxicity of breast and other cancers. Acknowledgments This work was financed by Slovenian Research and Innovation Agency grants No. J7-4540, P5- 0128, P5-0117, P5-0441 and P3-0429. References 6. Zafar SY. 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Available at: https://www.facit.org/ measures/facit-cost Radiol Oncol 2025; 59(1): 43-53. doi: 10.2478/raon-2025-0014 43 research article Early-time-point 18F-FDG-PET/CT and other prognostic biomarkers of survival in metastatic melanoma patients receiving immunotherapy Nezka Hribernik1,2, Katja Strasek3, Andrej Studen3,6, Katarina Zevnik7, Katja Skalic7, Robert Jeraj3,4,5,6, Martina Rebersek1,2 1 Department of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia 2 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 3 Faculty of Mathematics and Physics, University of Ljubljana, Ljubljana, Slovenia 4 University of Wisconsin Carbone Cancer Centre, Madison, WI, USA 5 Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, USA 6 Experimental Particle Physics Department, Jozef Stefan Institute, Ljubljana, Slovenia 7 Department of Nuclear Medicine, Institute of Oncology Ljubljana, Ljubljana, Slovenia Radiol Oncol 2025; 59(1): 43-53. Received 12 December 2024 Accepted 4 January 2025 Correspondence to: Assoc. Prof. Martina Reberšek, M.D., Ph.D., Department of Medical Oncology, Institute of Oncology Ljubljana, Zaloška 2, SI-1000 Ljubljana, Slovenia. E-mail: mrebersek@onko-i.si Disclosure: Robert Jeraj is a cofounder and CSO of AIQ Solutions, Madison, WI, USA. Funding. No potential conflicts of interest are disclosed by the other co-authors. This is an open access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/). Background. A considerable proportion of metastatic melanoma (mM) patients do not respond to immune checkpoint inhibitors (ICIs). There is a great need to develop noninvasive biomarkers to detect patients, who do not respond to ICIs early during the course of treatment. The aim of this study was to evaluate the role of early [18F]2fluoro- 2-deoxy-D-glucose PET/CT (18F-FDG PET/CT) at week four (W4) and other possible prognostic biomarkers of survival in mM patients receiving ICIs. Patients and methods. In this prospective noninterventional clinical study, mM patients receiving ICIs regularly underwent 18F-FDG PET/CT: at baseline, at W4 after ICI initiation, at week sixteen and every 16 weeks thereafter. The tu- mor response to ICIs at W4 was assessed via modified European Organisation for Research and Treatment of Cancer (EORTC) criteria. Patients with progressive metabolic disease (PMD) were classified into the no clinical benefit group (no-CB), and those with other response types were classified into the clinical benefit group (CB). The primary end point was survival analysis on the basis of the W4 18F-FDG PET/CT response. The secondary endpoints were survival analysis on the basis of LDH, the number of metastatic localizations, and immune-related adverse events (irAEs). Kaplan-Meier analysis and univariate Cox regression analysis were used to assess the impact on survival. Results. Overall, 71 patients were included. The median follow-up was 37.1 months (95% CI = 30.1–38.0). Three (4%) patients had only baseline scans due to rapid disease progression and death prior to W4 18F-FDG-PET/CT. Fifty-one (72%) patients were classified into the CB group, and 17 (24%) were classified into the no-CB group. There was a statisti- cally significant difference in median overall survival (OS) between the CB group (median OS not reached [NR]; 95% CI = 17.8 months – NR) and the no-CB group (median OS 6.2 months; 95% CI = 4.6 months – NR; p = 0.003). Univariate Cox analysis showed HR of 0.4 (95% CI = 0.18 – 0.72; p = 0.004). median OS was also significantly longer in the group with normal serum LDH levels and the group with irAEs and cutaneous irAEs. Conclusions. Evaluation of mM patients with early 18F-FDG-PET/CT at W4, who were treated with ICIs, could serve as prognostic imaging biomarkers. Other recognized prognostic biomarkers were the serum LDH level and occurrence of cutaneous irAEs. Key words: early time-point 18F-FDG-PET/CT; prognostic biomarkers; immune-related adverse effects metastatic melanoma; immune-checkpoint inhibitor Radiol Oncol 2025; 59(1): 43-53. Hribernik N et al. / 18F-FDG-PET/CT and other prognostic biomarkers in melanoma patients on ICI44 Introduction Immunotherapy with immune checkpoint in- hibitors (ICIs) has greatly impacted the treatment landscape of metastatic melanoma (mM) patients. Final, 10-year results from pivotal randomized clinical trial have shown ongoing benefits, with 10-year overall survival (OS) rates of 34%, 37%, and 43% in mM patients receiving pembrolizumab, nivolumab, and ipilimumab/nivolumab, respec- tively.1,2 However, a considerable proportion of mM patients do not respond to ICIs. Normal serum levels of lactate dehydroge- nase (LDH) and a small number of organs with metastatic involvement are two very strong and well-recognized prognostic biomarkers of better survival in mM patients.3-5 In addition, immune- related adverse events (irAEs) have been proven in some studies to be biomarkers of improved re- sponse rates and longer survival in patients treated with ICIs.6,7 Specifically, endocrine and cutaneous irAEs were associated with favourable survival outcomes compared with patients without this type of irAE in a large retrospective multicohort study.6 There is a great need to develop other non- invasive imaging biomarkers (IBM) to detect mM patients who do not respond to ICIs early in the course of treatment. Positron emission tomography/computed to- mography with [18F]2fluoro-2-deoxy-D-glucose PET/CT (18F-FDG PET/CT) is a noninvasive method that combines anatomical and functional data. It is generally used as a diagnostic tool for the staging of melanoma patients and is now gaining valuable value in immunotherapy treatment response eval- uation and prognosticating outcomes.7,8 In addi- tion to staging and response monitoring, 18F-FDG PET/CT has also shown some potential for detect- ing immune-related side effects (irAEs), such as the use of organ 18F-FDG uptake, quantified by percentiles of standardized uptake values (SUV) distribution as a quantitative IBM of irAEs.9-11 The optimal timing of the first on-treatment 18F-FDG PET/CT evaluation of mM patients on ICIs is a matter of ongoing investigations. Joint EANM/ SNMMI/ANZSNM practice guidelines/procedure standards recommended an interim 18F-FDG PET/ CT scan during immunomodulatory treatment in patients with solid tumors at 8–12 weeks after the start of treatment (i.e., after 3–4 cycles of immu- notherapy).7 However, there are studies analysing 18F-FDG PET/CT scans performed earlier after ICI initiation. In a prospective study with 20 mM pa- tients treated with ipilimumab, 18F-FDG PET/CT was performed between 21-28 days after treatment start. They concluded that the combination of changes in lesion dimensions along with changes in 18F-FDG uptake may be associated with immune activation and a favourable outcome.12 We previously reported the results of our pro- spective study regarding the role of quantitative IBM in early 18F-FDG PET/CT, which was per- formed four weeks after ICI initiation, for the de- tection of immune-related adverse events in mela- noma patients.10 Here, we evaluated the role of ear- ly 18F-FDG-PET/CT at week four and other possible prognostic biomarkers of survival in mM patients receiving ICIs. Patients and methods Patients We enrolled patients 18 years of age or older who had histologically confirmed, unresectable, ad- vanced melanoma and were planned to be treated per standard of care with ICIs with anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) and/or anti-programmed death-1 (anti-PD-1) treatment in the first or second line of systemic treatment at the Institute of Oncology Ljubljana, Slovenia. The key exclusion criteria included symptomatic brain metastases and malignant dis- eases other than melanoma. Trial design In this noninterventional, prospective study, pa- tients underwent baseline 18F-FDG PET/CT within four weeks before treatment initiation and were monitored regularly with serial 18F-FDG PET/CT: at week four (W4) (+/- 5 days), week 16 (W16) (+/- 7 days), and week 32 (W32) (+/- 7 days) after treat- ment initiation and every 16 weeks thereafter. The first follow-up 18F-FDG PET/CT at W4 was per- formed for investigational purposes and was not necessarily used to guide treatment decisions. The clinical data and images included in this analysis were obtained from disease diagnosis up to 1st September 2024. All 18F-FDG PET/CT data were acquired before and during ICI treatment, and all clinical data were collected for review. The irAE grade was as- signed prospectively and scored with the use of the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, v.5.0).13 The irAE were classified as serous irAE in case of high- er grade of irAE of 3 and above. Imaging and clini- Radiol Oncol 2025; 59(1): 43-53. Hribernik N et al. / 18F-FDG-PET/CT and other prognostic biomarkers in melanoma patients on ICI 45 cal data were anonymized and stored in a secure LabKey database server.14 The clinical protocol was approved by the Ethics Committee ERIDEK-0034/2020 and the Clinical Trials Protocol Review Committee ERID- KSOPKR-0032/2020 at the Institute of Oncology Ljubljana and by the Commission of the Republic of Slovenia for Medical Ethics (approval number: 0120-256/2020-14, September 15th 2020). It was con- ducted following the ethical standards defined by the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. The study was registered with ClinicalTrials.gov under the registration number NCT06207747. The study was conducted with the acknowledg- ment and consent of the subjects. All patients pro- vided signed informed consent for treatment and consent allowing the use of their data for scientific purposes. 18F-FDG PET/CT acquisition and analysis All 18F-FDG PET/CT scans were obtained on Biograph mCT PET/CT (Siemens, Knoxville, TN). Imaging protocol required patients to fast for 6 hours prior to injection of the radiotracer and have a blood glucose level below 10 mmol/L at the time of the scan. Patients were required to hold all diabetic medication, including metformin, for 6 hours prior to radiotracer injection. All scans were acquired per standard of care. CT that meets response evaluation criteria in solid tumours (RECIST) analysis needs was acquired according to adjusted protocol including sinogram affirmed iterative reconstruction (SAFIR) to minimize dose. Following reconstruction, PET images were nor- malized by patient weight and injected dose to compute SUV. More details about image acquisi- tion can be found in our previous paper, where the same cohort of patients was used for analysis.11 The tumor response to ICIs on 18F-FDG PET/ CT was evaluated by a nuclear medicine special- ist combining the European Organisation for Research and Treatment of Cancer (EORTC) crite- ria and visual response assessment.15 The SUVmax and size of the lesions were measured in all most representative tumor lesions, which are the largest lesions of a certain area or organ with the high- est FDG uptake at baseline, W4 and all consecu- tive 18F-FDG PET/CT scans. Patients were classified into four major categories on the basis of the tu- mor response to ICIs: complete metabolic response (CMR), partial metabolic response (PMR), stable TABLE 1. Patient demographics, cancer staging, treatment details, and outcomes Characteristics No = 71 (%) Age; mean (+/-SD) (yr) 62 ± 12 Gender Male 43 (61) Female 28 (39) ECOG performance status 0 30 (42) 1 41 (58) AJCC III.D 1 (1) M1a 16 (23) M1b 10 (14) M1c 32 (45) M1d 12 (17) Anatomic site of primary Cutaneous 58 (82) Ocular 4 (6) Mucosal 3 (4) Unknown primary 6 (8) Line of systemic treatment for metastatic disease 1st line 63 (89) 2nd line 8 (11) Baseline LDH Elevated 23 (32) Normal 49 (68) Number of organs with metastatic involvement 1 25 (35) 2 21 (30) 3 11 (15) > 3 14 20) Actionable mutation BRAF wild type 21 (30) BRAF V600E 28 (39) BRAF V600K 10 (14) BRAF V600 - others 1 (1) NRAS 11 (16) Type of systemic treatment PD-1 inhibitors 47 (66) Combination of PD-1 and CTLA-4 inhibitors 24 (34) Tumor response on week 4 18F-FDG PET/CT Complete metabolic response 3 (4) Partial metabolic response 12 (17) Stable metabolic disease 10 (14) Heterogenous response 6 (8) Possible pseudoprogression 20 (28) Progressive metabolic disease 17 (24) AJCC = American Joint Classification of Cancer; BRAF = V-Raf murine sarcoma viral oncogene homolog B; CTLA-4 = Cytotoxic T lymphocyte-associated antigen 4; ECOG = Eastern Cooperative Oncology Group; ICI = Immune checkpoint inhibitors; No = number of patients; NRAS = neuroblastoma RAS viral homolog; PD-1 = programmed death-1; SD = standard deviation Radiol Oncol 2025; 59(1): 43-53. Hribernik N et al. / 18F-FDG-PET/CT and other prognostic biomarkers in melanoma patients on ICI46 metabolic disease (SMD) and progressive meta- bolic disease (PMD).15 According to the informa- tion gathered after the whole -body 18F-FDG PET/ CT visual assessment, two new categories, of het- erogenous response (HGR) and possible pseudo- progressive disease (PPD), were added for tumor response evaluation. HGR was assigned when multiple lesions were variably meeting the crite- ria of PMD, SMD, PMR and CMR and could not be classified into only one response evaluation category. PPD was assigned in the case of moder- ate metabolic progression of the baseline tumor lesions with few locally distributed new lesions. Obvious progression with multiple new tumor le- sion sites was classified as true progression (PMD). The patients were further stratified into two groups: patients with PMD were classified into the no clinical benefit (no-CB) group and patients with other response categories into the clinical benefit (CB) group. A summary of the response criteria is presented in Supplementary Table 1. Outcomes and statistical analysis The primary end point of this study was the analy- sis of median OS based on the W4 18F-FDG PET/CT response. The secondary endpoint was the median OS, which was analysed on the basis of the level of LDH, the number of organs with metastatic in- volvement at the beginning of ICI treatment, oc- currence of irAE, higher irAE, cutaneous irAEs, endocrine irAEs and immune-related thyroiditis (irThyroiditis). Patient characteristics were summarized via descriptive statistics. Survival analysis was per- formed via the Kaplan‒Meier method, and 95% confidence intervals (CIs) were calculated. The associations of each of the eight metrics with OS were assessed with a univariate Cox proportional hazard model. With the use of the Bonferroni cor- rection for testing multiple hypothesis, probability values p < 0.006 were considered statistically sig- nificant. Results From September 2020 through September 2022, a total of 71 patients were enrolled. The character- istics of the patients are summarized in Table 1. At the cut-off date of the observational period for this analysis on 1st September 2024, the median follow-up was 37.1 months (95% CI = 30.1-38.0). The median duration of ICI therapy was 10.2 months (range: 1-39.4 months). Three (4%) patients had on- ly baseline scans due to rapid disease progression and death prior to W4 18F-FDG-PET/CT. The timing of 18F-FDG PET/CT relative to ICI treatment initia- tion and the number of 18F-FDG-PET/CT images are shown in the Supplementary Table 2. FIGURE 1. Kaplan-Meier curves show overall survival (OS) probability (A) and progression-free survival (PFS) probability (B) over time in patients with metastatic melanoma treated with immune checkpoint inhibitors. The grey shading reflects the 95% confidence interval. Radiol Oncol 2025; 59(1): 43-53. Hribernik N et al. / 18F-FDG-PET/CT and other prognostic biomarkers in melanoma patients on ICI 47 FIGURE 2. Swimmer plot shows individual patient’s treatment progression in each horizontal line. Colourful bars and lines indicate type and duration of treatment, while dots indicate specific action - 18F-FDG-PET/CT imaging or reason for end-of-study (if applicable). Vertical dashed lines indicate a time when 18F-FDG-PET/CT scan should be performed for patients in this study. Radiol Oncol 2025; 59(1): 43-53. Hribernik N et al. / 18F-FDG-PET/CT and other prognostic biomarkers in melanoma patients on ICI48 reached [NR]) and 8.1 months (95% CI = 4.3–26.3 months), respectively (Figure 1). Among the whole group, 39 (55%) patients died, and 44 (62%) patients progressed to immunotherapy before the cut-off date. On Figure 2, the swimmer plot displays data for individual patients, where each horizontal line or bar shows type and duration of treatment, and each point represents either 18F-FDG-PET/CT or end-of-study reason (if applicable). W4 18F-FDG PET/CT and survival outcomes Among the 68 (96%) patients who underwent W4 18F-FDG PET/CT, 51 (72%) patients were classified into the CB group, and 17 (24%) were classified into the no-CB group. The median OS was not reached (NR) (95% CI = 17.8 months - NR) in the CB group and was 6.2 months (95% CI = 4.6 months - NR) in the no-CB group (Figure 3). In univariate Cox analysis classification was statistically significant- ly correlated to OS with hazard ratio (HR) of 0.4 (95% CI = 0.18–0.72; p = 0.004). Among the 17 patients with PMD, who were classified into the no-CB group, 7 (42%) died be- fore the W16 18F-FDG PET/CT scan. Three (18%) pa- tients had PMD on W16 18F-FDG PET/CT, 6 (35%) had PMR, and one (6%) patient had CMR. Two (12%) patients with PMD on W4 18F-FDG PET/CT changed systemic therapy from ICI therapy to tar- geted therapy because of clinical and radiological signs of rapid progression affecting vital organs. Three patients were classified as CMR on W4 18F-FDG PET/CT. One patient achieved a durable response with CMR, one patient experienced fatal grade 5 immune-related encephalitis during treat- ment and one experienced local progression in soft tissues 25 months after CMR imaging on W4 18F-FDG PET/CT. The site of progression was ame- nable for local treatment with radiotherapy, and a complete metabolic response was achieved. In Figure 4, the alluvial plot shows the respons- es on 18F-FDG PET/CT scans for each patient at week 4, 16, 48 and 96. Other biomarkers and survival outcomes LDH and the number of organs with metastatic involvement Twenty-three (32%) patients had elevated serum LDH at ICI initiation. The median OS of patients with normal LDH levels was NR (95% CI = 17.8 months - NR), and that of patients with elevated TABLE 2. Clinical diagnosis of immune-related adverse events Immune-related adverse event Any grade No (%) Grade 3-5 No (%) Time to onset of irAE (mean ± SD) [weeks] No. of pts with at least one irAE 56 (79) 13 (18) - Number of all irAE events 144 14 144 ± 161 Gastrointestinal Diarrhea 14 (20) 2 (3) 31.7 ± 30.6 Colitis 7 (10) 2 (3) 39 ± 32 Xerostomia 2 (3) 0 30.1 ± 4.4 Gastritis 2 (3) 0 64.4 ± 7.7 Stomatitis 1 (1) 0 3 ± 0 Respiratory Pneumonitis 5 (7) 0 (0) 40.9 ± 45.7 Sarcoid reaction 2 (3) 0 (0) 6.3 ± 0.3 Hepatic Increased AST/ALT 16 (23) 4 (6) 7.7 ± 8.3 Endocrine Hypothyroidism 10 (14) 0 12.3 ± 6 Hyperthyroidism 7 (10) 0 7.3 ± 7.1 Adrenal insufficiency 2 (3) 2 (3) 34.4 ± 20.1 Diabetes mellitus 1 (1) 1 (1) 72.7 ± 0 Pancreatitis 1 (1) 1 (1) 32.4 ± 0 Cutaneous Pruritus 23 (32) 0 10.7 ± 10 Skin rash 16 (23) 0 14 ± 16.3 Vitiligo 9 (13) 0 37.4 ± 31.6 Poliosis of hair 1 (1) 0 34.7 ± 0 Musculoskeletal Arthritis 10 (14) 0 28.7 ± 27.3 Myalgia 2 (3) 0 16.7 ± 12.3 Arthralgia 1 (1) 0 14 ± 0 Synovitis 1 (1) 0 65.4 ± 0 Neurological Encephalitis 2 (3) 1 (1) 36.4 ± 32.9 Psychosis 1 (1) 0 25.4 ± 0 Other Fatigue 6 (8) 0 6.5 ± 4.9 Hypophosphatemia 1 (1) 0 17 ± 0 AST/ALT = aspartate transaminase / alanín aminotransferaza; irAE = immune-related adverse events Survival outcomes The Kaplan–Meier estimated OS and progression- free survival (PFS) for the whole patient group were 18.5 months (95% CI = 14.4 months – not Radiol Oncol 2025; 59(1): 43-53. Hribernik N et al. / 18F-FDG-PET/CT and other prognostic biomarkers in melanoma patients on ICI 49 LDH levels was 6.5 months (95% CI = 4.0 months - NR). The difference in OS was statistically sig- nificant between these two groups (p = 0.004) (Figure 5A); Univariate Cox analysis showed a HR = 0.4 (95% CI = 0.21–0.76; p = 0.005). The difference in OS based on the number of or- gans with metastatic involvement was not statisti- cally significant (p = 0.094) (Figure 5B). Immune-related adverse events (irAEs) Among the 71 included patients, 56 (79%) devel- oped irAEs, including 13 (18%) with grade 3 or higher irAEs. All irAE, their number and time to onset, are presented in Table 2. One (2%) patient died of immune-related encephalitis. Due to irAEs, 7 (10%) patients were hospitalized. Three (4%) pa- tients were diagnosed with autoimmune disease prior to ICI initiation: one had vitiligo, one had scalp psoriasis, and one was diagnosed with rheu- matoid arthritis at the time of ICI initiation. None of them experienced an exacerbation of their au- toimmune disease or needed special treatment for that reason. The median OS was 25.3 months (95% CI = 17 months - NR) in patients with irAEs and 4.6 months (95% CI = 3.7 months - NR) in patients without irAEs (p = 0.004) (Figure 6A). Univariate Cox analysis showed a HR 0.9 (95% CI = 0.18–0.75; p = 0.006). The median OS was not reached (95% CI = 23.7 months - NR) in patients who experi- enced cutaneous irAEs and was 8.2 months (95% CI = 4.6–17.8) in patients without cutaneous irAEs (p < 0.0001) (Figure 6C); Cox analysis showed a HR 0.36 (95% CI = 0.19–0.66; p = 0.001). Using Kaplan- Meier analysis, a significant statistical difference in OS was not observed between patients with and without higher-grade irAEs (p = 0.783) (Figure 6B), endocrine irAEs (p = 0.7) (Figure 6D) or immune- related thyroiditis (p = 0.711) (Supplementary Figure 1). Discussion The evaluation of mM pts with early 18F-FDG-PET/ CT at W4, when treated with ICIs, can serve as a survival imaging biomarker (IBM). Based on our results, patients with no-CB at W4 had a shorter survival compared with the CB group (p = 0.001). This was also observed in the study by Cho et al., where early 18F-FDG-PET/CT scans of 20 patients 21–28 days after treatment started showed a pre- dictive role for response. Unlike in our group, pa- FIGURE 3. Kaplan-Meier curves showing probability of median overall survival (OS) between clinical benefit (CB) and no-CB group as classified by findings on week four (W4) 18F-FDG PET/CT. The curves are statistically significantly different (p = 0.03). FIGURE 4. Alluvial plot illustrates the flow of patients between different response categories on 18F-FDG PET/CT scan across four evaluation time points: at week 4 (W4), week 16 (W16), week 48 (W48) and week 96 (W96). CMR = complete metabolic response; HGR = heterogeneous response; PMD = progressive metabolic disease; PPD = pseudoprogressive disease; SMD = stable metabolic disease; PMR = partial metabolic response; n = number of patients tients in their study were mostly treated with the CTLA-4 inhibitor ipilimumab and tumor response was assessed according to RECIST, immune-related response criteria, PERCIST and EORTC criteria.12 In another study by Anderson et al., 18F-FDG-PET/ CT was performed after a single dose of pembroli- zumab, at a median of 7 days (range: 3–21 days) after the start of treatment. They concluded that early scan could identify metabolic changes in me- tastases that are potentially predictive of response to ICIs.16 Additionally, in recent studies on neoad- Radiol Oncol 2025; 59(1): 43-53. Hribernik N et al. / 18F-FDG-PET/CT and other prognostic biomarkers in melanoma patients on ICI50 FIGURE 5. Kaplan-Meier curves show the median overall survival (OS) probability of patients with metastatic melanoma treated with immune checkpoint inhibitors according to (A) LDH level and (B) the number of organs with metastatic involvement. The shading reflects the 95% confidence interval. A B FIGURE 6. Kaplan-Meyer curves of the median overall survival (OS) over time in patients with metastatic melanoma treated with immune checkpoint inhibitors according to (A) occurrence of immune-related adverse events, (B) occurrence of serious immune-related adverse events, (C) cutaneous immune-related side effects, (D) immune-related endocrine immune-related side effects. The blue and pink shading reflects the 95% confidence intervals for respecting groups. A B C D Radiol Oncol 2025; 59(1): 43-53. Hribernik N et al. / 18F-FDG-PET/CT and other prognostic biomarkers in melanoma patients on ICI 51 juvant immunotherapy in melanoma patients, re- sponses were reported as early as two weeks after ICI initiation, and pathological responses were reported at 4-6 weeks after treatment start.17,18 The use of this strategy with early evaluation is not yet fully understood, but it may lead to new imaging evaluation strategies for patients undergoing im- munotherapy. Seven (10%) patients in our study who were clas- sified as PMD on W4 18F-FDG-PET/CT showed a later response, as seen on subsequent 18F-FDG PET/ CT scans (Figure 4). For this subgroup of patients, FIGURE 7. A 67-year-old male patient, diagnosed with metastatic NRAS-mutated cutaneous melanoma with lung metastases in January 2021, was treated with pembrolizumab in the first-line setting. Serial 18F-FDG PET/CT scans were obtained per the study protocol. The images above show the maximal intensity projection (MIP) on the baseline PET/CT (left), on the week 4 evaluation PET/CT (middle) and at the endpoint of the study (right). The images below show transverse sections of the lungs in different planes, revealing three FDG-avid metastatic nodules in the right lung (lower left images, red arrows), only small nodules with no FDG uptake on week 4 PET/CT (lower middle images, yellow arrows), a complete metabolic response, and no residual nodules found at the end point of the PET/CT images with persistent complete remission (lower right images). Radiol Oncol 2025; 59(1): 43-53. Hribernik N et al. / 18F-FDG-PET/CT and other prognostic biomarkers in melanoma patients on ICI52 early cessation of ICI therapy has a detrimental ef- fect. More analysis is needed to identify optimal early timepoint scans and to find more specific biomarkers, perhaps using artificial intelligence with automated deep learning-based lesion seg- mentation, to distinguish patients and lesions that are in progress from those patients who are just late responders to ICIs.19,20 18F-FDG-PET/CT seems to play an important role not only at the early beginning of treatment with ICIs at W4 but also later during treatment. In a retrospective analysis of 104 patients with base- line and 1-year CT and PET/CT scans, Dimitriou et al. reported that almost all patients with CMR at one year had an ongoing response to ICIs thereaf- ter.8 In our cohort of patients, most of the patients with CMR at week 42 remained in remission, as shown in the alluvial plot in Figure 4. The case presentation in Figure 5 shows a patient with early and long-lasting CMR. In our cohort, occurrence of cutaneous irAEs was clearly associated with longer survival. Cutaneous irAEs, especially vitiligo, are more common in patients with melanoma than in other cancers. The higher frequency can be explained by shared immunogenic antigens between healthy tissue and tumors.21,22 Cutaneous irAEs are usual- ly lower grade and vigorous immunosuppressive management is not necessary; therefore, there is no unfavorable effect of irAE management on ICI efficacy or survival.22 Contrary to the results from a large retrospective multicohort study6, our study proved no survival benefit for patients with irThy- roiditis or endocrine irAEs, possibly due to the low number of patients with this type of adverse event. Further studies will clarify the prognostic role of this type of irAE. Our study is limited by not performing analy- sis of circulating tumor DNA in plasma, not avail- able at Institute of Oncology Ljubljana when the study started, and not using other volumetric PET parameters, like metabolic tumor volume or total lesion glycolysis.16,23,24 Another limitation of this study is that we did not perform lesion-level response analysis, which would provide even better insights into lesion-level and patient-level response patterns. Regarding response criteria to ICIs, a wide range of criteria have been proposed and compared in recent years: PERCIST, PECRIT, PERCIMT iPERCIST and imPERCIST5.7,24-26 As fur- ther evaluation of these newly proposed criteria is still warranted, our decision was to use standard EORTC criteria, adapted based on recommenda- tions from the EANM/SNMMI/ANZSNM. Whole-body PET imaging has great potential for future work, especially the use of artificial in- telligence.27 In line with this, our future work will include segmentation of all disease with lesion- by-lesion analysis on W4 and later 18F-FDG-PET/ CT images in our cohort of patients. With more in- depth analysis, we hope to identify specific lesions that do not respond to treatment early in the start of the treatment and offer our patients more per- sonalized treatment. Larger, possibly multicenter studies using same steps in analysis are needed to develop new biomarkers, including imaging bio- markers, to guide patient and treatment selection.28 Conclusions The evaluation of mM patients with early 18F-FDG- PET/CT at W4 who were treated with ICIs revealed a strong prognostic IBM. To obtain more informa- tion from early 18F-FDG-PET/CT, artificial intelli- gence will likely play an important role. 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Facts and hopes for PET imaging-derived immunotherapy biomarkers. Clin Cancer Res 2024; 30: 5252-9. doi: 10.1158/1078-0432.CCR-24-1427 Radiol Oncol 2025; 59(1): 54-62. doi: 10.2478/raon-2025-0008 54 research article Prevalence of diffuse idiopathic skeletal hyperostosis and association with coronary artery calcifications in Slovenia Vesna Lesjak1, Timea Hebar1, Maja Pirnat1,2 1 Radiology Department, University Medical Centre Maribor, Maribor, Slovenia 2 Medical Faculty, University of Maribor, Maribor, Slovenia Radiol Oncol 2025; 59(1): 54-62. Received 4 August 2024 Accepted 19 November 2024 Correspondence to: Vesna Lesjak, M.D., Radiology Department, University Medical Centre Maribor, Ljubljanska 5, SI-2000 Maribor, Slovenia. E-mail: vesna.lesjak@ukc-mb.si Disclosure: No potential conflicts of interest were disclosed. This is an open access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/). Background. The aim of this study was to analyze the epidemiological aspects of diffuse idiopathic skeletal hyper- ostosis (DISH) patients in Slovenia, to evaluate the relationship between coronary CT angiography (CCTA)-derived epicardial adipose tissue (EAT) density and coronary artery calcifications (CAC) in patients with and without DISH, and study influencing factors of these parameters. Patients and methods. The research comprised patients referred for CCTA due to a clinical suspicion of coronary artery disease. DISH, CAC score and EAT attenuation were quantified using non-contrast imaging. Diagnosis of DISH was based on Resnick criteria. The CCTA was assessed for the presence of obstructive coronary artery disease (CAD). The association between DISH and the extent of CAC was explored, using correlation analysis and multivariate regres- sion. Results. The study cohort included 219 participants. The prevalence of DISH was 7.8%. In univariate logistic regression, body mass index (BMI) (odds ratio [OR] 1.133, p = 0,005), age (OR 1.055, p = 0,032) and diabetes (OR 3.840, p = 0,015) were significantly associated with the condition. However, this association did not persist on multinomial multivariate analysis, but gender, age, hypertension and EAT attenuation were found to be significantly associated with the in- creasing CAC strata. Conclusions. The prevalence of DISH found is comparable with prior literature. There was no independent relation- ship between the prevalence of DISH and CAC. Our data point to a more nuanced and perhaps non-causal link between coronary artery disease and DISH. Key words: diffuse idiopathic skeletal hyperostosis; coronary artery calcification; epicardial adipose tissue; metabolic syndrome; body mass index; coronary artery disease Introduction Diffuse idiopathic skeletal hyperostosis (DISH) is a systemic condition, originally described in 1950 by Forestier and Querol.1 In 1976 most commonly used criteria to diagnose DISH were introduced by Resnick and Niwayama.2 New bone formation, partially in entheses, is the condition’s defining feature.3 It is known that DISH affects more men than women, and its incidence rises with age.4 Prevalence in Asian countries varies between 3.8% and 27.0%, in the USA between 7.7% and 13.2%, and in Italy 12.8%.5,6 The etiology of DISH is not utterly understood. The disorder is linked to meta- bolic syndrome and its components, including diabetes, obesity, and hypertension7,8, associations were reported with large waist circumference, cardiomegaly, hyperinsulinaemia, dyslipidaemia and hyperuricaemia.3 DISH is associated with in- creased calcifications in coronary arteries3, and Radiol Oncol 2025; 59(1): 54-62. Lesjak V et al. / Epidemiological aspects of diffuse idiopathic skeletal hyperostosis 55 also in thoracic9 and abdominal aorta.10 The risk of myocardial infarction is considerably higher in DISH patients.11 Between the myocardium and the visceral peri- cardium is a visceral fat deposit called epicardial adipose tissue (EAT).12 It surrounds the heart and coronary arteries, being vascularized by branches of the coronary arteries.12,13 EAT is metabolically active, has a thermogenic role, secretes cytokines with pro- and anti-atherosclerotic qualities, and is hypothesized to defend against mechanical inju- ries to the heart and coronary vessels.14 It is thought to have a role in the onset of atherosclerosis, al- though it is unclear whether systemic processes or paracrine effects of EAT directly contribute to the development of atherosclerosis.15 The research has shown abundant evidence of the correlation between EAT volume and cardiovascular risk factors, coronary artery calcification and major adverse cardiac events.16 There has been recently increased interest in EAT attenuation as a marker of risk.17 In some studies a lower EAT attenuation on non-contrast enhanced cardiac CT scans has been linked to the risk of future events18, whereas in other studies a higher EAT attenuation has been linked to an increased risk.19 Up until recently, vascular calcification was thought to be an inevitable result of aging, and the development of coronary artery calcification (CAC) was thought to be a passive process. The de- velopment of CAC is now recognized as an active pathogenic process. The common feature of atherosclerosis - ectopic bone production is known as the cause of coronary artery calcification, and new bone formation being the defining feature of DISH led us to hypothesize that arterial calcification and the occurrence of DISH are strongly correlated. To our knowledge, the prevalence of DISH in the Slovenian population has not been evaluated. Based on this framework, the objective of our study is to analyze the epidemiological aspects of DISH patients in Slovenia, to evaluate the relation- ship between coronary CT angiography (CCTA)- derived EAT density and CAC in patients with and without DISH, and study influencing factors of these parameters. Patients and methods This cross-sectional study was conducted at the Department of Radiology, University Medical Centre Maribor. This study was conducted with approval of local ethics committee (UKC-MB- KME-24/21) and performed accordingly to the Declaration of Helsinki. All participants gave writ- ten informed consent. Study protocol Between January 2022 and January 2024, adult pa- tients referred for CCTA were included in the study. Participants responded to questionnaires assess- ing socio-demographic information, lifestyle and health-related factors, which contains self-reported information on age, gender, weight status, chronic diseases, smoking and physical activity. Exclusion criteria were age < 18 years, known malignancy and prior coronary artery bypass surgery. A total of 219 cases were included in the study. Body mass index (BMI) We calculated the BMI by using self-reported height and weight following the formula: weight (kg) divided by height (m) squared. According to WHO standards, BMI was categorized into un- derweight (BMI < 18.5), normal (18,5–24.99), over- weight (BMI ≥ 25) and obese (BMI ≥ 30).20 CT acquisition protocol All examinations were performed on Somatom Drive CT scanner (Siemens Medical Solutions, Erlengen, Germany). Noncontrast, non-gated CT scan was performed to measure the Agatson coronary artery calcification score (CACS), as de- scribed previously.21 The sum of the individual le- sion scores from the four vessels; left main (LM), left anterior descending (LAD), circumflex (LCX), and right coronary artery (RCA) produced the total coronary calcium score. The Agatson Units were classified into four categories: 0, > 0 and < 100, 100−400, and > 400. These categories repre- sent no, mild/minimal, moderate, and substantial plaque burden. In the same way the calcium score (Agatson) was measured for proximal thoracic aor- ta (from aortic root to the first branch of the aortic arch), aortic root and ascending aorta. The EAT attenuation was measured on the same axial images used for CACS. Epicardial adipose tissue Hounsfield units (HU) were measured us- ing regions of interest (ROI) near the proximal part of RCA, between the right atrium and right ven- tricular outflow tract, as previously described.15 Hepatic and splenic HU attenuation values were quantified by placing two ROI in the liver Radiol Oncol 2025; 59(1): 54-62. Lesjak V et al. / Epidemiological aspects of diffuse idiopathic skeletal hyperostosis56 and one in spleen, in the same axial slice. Liver to spleen ratio was calculated by dividing the mean liver attenuation by the splenic HU. Nonalcoholic fatty liver disease (NAFLD) was defined as liver to spleen ratio < 1 and/or mean liver attenuation < 40 HU.22 A retrospective ECG-gated CCTA examination was done in all participants, to assess coronary artery disease (CAD). CCTA datasets were trans- ferred to a workstation (Syngo.via VB10. Siemens Healthcare, Forchheim, Germany), and coronary arteries were evaluated for the presence of obstruc- tive CAD (defined as at least one lesion causing the stenosis of lumen ≥ 50%). CCTA images were re- constructed with a slice thickness of 0.6 mm. The CT studies were evaluated by radiologists having more than five years of experience in cardiac imag- ing. Diffuse idiopathic skeletal hyperostosis (DISH) Resnick classification criteria were used to define DISH: the presence of flowing bridging ossifica- tion of at least four contiguous vertebrae, (relative) preservation of the intervertebral disc height and the absence of apophyseal joint bony ankylosis, as described. The prevalence of DISH was diagnosed by a single musculoskeletal radiologist evaluating CT images. Metabolic syndrome The metabolic syndrome (MetS) was defined ac- cording to the International Diabetes Federation (IDF) definition23: BMI greater than 30 kg/m2 (in this case the central obesity can be assumed and waist circumference measure is not necessary) plus any two of the four factors: 1 raised triglyc- erides (≥ 1.7 mmol/l) or specific treatment for this abnormality, 2 reduced HDL cholesterol (< 1.03 mmol/l in males or < 1.29 mmol/l in females) or specific treatment, 3 raised blood pressure (systolic BP ≥ 130 or diastolic ≥ 85 mmHg) or treatment for diagnosed hypertension, and 4 raised fasting plas- ma glucose (≥ 5.6 mmol/l) or previously diagnosed diabetes type 2. Covariates Additional data were collected: age in years, sex (male, female), smoking behavior (current smoker yes/no) and physical activity (days per week). The presence of hypertension, diabetes mellitus type 2 and hypercholesterolemia was established by the question ‘Have you had these condition?’ and/or the self-reported usage of antihypertensive drugs, glucose lowering and lipid lowering drugs. Other chronic health conditions included angina pecto- ris, and previous myocardial infarction. Statistical analysis All continuous variables were tested for normal distribution (Shapiro-Wilk test). Normally distrib- uted variables are given as means and standard de- viations (SD), non-normally distributed variables are given as median (interquartile range [Q1−Q3]) and categorical variables are presented as numbers and percentages (%). Comparisons of demographic characteristics and potential covariates between the DISH and no DISH groups were conducted us- ing Mann-Whitney U test and independent sample t-test for continuous variables, and Chi-square test for categorical variables. Group-wise compari- sons were performed with the Kruskal-Wallis test. Independent sample t-test, Pearson or Spearman rank correlations were calculated to determine the relationships between EAT attenuation and risk factors. We also evaluated the relationship between EAT attenuation and CT parameters using multi- variable linear regression analyses. To determine the association between the presence of DISH, EAT and CAC, univariate and multivariate logistic re- gression analyses were performed. The models in- cluded DISH status (present or absent) as depend- ent factor and age, gender, BMI, eight, smoking status, diabetes, hypertension and hypercholes- terolemia as independent variables. A multivari- FIGURE 1. A 68-year old male with diffuse idiopathic skeletal hyperostosis (DISH) coronary artery calcification score (CACS) > 400. (A) Typical appearance of DISH in thoracic spine, sagittal plane. (B) Calcifications in LAD = left anterior descending artery A B Radiol Oncol 2025; 59(1): 54-62. Lesjak V et al. / Epidemiological aspects of diffuse idiopathic skeletal hyperostosis 57 ate multinomial logistic regression was performed with CAC categories (> 0 and < 100, 100−400, > 400) as independent factor and CACS = 0 as refer- ence category and DISH status as dependent fac- tor. Multivariate analyses were done in a stepwise backward elimination based on a p-value < 0,10. We analyzed the prevalence of DISH and CACS in the relation to the amount of risk factors (diabetes, BMI > 30, hypertension, hypercholesterolemia) pre- sent. Comparisons between the DISH and no DISH groups were conducted using Chi-square test. All statistical analyses were performed using the SPSS 29.0 software package (IBM, Armonk, NY, USA). All tests were 2-sided and a ‘P’ value of less than 0.05 was considered statistically significant. Results A total of 219 participants were included in the study. The overall prevalence of DISH was 7.8%. The prevalence of DISH was about twice as high in males than in females (10.4% vs. 4.8%). The char- acteristics of the demographics and cardiovascu- lar risk factors of participants with and without DISH are shown in Table 1. Compared to patients without DISH, those with DISH were significantly older (67.3 vs. 60.5 years). 42.6% of subjects were obese (45.5% men and 39.4% women). Among subjects with DISH, 68.8% were obese, compared to 40.4% of patients without DISH. NAFLD was present in 26.3% of participants; in 29.4 % of pa- tients with DISH and in 26.0% of patients without DISH. Metabolic syndrome was present in 15.4% of participants, in subjects with DISH in 43.8%, com- pared to 13.0% of subjects without DISH. Additionally, in subjects with DISH a signifi- cantly higher BMI was noted (32.8 vs. 28.9) and more diabetes (35.3% vs. 12.4%). Figure 1 shows an example of a male patient with DISH and abun- dant calcifications in left anterior descending coro- nary artery. Subjects without DISH were about three times more likely to not have coronary artery calcifica- TABLE 1. Characteristics of the cohort DISH no DISH p-value Age (years), mean (SD) 67.3 ± 10.1 60.5 ± 12.2 0.029 Gender (f/m), N 5/12 99/103 0.120 Weight (kg), mean (SD) 96.6 ± 20.3 84.5 ± 17.5 0.008 Height (cm), mean (SD) 170.9 ± 6.5 171.0 ± 9.7 0.980 BMI (kg/m2), mean (SD) 32.8 ± 7.2 28.9 ± 5.3 0.011 Family history of cardiovascular disease, N (%) 11 (64.7%) 119 (59.2%) 0.657 Diabetes, N (%) 6 (35.3%) 25 (12.4%) 0.010 Hypercholesterolemia, N (%) 6 (35.3%) 51 (25.4%) 0.371 Hypertension, N (%) 12 (70.6%) 110 (54.7%) 0.206 Current smoker, N (%) 2 (11.8%) 38 (18.9%) 0.465 Angina pectoris, N (%) 4 (23.5%) 92 (44%) 0.076 Metabolic syndrome, N (%) 7 (43.8%) 25 (13.0%) 0.001 EAT attenuation (HU), mean (SD) -98.5 ± 11.8 -101.7 ± 13.0 0.347 NAFLD 5 (29.4%) 52 (26.0%) 0.759 CACS (au) = 0 2 (11.8%) 68 (33.8%) 0.063 CACS (au), median (IQR) 101.0 (4.7-569.0) 27.3 (0-391.8) 0.241 Calcifications in proximal thoracic aorta, median (IQR) 196.4 (12.3-759.5) 14.3 (0-244.6) 0.023 Calcifications in aortic root, median (IQR) 146.8 (8.3-758.0) 1.8 (0-175.0) 0.013 Calcifications in ascending aorta, median (IQR) 2.1 (0-35.2) 0.0 (0-3.9) 0.109 Myocardial infarction, N (%) 1 (6.0%) 12 (6.0%) 0.988 BMI = body mass index; CACS (au) = Agatson coronary artery calcification score; DISH = diffuse idiopathic skeletal hyperostosis (DISH); EAT = epicardial adipose tissue; f/m = female/male; IQR = interquartile range; N = number, NAFLD = nonalcoholic fatty liver disease; SD = standard deviation Radiol Oncol 2025; 59(1): 54-62. Lesjak V et al. / Epidemiological aspects of diffuse idiopathic skeletal hyperostosis58 tions compared to subjects with DISH (33.8% vs. 11.0%). In subjects with a CACS > 400, DISH was present in 13.3%, while in subjects with CACS = 0 DISH was present in 2.8% (Table 2). Associations between EAT attenuation, cardio- vascular risk factors and CT parameters are de- picted in Table 3. There is a significant correlation between EAT attenuation and BMI (rho = 0.243, p < 0.001), CACS (rho = 0.256, p < 0.001) and calcifi- cations in ascending aorta (rho = 0.052, p = 0.011), as well as significant association between EAT at- tenuation and gender (p < 0.001) and NAFLD (p = 0.022). Figure 2A shows EAT attenuation for patients with different Agatson score CACS category. Mean EAT attenuation was lower in patients with CACS = 0 than in patients with CACS > 400 (-103.7 ± 13.8 HU vs. -95.9 ± 11.3 HU [p < 0.001]), also in patients with CACS > 0 and < 100 the mean EAT attenuation was lower than in patients with CACS > 400 (-104.5 ± 12.2 HU vs. -95.9 ± 11.3 HU (p < 0.001)). Group-wise comparisons between BMI catego- ries showed significant differences in EAT attenu- ation (p = 0.007), as shown in Figure 2B. In patients with BMI < 18.5 EAT attenuation was -96.0 ± 9.9 HU (there were only two patients in this group). In patients with BMI 18.5−24.9 -107.1 ± 13.9 HU, with BMI between 25 and 29.9 -102.1 ± 13.2 HU and in patients with BMI > 30 -98.4 ± 11.6 HU. On univariate analysis, it was observed that age (p = 0.032), BMI (p = 0.005) and diabetes (p = 0.015) were found to be significantly associated with the presence of DISH (Table 4). In multiple logistic regression model age and BMI were found to be significantly associated with the presence of DISH, odds ratio (OR) 1.060, p = 0.029 and OR 1.132, p = 0.009. In the multinomial multivariate logistic regres- sion analysis with the different CACS categories as outcome and those without coronary artery calcifi- cations (CACS = 0) as a reference category, gender, age, hypertension and epicardial fat attenuation were found to be significantly associated with the increasing CAC strata (Table 5). Male gender has a 16.786 time greater odds of having CACS > 400 than female gender, compared to subjects with CACS = 0 (p < 0.001). Subjects with hypertension have a 5.423 times greater odds of having CACS > 400 than sub- jects without hypertension, compared to subjects with CACS = 0 (p < 0.001). There is a 1.227-fold in- crease in the likelihood of having CACS > 400 with every additional year of age, compared to subjects with CACS = 0 (p < 0.001). Every additional unit of EAT attenuation (HU) increases the odds of hav- TABLE 2. Prevalence of diffuse idiopathic skeletal hyperostosis (DISH) among Agatson coronary artery calcification score (CACS) categories CACS = 0 (N = 70) CACS > 0 and < 100 (N = 62) CACS = 100−400 (N = 33) CACS > 400 (N = 53) DISH 2.8% 10.3% 6.6% 13.3% No DISH 97.2% 89.7% 93.4% 86.7% TABLE 3. Association of epicardial adipose tissue (EAT) attenuation with conventional coronary artery disease (CAD) risk factors and CT parameters Variable EAT attenuation (HU) p-value Gender M - 98.3 ± 11.3 < 0.001 F - 105.4 ± 13.6 NAFLD Y - 98.3 ± 12.8 0.022 N - 102.7 ± 12.8 Family history of cardiovascular disease Y - 100.1 ± 12.8 0.261 N - 104.5 ± 14.1 Diabetes Y - 104.2 ± 14.3 0.883 N - 101.3 ± 13.3 Hypercholesterolemia Y - 99.4 ± 13.5 0.402 N - 102.6 ± 13.3 Hypertension Y - 99.2 ± 12.4 0.129 N - 105.2 ± 14.1 Smoking Y - 97.8 ± 13.3 0.361 N - 102.9 ± 13.3 Regular physical activity Y - 101.6 ± 12.8 0.653 N - 101.9 ± 14.4 Correlation coefficient CACS (Agatson) 0.306 < 0.001 CACS per vessel LM 0.159 0.018 LAD 0.247 < 0.001 LCX 0.269 < 0.001 RCA 0.289 < 0.001 Calcifications in proximal thoracic aorta 0.110 0.103 Calcifications in aortic root 0.082 0.226 Calcifications in ascending aorta 0.172 0.011 Age 0.006 0.834 BMI 0.243 < 0.001 BMI = body mass index; CACS = coronary artery calcification score; f = female; HU = Hounsfield units; LAD = left anterior descending artery; LCX = left circumflex artery; m = male; LM = left main coronary artery; NAFLD = nonalcoholic fatty liver disease; RCA = right coronary artery Radiol Oncol 2025; 59(1): 54-62. Lesjak V et al. / Epidemiological aspects of diffuse idiopathic skeletal hyperostosis 59 ing CACS > 400 by 1.052 times when compared to subjects with CACS = 0 (p = 0.022). DISH, smoking status, diabetes, hypercholesterolemia and meta- bolic syndrome were excluded from the model, since they did not meet the criteria (p < 0.1). Discussion Despite the fact that DISH is a common condition, epidemiology of the disease in Slovenia is un- known. The overall prevalence of DISH in our co- hort was 7.8% (10.4% in men and 4.8% in women). Our results are consistent with the literature, var- ying from 3.8% in China24 to 30.8% in Pakistan25, 7.8% in Iceland26 and 12.8% in Italy.5 The differ- ences can to some extent be explained by the dif- ferences in study population, diagnostic criteria and variety of imaging methods used – chest x-ray or CT scan, whole- spine scans or partial (chest) scans.26 Prevalence of DISH increases with age and male to female prevalence ratio is 2:1.27 In the cur- rent study, subjects with DISH were significantly older than patients without DISH, however, the lo- gistic analysis confirmed ageing to influence the prevalence of DISH significantly. Previous studies reported higher BMI in pa- tients with DISH than in those without DISH.26-28 Also, various metabolic variables are associated with DISH, in particular obesity and type 2 dia- betes mellitus.29,30 Several paleopathological stud- ies showed that the prevalence of DISH varied significantly between groups of different social standing, with speculation that the upper socioec- onomic status groups were excessively nourished, with likely increased incidence of obesity, in com- parison with the individuals with lower social status.29 In the present study, diabetes and BMI significantly affected the prevalence of DISH in logistic regression analysis. Insulin, a peptide that promotes bone development, is raised in diabetes. It is speculated, that in patients with diabetes, in- sulin can promote the new bone growth and there- by excess bone formation.31 Chondrocytes and periosteal mesenchymal cells inside the enthesis can proliferate under the impact of several factors (i.e. insulin, transforming growth factor-β1,…) to form osteoblasts, fibroblasts and myoblasts. Furthermore, different metabolic agents (i.e. insu- lin, insulin-like growth factor 1,…) have the po- tential to induce bone formation by stimulating the proliferation of chondrocytes, fibroblasts and osteoblasts.29 Increased rates of obesity in DISH patients may indicate that certain adipokines have TABLE 4. Univariate logistic regression analysis with diffuse idiopathic skeletal hyperostosis (DISH) status as the dependent factor Variable units OR p-value Age + 1 year 1.055 0.032 Gender Male vs. female 2.307 0.129 BMI + 1 kg/m2 1.133 0.005 Diabetes Present vs. absent 3.840 0.015 Hypertension Present vs. absent 1.985 0.213 Hypercholesterolemia Present vs. absent 0.623 0.375 Smoking Present vs. absent 1.748 0.470 BMI = body mass index; OR = odds ratio A B FIGURE 2. Epicardial fat attenuation in subjects with (A) different coronary artery calcium score and (B) different body mass index (BMI) categories. Data are presented as box plots, where boxes represent the interquartile range (IQR), the lines within the box represent the median, and the lines outside the boxes represent the upper quartile plus 1.5 times IQR or the lower quartile minus 1.5 times the IQR. CACS = coronary artery calcification score Radiol Oncol 2025; 59(1): 54-62. Lesjak V et al. / Epidemiological aspects of diffuse idiopathic skeletal hyperostosis60 a role in the disorder’s development. Several of these fat-derived hormones (i.e. leptin) have an as- sociation with bone metabolism growth.3 Obesity- related chronic inflammation with proinflamma- tory cytokines such as IL-6, TNF-α etc. could con- tribute to the formation of calcifications, as discs and ligaments of the spine may have receptors for them. Leptin causes chondrocytes to release more chondrocyte degradation mediators and promotes the proliferation of intervertebral disc cells. Leptin stimulates the inflammatory response by raising IL-6, which causes ligamentum flavum hyper- trophy and fibrosis.32 In this study, subjects with DISH had a higher prevalence of metabolic syn- drome and NAFLD than those without DISH. The prevalence of NAFLD and metabolic syndrome rises with obesity; and NAFLD is considered as both, a cause and a result of metabolic syndrome. It is widely documented that NAFLD increases the risk of development of atherosclerosis and cardiac events. Studies showed that NAFLD diag- nosed on non-contrast CT to be a strong predictor of MACE (major adverse cardiovascular events) at 14-year follow-up.22 We found no correlation be- tween NAFLD and DISH, however there is a sig- nificant association between EAT attenuation and NAFLD. Our study’s findings support earlier research suggesting that DISH is linked to a greater extent of calcifications in blood vessels.3,9,33 Indeed, we observed an increase of DISH prevalence across CACS categories. CACS was higher in subjects with DISH compared to the non-DISH group, but the association did not perseverate on multivariate analysis, similar as in previous studies.34 It is hy- pothesized that subjects with DISH may be prone to form calcifications in arteries and in aortic valve, amongst other locations, however, our data point to a more nuanced, maybe non-causal link between CAD and DISH. The relationship between EAT volume and attenuation, coronary artery plaque load, and coronary artery disease is widely recognized in the literature. In our study EAT attenuation was significantly higher in subjects with CACS > 400 compared to subjects with CACS = 0. Higher EAT attenuation might reflect inflammation in epi- cardial fat, which was described in patients with acute coronary syndrome.35 EAT also increases with vascularization and higher amount of mito- chondria and decreases with fatty acids overload.19 Statins also decrease EAT attenuation over time, via reducing metabolic activity within the EAT by reducing vascularity, cellularity and inflam- mation15, therefore, an influence of therapy with statins might have influenced the observed EAT attenuation. Among patients with coronary artery disease having open heart surgery, an increase in pro-inflammatory mediators and cytokines in the EAT was reported, as EAT regulates local inflam- mation in the immediate vicinity of the coronar- ies.36 In our study, chronic, low-grade inflamma- tion might be a significant pathophysiologic con- nection between DISH, NAFLD, EAT, and CAC. However, to further understand the underlying processes, more research should be conducted correlating EAT attenuation to local and systemic metabolic and inflammatory mechanisms. The limitations of the current study include its small sample size, the possibility of selection bi- as due to the inclusion of many individuals with medical disorders, and a cross-sectional design of the study, as a result of which, the possible impact of DISH on mortality cannot be assessed. To understand the mechanism connecting DISH and coronary artery calcification a multidiscipli- nary approach that investigates inflammatory, metabolic, genetic, molecular, and environmental factors is required. Future research needs to focus on elucidating common signaling pathways and TABLE 5. Multinomial multivariate logistic regression analysis on the association of diffuse idiopathic skeletal hyperostosis (DISH) and coronary artery calcification score (CACS) category CACS category gender age hypertension EAT attenuation OR p-value OR p-value OR p-value OR p-value >0 and <100 3.515 0.008 1.087 <0.001 3.956 0.001 0.980 0.225 100-400 7.583 <0.001 1.156 <0.001 5.023 0.003 1.005 0.804 > 400 16.786 <0.001 1.227 <0.001 5.423 0.001 1.052 0.022 OR = odds ratio Coronary artery calcifications (CAC) category is the outcome compared to the subjects without CAC (CACS = 0) as reference category Radiol Oncol 2025; 59(1): 54-62. Lesjak V et al. / Epidemiological aspects of diffuse idiopathic skeletal hyperostosis 61 risk factors that underlie both conditions, employ- ing a combination of molecular, imaging, genetic, and clinical methodologies, with prospective stud- ies and clinical trials, to enhance our comprehen- sion of the fundamental mechanisms. Conclusions There was no independent relationship identified between the prevalence of DISH and CACS. The specific processes that lead to new bone develop- ment in DISH patients, particularly in entheses, still remain unclear. Acknowledgements The authors would like to thank Laura Kocet for her assistance with statistical processing. The pro- ject described was funded by University Medical Centre Maribor, internal research grant number IRP-2021/01-11. References 1. Forestier J, Rotes-Querol J. Senile ankylosing hyperostosis of the spine. Ann Rheum Dis 1950; 9: 321-30. doi: 10.1136/ard.9.4.321 2. Resnick D, Niwayama G. Radiographic and pathologic features of spinal in- volvement in diffuse idiopathic skeletal hyperostosis (DISH) Radiology 1976; 119: 559-68. doi: 10.1148/119.3.559 3. Oudkerk SF, Mohamed Hoesein FAA, W PTM, Öner FC, Verlaan JJ, de Jong PA, et al. Subjects with diffuse idiopathic skeletal hyperostosis have an increased burden of coronary artery disease: an evaluation in the COPDGene cohort. Atherosclerosis 2019; 287: 24-9. doi: 10.1016/j.athero- sclerosis.2019.05.030 4. Weinfeld RM, Olson PN, Maki DD, Griffiths HJ. The prevalence of diffuse idiopathic skeletal hyperostosis (DISH) in two large American Midwest met- ropolitan hospital populations. Skelet Radiol 1997; 26: 222-5. doi: 10.1007/ s002560050225 5. Ciaffi J, Borlandelli E, Visani G, Facchini G, Miceli M, Ruscitti P, et al. F. Prevalence and characteristics of diffuse idiopathic skeletal hyperostosis (DISH) in Italy. Radiol Med 2022; 127: 1159-69. doi: 10.1007/s11547-022- 01545-x 6. Yoshihara H, Nadarajah V, Horowitz E. Prevalence and characteristics of thoracic diffuse idiopathic skeletal hyperostosis in 3299 black patients. Sci Rep 2021; 11: 22181. doi: 10.1038/s41598-021-01092-x 7. Mader R, Novofestovski I, Adawi M, Lavi I. Metabolic syndrome and cardio- vascular risk in patients with diffuse idiopathic skeletal hyperostosis. Semin Arthritis Rheum 2009; 38: 361-5. doi: 10.1016/j.semarthrit.2008.01.010 8. Mattera M, Reginelli A, Bartollino S, Russo C, Barile A, Albano D, et al. Imaging of metabolic bone disease. Acta Biomed 2018; 89(1-S): 197-207. doi: 10.23750/abm.v89i1-S.7023 9. Harlianto NI, Westerink J, Hol ME, Wittenberg R, Foppen W, van der Veen PH, et al. Patients with diffuse idiopathic skeletal hyperostosis have an in- creased burden of thoracic aortic calcifications. Rheumatol Adv Pract 2022; 6: rkac060. doi: 10.1093/rap/rkac060 10. Pariente-Rodrigo E, Sgaramella GA, Olmos-Martínez JM, Pini-Valdivieso SF, Landeras-Alvaro R, Hernández-Hernández JL. Relationship between diffuse idiopathic skeletal hyperostosis, abdominal aortic calcification and associ- ated metabolic disorders: data from the Camargo cohort. Med Clin 2017; 149: 196-202. doi: 10.1016/j.medcli.2017.01.030 11. Glick K, Novofastovski I, Schwartz N, Mader R. Cardiovascular disease in diffuse idiopathic skeletal hyperostosis (DISH): from theory to reality-a 10-year follow-up study. Arthritis Res Ther 2020; 22: 190. doi: 10.1186/ s13075-020-02278-w 12. Wu Y, Zhang A, Hamilton DJ, Deng T. Epicardial fat in the maintenance of cardiovascular health. Methodist Debakey Cardiovasc J 2017; 13: 20-4. doi: 10.14797/mdcj-13-1-20 13. Bertaso AG, Bertol D, Duncan BB, Foppa M. Epicardial fat: definition, meas- urements and systematic review of main outcomes. Arq Bras Cardiol 2013; 101: e18-28. doi: 10.5935/abc.20130138 14. Iacobellis G. Aging effects on epicardial adipose tissue. Front Aging 2021; 2: 666260. doi: 10.3389/fragi.2021.666260 15. Raggi P, Gadiyaram V, Zhang C, Chen Z, Lopaschuk G, Stillman AE. Statins reduce epicardial adipose tissue attenuation independent of lipid lower- ing: a potential pleiotropic effect. J Am Heart Assoc 2019; 8: e013104. doi: 10.1161/JAHA.119.013104 16. Rosito GA, Massaro JM, Hoffmann U, Ruberg FL, Mahabadi AA, Vasan RS, et al. Pericardial fat, visceral abdominal fat, cardiovascular disease risk factors, and vascular calcification in a community-based sample the Framingham heart study. Circulation 2008; 117: 605-13. doi: 10.1161/ CIRCULATIONAHA.107.743062 17. Archer JM, Raggi P, Amin SB, Zhang C, Gadiyaram V, Stillman AE. Season and clinical factors influence epicardial adipose tissue attenuation measurement on computed tomography and may hamper its utilization as a risk marker. Atherosclerosis 2021; 321: 8-13. doi: 10.1016/j.atherosclerosis.2021.01.025 18. Goeller M, Achenbach S, Marwan M, Doris MK, Cadet S, Commandeur F, et al. Epicardial adipose tissue density and volume are related to sub- clinical atherosclerosis, inflammation and major adverse cardiac events in asymptomatic subjects, J Cardiovasc Comput Tomogr 2018; 12: 67-73. doi: 10.1016/j.jcct.2017.11.007 19. Mahabadi AA, Balcer B, Dykun I, Forsting M, Schlosser T, Heusch G, et al. Cardiac computed tomography-derived epicardial fat volume and attenua- tion independently distinguish patients with and without myocardial infarc- tion. PLoS One 2017; 12: e0183514. doi: 10.1371/journal.pone.0183514 20. World Health Organization. Obesity and overweight. [internet]. [cited 2024 Mar 13]. Available at: https://www.who.int/news-room/fact-sheets/detail/ obesity-and-overweight 21. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990; 15: 827-32. doi: 10.1016/0735- 1097(90)90282-t 22. Lin A, Wong ND, Razipour A, McElhinney PA, Commandeur F, Cadet SJ, et al. Metabolic syndrome, fatty liver, and artificial intelligence-based epicar- dial adipose tissue measures predict long-term risk of cardiac events: a prospective study. Cardiovasc Diabetol 2021; 20: 27. doi: 10.1186/s12933- 021-01220-x 23. Alberti KG, Zimmet P, Shaw J. Metabolic syndrome − a new world-wide defi- nition. A Consensus Statement from the International Diabetes Federation. Diabet Med 2006; 23: 469-80. doi: 10.1111/j.1464-5491.2006.01858.x 24. Liang H, Liu G, Lu S, Chen S, Jiang D, Shi H, et al. Epidemiology of ossification of the spinal ligaments and associated factors in the Chinese population: a cross-sectional study of 2000 consecutive individuals. BMC Musculoskelet Disord 2019; 20: 253. doi: 10.1186/s12891-019-2569-1 25. Adel H, Khan SA, Adil SO, Huda F, Khanzada U, Manohar M, et al. CT-based evaluation of diffuse idiopathic skeletal hyperostosis in adult population; prevalence, associations and interobserver agreement. J Clin Densitom 2020; 23: 44-52. doi: 10.1016/j.jocd.2018.12.001 26. Auðunsson AB, Elíasson GJ, Steingrímsson E, Aspelund T, Sigurdsson S, Launer L, et al. Diffuse idiopathic skeletal hyperostosis in elderly Icelanders and its association with the metabolic syndrome: the AGES-Reykjavik Study. Scand J Rheumatol 2021; 50: 314-8. doi: 10.1080/03009742.2020.1846779 Radiol Oncol 2025; 59(1): 54-62. Lesjak V et al. / Epidemiological aspects of diffuse idiopathic skeletal hyperostosis62 27. Harlianto NI, Oosterhof N, Foppen W, Hol ME, Wittenberg R, van der Veen PH, van Ginneken B, et al. Diffuse idiopathic skeletal hyperostosis is as- sociated with incident stroke in patients with increased cardiovascular risk. Rheumatology 2022; 61: 2867-74. doi: 10.1093/rheumatology/keab835 28. Ishimura D, Morino T, Murakami Y, Yamaoka S, Kinoshita T, Takao M. Examining the association between the extent of anterior longitudinal ligament ossification progression and comorbidities in diffuse idiopathic skeletal hyperostosis. Cureus 2023; 15: e51357. doi: 10.7759/cureus.51357 29. Pillai S, Littlejohn G. Metabolic factors in diffuse idiopathic skeletal hyper- ostosis-a review of clinical data. Open Rheumatol J 2014; 8: 116-28. doi: 10.2174/1874312901408010116 30. Okada E, Ishihara S, Azuma K, Michikawa T, Suzuki S, Tsuji O, et al. Metabolic syndrome is a predisposing factor for diffuse idiopathic skeletal hyperosto- sis. Neurospine 2021; 18: 109-16. doi: 10.14245/ns.2040350.175 31. Sencan D, Elden H, Nacitarhan V, Sencan M, Kaptanoglu E. The prevalence of diffuse idiopathic skeletal hyperostosis in patients with diabetes mellitus. Rheumatol Int 2005; 25: 518-21. doi: 10.1007/s00296-004-0474-9 32. Chaput CD, Siddiqui M, Rahm MD. Obesity and calcification of the liga- ments of the spine: a comprehensive CT analysis of the entire spine in a random trauma population. Spine J 2019; 19: 1346-53. doi: 10.1016/j. spinee.2019.03.003 33. Orden AO, David JM, Díaz RP, Nardi NN, Ejarque AC, Yöchler AB. Association of diffuse idiopathic skeletal hyperostosis and aortic valve sclerosis. Medicina (B Aires) 2014; 74: 205-9. PMID: 24918668 34. Lantsman CD, Brodov Y, Matetzky S, Beigel R, Lidar M, Eshed I, et al. No correlation between diffuse idiopathic skeletal hyperostosis and coronary artery disease on computed tomography using two different scoring sys- tems. Acta Radiol 2023; 64: 508-14. doi: 10.1177/02841851221090890 35. Konishi M, Sugiyama S, Sato Y, Oshima S, Sugamura K, Nozaki T, et al. Pericardial fat inflammation correlates with coronary artery dis- ease. Atherosclerosis 2010; 213: 649-55. doi: 10.1016/j.atherosclero- sis.2010.10.007 36. Baker AR, Silva NF, Quinn DW, Harte AL, Pagano D, Bonser RS, et al. Human epicardial adipose tissue expresses a pathogenic profile of adipocytokines in patients with cardiovascular disease. Cardiovasc Diabetol 2006; 5: 1. doi: 10.1186/1475-2840-5-1. Radiol Oncol 2025; 59(1): 63-68. doi: 10.2478/raon-2025-0007 63 research article Accuracy of transthoracic echocardiography in diagnosis of cardiac myxoma: single center experience Polona Kacar1, Nejc Pavsic1, Mojca Bervar1, Zvezdana Dolenc Strazar2, Katja Prokselj1,2 1 Department of Cardiology, University Medical Center Ljubljana, Ljubljana, Slovenia 2 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia Radiol Oncol 2025; 59(1): 63-68. Received 10 February 2024 Accepted 8 December 2024 Correspondence to: Assoc. Prof. Katja Prokšelj, M.D., Ph.D., Department of Cardiology, University Medical Center Ljubljana, Zaloška cesta 7, SI-1525 Ljubljana, Slovenia. E-mail: katja.prokselj@gmail.com Disclosure: No potential conflicts of interest were disclosed. This is an open access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/). Background. The differential diagnosis of cardiac myxomas (CM), the most common benign primary cardiac tu- mors, is broad and a thorough diagnostic workup is required to establish accurate diagnosis prior to surgical resection. Transthoracic echocardiography (TTE) is usually the first imaging modality used for diagnosis of suspected CM. In a single tertiary centre study, we sought to determine the accuracy, sensitivity, and specificity of TTE in the diagnosis of CM and to determine echocardiographic characteristics indicative of CM. Patients and methods. We retrospectively analyzed clinical, echocardiographic, and pathohistological findings of 73 patients consecutively admitted for suspected CM. Results. After diagnostic workup, 53 (73%) patients were treated surgically at our institution. Based on preoperative TTE, patients were divided into a CM group (n=45, 85%) and non-myxoma (NM) group. Of the 53 pathohistological specimens obtained during surgery, 39 (73%) were CM. The sensitivity and specificity of preoperative echocardiogra- phy were 97% and 50%, respectively. The overall accuracy was 85%. All NM tumors were found in an atypical location and 72% of CM were found in a typical position in the left atrium (p < 0.001). Tumors in NM group were significantly smaller than CM (24.3 ± 13.2 mm vs. 37.9 ± 18.3 mm, p = 0.017). Conclusions. Our study confirms very good accuracy of TTE in the diagnosis of CM. The most important echocar- diographic characteristics to differentiate between CM and tumors of different etiology are tumor location and size. Smaller tumors presenting at an atypical location are less likely to be diagnosed as CM, and these require additional imaging modalities for accurate diagnosis. Key words: cardiac mass; cardiac myxoma; cardiovascular imaging; echocardiography Introduction Although rare, cardiac myxoma (CM) represents the most common benign primary cardiac tumor.1 Many patients are asymptomatic and CM is often an incidental finding.2 Potentially life-threatening complications such as tumor obstruction or em- bolization can occur, making accurate diagnosis crucial.3,4 However, diagnosis is challenging due to the broad differential diagnosis of CM, which includes other cardiac tumors and cardiac masses such as thrombi, vegetations, calcific lesions, and other rare conditions. Transthoracic echocardiography (TTE) nowa- days represents the most commonly used initial imaging modality in the diagnostic workup of CM. It provides information on tumor size, loca- tion, attachment point, morphology, mobility, and its relation to surrounding structures. The major- ity of CM are located in the left atrium, attached to Radiol Oncol 2025; 59(1): 63-68. Kacar P et al. / Echocardiography in cardiac myxoma64 the atrial septum in the region of the fossa ovalis. These are considered as typical CM, but atypical localizations outside the left atrium have been de- scribed in around 30%.5 Size and appearance (solid and round or polypoid) may also vary consider- ably in CM.6 TTE has an excellent detection rate for CM and a sensitivity of 90–96% in diagnosing CM has been reported.4 However, the heterogeneous morpho- logical presentation leads to overlap with other cardiac masses and may affect the specificity and accuracy of TTE in CM diagnosis. Furthermore, TTE lacks tissue characterization.7 Multimodality cardiac imaging ensures a more detailed analysis. Ultimately, the final diagnosis is made by histo- pathological examination of the excised tumor.8 The aim of our single-center study was to evalu- ate the utility and accuracy of TTE in the diagnosis of CM and to determine echocardiographic char- acteristics indicative of pathohistologically con- firmed CM. Patients and methods The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by national ethics committee of Slovenia (NO.: 0120-512/2020-3) and informed consent was obtained from individual partici- pants. We retrospectively analyzed clinical, echo- cardiographic, and pathohistological findings of all consecutive adult patients (≥ 18 years of age) referred to our Department of Cardiology in the largest tertiary hospital in Slovenia for suspected CM between 2005 and 2020. Our tertiary centre receives approximately 75% of all referrals for sus- pected CM in the country. All patients had TTE performed as part of the standard diagnostic workup. Echocardiographic characteristics of the cardiac mass were obtained, including mass location, surface (smooth or lobu- lated vs. villous) and appearance (homogenous vs. heterogenous). The mobility of the mass and the presence or absence of obstruction were also noted. Based on TTE findings, patients were diag- nosed with either CM, other non-myxomal (NM) cardiac tumor, or cardiac masses of other etiology (thrombus, infective endocarditis, etc.). Diagnosis of CM was made individually by the cardiologist performing TTE based on typical morphological characteristics of the cardiac mass. In some cases, additional imaging methods were used, either due to poor TTE acoustic windows or atypical tumor presentation. TTE contrast imaging was not per- formed in any of the cases. Patients with CM or NM cardiac tumors were referred for surgery and pathohistological sam- ples of the tumors were collected and analyzed to determine the final diagnosis. The accuracy, sen- sitivity, and specificity of TTE were determined by comparing echocardiographic and pathohisto- logical diagnosis. Furthermore, echocardiographic characteristics of pathohistologically proven CM were compared to NM cardiac tumors. Statistical analysis Continuous variables are presented as mean ± standard deviation and categorical variables as numbers and percentage. The independent Student’s t-test was used to compare continuous variables. Categorical variables were analyzed us- ing the χ2test. The sensitivity, specificity, negative predictive value, and positive predictive value of echocardiographic diagnosis of CM were calcu- lated using the results of pathohistological exami- nation as the gold standard. Accuracy was deter- mined as the sum of true negative and positive tests divided by all tests. All statistical analyzes were performed using SPSS version 26.0 software. Values of p < 0.05 were considered statistically sig- nificant. Results Baseline characteristics During the 15-year period, 73 patients were re- ferred for evaluation of suspected CM. All patients underwent TTE and 63 (86%) were diagnosed with CM or NM cardiac tumor. Of the remaining 10 (14%) patients, five were diagnosed with thrombus and were treated accordingly with anticoagula- tion therapy. In three cases pseudotumor was di- agnosed; one had a prominent Eustachian valve, one had a prominent Chiari network, and one had lipomatous hypertrophy of the interatrial septum. In two patients no obvious cardiac mass was found on repeat TTE. Out of 63 patients diagnosed with either CM or NM, 35 (56%) underwent one or more additional imaging techniques to confirm the diagnosis, ei- ther due to suboptimal image quality on TTE or atypical tumor presentation. CMR was used most frequently (n = 23, 66%), followed by TEE (n = 20, 57%) and CT (n = 3, 9%). In two patients PET-CT Radiol Oncol 2025; 59(1): 63-68. Kacar P et al. / Echocardiography in cardiac myxoma 65 was performed to detect possible distant metas- tases. No working diagnosis changed after addi- tional imaging techniques. After complete diagnostic workup, 53 (84%) of the 63 patients diagnosed with either CM or NM underwent surgery at our institution and were included for further analysis in our study. Of the 10 remaining patients, one underwent surgery at another institution, 4 had very small intracardiac masses, prompting periodic TTE follow-up, 4 were unfit for surgery, and 1 declined surgical interven- tion. The mean age of the operated patients was 64 ± 14 years (26–85 years), 35 patients (66%) were fe- male. The most common complaint was dyspnea (18 patients, 34%), followed by embolic events in 8 patients (15%), chest pain in 5 patients (9%), consti- tutional signs in 3 patients (6%) and palpitations in 2 patients (4%). Seventeen patients (32%) were asymptomatic. The mass was an incidental finding in 23 patients (43%), most commonly on TTE (61%) and chest CT (39%) performed for other indication. Echocardiographic characteristics Based on preoperative echocardiographic find- ings, the 53 operated patients were divided into two groups: a CM group (45 patients, 85%) and a NM group (8 patients, 15%). Preoperative echocar- diographic characteristics are depicted in Table 1. All tumors were solitary. The mean tumor size in the CM group was 35.3 ± 18.6 mm (range: 10–81 mm). The majority of CM were located in the atria; 80% in the left atrium and 18% in the right atrium. One tumor was found in the left ventricle. Tumors found in the left atrium were most frequently at- tached to the atrial septum in the region of the fos- sa ovalis (n = 27, 75%) (Figure 1). Other attachment sites in the left atrium included the mitral valve (n = 4, two were attached to the posterior leaflet, one to the anterior leaflet, and one to the posterior an- nulus of the mitral valve), other areas of the atrial septum (n = 3, posterior part of the atrial septum), the free atrial wall (n = 1) and left atrial append- age (n = 1). The tumors were mostly mobile (n = 32, 71%). Mitral valve obstruction was observed in 10 (22%) patients and tricuspid valve obstruction in 1 (2%) patient. The mean tumor size in the NM group was 30.3 ± 16.9 mm (range: 8–50 mm) (Table 1). All NM tu- mors were found in an atypical location, most fre- quently in the right atrium (n = 4, 50%). Two were attached to the left atrial free wall or posterior mi- tral valve leaflet and one to the aortic valve. TTE sensitivity, specificity, and accuracy analysis Pathohistological samples were obtained from the resected tumors in all 53 surgical procedures per- formed at our institution. Pathohistological evalu- ation confirmed CM in 39 of 53 operated patients (73%) (Figure 1). The calculated sensitivity and specificity of preoperative echocardiography in 53 patients who underwent surgery at our institution were 97% and 50%, respectively. The overall accuracy of TTE in diagnosing CM in those patients was 85% (Figure 2). In 7 patients (13%) diagnosed as CM on A B FIGURE 1. (A) Transthoracic echocardiography, apical 4-chamber view. Cardiac mass in left atrium is attached to the interatrial septum in the region of the fossa ovalis (arrow). Histopathological characterization confirmed cardiac myxoma. (B) Abundant myxoid stroma with clusters of myxoma cells forming cords and ring structures (HE 100x). LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle Radiol Oncol 2025; 59(1): 63-68. Kacar P et al. / Echocardiography in cardiac myxoma66 preoperative TTE, pathohistology revealed differ- ent NM cardiac tumors: papillary fibroelastoma in 5 cases, one case of angioleiomyoma and one malignant melanoma metastasis. Only one patient preoperatively classified as NM cardiac tumor had CM. Pathohistologically confirmed NM cardiac tu- mors were significantly smaller than CM (24.3 ± 13.2 mm vs. 37.9 ± 18.3 mm, p = 0.017) (Table 2). There was also a statistically significant difference in tumor location between the two groups. All NM tumors were located at an atypical position (seven in the right atrium, five in the left atrium but at an atypical site and two in the left ventricle) and 72% of CM were found at the typical location within the left atrium (p < 0.001). The calculated sensitiv- ity and specificity of tumor location in diagnosis of myxoma was 100% and 56%, respectively. There was no significant difference in other demograph- ic (age, sex) or echocardiographic characteristics (mobility, surface, appearance) between groups. Discussion Our single-center study confirms very good over- all accuracy of TTE in CM diagnosis. This is clini- cally important as accurate assessment of cardiac masses is essential for appropriate clinical man- agement and treatment of these patients. Diagnosis of CM can be challenging since pa- tients are frequently asymptomatic or have only non-specific signs and symptoms. Dyspnea, a frequent and non-specific symptom of cardiac disease, was the most common complaint in our CM group, which is consistent with previous re- ports.9–11 Clinical presentation itself rarely sug- gests the diagnosis of CM; therefore, cardiac im- aging is essential in the evaluation of patients with suspected CM. Echocardiography is the most widely used imaging modality that provides im- portant information about the location, size, and appearance of the cardiac mass, as well as possible complications (e.g. obstruction). Previous studies have shown that CM are typically solitary, located in the left atrium, smooth in surface and mobile.12,13 However, the morphological presentations of CM are often atypical and heterogeneous, leading to overlap with other NM cardiac tumors and cardiac masses. The results of our study show very good overall accuracy (85%) of TTE in CM diagnosis with ex- cellent sensitivity (97%). However, the specificity of TTE is modest (50%) and caution is warranted TABLE 1. Preoperative echocardiographic characteristics of the cardiac myxoma (CM) and non-myxoma (NM) group Echocardiographic characteristics CM (n=45) NM (n =8 ) Mean size (mm) 35.3 ± 18.6 (range: 10–81) 30.3 ± 16.9 (range: 8–50) Location Left atrium 36 (80) 2 (25) Fossa ovalis 27 (75) Mitral valve 4 (11) 1 (50) Posterior interatrial septum 3 (8) Free left atrial wall 1 (3) 1 (50) Left atrial appendage 1 (3) Right atrium 8 (18) 4 (50) Left ventricle 1 (2) 1 (12) 1 (12) Aortic valve Mobility Mobile Non-mobile No data available 32 (71) 5 (11) 8 (18) 7 (88) 1 (12) Surface Smooth or lobulated 28 (62) 1 (12) Villous No data available 8 (18) 9 (20) 3 (38) 4 (50) Obstruction (present) 11 (24) 2 (25) Mitral valve 10 (21) 1 (50) Tricuspid valve 1 (9) 1 (50) Values are presented as mean ± standard deviation or number (percentage). FIGURE 2. Flow diagram showing the diagnostic accuracy of preoperative TTE in patients with suspected CM. The predictive value and accuracy of preoperative TTE was calculated using the results of pathohistological examination as the gold standard. FN = false negative; FP = false positive; TP = true positive; TN = true negative; TTE = transthoracic echocardiography Radiol Oncol 2025; 59(1): 63-68. Kacar P et al. / Echocardiography in cardiac myxoma 67 as misdiagnosis of CM is possible. In our study, 5 of the misdiagnosed cases of CM were actually papillary fibroelastoma, which is also a common primary benign cardiac tumor. One of the sus- pected CM was actually a metastasis of malignant melanoma, underlying the importance of surgical excision and pathohistological examination of all suspected CM. According to our results tumor localization and tumor size are the best echocardiographic charac- teristics to distinguish between CM and NM car- diac tumors. CM are typically located in the left atrium attached to the interatrial septum at the re- gion of fossa ovalis, which was also shown in our study.14 In our patients, 72% of CM were located typically. However, all tumors preoperatively mis- diagnosed as CM were located in atypical loca- tions, such as the right atrium and left ventricle. Tumors in the NM group were also significantly smaller compared to tumors in the CM group. However, there was no significant difference in age, sex, and other echocardiographic character- istics (mobility and surface) between the groups. The differential diagnosis of CM is broad and definite diagnosis is crucial, as treatment varies depending on the diagnosis. Multimodality car- diac imaging improves the diagnostic accuracy of different cardiac masses. In the majority of our patients, at least one additional imaging modal- ity was used as a part of the diagnostic workup. TEE improves image quality and provides more morphological information than TTE.15 Computed tomography and cardiac magnetic resonance pro- vide additional information on topographic rela- tionships and tissue characteristics, and may de- tect other pathological conditions within the tho- rax.16,17 Assessment of cardiac tumors by CMR is more accurate than echocardiography and can re- liably distinguish between benign and malignant cardiac tumors.18-20 There are some limitations to this study. First, this is a retrospective study with a relatively small study population, precluding further analyses (e.g. Receiver Operating Characteristic). However, the population size is comparable to other studies on CM. Due to the low incidence of cardiac tumors, only multicenter studies can provide a larger scale patient population. Second, preoperative echocar- diography was performed by different echocar- diographers, potentially exposing the results to inter-investigator variability in determining the diagnosis. Due to the study inherently including participants already given a working diagnosis of CM, any cardiologist performing TTE was likely influenced by the information provided upon re- ferral. A larger, multicenter, prospective study could serve to identify echocardiographic and clinical characteristics specific to CM, as well as other cardiac tumors, further increasing the utility of preoperative diagnostic modalities. Conclusions TTE is very accurate in diagnosing CM. Tumor lo- calization and size are the most important echo- cardiographic characteristics that can differenti- ate between CM and NM. The diagnosis of CM is less likely in atypical tumor location and smaller tumor size. In such cases, caution is advised and other non-invasive imaging modalities, such as CMR or CT, should be performed to confirm the diagnosis. Acknowledgments Funding: The study was financially supported by the Slovenian Research Agency -research core funding No. P3-0429, Slovenian research programme for comprehensive cancer control SLORApro. References 1. Roberts WC. Primary and secondary neoplasms of the heart. Am J Cardiol 1997; 80: 671-82. doi: 10.1016/S0002-9149(97)00587-0 2. Karabinis A, Samanidis G, Khoury M, Stavridis G, Perreas K. Clinical presenta- tion and treatment of cardiac myxoma in 153 patients. Medicine 2018; 97: e12397-97. doi: 10.1097/MD.0000000000012397 3. Lee S, Kim JH, Na CY, Oh SS. Eleven years’ experience with korean cardiac myxoma patients: focus on embolic complications. Cerebrovasc Dis 2012; 33: 471-9. doi: 10.1159/000335830 TABLE 2. Comparison of demographic and echocardiographic characteristics between pathohistologically confirmed cardiac myxoma (CM) and non-myxoma (NM) groups Characteristic CM (n= 39) NM (n = 14) p value Age (years) 63.1 ± 13.6 66.6 ± 15.1 0.434 Sex (female) 25 (64) 10 (71) 0.620 Location Typical 28 (72) 0 P < 0.001 Atypical 11 (28) 14 (100) P < 0.001 Size (mm) 37.9 ± 18.3 24.3 ± 13.2 0.017 Values are presented as mean ± standard deviation or number (percentage). Radiol Oncol 2025; 59(1): 63-68. Kacar P et al. / Echocardiography in cardiac myxoma68 4. Samanidis G, Khoury M, Balanika M, Perrea DN. Current challenges in the diagnosis and treatment of cardiac myxoma. Kardiol Pol 2020; 78: 269-77. doi: 10.33963/KP.15254 5. Poterucha TJ, Kochav J, O’Connor DS, Rosner GF. Cardiac tumors: clinical presentation, diagnosis, and management. Curr Treat Options Oncol 2019; 20: 1-15. doi: 10.1007/s11864-019-0662-1 6. Tyebally S, Chen D, Bhattacharyya S, Mughrabi A, Hussain Z, Manisty C, et al. Cardiac tumors JACC CardioOncology State-of-the-Art Review. Jacc Cardiooncology 2020; 2: 1-19. doi: 10.1016/j.jaccao.2020.05.009 7. Colin GC, Gerber BL, Amzulescu M, Bogaert J. Cardiac myxoma: a contem- porary multimodality imaging review. Int J Cardiovasc Imaging 2018; 34: 1789-808. doi: 10.1007/s10554-018-1396-z 8. Basso C, Rizzo S, Valente M, Thiene G. Cardiac masses and tumours. Heart 2016; 102: 1230-45. doi: 10.1136/heartjnl-2014-306364 9. Pinede L, Duhaut P, Loire R. Clinical presentation of left atrial cardiac myxoma: a series of 112 consecutive cases. Medicine 2001; 80: 159-72. doi: 10.1097/00005792-200105000-00002 10. Cianciulli TF, Cozzarin A, Soumoulou JB, Saccheri MC, Méndez RJ, Beck MA, et al. Twenty years of clinical experience with cardiac myxomas: diagnosis, treatment, and follow up. J Cardiovasc Imaging 2019; 27: 37-47. doi: 10.4250/jcvi.2019.27.e7 11. Yu SH, Lim SH, Hong YS, Yoo KJ, Chang BC, Kang MS. Clinical experi- ences of cardiac myxoma. Yonsei Med J 2006; 47: 367-71. doi: 10.3349/ ymj.2006.47.3.367 12. Bjessmo S, Ivert T. Cardiac myxoma: 40 years’ experience in 63 patients. Ann Thorac Surg 1997; 63: 697-700. doi: 10.1016/S0003-4975(97)00003-9 13. Grebenc ML, Rosado-De-Christenson ML, Green CE, Burke AP, Galvin JR. Cardiac myxoma: imaging features in 83 patients. Radiographics 2002; 22: 673-89. doi: 10.1148/radiographics.22.3.g02ma02673 14. Zipes D, Libby P, Bonow R, Mann D, Tomaselli G. Braunwald’s heart disease: a textbook of cardiovascular medicine. 11th Edition. Philadelphia: Elsevi 2018. p. 555-62. 15. Engberding R, Daniel WG, Erbel R, Kasper W, Lestuzzi C, Curtius JM, et al. Diagnosis of heart tumours by transoesophageal echocardiography: a mul- ticentre study in 154 patients. Eur Heart J 1993; 14: 1223-8. doi: 10.1093/ eurheartj/14.9.1223 16. Wintersperger BJ, Becker CR, Gulbins H, Knez A, Bruening R, Heuck A, et al. Tumors of the cardiac valves: imaging findings in magnetic resonance imaging, electron beam computed tomography, and echocardiography. Eur Radiol 2000; 10: 443-9. doi: 10.1007/s003300050073 17. Mendes GS, Abecasis J, Ferreira A, Ribeiras R, Abecasis M, Gouveia R, et al. Cardiac tumors: three decades of experience from a tertiary center: are we changing diagnostic work-up with new imaging tools? Cardiovasc Pathol 2020; 49: 107242. doi: 10.1016/j.carpath.2020.107242 18. Hoey ETD, Mankad K, Puppala S, Gopalan D, Sivananthan MU. MRI and CT appearances of cardiac tumours in adults. Clin Radiol 2009; 64: 1214-30. doi: 10.1016/j.crad.2009.09.002 19. Pazos-López P, Pozo E, Siqueira ME, García-Lunar I, Cham M, Jacobi A, et al. Value of CMR for the differential diagnosis of cardiac masses. JACC Cardiovasc Imaging 2014; 7: 896-905. doi: 10.1016/j.jcmg.2014.05.009 20. Giusca S, Mereles D, Ochs A, Buss S, André F, Seitz S, et al. Incremental value of cardiac magnetic resonance for the evaluation of cardiac tumors in adults: experience of a high volume tertiary cardiology centre. Int J Cardiovasc Imaging 2017; 33: 879-88. doi: 10.1007/s10554-017-1065-7 Radiol Oncol 2025; 59(1): 69-78. doi: 10.2478/raon-2025-0016 69 research article Comparison of 2D and 3D radiomics features with conventional features based on contrast- enhanced CT images for preoperative prediction the risk of thymic epithelial tumors Yu-Hang Yuan1, Hui Zhang1, Wei-Ling Xu1, Dong Dong1, Pei-Hong Gao1, Cai-Juan Zhang1, Yan Guo2, Ling-Ling Tong3, Fang-Chao Gong4 1 Department of Radiology, The First Hospital of Jilin University, Jilin, China 2 GE Healthcare, China 3 Department of Pathology, The First Hospital of Jilin University, Jilin, China 4 Department of Thoracic Surgery, The First Hospital of Jilin University, Jilin, China Radiol Oncol 2025; 59(1): 69-78. Received 31 July 2024 Accepted 27 January 2025 Correspondence to: Fang-Chao Gong, Department of Thoracic Surgery, The First Hospital of Jilin University, No. 71 Xinmin Street, Chaoyang District, Changchun 130021, Jilin, China. E-mail: fangchao_gong@163.com Yu-Hang Yuan and Hui Zhang contributed equally to this work. Disclosure: No potential conflicts of interest were disclosed. This is an open access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/). Background. This study aimed to develop and validate 2-Dimensional (2D) and 3-Dimensional (3D) radiomics signa- tures based on contrast-enhanced computed tomography (CECT) images for preoperative prediction of the thymic epithelial tumors (TETs) risk and compare the predictive performance with conventional CT features. Patients and methods. 149 TET patients were retrospectively enrolled from January 2016 to December 2018, and divided into high-risk group (B2/B3/TCs, n = 103) and low-risk group (A/AB/B1, n = 46). All patients were randomly as- signed into the training (n = 104) and testing (n = 45) set. 14 conventional CT features were collected, and 396 radi- omic features were extracted from 2D and 3D CECT images, respectively. Three models including conventional, 2D radiomics and 3D radiomics model were established using multivariate logistic regression analysis. The discriminative performances of the models were demonstrated by receiver operating characteristic (ROC) curves. Results. In the conventional model, area under the curves (AUCs) in the training and validation sets were 0.863 and 0.853, sensitivity was 78% and 55%, and specificity was 88% and 100%, respectively. The 2D model yielded AUCs of 0.854 and 0.834, sensitivity of 86% and 77%, and specificity of 72% and 86% in the training and validation sets. The 3D model revealed AUC of 0.902 and 0.906, sensitivity of 75% and 68%, and specificity of 94% and 100% in the training and validation sets. Conclusions. Radiomics signatures based on 3D images could distinguish high-risk from low-risk TETs and provide complementary diagnostic information. Key words: thymic epithelial tumors; radiomics; computed tomography; World Health Organization; classification Introduction Thymic epithelial tumors (TETs) are the most prev- alent neoplasms in the anterior mediastinum. They generally exhibit low malignancy in both histologi- cal and clinical presentations.1 The WHO classifi- cation of TETs, based on lymphocyte-to-epithelial cell ratio and epithelial cell morphology, is widely adopted. According to the 2015 criteria, TETs are categorized into thymomas (with six subtypes) Radiol Oncol 2025; 59(1): 69-78. Yuan YH et al. / Radiomics in preoperative prediction of risk of the thymic epithelial tumors70 and thymic carcinomas (TCs).2,3 This classification serves as an independent prognostic factor and is simplified into low-risk (Type A, AB, B1) and high- risk (Type B2, B3, TCs) categories, influencing pa- tient outcomes.4 The WHO classification reflects the tumor’s clinical and functional features, aiding preoperative diagnosis and treatment planning.5 Accurate, noninvasive identification and subgroup classification of TETs prior to treatment hold sig- nificant clinical value. CT imaging is the primary diagnostic tool for TETs, revealing a wide range of biological and morphological features.6,7 Studies have reported specific CT characteristics of TETs.8,9 While chest contrast-enhanced computed tomography (CECT) provides general morphological parameters, distin- guishing between histological subgroups remains challenging due to significant overlap. Radiomics, leveraging radiomic signatures, extracts diverse, high-throughput imaging features, transforming medical images into mineable data.10,11 Radiomic features can predict disease, cancer, metastasis, and prognosis.12 Previous studies have used 2D radiomics to determine thymoma risk levels.13,14 Wang et al. differentiated low-risk from high-risk thymomas and early from advanced tumors using contrast-enhanced CECT and non-enhanced CT15, but their study had a small sample size and the sample size was imbalanced. Despite several CT-based radiomics analyses be- ing used to classify TET risk, most studies rely on 2D imaging features. Further research is needed to explore 3D radiomic signatures, which may provide more comprehensive and accurate information for TET diagnosis and risk assessment. The available models still require refinement and validation. This study aimed to develop conventional and 2D/3D radiomics signatures using the convention- al and texture features extracted from CECT im- ages for preoperative prediction of the WHO’s TET risk classification. Patients and methods Patients This retrospective study was approved by the Ethics Committee of the First Hospital of Jilin University, and the requirement for informed consent was waived due to the retrospective nature of the study (Studi Approval Number: 2020-541). From January 2016 to December 2018, data from 175 patients who undergoing CECT examination within one week to two months before surgery who were pathologi- cally diagnosed as TET were collected in our hos- pital consecutively. The inclusion criteria were: 1) underwent CECT within one week to two months before surgery without chemotherapy; 2) high CT image quality without artifacts; and 3) available clinical and surgical data. The exclusion criteria were shown in Figure 1. Finally, 149 patients with pathologically confirmed TET were enrolled in this study. The baseline characteristics of all patients including age, sex and symptoms (thoracalgia and myasthenia gravis) were collected. The patients were divided into the high-risk group (B2/B3/TCs, n = 103) and the low-risk group (A/AB/B1, n = 46) according to the WHO classification criteria of TET. All patients were randomly assigned into the training group (n = 104) and test (n = 45) group at a ratio of 7:3. Figure 1 illustrates the flow chart of the case selection process. CT scanning All patients underwent routine two-phase chest CECT scans using either a 64-MDCT scan- ner (Definition, Siemens Healthcare, Erlangen, Germany) or a 128-MDCT scanner (iCT, Philips Healthcare, Amsterdam, Netherlands). The scan- ning parameters were as follows: (1) Philips iCT: tube voltage 120 kV, automatic mAs, layer thick- ness 5 mm, pitch 0.980; (2) GE Lightspeed VCT: tube voltage 120 kV, automatic mAs, slice thick- ness 5 mm, pitch 0.992. All patients were examined in a supine position, arms up, deep inspiration and scanning. The contrast agent was injected into the patient using a high-pressure syringe (Visipaque 320, Amersham Health, Cork, Ireland). A total of 60-80 mL of contrast agent was administered through the antecubital vein at a rate of 3 ml/s, which was followed by 30 ml of saline injection at the same rate. Conventional CT features measurement The CT images were reviewed on the picture ar- chiving and communication system (PACS). The conventional CT features of all patients were ana- lyzed and recorded, including tumor’s long diam- eter, short diameter, vertical diameter, area, pe- rimeter and CT values. The tumor heterogeneity evaluated by the radiologist is also recorded, con- sisting of location (right, middle or left), morphol- ogy (lobular, /shallowly-lobulated or non-lobular), demarcation (clear, unclear or infiltrating), internal calcification and necrosis. The workflow of conven- tional CT feature analysis was shown in Figure 2. Radiol Oncol 2025; 59(1): 69-78. Yuan YH et al. / Radiomics in preoperative prediction of risk of the thymic epithelial tumors 71 2D and 3D Tumor segmentation The original CT images with a thickness of 5 mm were uploaded to the A.K. software (Artificial Intelligence Kit, A.K., GE Healthcare, China) for 2D and 3D manual segmentation. First, using a linear interpolation algorithm, the raw data were resampled to a common voxel spacing of 1 mm3 to construct new data points within the range of a discrete set of known data points, and the voxel would be isotropic. The data with a window width of 350 HU and a window level of 50 HU were used. The 2D and 3D regions of interest (ROIs) were de- lineated by two independent experienced radiolo- gists (reader 1, XWL with 15 years of experience in chest imaging and reader 2, ZH with 10 years of experience in chest imaging) who were blinded to the pathology results. The 2D ROIs were deline- ated at the level of the single largest cross-sectional area around the tumor outline. The 3D ROIs were achieved from different continuous levels. To seg- ment the ROI in axial CT images, a manual meth- od was used on the AK software. The lesion was manually separated from the large blood vessels, lung, air, fat tissue and chest wall. The workflow of radiomics analysis was shown in Figure 2. 2D and 3D radiomic features extraction According to the CECT images of each patient, a total of 396 radiomic features were extracted au- tomatically from the 3D and 2D ROI respectively using A.K. software. The radiomic features were composed of the following classes: first-order his- togram features (N = 42), second-order texture fea- tures (N = 345, including the Haralick texture (N = 10), gray level co-occurrence matrix (N = 144), gray level run length matrix (N = 180) and gray level size zone matrix (N = 11), and morphological features (N = 9). Details of the radiomics features were de- scribed in Supplementary Figure. S1. Features selection To reduce the dimensionality of the conventional and 2D/3D radiomic features, the least absolute shrinkage and selection operator (LASSO) method was applied to identify the most valuable features from the training dataset. For better performance of the model, the best penalty parameters λ was obtained based on the loss function with the least squares during 10-fold-cross-validation proce- dure. FIGURE 1. The flow chart of the case selection process. Radiol Oncol 2025; 59(1): 69-78. Yuan YH et al. / Radiomics in preoperative prediction of risk of the thymic epithelial tumors72 Model building and evaluation Three models, including the conventional model, 2D radiomics model and 3D radiomics model, were established using multi-variate logistic re- gression based on the selected features. Then the conventional score, 2D radiomics score and 3D ra- diomics score were calculated for each patient via a linear combination of selected features weighted by coefficients. The discriminative performance of the three models were evaluated by ROC curves. The area under the curves (AUC), sensitivity, specificity and the optimal cutoff value were obtained from ROC analysis. Delong test was used to identify the dif- ference of AUC between different models, and P < 0.05 indicated a significant difference. The degree of calibration was assessed in the calibration curve of the Hosmer-Lemeshow test, and P > 0.05 indicat- ed a good fit. Furthermore, decision curve analy- sis (DCA) was conducted to determine the clinical applicability of the models by quantifying the net benefit under different threshold probabilities. Statistical analysis Continuous data with a normal distribution (ac- cording to the Kolmogorov-Smirnov test) were ex- pressed as mean ± standard deviation (SD) and an- alyzed using Student’s t-test. Continuous variables with a non-normal distribution were expressed as medians (interquartile range) and analyzed using the Mann-Whitney test. Categorical variables were represented as frequencies and percentages and analyzed using the chi-square test. The statistical analysis was conducted using R software (v. 3.6.1, http://www.R-project.org). A two-tailed p value of less than 0.05 was considered significant. Results Baseline characteristics of the patients There were 104 patients in the training set, among which 72 (69.2%) cases were in the high-risk group. The testing set involved 45 patients, and 31 (68.9%) cases were in the high-risk group. Age, sex, and FIGURE 2. The flow chart of the CT imaging analysis. (A) shows the workflow of conventional analysis and 14 conventional features were recorded. (B) shows the workflow of radiomics analysis. 2D and 3D segmentation were performed on the CT images and 396 radiomics features were extracted respectively. The most predictive feature variables were selected, and the multivariate logistic regression analysis was applied to build the prediction models. The predicting abilities of the conventional and radiomics models were demonstrated by receiver operating characteristic (ROC) curves. The goodness of fit was assessed using calibration curve of the Hosmer-Lemeshow test. Additionally, decision curve analysis (DCA) was conducted to determine the clinical usefulness of the models. Radiol Oncol 2025; 59(1): 69-78. Yuan YH et al. / Radiomics in preoperative prediction of risk of the thymic epithelial tumors 73 frequency of myasthenia gravis and thoracalgia were similar between the high-risk and low-risk groups in both the training and testing sets (all P > 0.05). The characteristics of the patients are pre- sented in Table 1. Three models building Conventional model In the training set, compared with the low-risk group, the high-risk group had a lower mean HU value (62.0 vs. 79.5 HU, P < 0.001), a lower maxi- mum HU value (118.0 vs. 148.5 HU, P < 0.001), a smaller short diameter 23.2 vs. 34.7 mm, P = 0.009), a smaller area (628.5 vs. 1321.5 mm2, P = 0.008), and a smaller perimeter (112.5 vs. 143.0 mm, P = 0.021). In addition, the lesions in the high-risk group were often non-lobular (P = 0.010), and there was no clear demarcation (P = 0.023). The patient’s CT con- ventional parameters are listed in Table 2. In the testing set, the maximum HU value of the high-risk group was lower than that of the low-risk group (median HU 129.0 vs. 162.0, P = 0.002). The le- sions in the high-risk group tended to be non-lobu- lar (P < 0.001), with no clear demarcation (P = 0.010). After LASSO regression analysis, seven conven- tional CT features with non-zero coefficients were remained. The calculation formula of the conven- tional score was as follows: Conventional Score = 5.71-0.012*Circle.mm- 0.051*Mean CT value + 0.023*Minimum CT val- ue-0.009*Maximum CT value-0.903*Necrosis + 1.859*adjacent-0.595*Location. 2D Radiomics model After LASSO regression analysis, five CT features including Min Intensity, Percentila75, Correlation_ angle0_offset7, LongRunEmphasis_angle90_off- set1, and Small Area Emphasis were retained. The formula for the calculation of the 2D radiomics score was as follows: 2D Radiomics Score = 1.343-0.528 *Min intensi- ty-0.805* Percentile75-0.557* Correlation_angle0_ offset7 + 1.343* LongRunEmphasis_angle90_offset 1-0.900* SmallAreaEmphasis 3D radiomics model The 3D radiomics model was established using eight selected CT features, and the calculation for- mula of the 3D radiomics score was as follows: 3D Radiomics Score = 1.330-1.731 *Percentile75-0.915* ClusterProminence_an- gle135_offset4-1.266 *GLCMEnergy_angle0_off- set7 + 0.635* AngularSecondMoment-0.559 *LongRunEmphasis_AllDirection_offset1 + 0.678* LowGreyLevelRunEmphasis_AllDirect ion_ offset7_SD-0.573 *Compactness1-0.714* IntensityVariability. The performance of the three models Discriminative degree In the training set, this conventional model had an AUC of 0.863 (95% confidence interval (CI): 0.786-0.940), a sensitivity of 78%, and a specific- ity of 88%. In the testing set, the AUC was 0.853 (95% CI: 0.740-0.965), the sensitivity was 55%, and the specificity was 100%. The 2D radiomics model yielded an AUCs of 0.854 (95% CI: 0.7-0.931) and 0.834 (95%CI: 0.714-0.954), a sensitivity of 86% and 77%, and a specificity of 72% and 86% in the training and testing set, respectively. For the 3D radiomics model, the AUC of the training and test- ing set was 0.902 (95%CI: 0.842-0.963) and 0.906 (95%CI: 0.820-0.991), respectively, the sensitivity was 75% and 68%, respectively, and the specificity was 94% and 100%, respectively. The ROC curves and the detailed results were shown in Figure 3 and Table 3. As shown in Figure 3, the AUC of 3D model was usually higher compared with the conven- tional parameter model and 2D model. However, TABLE 1. Baseline characteristics of the patients in training and testing dataset Training set Testing set Low-risk (n=32) High-risk (n= 72) P Low-risk (n=14) High-risk (n=31) P Age, (Mean ± SD) years 53.6±11.2 52.5±11.4 0.656 54.0±10.7 56.4±8.9 0.446 Sex (male, No. (%)) 14 (43.8) 37 (51.4) 0.472 7 (50.0) 18 (58.1) 0.614 Myasthenia gravis, No. (%) 7 (21.9) 24 (33.3) 0.238 0 (0.0) 8 (25.8) 0.094 Thoracalgia, No. (%) 3 (9.4) 18 (25.0) 0.067 1 (7.1) 11 (35.5) 0.104 Radiol Oncol 2025; 59(1): 69-78. Yuan YH et al. / Radiomics in preoperative prediction of risk of the thymic epithelial tumors74 due to the limited data size, Delong test suggested that there was no statistical difference of AUCs among conventional, 2D and 3D models. The pro- cess and results of the Delong test are described in Supplementary Figure S2. Calibration degree The calibration curves of the three models were illustrated in Figure 4, which demonstrated good agreement between the predictive and actual prob- ability. All the P value of the Hosmer-Lemeshow test were more than 0.05 in both training and test- ing datasets for the conventional model (P = 0.735 and 0.266, respectively), 2D model (P = 0.665 and 0.492, respectively) and 3D model (P = 0.562 and 0.448, respectively). Clinical usefulness DCA for the three models was performed in both training and testing datasets (Figure 5). The deci- sion curve showed that all the three models added more benefit than using treat-all scheme (assum- ing all TETs are high risk) or the treat-none scheme (assuming all TETs are low risk) if the threshold probability was > 10%. When the threshold prob- ability was betwen 25% to 60% or between 70% to 95%, using the 3D radiomics model to predict the TETs risk added more benefit than either the con- TABLE 2. Distribution of conventional CT features in training and testing dataset Training set Testing set Low-risk (n=32) High-risk (n= 72) P Low-risk (n=14) High-risk (n=31) P Mean CT value (HU) 79.5 (68.4, 91.6) 62.0 (51.0, 78.8) <0.001 88.5 (76.0, 95.1) 67.0 (59.2, 74.0) <0.001 Standard deviation 18.0 (16.0, 22.6) 16.5 (14.0, 19.0) 0.050 18.0 (15.9, 26.2) 17.0 (14.2, 21.6) 0.548 Minimum CT value (HU) -6.10±30.2 -8.5±25.0 0.678 -0.7±31.6 -7.3±17.9 0.477 Maximum CT value (HU) 148.5 (131.0, 172.1) 118.0 (105.5, 138.6) <0.001 162.0 (148.9, 166.1) 129.0 (105.4, 146.8) 0.002 Long diameter (mm) 50.6±17.0 44.1±19.4 0.106 47.8 (40.9, 57.8) 38.0 (27.7, 61.3) 0.198 Short diameter (mm) 34.7 (23.9, 41.7) 23.2 (17.7, 34.6) 0.009 36.5 (26.0, 45.4) 25.6 (19.0, 39.3) 0.073 Vertical diameter (mm) 48.6 (44.1, 60.2) 40.4 (29.1, 55.2) 0.204 50.5 (44.4, 63.6) 38.9 (33.1, 55.1) 0.059 Area (mm2) 1321.5 (692.0, 1889.8) 628.5 (397.4, 1409.7) 0.008 1024.0 (747.7, 1623.3) 651.0 (346.0, 1362.8) 0.315 Perimeter (mm) 143.0 (110.8, 167.7) 112.5 (78.6, 153.8) 0.021 143.5 (118.6, 255.4) 100.0 (84.1, 194.8) 0.098 Location 0.373 0.790 Right mediastinum 10 (31.3%) 33 (45.8%) 7 (50.0%) 11 (35.5%) Middle 8 (25.0%) 15 (20.8%) 1 (7.1%) 3 (9.7%) Left mediastinum 14 (43.8%) 24 (33.3%) 6 (42.9%) 17 (54.8%) Morphology 0.010 <0.001 Lobular 5 (15.6%) 10 (13.9%) 7 (50.0%) 2 (6.5%) Shallowly-lobulated 15 (46.9%) 14 (19.4%) 7 (50.0%) 15 (48.4%) Non-lobular 12 (37.5%) 48 (66.7%) 0 (0.0%) 14 (45.2%) Demarcation 0.023 0.010 Clear 15 (46.9%) 17 (23.6%) 10 (71.4%) 8 (25.8%) Unclear 16 (50.0%) 43 (59.7%) 4 (28.6%) 17 (54.8%) Infiltration 1 (3.1%) 12 (16.7%) 0 (0%) 6 (19.4%) Internal calcification 8 (25.0%) 13 (18.1%) 0.416 4 (28.6%) 9 (29.0%) 0.746 Necrosis 12 (37.5%) 20 (27.8%) 0.321 9 (64.3%) 12 (38.7%) 0.111 Continuous variables that conformed to the normal distribution were expressed as mean ±SD. Continuous variables that did not conform to the normal distribution were represented by median values (25%, 75%). Categorical variables were expressed as No. (%). Coarse P values represented statistically significant. Radiol Oncol 2025; 59(1): 69-78. Yuan YH et al. / Radiomics in preoperative prediction of risk of the thymic epithelial tumors 75 ventional model or the 2D radiomics model in both training and testing datasets. Discussion This study evaluates three models using conven- tional and radiomic signatures, revealing that ra- diomic features from 2D and 3D imaging serve as noninvasive biomarkers for thymic epithelial tumors (TETs). These features enable preoperative risk stratification, guiding the surgical approach and resection extent. Importantly, risk stratifica- tion aids in personalized treatment planning for high-risk patients, often needing adjuvant therapy. A Phase II studies show that preoperative chemo- therapy and radiotherapy enhance R0 resection rates.16Thus, this study highlights the significance of radiomic signatures in preoperative risk assess- ment and treatment planning for TETs. In this study, three established models obtained using the conventional and radiomics signatures FIGURE 3. Receiver operating characteristic (ROC) curve analysis of the conventional, 2D and 3D radiomics models: (A) the training set; (B) the testing set. FIGURE 4. The calibration curves of the conventional, 2D and 3D radiomics models:(A) the training set; (B) the testing set. Radiol Oncol 2025; 59(1): 69-78. Yuan YH et al. / Radiomics in preoperative prediction of risk of the thymic epithelial tumors76 were examined. The results indicated that the ra- diomics signatures based on conventional, 2D and 3D images could be used as noninvasive biomark- ers to differentiate high-risk from low-risk TETs. Specifically, these models can provide preopera- tive risk stratification which informs the choice of surgical approach (minimally invasive surgery or thoracotomy) and helps define the extent of resec- tion. By accurately predicting the risk, this mod- el could aid in minimizing unnecessary tissue damage and reducing complications, potentially improving surgical outcomes and postoperative recovery. Since high-risk TET patients generally have poorer prognosis and often require adjuvant therapy, this stratification can guide treatment planning and improve patient outcomes by facili- tating more personalized interventions. Radiomics has shown significant potential in personalized medicine by providing non-invasive insights into tumor characteristics.10,12 It has been applied in various diseases, such as predicting thyroid cancer nodules, differentiating the benign and malignant nature of pulmonary nodules, and supporting clinical decision-making for liver can- cer patients. Radiomics studies using different imaging modalities (including ultrasound, MRI, and CT) have increasingly played a crucial role in clinical decision-making, providing new tech- nological support for prediction, diagnosis, and prognosis.17,18,19 Radiomics can be used to determine the TET classification according to WHO criteria. Previous studies have applied radiomics to classify the risk levels of thymomas and predict their inva- siveness15,20,21, but the available models still need refinement and validation. Therefore, this study aimed to use radiomics based on CECT images to develop conventional and radiomics signatures, which may help the preoperative prediction of the risk of TET classified by WHO guideline. We used a simplified classification that defines Type A, AB, and B1 thymomas as low-risk and Type B2 and B3 thymomas and TC as high-risk, which is related to patient outcome. High-risk thymic epithelial tumors reportedly have a much poorer prognosis compared with low-risk thymic epithelial tumors, the former need adjuvant ther- apy to improve survival. With complete resection of the tumor, the prevalence of recurrence of LTET seems low. TABLE 3. Diagnostic performance of the three models Model Training dataset Testing dataset Sensitivity Specificity AUC (95%CI) Sensitivity Specificity AUC (95%CI) Conventional models 77.8% 87.5% 0.863(0.786-0.940) 54.8% 100.0% 0.853(0.740-0.965) 2D radiomics model 86.1% 71.9% 0.854(0.777-0.931) 77.4% 85.7% 0.834(0.714-0.984) 3D radiomics model 75.0% 93.8% 0.902(0.842-0.963) 67.7% 100.0% 0.906(0.820-0.991) AUC = area under the curve; CI = confidence interval; CT = computed tomography FIGURE 5. Decision curve analysis (DCA) to determine the clinical usefulness of the models by quantifying the net benefits under different threshold probabilities: (A) the training set; (B) the testing set. Radiol Oncol 2025; 59(1): 69-78. Yuan YH et al. / Radiomics in preoperative prediction of risk of the thymic epithelial tumors 77 Our 3D radiomics model performed better in terms of AUC, sensitivity, and specificity com- pared to prior models reported in the literature. For instance, Wang et al. reported an AUC of 0.801, with a sensitivity of 75% and specificity of 77%, while Sui et al. found sensitivities ranging from 71% to 74% and specificities from 65% to 74% for differentiating low-risk and high-risk TETs. The improved performance of our model may be at- tributed to the enhanced information captured by 3D imaging features, which provide a more com- prehensive representation of tumor morphology and texture heterogeneity than 2D features. This suggests that using 3D data could offer a substan- tial advantage in capturing the complex structural characteristics of TETs, which is consistent with findings from previous studies on the added value of 3D features. However, it should also be noted that 3D feature extraction and analysis increase computational complexity, highlighting a poten- tial trade-off between accuracy and practicality. In this study, the images with 5 mm thickness in CECT were used for radiomics analysis, which not only saves time but also yields satisfactory results. Due to the small sample size, the fluctuation of individual samples affected the results greatly. The Hosemer-Lemeshow test was greater than 0.05. Although there were small fluctuations in the cali- bration map images of the test set, it still showed good consistency between predicted probability and true possibility without statistical deviation. In the clinical usefulness, the 3D radiomics model was valid from 25% to 60% and from 70% to 95% for the training set, and valid from 25% to 57% and from 75% to 90% for the test set. The DCA analysis showed the 3D model to be more effective and reliable than the other two models to deter- mine the clinical management. Conventional features such as contour, capsule, septum and homogeneous enhancement can be used to distinguish low-risk and high-risk TETs.7-9 Our study also compared the parameters obtained through the conventional CT features rather than software calculations, which also has some clini- cal significance for distinguishing high-risk from low-risk groups. Except CT, magnetic resonance imaging (MRI) could also be used to differentiate the grading of TETs according to WHO criteria.22,23 Nevertheless, the use and combination of multiple imaging mo- dalities could maximize the diagnostic value, pro- vided that all modalities are available at a given hospital, but this is not always the case, especially in developing countries like China. This study has several limitations. First, it is a single-center, small-sample, retrospective study, which may limit the generalizability of the find- ings and lead to overfitting. The small sample size also means that individual sample fluctuations could have a more significant impact on the mod- el’s performance, thus affecting its robustness. To address this, we plan to expand the sample size and conduct a multi-center study for further inves- tigation. Second, the absence of Masaoka staging information limits the model’s applicability in dis- tinguishing between different stages of thymic ep- ithelial tumors (TETs), which is crucial for clinical decision-making. In future studies, we will incor- porate this information. Third, variability in CT scan parameters and reconstruction techniques could affect the consistency and reproducibility of radiomics features, further impacting model performance. Standardizing imaging acquisi- tion and processing methods will be essential in future studies to enhance both model robustness and clinical applicability. Additionally, AI-based automated recognition methods will be employed for more in-depth tumor analysis. Although the model demonstrates excellent performance in dis- tinguishing risk groups, additional factors, such as tumor heterogeneity or genetic information, may further enhance predictive accuracy24. Conclusions In conclusion, radiomics signatures based on con- ventional, 2D and 3D images could be used as non- invasive biomarkers to differentiate high-risk TETs from low-risk TETs. The 3D radiomics signature can provide complementary diagnostic informa- tion and as the most useful method to determine the clinical management. References 1. Engels EA. Epidemiology of thymoma and associated malignancies. J Thorac Oncol 2010; 5(10 Suppl 4): S260-5. doi: 10.1097/JTO.0b013e3181f1f62d 2. Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, et al. The 2015 World Health Organization Classification of Lung Tumors: im- pact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol 2015; 10: 1243-60. doi: 10.1097/JTO.0000000000000630 3. Meurgey A, Girard N, Merveilleux du Vignaux C, Maury JM, Tronc F, Thivolet- Bejui F, et al. Assessment of the ITMIG statement on the WHO histological classification and of the eighth TNM staging of thymic epithelial tumors of a series of 188 thymic epithelial tumors. J Thorac Oncol 2017; 12: 1571-81. doi: 10.1016/j.jtho.2017.06.072 4. Suster S, Moran CA. Histologic classification of thymoma: the World Health Organization and beyond. Hematol Oncol Clin North Am 2008; 22: 381-92. doi: 10.1016/j.hoc.2008.03.001 Radiol Oncol 2025; 59(1): 69-78. Yuan YH et al. / Radiomics in preoperative prediction of risk of the thymic epithelial tumors78 5. Kondo K, Yoshizawa K, Tsuyuguchi M, Kimura S, Sumitomo M, Morita J, et al. WHO histologic classification is a prognostic indicator in thymoma. Ann Thorac Surg 2004; 77: 1183-8. doi: 10.1016/j.athoracsur.2003.07.042 6. Nishino M, Ashiku SK, Kocher ON, Thurer RL, Boiselle PM, Hatabu H. The thymus: a comprehensive review-erratum. Radiographics 2017; 37: 1004. doi: 10.1148/rg.2017174002 7. Sadohara J, Fujimoto K, Müller NL, Kato S, Takamori S, Ohkuma K, et al. Thymic epithelial tumors: comparison of CT and MR imaging findings of low- risk thymomas, high-risk thymomas, and thymic carcinomas. Eur J Radiol 2006; 60: 70-9. doi: 10.1016/j.ejrad.2006.05.003 8. Ozawa Y, Hara M, Shimohira M, Sakurai K, Nakagawa M, Shibamoto Y. Associations between computed tomography features of thymomas and their pathological classification. Acta Radiol 2016; 57: 1318-25. doi: 10.1177/0284185115590288 9. Tomiyama N, Johkoh T, Mihara N, Honda O, Kozuka T, Koyama M, et al. Using the World Health Organization Classification of thymic epithelial neoplasms to describe CT findings. AJR Am J Roentgenol 2002; 179: 881-6. doi: 10.2214/ajr.179.4.1790881 10. Lambin P, Leijenaar RTH, Deist TM, Peerlings J, de Jong EEC, van Timmeren J, et al. Radiomics: the bridge between medical imaging and personal- ized medicine. Nat Rev Clin Oncol 2017; 14: 749-62. doi: 10.1038/nr- clinonc.2017.141 11. Aerts HJ. The potential of radiomic-based phenotyping in precision medi- cine: a review. JAMA Oncol 2016; 2: 1636-42. doi: 10.1001/jamaon- col.2016.2631 12. Song J, Yin Y, Wang H, Chang Z, Liu Z, Cui L. A review of original articles pub- lished in the emerging field of radiomics. Eur J Radiol 2020; 127: 108991. doi: 10.1016/j.ejrad.2020.108991 13. Iannarelli A, Sacconi B, Tomei F, Anile M, Longo F, Bezzi M, et al. Analysis of CT features and quantitative texture analysis in patients with thymic tu- mors: correlation with grading and staging. Radiol Med 2018; 123: 345-50. doi: 10.1007/s11547-017-0845-4 14. Yasaka K, Akai H, Nojima M, Shinozaki-Ushiku A, Fukayama M, Nakajima J, et al. Quantitative computed tomography texture analysis for estimating histological subtypes of thymic epithelial tumors. Eur J Radiol 2017; 92: 84- 92. doi: 10.1016/j.ejrad.2017.04.017 15. Wang X, Sun W, Liang H, Mao X, Lu Z. Radiomics signatures of computed to- mography imaging for predicting risk categorization and clinical stage of thy- momas. Biomed Res Int 2019; 2019: 3616852. doi: 10.1155/2019/3616852 16. Lee GD, Kim HR, Choi SH, Kim YH, Kim DK, Park SI. Prognostic stratifica- tion of thymic epithelial tumors based on both Masaoka-Koga stage and WHO classification systems. J Thorac Dis 2016; 8: 901-10. doi: 10.21037/ jtd.2016.03.53 17. Zhu H, Luo H, Li Y, Zhang Y, Wu Z, Yang Y. The superior value of radiomics to sonographic assessment for ultrasound-based evaluation of extrathyroidal extension in papillary thyroid carcinoma: a retrospective study. Radiol Oncol 2024; 58: 386-96. doi: 10.2478/raon-2024-0040 18. Bo Z, Song J, He Q, Chen B, Chen Z, Xie X, et al. Application of artificial intelligence radiomics in the diagnosis, treatment, and prognosis of hepa- tocellular carcinoma. Comput Biol Med 2024; 173: 108337. doi: 10.1016/j. compbiomed.2024.108337 19. Warkentin MT, Al-Sawaihey H, Lam S, Liu G, Diergaarde B, Yuan JM, et al. Radiomics analysis to predict pulmonary nodule malignancy using machine learning approaches. Thorax 2024; 79: 307-15. doi: 10.1136/ thorax-2023-220226 20. Sui H, Liu L, Li X, Zuo P, Cui J, Mo Z. CT-based radiomics features analysis for predicting the risk of anterior mediastinal lesions. J Thorac Dis 2019; 11: 1809-18. doi: 10.21037/jtd.2019.05.32 21. Marom EM, Milito MA, Moran CA, Liu P, Correa AM, Kim ES, et al. Computed tomography findings predicting invasiveness of thymoma. J Thorac Oncol 2011; 6: 1274-81. doi: 10.1097/JTO.0b013e31821c4203 22. Abdel Razek AAK, Khairy M, Nada N. Diffusion-weighted MR imaging in thymic epithelial tumors: correlation with World Health Organization clas- sification and clinical staging. Radiology 2014; 273: 268-75. doi: 10.1148/ radiol.14131643 23. Xiao G, Rong WC, Hu YC, Shi ZQ, Yang Y, Ren JL, et al. MRI radiomics analysis for predicting the pathologic classification and TNM Staging of thymic epi- thelial tumors: a pilot study. AJR Am J Roentgenol 2020; 214: 328-40. doi: 10.2214/AJR.19.21696 24. Kostic Peric J, Cirkovic A, Srzentic Drazilov S, Samardzic N, Skodric Trifunovic V, Jovanovic D, et al. Molecular profiling of rare thymoma using next- generation sequencing: meta-analysis. Radiol Oncol 2023; 57: 12-19. doi: 10.2478/raon-2023-0013 Radiol Oncol 2025; 59(1): 79-90. doi: 10.2478/raon-2025-0012 79 research article Cardiac MRI for differentiating chemotherapy- induced cardiotoxicity in sarcoma and breast cancer El-Sayed H Ibrahim1, Lubna Chaudhary1, Yee-Chung Cheng1, Antonio Sosa1, Dayeong An2, John Charlson1 1 Medical College of Wisconsin, Milwaukee, USA 2 Northwestern University, Evanston, USA Radiol Oncol 2025; 59(1): 79-90. Received 12 August 2024 Accepted 21 November 2024 Correspondence to: El-Sayed H. Ibrahim, Ph.D., Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA. E-mail: sayed.phd@gmail.com Disclosure: No potential conflicts of interest were disclosed. This is an open access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/). Background. Over the past few decades, many studies have focused on anthracyclines effect on the heart (car- diotoxicity), but only a few have focused on sarcoma. In this study, we harness the capabilities of advanced cardiac magnetic resonance imaging (MRI) for characterizing anthracyclines-induced cardiotoxicity in sarcoma and com- pare the results to those from breast cancer patients. Patients and methods. The patients receive an MRI exam at three timepoints: baseline (pre-treatment), post- treatment, and at 6-months follow-up. Results. The results demonstrated a differential response in sarcoma, characterized by increasing left-ventricular (LV) mass and decreasing right ventricular ejection fraction (RVEF). In all patients, left ventricular ejection fraction (LVEF) remained > 50% at all timepoints. Myocardial strain was always lower than the normal threshold values and showed small changes between different timepoints. Myocardial T2 and extracellular volume (ECV) showed increasing and decreasing patterns, respectively, in sarcoma, which were the opposite patterns of those in breast cancer. While myo- cardium T1 showed increasing values in breast cancer, T1 in sarcoma increased post-treatment and then decreased at the 6-months follow-up. The results showed inverse correlation between dose and different strain components in sar- coma, which was not the case in breast cancer. Certain myocardial segments showed high correlation coefficients with dose, which may reflect their increased sensitivity to cardiotoxicity. Conclusions. Cardiac MRI proved to be a valuable technique for determining anthracycline-induced changes in cardiac function and myocardial tissue composition in sarcoma and differentiating it against breast cancer. It also provides a comprehensive assessment of heart health at baseline, which is important for risk stratification. Key words: cardiotoxicity; MRI; chemotherapy; sarcoma; breast cancer Introduction Despite being rare in the general population, sarco- ma is the second most common cancer among chil- dren and young adults. Sarcoma tumors originate from mesenchymal cells in different body areas.1 The number of cancer survivors has significantly increased over the past few decades due to treat- ment improvements.2 Despite the development of advanced cancer therapies, anthracyclines remain a commonly used treatment for cancer, including sarcomas and breast cancer.3 In particular, doxoru- bicin is considered a standard, first-line treatment of sarcoma.4 Nevertheless, treatment with doxoru- bicin has the side effect of cardiotoxicity with po- tential development of heart failure if not prompt- Radiol Oncol 2025; 59(1): 79-90. Ibrahim ESH et al. / Differentiating chemotherapy-induced cardiotoxicity by MRI80 ly treated.5 Sarcoma patients are more likely than other cancer patients to develop cardiotoxicity af- ter receiving anthracyclines.6 In pediatric sarcoma patients enrolled in the prospective Late Effects Surveillance System study, which included 265 patients, the cardiotoxicity incidence was 7.5%.7 Another registry showed a 14% incidence of car- diotoxicity in 43 adult patients.8 Early onset cardiotoxicity is a major challenge in clinical practice due to the reliance on anthra- cyclines and relative lack of other systemic ther- apy options for treatment of advanced sarcomas.3 Cardiotoxicity is defined by the development of heart failure symptoms or by asymptomatic de- crease in baseline left ventricular ejection fraction (LVEF) ≥ 10% to a level < 50%.1,9,10 Cardiotoxicity can cause cardiovascular complications, includ- ing ventricular dysfunction, myocardial ischemia, hypertension, arrhythmias, and heart failure.1-14 A potential mechanism of cardiotoxicity devel- opment is myocyte free radical damage, which is emphasized by repetitive damage to myocyte mitochondria and high peak levels of plasma.15,16 Cardiotoxicity has been well studied among pa- tients with breast cancer8,17; however, there is limited data regarding cardiotoxicity and mortal- ity rates in sarcoma patients.18 The treatment and prognosis of sarcoma and breast cancer are differ- ent, and using results from breast cancer studies to interpret those from sarcomas may not be appro- priate. Anthracyclines induced cardiotoxicity can occur after both high- and low-dose doxorubicin therapy19 due to wide variation in individual vul- nerability20 with no clear threshold regarding safe doses of anthracyclines.21,22 Actually, the cumula- tive dosage of anthracyclines used in sarcoma is higher than that in many other cancers23 as using doxorubicin beyond the recommended cumulative dose is a promising option to improve survival in patients with advanced sarcomas.24 Although long- term surveillance guidelines of cancer patients re- ceiving anthracyclines are addressed in the litera- ture, there is no clear guidelines regarding surveil- lance during and shortly after treatment.25 In clinical practice, a decrease in LVEF is the most common form of cardiotoxicity.5,26 However, a large reduction in LVEF occurs late in the pro- cess of cancer therapy induced cardiotoxicity.27 Therefore, it is important to stratify patients early on such that cardiac protection can be initiated as early as possible in those with increased risk of cardiotoxicity. It has been shown that MRI global longitudinal strain (GLS) is more sensitive than LVEF for detecting early signs of systolic myocar- dial dysfunction.22,28 GLS may also identify pa- tients at risk of cardiotoxicity, possibly through de- tection of baseline subclinical cardiac dysfunction, which may advance to heart failure.29 Either a low absolute GLS value early during chemotherapy or a threshold relative reduction in GLS compared with baseline can be used to identify individuals at high risk of developing heart failure.29 GLS less than 17% (in absolute value) or relative reduction in GLS by >15% from baseline has been used as a threshold for patients at risk.27,30 Changes in oth- er strain components, e.g., global circumferential strain (GCS), have been also reported in sarcoma.31 It has been reported that patients with subse- quent cardiotoxicity may have low myocardial T1 times and decreased LV mass; but patients do not typically develop myocardial scars or focused fi- brosis from anthracyclines.32 Nevertheless, anthra- cyclines can induce diffuse myocardial fibrosis later, which can be confirmed by elevated MRI T1 times.33 However, it has been reported that myo- cardial MRI T2 times and serum biomarkers were not able to stratify patients and identify those at risk of developing cardiotoxicity.32 Therefore, it is obvious that there is an ongoing myocardial remodeling process following treatment with an- thracyclines. While there may be T1 reduction shortly post anthracyclines, on the long run myo- cardial remodeling may lead to elevated T1 times and ECV values because of diffuse interstitial fi- brosis in the myocardium.34 We conducted a single-center, observational, prospective study to evaluate the value of cardiac MRI parameters for revealing and characterizing cardiac dysfunction associated with anthracy- clines in sarcoma and breast cancer patients. Patients and methods All work has been conducted in accordance with the Declaration of Helsinki (1964). The study was approved by our institutional review board (IRB) and informed consent forms were collected from all subjects. Eighteen patients (5 males and 13 fe- males; 8 sarcoma and 10 breast cancer) scheduled for doxorubicin chemotherapy were included in the study. The patients underwent a baseline (pre- treatment (18 patients)) and two follow-up (post- treatment completion (14 patients) and 6-months after treatment completion (10 patients)) visits. The treatment duration was 143 ± 65 days. Each visit in- cluded an optimized cardiac MRI exam and blood analysis. A questionnaire about risk factors and Radiol Oncol 2025; 59(1): 79-90. Ibrahim ESH et al. / Differentiating chemotherapy-induced cardiotoxicity by MRI 81 comorbidities was collected from the patients at the first visit. The MRI exams were conducted on a 3T GE MRI scanner (GE Healthcare, Waukesha, WI, USA)) and included the following sequences: cine, tagging, modified Look-Locker (MOLLI) T1 mapping (both pre and post gadolinium (Gd) in- jection), T2 mapping, perfusion, and late gadolini- um enhancement (LGE). The acquired cine images included a stack of parallel short-axis slices (SAX) covering the heart from base to apex in addition to 2-chamber, 3-chamber, and 4-chamber long-axis slices. The optimized cine imaging parameters were as fol- lows: fast imaging employing steady-state acqui- sition (FIESTA) acquisition, repetition time (TR) = 3.6 ms, echo time (TE) = 1.3 ms, flip angle = 55°, views per segment = 14, # averages = 1, matrix = 256 × 256, slice thickness = 8 mm, and readout band- width = 488 Hz/pixel. The acquired tagged images included a 3 equidistant short-axis slices (basal, mid-ventricular, and apical) in addition to 2-cham- ber, 3-chamber, and 4-chamber long-axis slices. Optimized tagging imaging parameters different from cine imaging were as follows: TR = 5.7 ms, TE = 3.1 ms, flip angle = 8°, views per segment = 14, readout bandwidth = 391 Hz/pixel, tag spacing = 7mm, and number of heart phases = 25. The MOLLI images were acquired at the same 3 SAX tagged slices (basal, mid-ventricular, and api- cal). Optimized MOLLI imaging parameters dif- ferent from cine imaging were as follows: 8 images acquired using the 5(3 s)3 acquisition pattern, TR = 2.9 ms, TE = 1.3 ms, flip angle = 35°, and readout bandwidth = 977 Hz/pixel. The T2 mapping im- ages were acquired at the same 3 SAX tagged slices (basal, mid-ventricular, and apical). Optimized T2 mapping imaging parameters different from cine imaging were as follows: multi-echo fast spin echo sequence, TR = 895 ms, TE = 11 − 77 ms (4 echoes with 22 ms increments), echo train length (ETL) = 16, flip angle = 90°, and readout bandwidth = 651 Hz/pixel. The perfusion images were acquired at the same 3 SAX tagged slices (basal, mid-ventricular, and apical). Optimized perfusion imaging param- eters different from cine imaging were as follows: Fast gradient echo (FGRE) acquisition, TR = 2.5 ms, TE = 1.7 ms, flip angle = 20°, inversion time (TI) = 173 ms, ETL = 1, # averages = 0.75, number of multi- phase images = 60, and readout bandwidth = 326 Hz/pixel. The LGE images were acquired at the same SAX and LAX cine slices. Optimized LGE imaging parameters different from cine imaging were as follows: TR = 5.1 ms, TE = 2.3 ms, flip angle = 25°, TI = 275 − 325 ms based on Look-Locker im- ages, and readout bandwidth = 139 Hz/pixel. Image analysis was conducted by a MRI physi- cist with 18 years of experience in cardiac MRI (E.I.) and independently reviewed by a cardiotho- racic radiologist with 13 years of experience (A.S.). The cine images were analyzed using the cvi42 software (Circle, Calgary, Canada) function mod- ule to measure EF and myocardial mass. The T1 and T2 images were analyzed using the cvi42 soft- ware T1 and T2 mapping modules, respectively, to generate T1, T2, and ECV maps. The SinMod meth- od (InTag, Leon, France) (35) was used to analyze the tagged images to measure myocardial global longitudinal (GLS), circumferential (GCS), and radial (GRS) strains. Finally, the cvi42 software perfusion and tissue characterization modules were used to determine the existence of ischemic perfusion defects and myocardial infarction/scars, respectively. Inter- and intra-observer variabilities of strain analysis using this technique have been previously demonstrated.35 The blood samples drawn at each timepoint were analyzed to measure the following biomark- ers: N-terminal pro b-type natriuretic peptide (NT-proBNP), Troponin I (TnI), Troponin T (TnT), Interleukin 6 (IL-6), Tumor necrosis factor alpha (TNFα), C-reactive protein (CRP), and Galectin 3 (gal-3), as parameters associated with cardiac damage and heart failure. Statistical analysis was conducted using Excel (Microsoft, Redmond, Washington, USA) and Python (Python Software Foundation, Wilmington, Delaware, USA) to compare measure- ments pre- and post-treatment or between patient subgroups and to assess correlation between dif- ferent MRI parameters and dose. When examin- ing serial longitudinal measurements, a one-way analysis of variance (ANOVA) was used. Three groups were formed depending on timepoints: baseline, post-treatment, and 6-months follow-up. The Shapiro-Wilk test and the Levene’s test were performed for normality and homogeneity of vari- ances, respectively. If either of these tests has a p-value less than or equal to 0.05, non-parametric alternatives such as the Kruskal-Wallis H-test was performed. Correlation maps between dose and different post-treatment strain components indi- cated a need for regional analysis at the LV base, mid-ventricle, and apex levels. Correlation coef- ficients greater than 0.7 were considered high, in- dicating high dose-response or segment-response relationships. p values < 0.05 was considered sig- nificant. Radiol Oncol 2025; 59(1): 79-90. Ibrahim ESH et al. / Differentiating chemotherapy-induced cardiotoxicity by MRI82 Results The demographic data of all patients as well as of the sarcoma and breast cancer subgroups is shown in Table 1. Figure 1 and Figure 2 show tissue characteris- tics and myocardial strains, respectively, in both sarcoma and breast cancer patients at different study timepoints. The MRI measurements for all patients as well as for the sarcoma and breast can- cer subgroups at the three timepoints: (A) baseline, (B) post-treatment, and (C) 6-months follow-up are shown in Table 2. One-way ANOVA showed insignificant differences in most MRI parameters between the three timepoints (baseline, post-treat- ment, and 6-months follow-up). However, it should be noted that all strain values at baseline (pre- treatment) were lower than normal strain thresh- old of 17%, which emphasizes the importance of baseline strain measurements as they reflect un- derlying risk factors. Different strain measurements (GLS, GCS, and GRS) at the three study timepoints in sarcoma and breast cancer patients are shown in Figure 3. GLS and GCS are presented in absolute value (origi- nal numbers are negative) for clearer presentation along with the positive GRS. In general, in both pa- tient subgroups, GRS was lower than GCS, which in turn was lower than GLS. In both patient sub- groups, the 6-months follow-up strain were slight- ly higher than the post-treatment strain, especially for GCS and GRS (p > 0.05 for both groups). Global measures of cardiac function (LV EF, RV EF, and LV mass) in both sarcoma and breast can- cer patients at the three timepoints are shown in Figure 4. LVEF decreased at post-treatment, then TABLE 1. Patients’ demographic parameters Parameter All Sarcoma Breast Number of patients (m/f) 5/13 4/4 1/9 Number of patients – visit A (baseline) 18 8 10 Number of patients – visit B (post treatment) 14 6 8 Number of patients – visit C (6 months post follow-up) 10 4 6 Age (years) 56 ± 13 56 ± 15 55 ± 12 Body mass index (BMI) (kg/m2) 29 ± 6 27 ± 8 31 ± 4 White/Black race (n) 17/1 8/0 9/1 Non-Hispanic / Hispanic (n) 18/0 8/0 10/0 Patients with cardiovascular risk factors (n) 3 1 2 Patients with comorbidities (n) 7 5 2 Patients with cardiovascular disease (n) 1 1 0 Smoker patients (n) 7 3 4 Alcohol consumer patients (n) 8 3 5 Patients receiving cardiac medications (n) 4 3 1 Accumulative Dox dose (mg) 514 ± 190 564 ± 277 469±42 Dox = doxorubicin; f = female; m = male FIGURE 1. MRI tissue characterization maps in (A) sarcoma and (B) breast cancer. The figure shows myocardial T1, extracellular volume (ECV), and T2 maps. Note changes in the maps between sarcoma and breast cancer patients as well as between different study timepoints (baseline, post- treatment, 6-months follow-up). A B Radiol Oncol 2025; 59(1): 79-90. Ibrahim ESH et al. / Differentiating chemotherapy-induced cardiotoxicity by MRI 83 FIGURE 2. MRI strain curves in (A) sarcoma and (B) breast cancer patients. The figure shows circumferential (GCS), radial (GRS), and longitudinal (GLS) strain curves in both patient groups at different study timepoints. Myocardial strain for each case is represented by 6 segmental strain curves, color-coded based on the regional location as shown by the lower-right 6-segment illustration based on AHA standard LV model. Note changes in the strain curves between sarcoma and breast cancer patients as well as between different study timepoints (baseline, post-treatment, 6-months follow-up). Note also differences in segmental strain values within the same slice. A B Radiol Oncol 2025; 59(1): 79-90. Ibrahim ESH et al. / Differentiating chemotherapy-induced cardiotoxicity by MRI84 increased back at the 6-months follow-up time- point. LVEF was larger in the sarcoma patients, compared to the breast cancer patients, at both baseline and post-treatment timepoints. However, it was smaller at the 6-months follow-up. RV EF showed slight decrease with time in the sarcoma patients. However, in the breast cancer patients, RV EF showed large decrease at post-treatment be- fore it increased back at the 6-months timepoint. LV mass increased with time in the sarcoma pa- tients, while in the breast cancer patients, it de- creased at post-treatment, then increased back at 6-months follow-up. Nevertheless, the changes were not statistically significant (p > 0.05). Myocardium tissue characterization (T1, T2, and ECV) measurements in sarcoma and breast cancer patients are shown in Figure 5. The patterns were different between the two patient subgroups. For T1 in sarcoma patients, it slightly increased at post- treatment, then decreased at 6-months follow-up; however, T1 continuously increased with time in the breast cancer patients. For T2 in sarcoma pa- tients, it slightly increased with time; however, it showed larger increase with time in the breast can- cer patients. For ECV, it continuously decreased and increased with time in the sarcoma and breast cancer patients, respectively. Perfusion analysis revealed ischemic defects in eleven subjects (5 sarcoma and 6 breast cancer patients), mostly in the basal septal region. LGE revealed scars in five subjects (2 sarcoma and 3 breast cancer patients). There were no significant differences (p > 0.05) in MRI parameters between patients with perfusion defects or scars and those without them. AA B B CFIGURE 3. Global longitudinal (GLS), circumferential (GCS), and radial (GRS) strains at baseline, post-treatment, and 6-months follow-up in (A) sarcoma and (B) breast cancer patients. Note different patterns of change in strain between the two patient groups. In general, GRS is lower than GCS, which is lower than GLS. GCS and GLS are represented by absolute value (original values are negative) for clearer presentation along with positive GRS. FIGURE 4. Global cardiac function parameters: (A) left ventricular ejection fraction (RVEF), (B) right ventricular ejection fraction (RVEF), and (C) LV mass at baseline, post- treatment, and 6-months follow-up timepoints in sarcoma and breast cancer patients. LVEF is normal in both groups at all timepoints. RV EF is lower in breast cancer compared to sarcoma. LV mass shows continuous increase with time in sarcoma. Radiol Oncol 2025; 59(1): 79-90. Ibrahim ESH et al. / Differentiating chemotherapy-induced cardiotoxicity by MRI 85 The patterns of change in the serum biomarkers are different in the two patient groups (Figure 6). In sarcoma patients, both TnT and NT-proBNP showed increase with time, TnI showed similar values at the three timepoints. CRP increased post-treatment then decreased at 6-months fol- low-up, while IL-6 showed the opposite pattern. Changes in Gal3 and TNFα showed small differ- ences between the three timepoints. In breast can- cer patients, both CRP and TNFα increased with time. NT-proBNP and Gal3 showed similar values at the three timepoints, while TnI, TnT, and IL- 6 increased at post-treatment then decreased at 6-months follow-up. TnI and IL-6 are presented in fluorescence intensity (FI) units as the observed values were too small (out-of-range) to report. Differences in serum biomarker measurements were not statistically significant. Correlation maps between dose and different strain components at the post-treatment timepoint are shown in Figure 7. The patterns are different for the two patient groups. In sarcoma (Figure 7), as shown in the left-most column, dose is positive- TABLE 2. Cardiac MRI parameters Parameter All Sarcoma Breast p LVEF (%) - A 59 ± 11 62 ± 10 57 ± 12 0.398 LVEF (%) - B 55 ± 11 57 ± 8 53 ± 14 0.547 LVEF (%) - C 60 ± 5 58 ± 8 61 ± 2 0.489 LV mass (g/m2) - A 48 ± 10 48 ± 11 47 ± 9 0.849 LV mass (g/m2) - B 46 ± 8 51 ± 9 42 ± 5 0.049* LV mass (g/m2) - C 49 ± 8 53 ± 9 47 ± 7 0.300 RVEF (%) - A 50 ± 10 53 ± 8 48 ± 11 0.256 RVEF (%) - B 45 ± 15 51 ± 11 40 ± 17 0.196 RVEF (%) - C 48 ± 6 50 ± 5 47 ± 7 0.468 GLS (%) - A -14 ± 2 -14 ± 2 -14 ± 2 0.849 GLS (%) - B -13 ± 2 -13 ± 2 -14 ± 2 0.272 GLS (%) - C -14 ± 1 -14 ± 1 -13 ± 1 0.468 GCS (%) - A -11 ± 2 -11 ± 3 -11 ± 1 0.880 GCS (%) - B -11 ± 3 -11 ± 3 -11 ± 2 0.733 GCS (%) - C -12 ± 2 -12 ± 2 -11 ± 2 0.546 GRS (%) - A 11 ± 3 9 ± 3 12 ± 3 0.042* GRS (%) - B 10 ± 3 9 ± 3 10 ± 2 0.705 GRS (%) - C 10 ± 3 10 ± 3 11 ± 3 0.555 T1 (ms) - A 1264 ± 53 1275 ± 58 1255 ± 50 0.444 T1 (ms) - B 1309 ± 72 1296 ± 48 1319 ± 87 0.543 T1 (ms) - C 1289 ± 97 1213 ± 71 1339 ± 80 0.034* T2 (ms) - A 49 ± 5 48 ± 5 49 ± 4 0.529 T2 (ms) - B 49 ± 3 48 ± 3 50 ± 3 0.204 T2 (ms) - C 50 ± 3 49 ± 2 52 ± 4 0.136 ECV (%) - A 36 ± 7 37 ± 8 35 ± 6 0.433 ECV (%) - B 35 ± 5 34 ± 6 36 ± 4 0.591 ECV (%) - C 37 ± 4 33 ± 4 39 ± 3 0.031* A, B, and C refer to the three study timepoints (baseline, post-treatment, and 6-months follow- up), respectively. p values are shown for all measurements. p < 0.05 is considered significant and marked by an asterisk (*). ECV = extracellular volume; EF = ejection fraction; GLS, GCS, GRS = global longitudinal, circumferential, and radial strains, respectively; LV = left ventricle; RV = right ventricle A B C FIGURE 5. Myocardial (A) T1, (B) T2, and (C) extracellular volume (ECV) measurements in sarcoma and breast cancer groups at different study timepoints. All parameters show continuous increase with time in breast cancer. Sarcoma shows different patterns of change, e.g., continuous decrease of ECV with time. Post-treatment and 6-months follow-up T1 values in sarcoma are lower than those in in breast cancer. T2 shows minimal increase with time in sarcoma. Radiol Oncol 2025; 59(1): 79-90. Ibrahim ESH et al. / Differentiating chemotherapy-induced cardiotoxicity by MRI86 ly correlated with longitudinal (Ell) and circum- ferential (Ecc) strains, while it is negatively corre- lated with radial (Err) strain. This behavior is con- sistent for global strain as well as regional values at the base, mid-ventricular, and apical levels. The correlation coefficient values were moderate for all regions except for apical radial strain (last com- ponent in the column). These relationships dem- onstrate that strain gets worse (higher Ell and Ecc and lower Err) with dose, which is expected in can- cer patients. However, in the breast cancer patients (Figure 7), the correlation pattern was not consist- ent and there existed small positive and negative correlations between dose and each of the strain components (Ell, Ecc, Err). The only (negative) high correlation existed between dose and apical radial strain, the opposite case of sarcoma patients. No correlations were statistically significant (p > 0.05). At 6-months follow-up, the correlation pat- terns changed as shown in Figure 8. In sarcoma patients, the positive correlations between dose and Ecc was maintained, even with higher corre- lation coefficient compared to the post-treatment timepoint (Figure 7). Significant correlation coeffi- cients existed between dose and both global Ecc (p = 0.017) and mid-ventricle Ecc (0.028), respectively. However, in the breast cancer patients, only basal Ell (p = 0.015) and mid-ventricular Ell (p = 0.107) showed high positive correlations with dose. In the myocardial segmental level, using AHA 16-segment model (segments 1-6, 7-12, and 13-16 represent basal, mid-ventricular, and apical re- gions, respectively, in the longitudinal (Ell), cir- cumferential (Ecc), and radial (Err) directions. By taking 0.7 as a threshold for correlation coefficients, the following myocardium segments showed high correlation coefficients (negative for Ell and Ecc and positive for Err) with dose in sarcoma patients at post-treatment: Ell8 (R = 0.71, p = 0.114), Ell9 (R = 0.86, p = 0.028), Ecc1 (R = 0.78, p = 0.067), Ecc7 (R = 0.84, p = 0.036), Ecc9 (R = 0.73, p = 0.099). At 6-months follow-up, the following segments had correlation coefficients above the 0.7 threshold: Ell2 (R = 0.84, p = 0.036), Ell8 (R = 0.82, p = 0.46), Ecc1 (R = 0.74, p = 0.093), Ecc4 (R = 0.79, p = 0.062), Ecc5 (R = 0.75, p = 0.086), Ecc8 (R = 0.9, p = 0.015), Ecc9 (R = 0.75, p = 0.085), Ecc11 (R = 0.70, p = 0.122), Ecc12 (R = 0.85, p = 0.032). In the breast cancer pa- tients, only Err13 (R = -0.89, p = 0.017) and Err14 (R = -0.74, p=0.093) showed high correlation coefficients post treatment. At 6-months, the following seg- ments showed high correlation coefficients: Ell2 (R = 0.95, p = 0.004), Ell5 (R = 0.99, p <0.001), Ell7 (R = 0.98, p <0.001), Ell9 (R = 0.8, p = 0.056), Ell11 (R = 0.75, p = 0.086), Ell14 (R = 0.92, p = 0.009), Ecc8 (R = 0.92, p = 0.009), Err2 (R = -0.92, p = 0.009), Err9 (R = -0.8, p = 0.06), Err14 (R = -0.8, p = 0.06). Discussion The study demonstrates important points about anthracycline-induced cardiotoxicity. The first point is that MRI strain parameters are sensitive bi- omarkers of cardiac dysfunction (Figure 2). While LVEF was always > 50% in both patient groups and at different study timepoints, strain parameters showed underlying subclinical dysfunction, even at baseline as all strain (absolute) values were less A B FIGURE 6. Changes in serum biomarkers at different timepoints in (A) sarcoma and (B) breast cancer. CRP = C-reactive protein (µg/mL); Gal3 = Galectin 3 (ng/mL); IL-6 = Interleukin 6 (fluorescence intensity units); NT-proBNP = N-terminal pro b-type natriuretic peptide (pg/mL); TNFα = tumor necrosis factor alpha (pg/mL); TnI = cardiac troponin I (florescence intensity units), TnT = cardiac troponin T (pg/mL). The figure shows different patterns of change in the biomarkers between sarcoma and breast cancer. Not all biomarkers increased post-treatment. Different parameters reflect different aspects of cardiac injury. Radiol Oncol 2025; 59(1): 79-90. Ibrahim ESH et al. / Differentiating chemotherapy-induced cardiotoxicity by MRI 87 than strain threshold of 17% for normal contrac- tility. Baseline strain parameters inform about un- derlying risk factors, which should be taken into consideration for patient stratification and progno- sis. RVEF (Table 2) in sarcoma was always higher than that in breast cancer, which may be related to the difference in tumor locations and sizes be- tween the two patient groups. Although previous reports pointed to de- creased LV mass post treatment with anthracy- clines32, this was only demonstrated in the breast cancer patients (Table 2). The opposite pattern oc- curred in the sarcoma patients where myocardial mass continuously increased post-treatment and at 6-months follow-up. This may represent an un- dergoing LV remodeling. The contractility pattern and changes in car- diac MRI parameters were different in sarcoma and breast cancer patients (Figure 3, Table 2). For example, while myocardial strain decreased post-treatment in breast cancer patients, this was not the case in sarcoma. This may imply differ- ent mechanisms in response to anthracyclines in breast cancer and sarcoma, especially that sarco- mas can have large tumors more often than those in breast cancers, where removing a large tumor would actually result in the body being healthier after treatment. The changes in myocardial function post-treat- ment were accompanied by changes in myocardial tissue characterization based on MRI relaxometry maps (Figure 5, Table 2). In breast cancer patients, all T1, T2, and ECV parameters showed continu- ous increase from baseline to post-treatment to 6-months follow-up, which was not the case in sarcoma. The increases in T1, T2, and ECV reflect increased diffuse fibrosis, edema, and collagen formation, respectively. These results show that breast cancer patients are more affected by chang- es in tissue composition compared to sarcoma pa- tients. Changes in serum biomarkers showed incon- sistent patterns between different parameters and between the sarcoma and breast cancer patients (Figure 6). For example, only TnT (biomarkers of damage to heart muscle) and NT-proBNP (bio- marker of heart failure) showed continuous in- crease post-treatment in sarcoma patients versus A B FIGURE 7. Correlation maps between dose and different post-treatment strain components in the (A) sarcoma and (B) breast cancer patients at the global level (G) and regional levels (base (B), mid-ventricular (M), and apical (A). Ell, Ecc, and Err represent longitudinal, circumferential, and radial strains, respectively. There is a clear inverse correlation between strain and dose in sarcoma, which is positive for Ell and Ecc and negative for Err, as shown in the left- most column. Such correlation pattern is not shown in the breast cancer correlation map. Radiol Oncol 2025; 59(1): 79-90. Ibrahim ESH et al. / Differentiating chemotherapy-induced cardiotoxicity by MRI88 CRP (biomarker for inflammation) and TNFα (bio- marker for heart failure) in breast cancer patients. This may reflect different mechanisms in response to anthracyclines in the two patient groups. Post-treatment myocardial strain (Figure 7) showed good correlation with anthracycline dose in the sarcoma patients (positive correlations with GLS and GCS and negative correlation with GRS), which means deteriorated strain value is associ- ated with higher dose. However, this pattern was not observed in breast cancer patients. At 6-months follow-up (Figure 8), only GCS in sarcoma patients showed an inverse correlation with dose, while ba- sal and mid-ventricular GLS showed inverse cor- relations in the breast cancer patients. This dem- onstrates the importance of regional myocardial strain as early marker of cardiac dysfunction that is correlated with dose, especially in sarcoma. On the segmental level (based on American Heart Association (AHA) 16-segment model of the LV), only few segments showed high correla- tion coefficients (> 0.7) with dose post-treatment. In sarcoma, these segments are septal mid-ven- tricular longitudinal strain, anterior circumfer- ential strain, and basal anteroseptal radial strain. In breast cancer patients, only apical anterior and septal segmental strains had correlation coefficient values above the threshold. These results may im- ply different regional myocardial sensitivity to an- thracyclines, a subject that is worth investigation in a separate study by itself. A few points to be considered about this study. First, one limitation of the study is the small sam- ple size and patients who did not complete the post-treatment or 6-months follow-up timepoints, which did not allow for statistically significant results. The small sample size also reduced the biological variability of our patient population. Although our study was underpowered to be able to detect large deteriorations in cardiac function, the clear trends in the results and differences be- tween the two patient groups warrant a follow-up larger study to confirm these results. Secondly, we used MRI in our study, which is more pow- erful than CT for examining cardiac function. In our study we used standard 8-mm slice thickness as slice thickness of 8-10 mm is typically used in MRI for functional and tissue characterization A B FIGURE 8. Correlation maps between dose and different 6-months follow-up strain components in the (A) sarcoma and (B) breast cancer patients at the global level (G) and regional level (base (B), mid-ventricular (M), and apical (A). Ell, Ecc, and Err represent longitudinal, circumferential, and radial strains, respectively. There is inverse correlation only between circumferential strain and dose in sarcoma, which is positive for Ecc. There is inverse correlation only between longitudinal base and mid-ventricular strains and dose in breast cancer, which is positive for Ell-B and Ell-M. Radiol Oncol 2025; 59(1): 79-90. Ibrahim ESH et al. / Differentiating chemotherapy-induced cardiotoxicity by MRI 89 analyses of the heart in humans, which does not compromise the in-plane resolution ~ 1-2 mm. It should be noted that reduction in slice thickness is associated with reduced signal-to-noise ratio (SNR), which compromises the results accuracy. However, we use thinner slices (1-mm slice thick- ness) in our small-animal preclinical work on rats36 to avoid partial volume effects in the small heart of the rat and we compensate for small SNR by ac- quiring multiple averages at the cost of increased scan time. Thirdly, unfortunately, histological analysis was not conducted in the patients in this study as neither biopsy nor surgery was conducted on the patients. However, we have conducted his- tological analysis on our recent preclinical work37, in which we conducted hematoxylin and eosin (H&E), Masson’s trichrome, and toluidine blue staining on a rat model of thoracic cancer. The his- topathological results confirmed the findings by the imaging biomarkers, which was demonstrated in the samples by increased fibrosis or collagen (Masson trichrome), hemorrhage, cellular vacuoli- zation, and/or cellular necrosis (H&E), and mast cells (toluidine) in the rat model compared to con- trol. Finally, we used the standard American Heart Association (AHA) 16-segment model on all stud- ied subjects and study timepoints. The model rep- resents segmental distribution of the left ventricle myocardium at three levels (base, mid-ventricle, and apex) and different regions (anterior, infe- rior, septal, and lateral). This model is extensively used for standard cardiac functional analysis as reported in the literature.38 We used the model to represent all strain components (circumferential, longitudinal, and radial) for each segment at base- line, post-treatment, and follow-up timepoints. We used correlation analysis between dose and strain parameters to examine the predictive value of dif- ferent myocardial segments in response to chemo- therapy. The results with high correlation (|R| ≥ 0.7) and especially those with significant measure- ment (p < 0.05) were considered of more influence and predictivity on the dose-response effect. The results showed different segments for sarcoma vs. breast cancer at both post-treatment and 6-months follow-up timepoints. In conclusion, cardiac MRI provides valuable information about heart function and changes in tissue composition in sarcoma receiving anthra- cyclines. Especially, myocardial strain is an early marker of cardiac dysfunction when EF > 50%. 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Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart. A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation 2002; 105: 539-42. doi: 10.1161/ hc0402.102975 Radiol Oncol 2025; 59(1): 91-99. doi: 10.2478/raon-2025-0004 91 research article Innovative strategies for minimizing hematoma risk in MRI-guided breast biopsies Michael P Brönnimann1,2, Matthew T McMurray1, Johannes T Heverhagen1, Andreas Christe1, Corinne Wyss1, Alan A Peters1, Adrian T Huber1,3, Florian Dammann1, Verena C Obmann1 1 Department of Diagnostic, Interventional and Pediatric Radiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland 2 Department of Radiology, Charité – Universitätsmedizin, Berlin, Berlin, Germany 3 Department of Nuclear Medicine and Radiology, Cantonal Hospital Lucerne, Lucerne, Switzerland Radiol Oncol 2025; 59(1): 91-99. Received 27 August 2024 Accepted 12 November 2024 Correspondence to: Michael P. Brönnimann, Department of Diagnostic, Interventional and Pediatric Radiology, Inselspital, Bern University Hospital, University of Bern, Rosenbühlgasse 27, 3010 Bern, Switzerland and Department of Radiology, Charité – Universitätsmedizin, Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail: michael.broennimann@insel.ch / michael.broennimann@charite.de Disclosure: No potential conflicts of interest were disclosed. This is an open access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/). Background. The study aimed to investigate the reduction of hematoma risk during MRI-guided breast biopsies by evaluating position-dependent intervention parameters and characteristics of the target lesion. Materials and methods. We retrospectively analyzed 252 percutaneous MRI-guided breast biopsies performed at a single center between January 2013 and December 2023. Two groups were built depending on the severity of relative hematoma formation (using a cut-off ≤ 7.62 cm3 or > 7.62 cm3). Potential influencing variables were assessed, such as patient demographics, interventional parameters related to anatomical landmarks, and lesion characteris- tics. Fisher’s exact test and Mann-Whitney-U-Test were used to calculate the statistical difference between groups of categorical, dichotomous, and continuous variables. Multivariable logistic regression was used to identify the strongest association with relative hematoma formation. Results. The univariate analysis showed that relatively larger hematoma occurred significantly more frequently when the patients were younger (P = 0.002), the relative distances from the target lesion to the nipple (P = 0.001) as well as alongside the access path (P = 0.001) were greater and when the vacuum-assisted biopsy system was used in contrast to the Spirotome® (P = 0.035). Multivariable logistic regression analysis also showed that these were independently associated with the occurrence of relatively larger hematomas. Epinephrine in the local anesthetic, lesion location classified by specific quadrant, and pathological findings did not influence the extent of the hematoma. Conclusions. Our findings underscore the importance of strategic procedural planning to minimize hematoma oc- currence and enhance patient safety during MRI-guided breast biopsy procedures. Key words: biopsy; interventional; image-guided biopsy; magnetic resonance imaging; breast neoplasms; female; hematoma Introduction MRI is more sensitive than alternative imaging methods like ultrasound or mammography for women at elevated risk of breast cancer, detect- ing over half of lesions exclusively on MRI.1,2 It can detect primary cancer in patients suspected of having occult breast cancer.3-5 As per the guide- lines of the American Cancer Society (ACR) and the European Society of Breast Imaging (EUSOBI), MR-guided biopsy is recommended for suspicious lesions exclusively detected by MRI (referred to as MR-only lesions).6-8 Radiol Oncol 2025; 59(1): 91-99. Brönnimann MP et al. / Strategies for reducing hematoma risk in MRI-guided breast biopsies92 To minimize sampling errors and not underes- timate the target lesions, percutaneous, stereotac- tic large core biopsies larger than 11 gauge, either with vacuum-assisted devices or with manual de- vices such as the Spirotome®, have prevailed over core biopsies.9-13 Hematoma is identified as the pri- mary complication of this procedure across differ- ent contexts, with the incidence of mammographi- cally evident hematoma reported to be as high as 45%.14-19 While many hematomas do not require additional intervention, the clinical significance of existing studies remains unclear.15-20 Furthermore, the study situation is also very inconsistent in re- cording hematomas. Most reports attempted to record these by external observation e.g.21 or indi- rectly e.g.19 To date, no intraprocedural factors have been identified to reduce the risk of hematoma oc- currence in MRI-guided breast biopsies. A decisive aspect in developing hematomas could be the asymmetrical blood supply to the breast. Thus, 60% of the breast is supplied by per- forating branches of the internal thoracic artery, which lies on the medial side.22 Of this, at least 60% is specifically provided by the superomedial perforators.23 Furthermore, the internal thoracic artery mainly supplies the nipple-areola complex (NAC).24 The prone position during MRI-guided breast biopsy could aggravate this. Also, the growth and advancement of breast cancers are associated with heightened neovascularization.25 We, therefore, hypothesize that larger hematomas are more likely to occur in the upper and outer quadrants near the NAC in malignant lesions. The study aimed to investigate the hematoma risk during MRI-guided breast biopsies by evalu- ating position-dependent intervention parameters and characteristics of the target lesion. Materials and methods The study received approval from the Ethics Committee of the Canton of Bern (BASEC Project- ID 2024-00805) and adhered to the principles out- lined in the Declaration of Helsinki. The authors had complete access to the data and assumed full responsibility for its integrity. Written informed consent was obtained from all patients. Study population This study retrospectively analyzed 306 percuta- neous MRI-guided breast biopsies conducted at our university hospital between January 2013 and December 2023 in 300 women with thus 6 women who underwent more than one biopsy. The exclusion criteria were defined consecu- tively to avoid possible bias due to non-physiolog- ical local conditions (breast implant; more than one lesion was biopsied at the same time; multiple biopsies of the target lesion with additional mo- dality) or rare intervention techniques (no large core biopsies e.g. 16 or 18 G and to homogenize the groups (Figure 1)). Two groups were formed based on the severity of the relative hematoma volume. The severity was categorized dichotomously according to whether the measured relative hematoma volumes were above or below the mean value. Baseline evaluation and biopsy technique Before the biopsy, all patients underwent a clini- cal evaluation, including a thorough medical his- tory review and standard blood tests. The proce- dure required an INR value below 1.5 or a Quick value above 60%, an Hb value exceeding 80 g/L, 306 patients undergoing MRI-guided breast biopsy from Jan 2013 to Dec 2023 Inclusion in the study for analysis of factors associated with hematoma (n=252) Exclusion criteria Consent refused (n=20) more than 1 lesion was biopsied at the same time (n=12) M ultiple biopsies of the target lesion with additional modality (ultrasound) (n=1) Breast implant present (n=1) No Large Core Biopsy (e.g. 16/18 G) (n=1) Incomplete data set (n=11) Waiver of biopsy (n=8) FIGURE 1. Flowchart shows the study population. Radiol Oncol 2025; 59(1): 91-99. Brönnimann MP et al. / Strategies for reducing hematoma risk in MRI-guided breast biopsies 93 and a platelet count of over 50 x 109/L. These blood values must not be older than 5 days. According to our guidelines, NSAIDs (non-steroidal anti- inflammatory drugs) and clopidogrel had to be stopped 5 days, heparin 6 hours, rivaroxaban 1 day, dabigatran and endoxaban each 3 days be- fore intervention. Eight interventionalists, each with more than 5 years of experience, performed the biopsies. Contraindications for MRI, such as pregnancy, inability to lie prone for 60 minutes, or the administration of contrast medium containing gadolinium, were explicitly requested in advance in the questionnaire. All biopsies were conducted utilizing a 1.5 T Siemens Magnetom Aera/SolaFit (Siemens Healthinieers, upgrade of the machine performed in 06/2022) paired with a dedicated four-channel open breast coil (Invivo Interventional Instruments, Wurzburg, Germany) and a needle positioning add-on device (Noras, Germany). Patients were po- sitioned in the prone position on the MRI table with the affected breast compressed within the biopsy device to minimize motion during the procedure. Imaging was performed before and after admin- istering 0.1 mmol/kg of contrast agent (Dotarem, Guerbet, France) using a T1-weighted dynamic con- trast-enhanced subtraction sequence lasting 103 seconds. This imaging protocol provided coverage of the breast with nearly isotropic voxels (slice thick- ness 1 mm, Repetition Time (TR) of 7.62 (millisec- onds) ms, Time to Echo (TE) of 4.77 ms), facilitating image reconstruction in any plane. Either the grid or pillar and post system was used. The specialized breast biopsy planning software (Siemens) was uti- lized to acquire lesion coordinates and guide nee- dle positioning. The needle path was planned ac- cording to our best practices to ensure the shortest distance from the skin to the lesion while avoiding larger vessels and maintaining a safety margin from the skin. After the initial imaging, the table was retracted from the bore to facilitate disinfec- tion and the administration of local anesthesia. Lidocaine 1% (maximum 20 ml, Streuli Pharma AG, Uznach, Switzerland), was administered to the skin, subcutaneous tissues and deep. The inter- ventionalist could choose whether to give the one mixed with epinephrine (Lidocain-Epinephrin 2% Streuli, Streuli Pharma AG, Uznach, Switzerland). A small incision was made in the skin to facilitate the smooth entry of the device. The introducer sty- let, was inserted through the needle guide to the predetermined depth. Subsequently, the stylet was withdrawn and replaced with a sterile plastic MRI- visible obturator. T1-weighted fat-saturation im- ages were then acquired to confirm the depth and position of the introducer. Either a large volume bi- opsy with a manual device Spirotome® 8 gauge (G) (Bioncise, Wellen, Belgium) and max. 3 samples or a Vacuum-assisted biopsy (VAB) with an EnCore® (BD, New Jersey, USA) 7G/ 10G and max. 24 sam- ples was done. After the marker (SenoMarkTM, BD, New Jersey, USA) was placed, a control sequence T1 and T2, again technical details were performed (Figure 2). The breast was compressed manually for 15 minutes followed by a compression bandage for the next 24 hours. A B C FIGURE 2. MRI-guided breast biopsy with hematoma as a sequela. (A) Target lesion in the lower outer quadrant. (B) Biopsy needle in target position. (C) After vacuum-assisted biopsy, a hematoma has formed. Within it, a recognizable susceptibility artifact is due to the marker. Radiol Oncol 2025; 59(1): 91-99. Brönnimann MP et al. / Strategies for reducing hematoma risk in MRI-guided breast biopsies94 Data collection All procedures were reviewed by a board-certified interventional radiologist with eight years of expe- rience and a radiology resident with four years of experience. Neither of them performed any of the interventions, and all were blinded to the patient̀ s medical history. The perpendicular distance from the pectoralis major muscle to the lesion (in mm) was recorded with the consideration of indirectly measuring the effect of gravity. Other patient- and technique- related variables assessed on the interventional MRI images included interventional date, birth date, age of the patient (in years), procedure time (in minutes), target lesion size (in mm), biopsy side, biopsy angle, distance lesion to nipple (LN in mm), access path length measured along the nee- dle from the skin to the lesion (in mm), lesion loca- tion according to the breast quadrants, breast and hematoma volume (cm3). All volumes were manu- ally obtained from the multiplanar reconstruction (MPR) of the three-dimensional (3D) T1-weighted sequence with spectral attenuated inversion re- covery (SPAIR) acquisition. The manually meas- ured hematoma volume and absolute distances were set in relation to the breast volume, as we ultimately rated this as the most meaningful in the overall context. For this purpose, we identified the mean of the relative hematoma volume of all measured volumes (7.62 cm3) and defined this as the cut-off. To evaluate the possible influence of surround- ing mammary gland tissue on hematoma forma- tion, a 5 mm larger circle was drawn around the target lesion to assess the amount of surrounding mammary gland tissue. The quarter rule was used for this purpose (Figure 3). A Sectra workstation was used to review the im- ages (IDS 7, version 24.2, 2022, Linköping, Sweden). We recorded the size of the biopsy system, type of local anesthetic and number of samples from the intervention report. The histological results from the target lesion and the patient̀ s history after intervention were also collected retrospectively from the electronic medical record. The following pathological reports were categorized into benign, high-risk lesions and malignancy. High-risk le- sions were defined according to Heller et al.26 as atypical ductal hyperplasia, lobular intraepithelial neoplasia, lobular carcinoma in situ, papilloma, atypical lobular hyperplasia, radial scar, and flat epithelial cell atypia. Statistical analysis We utilized IBM SPSS Statistics for Windows, version 28 (IBM, Armonk, NY), for all statistical analyses. Univariate analysis was conducted using Chi-Square and Fisher exact tests for categorical variables, and the Mann-Whitney-U-Test for con- tinuous variables, with a significance level set at P < 0.05. The Kolmogorov-Smirnov test was used to test for normal distribution. Multivariable logistic regression was used to assess potential confound- ers and risk factors for the development of hema- toma, with model goodness of fit evaluated using the Hosmer-Lemeshow test. To prevent overfit- ting, we adhered to the rule of ten by including five independent variables in the multiple logistic regression model, selected based on their signifi- cance or proximity to significance, while consider- ing a minimum group size of n ≥ 25 for categorical predictors. Therefore, we included the procedure time for the regression. The analysis was overseen by a senior statistician from the Clinical Trials Unit (CTU) of the Faculty of Medicine at the University of Bern. A B C FIGURE 3. Illustration of the measurements. (A) In blue, the distance from the lesion to the nipple. A circle was drawn around the target lesion to capture the proportion of the surrounding mammary gland. These measurements were taken after multiplanar reconstruction (MPR) of the dynamic T1 subtraction sequence. (B) Access route and biopsy angle. (C) Perpendicular distance from the pectoralis major muscle to the lesion in T1-weighted with spectral attenuated inversion recovery (SPAIR) sequence. Radiol Oncol 2025; 59(1): 91-99. Brönnimann MP et al. / Strategies for reducing hematoma risk in MRI-guided breast biopsies 95 Results Study population A total of 252 biopsies met the inclusion crite- ria, with a mean patient age of 51.96 ± 11.69 years (range 22–84 years). All variables in both groups were not normally distributed, as indicated by the Kolmogorov-Smirnov test (P < 0.001). There were no significant differences in pathological findings or their locations between the two groups. The major- ity of biopsied lesions were benign (63%, Figure 4), located in the outer quadrants of the breast (62%), and surrounded by 0–25% mammary gland tissue (42%). Slightly more than a quarter (26%) of the bi- opsied breasts had been previously treated (Table 1). Hematoma formation during MRI-guided breast biopsy On average, the MRI-guided breast biopsy lasted 41.9 minutes. In 90% of cases, the biopsy was per- formed as a VAB, with the majority of cases pre- ceded by the use of local anesthetic mixed with ephedrine (68%). A hematoma occurred in 70% (178/252) of cases, with a hematoma volume of ≥14 cm³ (diameter of 3 cm) detected in 6%, and a vol- ume of ≥ 33.5 cm³ (diameter of 4 cm) detected in 0.8%. The univariate analysis showed that relative- ly larger hematoma occurred significantly more frequently when the patients were younger (P = 0.002), the relative distances from LN (P = 0.001) as well as the access path (P = 0.001) were larger and when the VAB instead of a Spirotome system was used (P = 0.035). Both relatively smaller hemato- mas (11.5% vs. 88.5%) and relatively larger hema- tomas (2% vs. 98%) occurred significantly less with the Spirotome than the VAB. We did not observe a significantly increased frequency of relatively larger hematoma depending on epinephrine in the local anesthetic (P = 0.408), lesion location classi- fied by specific quadrant (P = 0.399), lesion size (P = 0.425), biopsy angle (P = 0.443), the perpendicular distance from the pectoralis muscle to the lesion (P = 0.143), adjacent glandular tissue (P = 0.215) or histopathological result (benignity, P = 0,749; high- risk lesions, P = 0.581, malignancy, P = 0.825). Association of lesion characteristics and technical parameters with the occurrence of relatively larger hematoma Multivariable logistic regression analysis showed that lower age (OR 0.969, 95% CI 0.934 –1, P = 0.048), the use of a VAB system (OR 11.798, 95% CI 1.341– 103.8, P = 0.026), the LN distance (P < 0.01) and access path length (P = 0.029) were independent- ly associated with relatively larger hematomas (Table 2). A good model fit with an R² = 0.222, P < 0.001. Cohen’s f2 is 0.28, corresponding to a good medium effect.27 Discussion This study aimed to assess factors influencing hematoma risk in MRI-guided breast biopsies. Through retrospective analysis of 252 cases, pa- tients were stratified by hematoma size, and vari- ous parameters including patient demographics, anatomical features, and lesion attributes were scrutinized. Univariate analysis unveiled sig- nificant associations between larger hematoma formation and younger patient age (P = 0.002), increased LN distance (P = 0.001) and access path length (P = 0.001), and utilization of VAB instead of Spirotome® (P = 0.035). Multivariable logistic regression confirmed these associations as inde- pendent predictors of relatively larger hematomas, while factors such as epinephrine in local anes- thetic, lesion location classified by specific quad- rant, and pathological findings did not influence hematoma extent. Overall, hematoma incidence FIGURE 4. Histological findings of breast biopsies. ADH = atypical ductal hyperplasia; DCIS; ductal carcinoma in situ; FEA = flat epithelial cell atypia; ILC = invasive lobular carcinoma; LCIS = lobular carcinoma in situ; LIN = lobular intraepithelial neoplasia; NST = non-special type Radiol Oncol 2025; 59(1): 91-99. Brönnimann MP et al. / Strategies for reducing hematoma risk in MRI-guided breast biopsies96 was observed in 70% of cases. The results suggest that asymmetric blood supply to the breast supply and the gravitational force play a less significant role in the development of hematomas during MRI-guided breast biopsies than previously an- ticipated. Our study findings align with prior research. Kettritz et al.28 documented 0.87% incidence of large hematomas (≥4 cm in diameter), while our study observed a rate of 0.8% (relative to a vol- ume of 33 cm3). Perlet et al.29 reported 1.75% occur- rence of hematomas with a size of ≥3 cm. In con- TABLE 1. Univariate analysis for relatively larger hematoma with patient demographics and lesion characteristics Survey of breast biopsies Parameter All (n=252) Relatively smaller hematoma (n = 200) Relatively larger hematoma (n = 52) P Value Age (y) 51.96 ±11.69 53.09 ±11.09 47.63 ±12.984 0.002* Procedure time (min) 41.83 ±13.39 42.58 ±13.80 38.96 ±11.324 0.072 Right biopsy side 117 46% 90 45% 27 52% 0.436 Number of samples 12.08 ± 4 11.81 ±4.08 13.1 ±3.533 0.243 Biopsy system 0.035* VABB 228 90% 177 88.5% 51 98% Spirotome 24 10% 23 11.5% 1 2% LAE 171 68% 133 67% 38 73% 0.408 Lesion size (mm) 11.2 ±6.612 11.27 ±6.55 10.94 ±6.89 0.425 Distance LN in RBV 0.079 ± 0.05 0.07 ± 0.04 0.11 ±0.04 0.001* Access path length in RBV 0.055 ± 0.046 0.05 ± 0.03 0.08 ±0.07 0.001* PDPectLesion in RBV 0.065 ± 0.036 0.06 ± 0.04 0.07 ± 0.04 0.143 Biopsy angle (degree) 90.79 ± 10.4 90.93 ± 9.55 90.27 ± 13.26 0.443 Pathological findings 0.831 Benignity 159 63% 125 63% 34 65% High-risk lesions 36 14% 28 14% 8 15% Malignancy 57 23% 47 24% 10 19% Pretreatment 65 26% 55 28% 10 19% 0.286 Lesion location 0.399 Upper inner q 47 19% 34 17% 13 25% Upper outer q 84 33% 64 32% 20 38% Lower inner q 24 10% 21 11% 3 6% Lower outer q 72 29% 61 31% 11 21% Areolar 25 10% 20 10% 5 10% Proportion of mammary gland 0.215 0−25% 105 42% 85 43% 20 38% 25−50% 48 19% 37 19% 11 21% 50−75% 47 19% 37 19% 10 19% 75−100% 52 21% 41 21% 11 21% Unless stated otherwise, data are number of biopsies. ± standard deviations. X2 (R X 2), Fisher’s exact test and Mann-Whitney-U-Test were used to calculate the statistical difference between groups of categorical, dichotomous, and continuous variables, respectively. Data are mean ± standard deviation. * Statistically significant (defined P < 0.05) LAE = local anesthesia mixed with epinephrine; LN= lesion to nipple; min = minutes; mm = millimeters; PDPectLesion = perpendicular distance from the pectoralis major muscle to the lesion; Pretreatment = affected breast pretreated; RBV = in Relation to Breast Volume; VABB = vacuum-assisted breast biopsy; q = quadrant; Y = Year Radiol Oncol 2025; 59(1): 91-99. Brönnimann MP et al. / Strategies for reducing hematoma risk in MRI-guided breast biopsies 97 trast, our study recorded a 6% incidence, slightly higher likely due to differing follow-up protocols. In instances of uncertainty, they conducted repeat MRI scans 24–48 hours post-biopsy. Our direct comparison between two biopsy modalities, VAB and Spirotome®, corroborates previous research. Hematoma occurrence rates were reported to be as high as 45% after VAB and 16% following large core biopsy with the Spirotome®.14-19,30 This dis- crepancy is likely attributed to the increased trau- matic injury associated with VAB, regardless of the sample size. Consequently, our study identified a significantly higher incidence of relatively larger hematomas associated with VAB (P = 0.035), a find- ing further supported as an independent predictor in multivariable logistic regression analysis. Our investigation indicates that gravitational forces do not exert a significant influence on hema- toma development in MRI-guided biopsies, as evi- denced by the absence of a significant occurrence of larger hematomas despite a greater relatively perpendicular distance from the pectoralis mus- cle to the lesion (P = 0.143). While it is established that lesion dimensions are overestimated and ex- hibit a higher wash-in peak in the prone position compared to the supine position31, McGrath et al.32 observed that breast compression during MRI- guided breast biopsy may diminish perfusion and result in inadequate parenchymal enhancement. This observation is further supported by the lack of a significant difference in procedure time. Our findings suggest that future investigations could explore the influence of varying compression pres- sures on the risk of developing larger hematomas during breast biopsy procedures. Effective breast compression pressure should be measured and analyzed in relation to hematoma size. Adjusting compression pressure may offer a promising ap- proach to reducing hematoma formation, meriting further investigation. The clear difference in the extent and type of angiogenesis of breast tumors25 is probably also reflected in our results. No significantly higher frequency of relatively larger hematomas occurred according to the different pathological findings. These potential local microvascular conditions may have little or no effect on biopsy-induced he- matomas, which is supported by the lack of a sig- nificant difference in our results when epinephrine was added to the local anesthetic. Therefore, the effective benefit of the vasoconstrictive effect of local anesthetics mixed with epinephrine in MRI- guided breast biopsies should be questioned33, as there is also a potential risk of skin necrosis.34 In a study by Yoen et al.35, it was observed that lesion location could influence the risk of hemor- rhage, with 43% of lesions experiencing hemor- rhagic complications located in the lower outer quadrant (P = 0.001). However, our findings did not reveal a significant difference in hemorrhage risk among different quadrants or in the areolar region (P = 0.399). Additionally, our conclusions find support in the research conducted by van Deventer et al.24, who demonstrated considerable variability in the blood supply pattern of the breast through cadav- TABLE 2. Results of multivariate logistic regression analysis for relatively larger hematoma B S.E. Wald test df P value Oddsratio 95% CI Variable - + Age (y) -0.031 0.160 3.927 1 0.048* 0.969 0.94 1 Biopsy system 2.468 1.11 4.947 1 0.026* 11.798 1.341 103.811 Distance LN in RBV 9.501 3.538 7.214 1 0.007* 13379 13.037 13.7 x 10^6 Access path length in RBV 7.622 3.49 4.77 1 0.029* 2043 2.186 1.9 x 10^6 Procedure time (min) -0.025 0.015 2.759 1 0.097 0.975 0.947 1.005 The total number of cases in the cohort for the multivariate analysis was n = 252 B = Regression coefficient; CI = Confidence interval; df = Degree of freedom; LN = Lesion to nipple; min. = minutes; RBV = in relation to breast volume; S.E. = standard error; * statistically significant (defined P < 0.05); Y = years Radiol Oncol 2025; 59(1): 91-99. Brönnimann MP et al. / Strategies for reducing hematoma risk in MRI-guided breast biopsies98 eric dissections. The independent predictors iden- tified for relatively larger hematomas, including younger age (P = 0.02), larger relative LN distances (P = 0.001), and access path length (P = 0.001), may indirectly reflect the anatomical distribution and characteristics of the perforator network relevant to our study. These perforators typically exhibit a larger diameter and closer proximity to each oth- er in the peripheral regions of the breast near the chest wall.24 They radiate towards the nipple and diminish in size peripherally, consistent with their nomenclature. Consequently, hypervascular zones have been delineated by Palmer and Taylor.24,36 Notably, advancing age is associated with a sig- nificant risk factor for complications in perforator- pedicled propeller flap procedures in the lower extremities, particularly beyond 60 years or in the presence of known arteriopathy such as diabetes. Consequently, age-related impairments in perfora- tor function may elucidate the significantly higher frequency of relatively larger hematomas observed in younger patients (P = 0.002). This phenomenon warrants further investigation, such as explor- ing MRI-guided biopsies and their complications in the context of recognized arteriopathy, which could yield valuable insights. Additionally, it may be worthwhile to investigate the antero-posterior approach, which is technically feasible today, and compare it to the commonly used latero-medial approach in upright tomosynthesis-guided breast biopsies e.g.37 In conjunction with the hypervascu- lar model of the breast proposed by Palmer and Taylor37, our findings underscore potential impli- cations regarding the risk of hemorrhage. Our study possesses several limitations that warrant acknowledgment. Firstly, it was conduct- ed as a retrospective analysis within a single cent- er, resulting in a relatively limited number of cas- es. Secondly, the classification distinguishing be- tween relatively smaller and larger hematomas re- lied on the average of our hematoma results, which may not be universally applicable and could vary in larger cohorts. Thirdly, due to the inadequate number of events in the smallest outcome catego- ries, we were unable to incorporate all investigated variables into the multivariable logistic regression analysis. Lastly, certain variables, such as operator skill, which may influence procedural outcomes, were not evaluated in this study, presenting an ar- ea for potential investigation in future research en- deavours. However, we believe that the guided ap- proach is likely to significantly reduce the impact of operator skill on procedural outcomes, making any differences minimal or negligible. Conclusions Our findings underscore the importance of stra- tegic procedural planning to minimize hema- toma occurrence and enhance patient safety during MRI-guided breast biopsy procedures. 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Radiographics 2021; 41: 1265-82. doi: 10.1148/rg.2021210017 Radiol Oncol 2025; 59(1): 100-109. doi: 10.2478/raon-2025-0017 100 research article Comparison of selective intra-arterial to standard intravenous administration in percutaneous electrochemotherapy (pECT) for liver tumors Tim Wilke1, Erschad Hussain2, Hannah Spallek3, Francesca de Terlizzi4, Lluis M Mir5, Peter Bischoff6, Andreas Schäfer6, Elke Bartmuß6, Matteo Cadossi4, Alessandro Zanasi4, Michael Pinkawa7, Attila Kovács6 1 Departement of Gastroenterology, Sinzig Medical Care Center, Linz/Rhein, Germany 2 Campus Lübeck, University Schleswig-Holstein, Lübeck, Germany 3 Clinic for Gynaecology and Obstetrics, University Hospital Mannheim, Mannheim, Germany 4 IGEA Clinical Biophysics, Laboratory Carpi, Modena, Italy 5 METSY UMR 9018, Université Paris-Saclay, CNRS, Gustave Roussy, Villejuif, France 6 Clinic for Diagnostic and Interventional Radiology and Neuroradiology, WEGE Klinik, Bonn, Germany 7 Clinic for Radiotherapy and Radiation Oncology, WEGE Klinik, Bonn, Germany Radiol Oncol 2025; 59(1): 100-109. Received 23 January 2025 Accepted 4 February 2025 Correspondence to: Prof. Dr. Attila Kovács, Clinic for Diagnostic and Interventional Radiology and Neuroradiology, WEGE Klinik, Villenstr. 8, 53129 Bonn, Germany. E-mail: Attila.Kovacs@wegeklinik.com Disclosure: No potential conflicts of interest were disclosed. This is an open access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/). Background. Electrochemotherapy (ECT) is a local nonsurgical effective tumor treatment in the hand of the clini- cian for the treatment of patients with liver tumors or metastases. The study aimed to test the technical feasibility and safety of intra-arterial (i.a.) bleomycin administration compared to the established intravenous (i.v.) administration in percutaneous electrochemotherapy (pECT). Furthermore, the equivalence hypothesis was tested between the 2 modalities in terms of local short-term response and progression-free survival. Patients and methods. Forty-four patients have been recruited and treated by pECT for hepatocellular carcinoma, cholangiocarcinoma and liver metastatic lesions from cancers of different origin: 18 were treated with standard i.v., 26 with bleomycin i.a. administration. Results. The 2 groups were similar for anagraphic and anamnestic data, as well as for most relevant disease specific characteristics. Technical success of the treatment was obtained in 95% and 100% of patients in i.v. and i.a. groups respectively. Short-term local response was similar in the 2 groups with a slightly higher complete remission (CR) rate in the i.a. group. There were 61.9% CR, 23.8% partial remission (PR), 4.8% stable disease (SD) in the i.v. group, and 80.6%, CR 12.9% PR, 3.2% PD (p = 0.3454). One-year progression free survival was 60% (C.I. 33%–88%) in the i.v. group and 67% (C.I. 42%–91%) in the i.a. group (p = 0.5849). Conclusions. The results of this study confirmed the safety and feasibility of super-selective i.a. bleomycin administra- tion. Analysis of local response and progression free survival confirmed the equivalence hypothesis of the new modal- ity compared to standard i.v. administration in the treatment of primary and secondary liver malignancies by pECT. Key words: electrochemotherapy; percutaneous ECT; liver metastasis; liver cancer; intra-arterial administration; bleo- mycin Radiol Oncol 2025; 59(1): 100-109. Wilke T et al. / Intra-arterial administration in liver pECT 101 Introduction Electrochemotherapy (ECT) is a local treatment that utilizes electric pulses application to deliver poorly permeant drugs, such as bleomycin and cis- platin, to cells by increasing permeability of the cell membrane.1,2 Over the past 20 years, ECT proved to be effective in the treatment of cutaneous, subcuta- neous, mucosal, or deep-seated tumors of various histologies and in different body sites.3-5 Since the results of the international, multicen- tre clinical study European Standard Operating Procedures for Electrochemotherapy (ESOPE) were published and were used to establish the Standard Operating Procedures for ECT on cutaneous tu- mors with the Cliniporator™ device (IGEA S.p.A., Carpi, Italy), a notable number of preclinical and clinical studies have been conducted on ECT by an European working-group of clinicians to confirm its safety and effectiveness on cutaneous tumors, such as malignant melanoma6,7, breast cancer8,9, basal cell carcinoma10, squamous cell carcinoma11 and others.3,12,13 Based on these experiences, ECT application was extended and had been shown indeed to be feasible, safe, and effective for deep- seated tumors, such as liver, pancreatic and bone tumors and metastases.14-19 In particular, in liver malignancies, either pri- mary or secondary, ECT can be used near collagen- ous structures such as vessels and bile ducts20, it is repeatable and also suitable as a local therapy be- tween chemotherapy cycles. Indeed, non-surgical interventional local tumor treatments are current- ly an additional option for the treatment of can- cer patients and The European Society of Medical Oncology (ESMO) included local therapies in the current consensus guidelines on the treatment of metastatic colorectal cancer (mCRC).21 Local treatments for the management of liver malignant lesions can be divided into thermal (radiofrequency or microwave ablation and cry- oablation) and nonthermal treatments (high pre- cision radiotherapy, brachytherapy, irreversible electroporation and ECT).14,19 All these treatments are ablative. Moreover, ECT is a method to vector- ize the chemotherapy, being therefore highly se- lectively against the tumor cells whilst preserving the normal cells. The choice of the therapy for each single case is determined by the number, size, configuration and location or environment of the target lesion. Contrary to Irreversible Electroporation (one sup- plementary ablative technique), ECT is also a se- lective approach for the vectorization of cytotoxic drugs and has gained a role in the armamentarium of local therapies available to the clinicians, ena- bling the treatment of i) lesions that are too large for thermal ablation, ii) non-radiosensitive tumors or iii) lesions located in the immediate vicinity of radiation- or temperature-vulnerable organs.14 Specifically, ECT can be used in the treatment of liver lesions located centrally, close to the capsule or in proximity of the major vessels and bile ducts, which may neither be resectable nor suitable for ra- diofrequency or microwave ablation. The safety of ECT in the treatment of lesions located near large liver vessels was also proven in animal models.22,23 Good tolerance, with few side effects and no rel- evant pain, nausea or systemic side effects were also observed.24-26 Conventional percutaneous ECT (pECT) in the liver is performed with intravenous (i.v.) admin- istration of bleomycin following the Standard Operating Procedures for ECT in cutaneous and subcutaneous lesions.27,28 A novel procedure for the administration of bleomycin in the liver has been introduced, based on the already established liver-directed endo- vascular therapies, hepatic artery infusion (HAI) and transarterial chemoembolization (TACE): the selective delivery of bleomycin intra-arterially to the lesion area to be treated. The vessels supplying the lesion are accessed from the groin via a guid- ing catheter and a coaxially used microcatheter. The complete volume coverage of the entire le- sion is ensured by contrast-enhanced Cone-Beam Computed Tomography (CBCT) scan. In this way bleomycin is directly delivered selectively into the lesion with higher concentration in loco. Since se- lective and superselective chemotherapy applica- tions are already well established in interventional oncology, the aim of this work is to translate this established approach in the ECT setting. We aimed to test the technical feasibility and safety of this approach and to demonstrate the equivalence of intra-arterial (i.a.) bleomycin administration com- pared to the established i.v. administration. In this study, the new method of administration is fully described and named “the intra-arterial pECT method”. Patients and methods Patients Forty-four patients have been recruited and treated by ECT in our centre for hepatocellular carcinoma, cholangiocarcinoma and liver metastatic lesions Radiol Oncol 2025; 59(1): 100-109. Wilke T et al. / Intra-arterial administration in liver pECT102 from cancers of different origin: colorectal cancer, breast cancer, ovarian cancer, anal cancer, non- small cell lung cancer (NSCLC), pancreatic cancer, parotid carcinoma, neuroendocrine carcinoma, uterus carcinoma, cancer of unknown primary ori- gin (CUP) and oesophageal carcinoma. Eighteen patients were treated with conventional intrave- nous administration of bleomycin (i.v. group), whilst twenty-six were treated using intra-arterial administration of the same drug (i.a. group). ECT treatments were performed between June 2018 and June 2024. The study was conducted accord- ing to the WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects. All patients signed an informed consent form and agreed to be included in the data collec- tion. The study was approved by the Committee for Medical Ethics of the Institution (Ethik Kommission der Ärztekammer Nordrhein Nr 2022314). Imaging Standard pretreatment evaluation of patients was performed including MRI (magnetic resonance imaging) with hepatospecific contrast agent and thorax plus abdomen CT (computed tomography), including also the pelvis, not more than 30 days before treatment. Details on MRI are reported in Spallek et al.14 Electrochemotherapy with conventional intravenous bleomycin administration Software-based treatment planning for the cor- rect positioning of the electrodes was performed on MRI preoperative images. The aim of the treat- ment planning is to obtain the electric field opti- mal coverage of the target lesions by including them within the needle geometry. A maximum of 6 electrodes can be activated synchronously by the pulse generator, but various spatial domains can be treated during the same session with the use of more than 6 electrodes. The needle electrodes were percutaneously inserted in and around the lesions following multimodal image guidance and stereotactic navigation, at a minimum/maximum distance of 0.5/3.0 cm one from the other. Needle electrodes have a diameter of 1.2 mm and a 16 to 24 mm length, with an active part of 3 or 4 cm long (IGEA®, Carpi, Italy). They are freely positionable and must be inserted in parallel, to ensure the cor- rect delivery of the electric field. The direction of access of the electrodes was determined by the per- forming surgeon. Once positioned, the electrodes were supplied by a suitable voltage to deliver sequential elec- tric pulses. The goal is to ensure complete cover- age of the clinical target volume with an electric field intensity above 400 V/cm and to maintain the maximum current delivered below 50A. The elec- tric pulses were delivered by the CliniporatorTM device (IGEA®, Carpi, Italy). When administering bleomycin intravenously, the same treatment protocol as defined by the SOP for ECT of cutaneous tumors was adopted27,28 with regard to drug administration, dose, and electri- cal parameters (i.e. pulse duration and number of pulses). After having correctly positioned the elec- trodes, under general anesthesia, the patients were given bleomycin at a dose of 15.000 IU/m2 body surface intravenously in bolus within 30 seconds. Eight minutes after the bleomycin administration the maximal pharmacological peak of bleomycin in the organs is expected and it is possible to start the electroporation process in liver, delivering 8 pulses of 100 μs duration between each pair of electrodes. Pulses delivery should be completed within 40 minutes. Care was also taken to ensure that the electrical pulses were delivered only in the refractory phase of the heart by synchronizing of the Cliniporator device with the ECG (electrocardiogram) to avoid interferences with the heart rhythm. Electrochemotherapy with intra-arterial bleomycin administration After a local anesthesia, retrograde puncture of the right common femoral artery and insertion of a 4F sheath system were performed. The vessels supplying the tumor were probed super-selec- tively using a guiding microcatheter (Sidewinder 4F, Terumo®) and microcatheter (Persue 2.0 Swan Neck, Merit®) in coaxial technique. The complete volume coverage of the entire tumor was assessed in CBCT, simulating the subsequent bleomycin distribution. The microcatheter was then secured in position and the patient was transferred to the interventional CT. In the CT, the target lesion was visualized by a super-selective contrast via the mi- crocatheter (10 cc of pure CT-contrast, followed by 10 cc saline each 1 cc/sec) and this volume data set was used for navigation. The electrodes were positioned under general anesthesia using multi- modal image guidance and stereotactic navigation (CAS One, Cascination®), with the same precau- tions adopted for the i.v. approach. A second i.a. contrast after electrode-placement was applied to Radiol Oncol 2025; 59(1): 100-109. Wilke T et al. / Intra-arterial administration in liver pECT 103 confirm adequate coverage of the lesion, includ- ing safety margins. As soon as the electrodes were correctly positioned, 50% of the total bleomycin volume (total bleomycin dose: 15000 IU/m2 body surface) was administered intra-arterially via the microcatheter in a continuous injection. When about 50% of drug was infused, the electric pulses delivery started and during the electric pulses’ de- livery, the remaining 50% of the bleomycin con- tinued to be administered intra-arterially. The in- jection of 100% bleomycin before electric pulses’ delivery was discarded because, due to the first pass effect, there is a risk that a relevant part of the drug has passed through the tumor, making it unavailable for electroporation. After the elec- tric pulses’ delivery, a CT scan was performed to rule out therapy-associated complications. After successful electric pulses delivery, the electrodes, catheter and sheath were removed, and the punc- ture site was manually compressed followed by the subsequent removal of the electrodes and the application of a sterile plaster dressing. The cath- eter and sheath material were then removed, fol- lowed by fifteen minutes of manual compression of the puncture site until hemostasis was achieved. Then, application of a sterile plaster bandage and a pressure bandage were applied. Further stand- ard procedures were adopted: patient monitoring, laboratory checks and post-interventional imaging according to ward protocol. Response to treatment evaluation Response to treatment was evaluated based on the multiparametric MRI of the liver, including mul- tiplanar ce T1w, transversal T2w fs and transver- sal DWI scans at 1 to 3 months follow-up. Lesion- based treatment success was assessed using the Modified Response Evaluation Criteria in Solid Tumours (mRECIST) in terms of complete remis- sion (CR), partial remission (PR), stable disease (SD), and progressive disease (PD). Local tumor control was defined as CR, PR or SD according to the RECIST criteria, version 1.1.29 Objective re- sponse is obtained by the sum of CR and PR. Statistical analysis Continuous variables are reported as the mean and standard deviation, median and range. Categorical variables are expressed as absolute numbers and percentages. Comparisons between the two groups were performed by heteroschedastic 2 tails Student t-test for continuous variables and contingency tables with Chi square calculation for categorical variables. Progression free survival time was calcu- lated in months as the time since ECT session date to last follow-up (in case of no progression) or to the date of progression. Progression free survival analysis was conducted by means of calculation of Kaplan Meier survival curves and logrank test for comparison between groups. A p value lower than 0.05 is considered statistically significant. Statistical analysis was performed with NCSS 9 (NCSS 9 Statistical Software [2013]). Results Patients were enrolled and treated in the period between June 2018 and June 2024 and were fol- lowed for a median time of 7 months (range 1–27; mean 7.8 ± 5.9 months). They were divided into two groups based on conventional intravenous or intra-arterial administration of bleomycin; 18 pa- tients were treated with conventional i.v. and 26 with i.a. administration of chemotherapy drug. Mean age in the two groups was similar (63 ± 11 yrs, median 64 range 41–83 in the i.v. group vs 68 ± 10 yrs, median 69 range 52–93 in the i.a. group, p = 0.2182). The two groups were similar for almost all characteristics reported in Table 1. In total 21 lesions were treated in the i.v. group, and 31 in the i.a. group. Lesions’ size was signifi- cantly larger in the i.v. group, with a mean LA (long axis) size of 5.9 ± 2.5 cm (median 4.6 cm, range 1.5–11.2), with respect to i.a. group, with a mean LA size of 4.4 ± 2.2 (median 4.0 cm, range 1.1–9.7) (p = 0.0300). Volume mean values on the other hand show only a slight not significant dif- ference: 130 ± 137 cm3 in the i.v. group vs 61.4 ± 81.4 cm3 (p = 0.0501). Characteristics of the target lesions are listed in Table 2. Mean number of elec- trodes used in the i.v. group is 5.5 ± 1.4 (median 6, range 2–8) and in the i.a. group it is 5.0 ± 1.0 (median 5, range 3–6), values not significantly dif- ferent (p = 0.1380). Safety/toxicity Side effects observed in both groups were only mild or moderate, such as mild pain at the treated site, C-reactive protein (CRP) elevation and leuco- cytosis, or haemoglobin drop. All side effects were successfully treated with appropriate medical treatments and disappeared within 10 days from occurrence. No differences were observed in the two groups with respect to onset of side effects. Radiol Oncol 2025; 59(1): 100-109. Wilke T et al. / Intra-arterial administration in liver pECT104 TABLE 1. Descriptive characteristics of the patients in the 2 groups PATIENTS i.v. pECT (N = 18) i.a. pECT (n = 26) P value N % N % Gender Males Females 8 10 44% 56% 15 11 58% 42% 0.5406 Diagnosis Colorectal cancer Breast cancer Hepato cellular carcinoma Cholangio cellular carcinoma Ovarian cancer Non-small cell lung cancer (NSCLC) Anal cancer Pancreatic cancer Parotis carcinoma Neuroendocrine carcinoma Uterus carcinoma Esophageal carcinoma Cancer of unknown primary origin (CUP) 7 4 2 0 2 1 1 0 0 0 0 0 1 39% 22% 11% 0% 11% 6% 6% 0% 0% 0% 0% 0% 6% 10 4 2 3 0 2 0 1 1 1 1 1 0 38% 15% 8% 12% 0% 8% 0% 4% 4% 4% 4% 4% 0% 0.4620 Liver metastases Synchronous Metachronous No 8 8 2 44% 44% 11% 16 8 2 62% 31% 7% 0.5343 Metastases location other than liver None Yes 9 9 50% 50% 17 9 65% 35% 0.3613 Other metastasis’ location Lung Bone Kidney Lung + bone + brain Bone + peritoneum Pleural + bone Retroperineal Adrenal gland Lymphnode Bone + lymphnode 3 1 1 1 1 1 1 0 0 0 17% 6% 6% 6% 6% 6% 6% 0% 0% 0% 3 2 1 0 0 0 0 1 1 1 12% 8% 4% 0% 0% 0% 0% 4% 4% 4% 0.6025 Previous treatments Systemic therapy Liver surgery Local treatments 16 4 11 89% 22% 61% 26 12 8 100% 46% 31% 0.1617 0.1251 0.0657 Type of local treatments TACE TACE+RFA TACE+CP TACE/MWA/CRYOTH CRYOTH IBT 8 1 1 0 1 0 43% 6% 6% 0% 6% 0% 4 0 0 2 0 2 15% 0% 0% 8% 0% 8% 0.1529 Comorbidities Cardiac diseases Pulmonary diseases Liver diseases 6 3 9 33% 17% 50% 7 7 0 27% 27% 0% 0.7422 0.4889 <0.0001 Number of target lesions per patient 1 2 15 3 83% 17% 21 5 81% 19% 1.000 CP = chemoperfusion; CRYOTH = cryotherapy; IBT = interstitial brachytherapy; i.a. = intra-arterial; i.v. = intravenous; MWA = microwave ablation; pECT = percutaneous electrochemotherapy; RFA = radiofrequency ablation; TACE = hepatic artery chemoembolization Radiol Oncol 2025; 59(1): 100-109. Wilke T et al. / Intra-arterial administration in liver pECT 105 Response to treatment Response to pECT treatment was evaluated for each target lesion within the first 3 months of fol- low-up and the result for each single group is re- ported in Table 3. Despite a higher CR rate in the i.a. group, no statistically significant difference has been observed between the groups. Objective re- sponse (OR) rate was 85.7% in the i.v. group and 93.5% in the i.a. group (Figure 1). Progression free survival is shown in Figure 2. No significant difference has been observed be- tween groups (p = 0.5849). One-year progression free survival is 60% (C.I. 33%–88%) in the i.v. group and 67% (C.I. 42%–91%) in the i.a. group. Discussion This study assesses the feasibility of intra-arterial administration of bleomycin for pECT of liver tu- mors. Since selective and super-selective chemo- therapy applications are already well established in interventional oncology, such as in TACE, HAI TABLE 2. Characteristics of target lesions in the 2 groups LESIONS i.v. pECT (N = 21) i.a. pEC (N = 31) P value N % N % Type Hypervascular Intermediate Hypovascular 2 14 5 9.5% 66.7% 23.8% 5 20 6 16.1% 64.5% 19.4% 0.7664 Challenging location* Yes No 19 2 90.5% 9.5% 21 10 67.7% 32.3% 0.0927 Vessels or bile ducts surrounding the metastases Distant (> 10 mm) Close (1 mm to 10 mm) Adjacent (< 1 mm) 4 6 11 19.0% 28.6% 52.4% 8 5 18 25.8% 16.1% 58.1% 0.5389 Previous local treatments on the lesion Yes No 7 14 33.3% 66.7% 8 23 25.8% 74.2% 0.7559 Type of local treatments on the lesion TACE (transarterial chemoembolization) CP (chemoperfusion) IBT (interstitial brachytherapy) TACE/MWA/CRYOTH 6 1 0 0 28.6% 4.8% 0.0% 0.0% 4 0 2 2 12.9% 0.0% 6.5% 6.5% 0.1474 Technical success Yes No 20 1 95.2% 4.8% 31 0 100.0% 0.0% 0.2199 * Challenging location represented in liver were liver dome, vicinity of portal vein main trunk, vicinity of main bile duct CP = chemoperfusion; CRYOTH = cryotherapy; IBT = interstitial brachytherapy; i.a. = intra-arterial; i.v. = intravenous; MWA = microwave ablation; pECT = percutaneous electrochemotherapy; TACE = hepatic artery chemoembolization TABLE 3. Response to percutaneous electrochemotherapy (pECT) treatment in the 2 groups RESPONSE i.v. pECT (N = 21) i.a. pECT (N = 31) P value P value N % N % Overall distribution CR vs. non CR CR 13 61.9% 25 80.6% 0.3454 0.1349 PR 5 23.8% 4 12.9% SD 1 4.8% 0 0.0% PD 0 0.0% 1 3.2% Lost to follow up 2 9.5% 1 3.2% CR = complete remission; i.a. = intra-arterial; i.v. = intravenous; pECT = percutaneous electrochemotherapy; PR = partial remission; SD = stable disease Radiol Oncol 2025; 59(1): 100-109. Wilke T et al. / Intra-arterial administration in liver pECT106 and IHP (isolated hepatic perfusion)30,31, the ra- tional was to combine this established approach with pECT. Specifically, the goal of intra-arterial therapies is to inflict lethal insult to tumors by se- lectively delivering anticancer treatment to its ar- terial supply. Regional delivery of a drug leads to its increased local concentration; this holds true for drugs demonstrating first-order kinetics (constant clearance) despite the higher dose, potentially lead- ing to an increased response. Moreover, regional drug delivery leads to decreased systemic expo- sure of that drug, potentially reducing side effects and toxicity.32 Even in pECT, the administration of the chemotherapy drug only in the tumor-bearing area to be treated, allows a higher concentration of the drug in loco, enabling a first pass effect, with less systemic bleomycin circulating in the body, i.e. decreased risk of side effects and lung toxicity, whilst off-target bleomycin already bearing low toxicity in non electroporated liver parenchyma. The intra-arterial application of bleomycin in the liver proved to be safe and effective in the treatment of liver haemangiomas, with doses up to 45.000 IU per session33, as well as in TACE doxorubicin resistant hepatocellular carcinomas.34 Sporadic reports about the intra-arterial applica- FIGURE 1. (A) Transverse contrast-enhanced T1w MR image of a pancreatic carcinoma metastasis with a maximum diameter of 7 cm in segments V/VI and VII, which no longer responds to systemic chemotherapy and is growing rapidly and progressively. (B) Corresponding slice to A in diffusion imaging. (C) Complete contrast of the metastasis in 2D angiography. (D) Documentation of complete contrast coverage of the metastasis in cone beam CT. (E). Stereotactic navigation (CAS-One® IR) of the electrodes for electroporation. (F). Parallel planning of the electrodes in the tumor to achieve homogeneous electroporation. (G). The transverse contrast-enhanced T1w MR image of the metastasis one month after the electrochemotherapy (ECT) procedure demonstrates the complete loss of perfusion in the entire metastasis. (H) Corresponding slice to G in diffusion imaging. FIGURE 2. Progression free survival in the 2 groups during the 18-month follow-up period. A B C D E G H F Radiol Oncol 2025; 59(1): 100-109. Wilke T et al. / Intra-arterial administration in liver pECT 107 tion of bleomycin in ECT of other tumor entities can also be found in the literature.35,36 To the best of our knowledge, this is the first study showing that the intra-arterial administration of bleomycin can be applied to pECT of liver tumors. Intra-arterial catheter-assisted pECT also allows real-time liver tumor visualization before, during, and after placement of the probes, which may help in: improving tumor conspicuity; guiding needle advancement; verifying probe position relative to the tumor and surrounding structures; evaluation of procedure-related complications and techni- cal success directly after the procedure, all with a significantly reduced contrast dose comparable to venous contrast and therefore reduced risk of com- promising renal function.37-39 In this cohort study, intra-arterial administra- tion of bleomycin is proposed as a new method of drug delivery in pECT. Here we compared this new method with the standard intravenous sys- temic administration of bleomycin in patients un- dergoing pECT for liver lesions of various histo- logical origins. The 2 groups were similar for age, gender, histology distribution, type of metastasis (synchronous, metachronous), metastasis location, previous treatments, and comorbidities, except for surrounding liver disease. A significant difference in LA size of the lesion is observed (p = 0.0300), even if when calculated the entire volume of the lesion, the difference is only marginally significant (p = 0.0501). The analysis of complications and side effects reveals that the conventional intravenous and the new intra-arterial methods bring the same risk of complications. Percutaneous ECT is well tolerated by the patients14,40, no serious adverse events have been observed during procedures and during fol- low-up; side effects appear to be limited in number and intensity, and when occurred they were suc- cessfully treated with appropriate medical treat- ments and disappeared within 10 days from oc- currence. Short term results indicate a substantial equiva- lence between i.v. and i.a. administration modality, as non-significant differences were observed in the outcome at 1 to 3 months of follow-up. Complete response rate was 61.9%, partial response 23.8%, stable disease 4.8% and progression 9.5% in the i.v. group. Interestingly, a slightly higher CR rate was observed in the i.a. group, 80.6% with a lower PR rate, 12.9%; this non-significant difference could be ascribed to the relatively smaller target lesions treated with i.a. procedure of bleomycin admin- istration, with a volume of 61.4 ± 81.4 cm3 with a marginal significance in comparison with the i.v. group. In any case the objective response rate in the 2 groups is 85.7% in the i.v. group and 93.5% in the i.a. group. These data are similar to previous experiences on ECT in the liver: Edhemovic et al.25 conducted a study on intraoperative ECT of colo- rectal liver metastases and obtained a response rate per patient of 75% (63% CR and 12% PR). In a similar study carried out on intraoperative ECT in hepatocellular carcinoma, Djokic et al.41 obtained a response rate per patient of 95.8% (79.2% CR and 16.6% PR). The complete response rate at 3–6 months was 80% per patient and 88% per treated lesion, with a median size of the treated lesions of 24 mm (range 8–41 mm), slightly smaller than those treated in our study. Considering the stud- ies on ECT of liver performed with percutane- ous insertion of the electrodes, the experience of Tarantino et al.42,43 on cholangiocellular carcinoma at hepatic hilum and on portal vein tumor throm- bosis at hepatic hilum in patients with hepatocel- lular carcinoma in cirrhosis is also relevant. Even if few patients were included, they could demon- strate for the first time the feasibility and efficacy of the percutaneous procedure in the liver with intra-arterial administration of bleomycin. No im- portant side effects and a complete response was obtained in 3 out of 5 patients and maintained for at least 18 months. Further authors reported their experiences in pECT of liver tumors24,44 and more recently Iezzi et al. proved the feasibility of per- forming pECT under analgo-sedation, obtaining 100% OR in 5 patients with liver lesions, reporting neither major nor minor complications.45 In our study, the follow-up time ranges from 1 to 30 months, with a median value of 7 months, thus it is not possible to provide a very long time pro- gression free survival evidence, nonetheless the data available show that within the first 12 months of follow-up the progression free survival is simi- lar between the i.v. and i.a. groups (p = 0.5849) and this result confirms the hypothesis of equivalence in the local tumor control of i.a. procedure with re- spect to i.v. pECT standard procedure. This result is very important because it is complemented by several theoretical advantages of i.a. pECT, such as: targeted drug application only in the tumor- bearing area to be treated, higher concentration of bleomycin in loco using the first pass effect, less systemic drug circulating in the body and less side effects, less lung toxicity, better timing of the EP as local infusion is quicker than systemic. By proving the equivalence of i.a. and i.v. ad- ministration, there is also the potential to reduce Radiol Oncol 2025; 59(1): 100-109. Wilke T et al. / Intra-arterial administration in liver pECT108 the bleomycin dose in the future due to the higher on-site concentration with i.a. administration; this might be the aim of further research. The present study has some limitations: the relatively small number of patients is mainly due to the feasibility aim of the study, and the short follow-up after treatment, even if feasibility and short-term efficacy have been clearly obtained. With a perspective of collecting more data on pa- tients treated with i.a. pECT in the liver, it will be possible to better define the optimal indications for this new procedure with respect to convention- al i.v. pECT, even if some indications can already be suggested: based on our experience, for exam- ple, for hypovascularized tumors, which seem to respond less well to i.v. ECT than hypervascular- ised tumors. Conclusions This study demonstrates the equivalence of super- selective i.a. bleomycin administration compared to standard i.v. administration in the context of percutaneous electrochemotherapy for primary and secondary liver malignancies and thus opens perspectives for reducing the bleomycin dose and the associated toxicity. References 1. Glass LF, Jaroszeski M, Gilbert R, Reintgen DS, Heller R. Intralesional bleomy- cin-mediated electrochemotherapy in 20 patients with basal cell carcinoma. J Am Acad Dermatol 1997; 37: 596-9. doi: 10.1016/S0190-9622(97)70178-6 2. Marty M, Sersa G, Garbay JR, Gehl J, Collins CG, Snoj M, et al. Electrochemotherapy – an easy, highly effective and safe treatment of cuta- neous and subcutaneous metastases: results of ESOPE (European Standard Operating Procedures of Electrochemotherapy) study. Eur J Cancer Suppl 2006; 4: 3-13. doi: 10.1016/j.ejcsup.2006.08.002 3. Clover AJP, de Terlizzi F, Bertino G, Curatolo P, Odili J, Campana LG, et al. Electrochemotherapy in the treatment of cutaneous malignancy: outcomes and subgroup analysis from the cumulative results from the pan-European International Network for Sharing Practice in Electrochemotherapy data- base for 2482 lesions in 987 patients (2008–2019). Eur J Cancer 2020; 138: 30-40. doi: 10.1016/j.ejca.2020.06.020 4. Plaschke CC, Bertino G, McCaul JA, Grau JJ, de Bree R, Sersa G, et al. European Research on Electrochemotherapy in Head and Neck Cancer (EURECA) project: results from the treatment of mucosal cancers. Eur J Cancer 2017; 87: 172-81. doi: 10.1016/j.ejca.2017.10.008 5. Bertino G, Sersa G, De Terlizzi F, Occhini A, Plaschke CC, Groselj A, et al. European Research on Electrochemotherapy in Head and Neck Cancer (EURECA) project: results of the treatment of skin cancer. Eur J Cancer 2016; 63: 41-52. doi: 10.1016/j.ejca.2016.05.001 6. Kunte C, Letulé V, Gehl J, Dahlstroem K, Curatolo P, Rotunno R, et al. Electrochemotherapy in the treatment of metastatic malignant melanoma: a prospective cohort study by InspECT. Br J Dermatol 2017; 176: 1475-85. doi: 10.1111/bjd.15340 7. Campana LG, Quaglino P, de Terlizzi F, Mascherini M, Brizio M, Spina R, et al. Health-related quality of life trajectories in melanoma patients after electrochemotherapy: real-world insights from the INSPECT register. Acad Dermatol Venereol 2022; 36: 2352-63. doi: 10.1111/jdv.18456 8. Matthiessen LW, Keshtgar M, Curatolo P, Kunte C, Grischke EM, Odili J, et al. Electrochemotherapy for breast cancer – results From the INSPECT data- base. Clin Breast Cancer 2018; 18: e909-17. doi: 10.1016/j.clbc.2018.03.007 9. Di Prata C, Mascherini M, Ross AM, Silvestri B, Kis E, Odili J, et al. Efficacy of electrochemotherapy in breast cancer patients of different receptor status: the INSPECT experience. Cancers 2023; 15: 3116. doi: 10.3390/ cancers15123116 10. Bertino G, Muir T, Odili J, Groselj A, Marconato R, Curatolo P, et al. Treatment of basal cell carcinoma with electrochemotherapy: insights from the InspECT registry (2008-2019). Curr Oncol 2022; 29: 5324-37. doi: 10.3390/ curroncol29080423 11. Bertino G, Groselj A, Campana LG, Kunte C, Schepler H, Gehl J, et al. Electrochemotherapy for the treatment of cutaneous squamous cell carci- noma: The INSPECT experience (2008-2020). Front Oncol 2022;12: 951662. doi: 10.3389/fonc.2022.951662 12. Campana LG, Kis E, Bottyán K, Orlando A, De Terlizzi F, Mitsala G, et al. Electrochemotherapy for advanced cutaneous angiosarcoma: a European register-based cohort study from the International Network for Sharing Practices of electrochemotherapy (InspECT). Int J Surg 2019; 72: 34-42. doi: 10.1016/j.ijsu.2019.10.013 13. Sersa G, Mascherini M, Di Prata C, Odili J, de Terlizzi F, McKenzie GAG, et al. Outcomes of older adults aged 90 and over with cutaneous malignancies after electrochemotherapy with bleomycin: a matched cohort analysis from the InspECT registry. Eur J Surg Oncol 2021; 47: 902-12. doi: 10.1016/j. ejso.2020.10.037 14. Spallek H, Bischoff P, Zhou W, de Terlizzi F, Jakob F, Kovàcs A. Percutaneous electrochemotherapy in primary and secondary liver malignancies – local tumor control and impact on overall survival. Radiol Oncol 2022; 56: 102-10. doi: 10.2478/raon-2022-0003 15. Granata V, Fusco R, D’Alessio V, Simonetti I, Grassi F, Silvestro L, et al. Percutanous electrochemotherapy (ECT) in primary and secondary liver malignancies: a systematic review. Diagnostics 2023; 13: 209. doi: 10.3390/ diagnostics13020209 16. Tafuto S, von Arx C, De Divitiis C, Tracey Maura C, Palaia R, Albino V, et al. Electrochemotherapy as a new approach on pancreatic cancer and on liver metastases. Int J Surg 2015; 21: S78-82. doi: 10.1016/j.ijsu.2015.04.095 17. Campanacci L, Bianchi G, Cevolani L, Errani C, Ciani G, Facchini G, et al. Operating procedures for electrochemotherapy in bone metastases: results from a multicenter prospective study on 102 patients. Eur J Surg Oncol 2021; 47: 2609-17. doi: 10.1016/j.ejso.2021.05.004 18. Deschamps F, Tselikas L, Yevich S, Bonnet B, Roux C, Kobe A, et al. Electrochemotherapy in radiotherapy-resistant epidural spinal cord com- pression in metastatic cancer patients. Eur J Cancer 2023;186: 62-8. doi: 10.1016/j.ejca.2023.03.012 19. Kovács A, Bischoff P, Haddad H, Zhou W, Temming S, Schäfer A, et al. Long- term comparative study on the local tumour control of different ablation technologies in primary and secondary liver malignancies. J Pers Med 2022; 12: 430. doi: 10.3390/jpm12030430 20. Gasljevic G, Edhemovic I, Cemazar M, Brecelj E, Gadzijev EM, Music MM, et al. Histopathological findings in colorectal liver metastases after elec- trochemotherapy. PLoS One 2017; 12: e0180709. doi: 10.1371/journal. pone.0180709 21. Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2016; 27: 1386-422. doi: 10.1093/ annonc/mdw235 22. Brloznik M, Boc N, Sersa G, Zmuc J, Gasljevic G, Seliskar A, et al. Radiological findings of porcine liver after electrochemotherapy with bleomycin. Radiol Oncol 2019; 53: 415-26. doi: 10.2478/raon-2019-0049 23. Zmuc J, Gasljevic G, Sersa G, Edhemovic I, Boc N, Seliskar A, et al. Large liver blood vessels and bile ducts are not damaged by electrochemotherapy with bleomycin in pigs. Sci Rep 2019; 9: 3649. doi: 10.1038/s41598-019-40395-y Radiol Oncol 2025; 59(1): 100-109. Wilke T et al. / Intra-arterial administration in liver pECT 109 24. Cornelis FH, Korenbaum C, Ben Ammar M, Tavolaro S, Nouri-Neuville M, Lotz JP. Multimodal image-guided electrochemotherapy of unresectable liver metastasis from renal cell cancer. Diagn Interv Imaging 2019; 100: 309- 11. doi: 10.1016/j.diii.2019.01.001 25. Edhemovic I, Brecelj E, Cemazar M, Boc N, Trotovsek B, Djokic M, et al. Intraoperative electrochemotherapy of colorectal liver metastases: a pro- spective phase II study. Eur J Surg Oncol 2020; 46: 1628-33. doi: 10.1016/j. ejso.2020.04.037 26. Mali B, Gorjup V, Edhemovic I, Brecelj E, Cemazar M, Sersa G, et al. Electrochemotherapy of colorectal liver metastases – an observational study of its effects on the electrocardiogram. BioMed Eng OnLine 2015; 14(Suppl 3): S5. doi: 10.1186/1475-925X-14-S3-S5 27. Mir LM, Gehl J, Sersa G, Collins CG, Garbay JR, Billard V, et al. Standard operating procedures of the electrochemotherapy: instructions for the use of bleomycin or cisplatin administered either systemically or locally and electric pulses delivered by the CliniporatorTM by means of invasive or non-invasive electrodes. Eur J Cancer Suppl 2006; 4: 14-25. doi: 10.1016/j. ejcsup.2006.08.003 28. Gehl J, Sersa G, Matthiessen LW, Muir T, Soden D, Occhini A, et al. Updated standard operating procedures for electrochemotherapy of cutaneous tumours and skin metastases. Acta Oncologica 2018; 57: 874-82. doi: 10.1080/0284186X.2018.1454602 29. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-47. doi: 10.1016/j.ejca.2008.10.026 30. Dudeck O, Ricke J. Advances in regional chemotherapy of the liver. Expert Opin Drug Deliv 2011; 8: 1057-69. doi: 10.1517/17425247.2011.574125 31. De Baere T, Ronot M, Chung JW, Golfieri R, Kloeckner R, Park J-W, et al. Initiative on Superselective Conventional Transarterial Chemoembolization Results (INSPIRE). Cardiovasc Intervent Radiol 2022; 45: 1430-40. doi: 10.1007/s00270-022-03233-9 32. Lewandowski RJ, Geschwind JF, Liapi E, Salem R. Transcatheter intraarte- rial therapies: rationale and overview. Radiology 2011; 259: 641-57. doi: 10.1148/radiol.11081489 33. Akhlaghpoor S, Torkian P, Golzarian J. Transarterial bleomycin-lipiodol em- bolization (B/LE) for symptomatic giant hepatic hemangioma. Cardiovasc Intervent Radiol 2018; 41: 1674-82. doi: 10.1007/s00270-018-2010-4 34. Fu J, Wang Y, Zhang J, Yuan K, Yan J, Yuan B, et al. The safety and efficacy of transarterial chemoembolisation with bleomycin for hepatocellular carci- noma unresponsive to doxorubicin: a prospective single-centre study. Clin Radiol 2021; 76: 864.e7-864.e12. doi: 10.1016/j.crad.2021.07.013 35. Shimizu T, Nikaido T, Gomyo H, Yoshimura Y, Horiuchi A, Isobe K, et al. Electrochemotherapy for digital chondrosarcoma. J Orthop Sci 2003; 8: 248- 51. doi: 10.1007/s007760300043 36. Domenge C, Orlowski S, Luboinski B, Baere TD, Schwaab G, Belehradek J, et al. Antitumor electrochemotherapy: new advances in the clini- cal protocol. Cancer 1996; 77: 956-63. doi: 10.1002/(SICI)1097- 0142(19960301)77:5<956::AID-CNCR23>3.0.CO;2-1 37. Van Tilborg AAJM, Scheffer HJ, Van Der Meijs BB, Van Werkum MH, Melenhorst MCAM, Van Den Tol PM, et al. Transcatheter CT hepatic arteri- ography-guided percutaneous ablation to treat ablation site recurrences of colorectal liver etastases: the incomplete ring sign. J Vasc Interv Radiol 2015; 26: 583-7.e1. doi: 10.1016/j.jvir.2014.12.023 38. Puijk RS, Nieuwenhuizen S, Van Den Bemd BAT, Ruarus AH, Geboers B, Vroomen LGPH, et al. Transcatheter CT hepatic arteriography compared with conventional CT fluoroscopy guidance in percutaneous thermal ablation to treat colorectal liver metastases: A single-center comparative analysis of 2 historical cohorts. J Vasc Intervent Radiol 2020; 31: 1772-83. doi: 10.1016/j.jvir.2020.05.011 39. Puijk RS, Dijkstra M, Van Der Lei S, Schulz HH, Vos DJW, Timmer FEF, et al. The added value of transcatheter CT hepatic angiography (CTHA) image guidance in percutaneous thermal liver ablation: an experts’ opinion picto- rial essay. Cancers 2024;16: 1193. doi: 10.3390/cancers16061193 40. Djokic M, Dezman R, Cemazar M, Stabuc M, Petric M, Smid LM, et al. Percutaneous image guided electrochemotherapy of hepatocellular car- cinoma: technological advancement. Radiol Oncol 2020; 54: 347-52. doi: 10.2478/raon-2020-0038 41. Djokic M, Cemazar M, Popovic P, Kos B, Dezman R, Bosnjak M, et al. Electrochemotherapy as treatment option for hepatocellular carcinoma, a prospective pilot study. Eur J Surg Oncol 2018; 44: 651-7. doi: 10.1016/j. ejso.2018.01.090 42. Tarantino L, Busto G, Nasto A, Fristachi R, Cacace L, Talamo M, et al. Percutaneous electrochemotherapy in the treatment of portal vein tumor thrombosis at hepatic hilum in patients with hepatocellular carcinoma in cirrhosis: a feasibility study. World J Gastroenterol 2017; 23: 906. doi: 10.3748/wjg.v23.i5.906 43. Tarantino L, Busto G, Nasto A, Nasto RA, Tarantino P, Fristachi R, et al. Electrochemotherapy of cholangiocellular carcinoma at hepatic hilum: a feasibility study. Eur J Surg Oncol 2018; 44: 1603-9. doi: 10.1016/j. ejso.2018.06.025 44. Luerken L, Doppler M, Brunner SM, Schlitt HJ, Uller W. Stereotactic percu- taneous electrochemotherapy as primary approach for unresectable large HCC at the hepatic hilum. Cardiovasc Intervent Radiol 2021; 44: 1462-6. doi: 10.1007/s00270-021-02841-1 45. Iezzi R, Posa A, Caputo CT, De Leoni D, Sbaraglia F, Rossi M, et al. Safety and feasibility of analgosedation for electrochemotherapy of liver lesions. Life 2023; 13: 631. doi: 10.3390/life13030631 Radiol Oncol 2025; 59(1): 110-120. doi: 10.2478/raon-2025-0001 110 research article Investigation of GSTP1 and PTEN gene polymorphisms and their association with susceptibility to colorectal cancer Durr-e-Shahwar1, Hina Zubair1, Muhammad Kashif Raza1,2, Zahid Khan1, Lamjed Mansour3, Aktar Ali4, Muhammad Imran1 1 Biochemistry Section, Institute of Chemical Sciences, University of Peshawar, Peshawar, Pakistan 2 Department of Chemistry, Shaheed Benazir Bhutto University Sheringal Dir upper, Pakistan 3 Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia 4 Biological Screening Core, Warren Family Center for Drug Discovery, University of Notre Dame, Notre Dame, United States Radiol Oncol 2025; 59(1): 110-120. Received 12 July 2024 Accepted 25 October 2024 Correspondence to: Assoc. Prof. Muhammad Imran, Ph.D., Biochemistry Section, Institute of Chemical Sciences, University of Peshawar, Peshawar-25120, KP, Pakistan. E-mail: imrancl@uop.edu.pk Disclosure: No potential conflicts of interest were disclosed. This is an open access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/). Background. This study investigates the association of single nucleotide polymorphism in glutathione S transferase P1 (rs1695 and rs1138272) and phosphatase and TENsin homolog (rs701848 and rs2735343) with the risk of colorectal cancer (CRC). Patients and methods. In this case-control study, 250 healthy controls and 200 CRC patients were enrolled. All sub- jects were divided into 3 groups: healthy control, patients, and overall (control + patients). Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The demographic information, including age, gender, location, smoking status, cancer stage, and node involvement, were collected. Results. The allele frequencies of PTEN rs701848 in overall subjects were 0.78 for C and 0.22 for T. Similarly, in overall individuals, allele frequencies for PTEN rs2735343 were 0.65 and 0.35 for G and C alleles, respectively. The CC geno- type or C allele of rs701848 and CG/GG genotype of rs2735343 were observed to be a risk factor for CRC. In overall individuals, a significant (p ≤ 0.05)) association was observed between rs701848 and rs2735343 polymorphisms CRC. Allele frequencies for GSTP1 rs1695 were 0.68 and 0.32 for the A and G alleles, respectively. Allele frequencies for GSTP1 rs1138272 were 0.68 and 0.32 for C and T alleles, respectively. However, a significant (p < 0.05) association was found in males for rs1695, while a non-significant difference was observed for the distribution of any genotypes or alleles at GSTP1 (rs1138272). Conclusions. Both SNPs of PTEN rs701848 and rs2735343 polymorphisms were significantly associated with CRC. However, in GSTP1, rs1695 was significantly associated with CRC risk in males, and rs1138272 showed a non-significant association with colorectal cancer risk. Key words: colorectal cancer; GSTP1; PTEN; polymorphism; PCR-RFLP Introduction Colorectal cancer (CRC) is a major public health concern around the world, ranking among the top causes of cancer morbidity and mortality.1 CRC has the third-highest incidence and second- highest mortality rate of all cancers worldwide.2 Over 1918658 CRC cases and 900536 deaths were estimated in 2022.3 The incidence of CRC shows considerable variation among racially or ethnically defined populations in multiracial/ethnic coun- tries.4 The geographical and temporal burden of this cancer provides insights into risk factor preva- lence and progress in cancer control strategies.5 Radiol Oncol 2025; 59(1): 110-120. Shahwar D-e et al. / GSTP1 and PTEN polymorphism and risk of colorectal cancer 111 CRC causes include heterogeneous, controllable, and external factors related to lifestyle, such as diet and socioeconomic standing.6 Chromosomal insta- bility (CIN) or microsatellite instability (MIN) are the two main causes of the development of CRC and involve activation and inactivation of various proto-oncogenes and tumor-suppressor genes, re- spectively.7 Several genes have been connected to the etiology of CRC including GSTP1 (Glutathione S-Transferase Pi 1), APC (Adenomatous Polyposis Coli), and PTEN (Phosphatase and TENsin) etc.8 The GSTP1 gene has six introns and seven exons and is positioned on chromosome 11q13. From ab- errant crypt foci to advanced carcinomas, GSTP1 is overexpressed in all stages of CRC.9,10 GSTP1 dimers catalyze the conjugation of glutathione’s sulfur atom to endogenous and exogenous elec- trophiles, such as xenobiotics, reactive oxygen species (ROS), anticancer agents, and carcinogens in the process of detoxification.11,12 Two important genetic polymorphisms in GSTP1 include rs1695 (Ile-105Val) resulting from an AG transition at base 1578 (c.313A>G), and rs1138272 (Ala114Val), result- ing from a CT transition at base 2293 (c.341C>T).12 These polymorphisms may predispose to CRC through deficient detoxification of carcinogens and also may have an impact on a patient’s re- sponse to chemotherapy.13 A tumor suppressor gene called PTEN, which codes for a protein that has both lipid and protein phosphatase functions, is found on chromosome 10q23.3.14 Blocking the oncogenic PI3K/Akt/mTOR pathway is the primary function of PTEN. Genetic alterations in PTEN leading to its inactivation, fa- cilitate tumorigenesis, and are common in human cancers such as prostate cancer, breast cancer, glio- blastoma, and CRC.15 Single nucleotide polymor- phisms (SNPs) in PTEN can decrease its activity which may lead to downstream oncogene activa- tion and tumorigenesis.16 The PTEN gene’s intron and non-coding region contain SNPs like rs2735343 (located in the promoter region of the gene, C > G change) and rs701848 (found in the 3′ untranslated region (3′-UTR) of the gene T>C change), which may affect splicing, cell cycle, and protein expression.17 These genetic polymorphisms can affect the en- zymes by either modifying enzymatic activation, their interaction with partner proteins, or their detoxification potential, which can potentially in- fluence the susceptibility and prognosis to CRC based on ethnic disparities and inter-individual differences. The association of these polymor- phisms in the candidate genes with CRC risk in the Khyber Pakhtunkhwa population has not been established yet. This study was thus designed to investigate genetic/allelic polymorphism in GSTP1 (rs1695, rs1138272) and PTEN (rs701848, rs2735343), their frequency, and their association with the de- velopment of CRC. Patients and methods Samples collection In this study, 250 healthy controls and 200 CRC pa- tients of various stages from I-IV under chemother- apy or radiation therapy treatments were enrolled from Khyber Pakhtunkhwa, Pakistan. The sample size was calculated World Health Organization (WHO) formula.18 Ethical approval for this study was obtained from the Ethical Committee Faculty of Life & Environmental Sciences, University of Peshawar, Pakistan. For the controls, healthy in- dividuals with no sign of present or previous ma- lignancy and no indication of CRC nor any fam- ily history of cancer were included who have no blood relation with the patients. Individuals who were unable to provide informed consent and pa- tients who have developed CRC at the age > 60 years were excluded. Mixed ethnic backgrounds individuals and patients with comorbidities were also excluded. Blood samples (3 mL) were collect- ed through a sterile syringe from both the patients and controls visiting the Institute of Radiation and Nuclear Medicine (IRNUM), Peshawar, Pakistan. They were stored at −20°C in sterile vacutainer tubes containing ethylenediaminetetraacetic acid (EDTA) till further analysis. DNA extraction and genotyping Genomic DNA was extracted using a genomic DNA extraction kit (Gene JET Genomic DNA Purification kit, Thermoscientific, USA) and quan- tified using a spectrophotometer (752 PC, China). A 5–10 ng DNA sample was used for the genotyping of GSTP1 (rs1695, rs1138272) and PTEN(rs701848, rs2735343) polymorphisms using the polymerase chain reaction-restriction fragment length poly- morphism (PCR-RFLP) technique.19, 20 The PCR amplification was performed in a 25 mL reaction mixture, containing 100 ng genomic DNA, 0.2 mM dNTP, 0.2 mM of each primer, 2.5 U Taq DNA pol- ymerase, and Taq buffer (Thermo Fischer Scientific USA). The primer sequences were designed using Primer 3 or Primer BLAST. The sequence of prim- ers, PCR conditions, restriction enzymes, length of PCR, and digestion products for GSTP1 and PTEN Radiol Oncol 2025; 59(1): 110-120. Shahwar D-e et al. / GSTP1 and PTEN polymorphism and risk of colorectal cancer112 amplification have been described in Table 1. The PCR products were digested by respective restric- tion enzymes overnight at 37°C and then analyzed by electrophoresis on 2% agarose gel. The se- quences of the PCR products were confirmed by Sanger sequencing. Sanger sequencing (capillary sequencing) of random samples was carried out using Applied Biosystems 3730xl DNA Analyzer (Thermo Fischer Scientific, USA). Bioedit sequence alignment editor (BioEdit version 7.7.1) was used for sequencing data analysis. Statistical analysis The statistical package for social sciences version 20 (SPSSv.20) was used for analysis. Descriptive statistics were used to calculate proportions and percentages for each categorical variable used in univariate analysis. Adjusted odds ratios (OR) and 95% confidence interval (CI) for potential determi- nants of CRC were calculated by logistic regression analysis. The p ≤ 0.05 was considered to be statisti- cally significant. Hardy Weinberg equilibrium was tested by chi-square t-test for observed genotype frequencies. Results Demographic variables of the studied population Of the 450 individuals, 200 were CRC patients; 78 (39%) were female and 122 (61%) were males. The remaining 250 were controls; 81 (32%) female and 169 (68%) males. The inter-group differences relat- ed to age, gender, and food consumption patterns were non-significant (p > 0.05), while smoking sta- tus was a significant factor (Table 2). The tumor lo- cation among the CRC cases was non-significant (p > 0.05) as 98 (49%) patients were diagnosed with rectal carcinoma and 102 (51%) had colon carci- noma. TABLE 1. Primer sequences and amplification conditions for GSTP1 and PTEN polymorphisms Gene Primer sequence PCR conditions Amplicon length (bp) Restric- tion enzyme Length of digest products (bp) Enzyme specificity GSTP1 (rs1695) F:5′GGCTCTATGGGAAGGACCAGCAGG-3′ R:5′GCACCTCCATCCAGAAACTGGCG3′ 30 cycles of 1 min at 94°C,1 min at 66°C and 2 min at 72°C. 445 Alw261 330+115+270 5’GTCTC(N)1↓3’ 3’CAGAG(N) 5↑5’ GSTP1 (rs1138272) F:5′CAGCAGAGGCAGCGTGTGTGC-3′ R:5′CCCACAATGAAGGTCTTGCCTCC-3′ 30 cycles of 1 min at 94°C, 1 min at 64°C and 2 min at 72°C. 565 AciI 365+120+485+80 5’C↓CG↑C’33’G↓GC↑G’5 PTEN (rs701848) F:5’-GTGCTTTATTGATTTGCT-3’ R:5’AGTAGTTGTACTCCGCTT-3’ 5 min at 94°C, 35 cycles of 30 s at 94°C, 30 s at 55°C, 30 s at 72°C, and 10 min extension at 72°C. 199 HaeIII 199+81+118 5’GG↓CC3’ 3’CC↑G G5’ PTEN (rs2735343) F:5’-CTCTTCCTGTTCTCCATCGTG-3’ R:5’-TTCTCCAGGATTTCGTCTGC-3’ 5 min at 94°C, 35 cycles of 30 s at 94°C, 30 s at 63°C, 30 s at 72°C and 10 min at 72°C. 272 HhaI 272+72+200 5’G↑CG↓C3’ 3’C↑GC↓G’5 bp = base pair; F = forward; PCR = polymerase chain reaction; R = reverse TABLE 2. Demographic information and risk factors in colorectal cancer (CRC) cases and control Variable PatientsN = 200(%) Control n = 250(%) P value *Age (Years) ≥ 40 132 (66.0) 151 (60.4) 0.222 < 40 68 (34.0) 99 (39.6) Range 10-60 11-60 - Median 46 32 - *Gender Male 122 (61.1) 169(68) 0.273 Female 78 (39.0) 81(32) **Smoking status Never 165 (82.3) 22 (8.8) < 0.010 Ever 35 (17.6) 228 (91.1) *Site of tumor Colon 102(51.00) 0.984 Rectum 98(49.00) *p > 0.05 patients vs control; **p ≤ 0.05 patients vs controls Radiol Oncol 2025; 59(1): 110-120. Shahwar D-e et al. / GSTP1 and PTEN polymorphism and risk of colorectal cancer 113 Frequency of GSTP1 (rs1695 and rs113828) polymorphism and associated risk of CRC The risk association of rs1695 polymorphism and CRC is shown in Table 3. Representative im- ages of genotyping are shown in Supplementary Figure 1 and random sample sequencing analysis is in Supplementary Figure 2. Among the 450 in- dividuals, the A allele carriers of rs1695 were more prevalent compared to the G allele carriers. Allele and genotype frequency distribution for GSTP1 in the population are shown in Figure 1 and Figure 2 respectively. In overall individuals, allele frequen- cies for GSTP1 rs1695 were 0.68 and 0.32 for the A and G alleles, respectively. The genotypes (A/ G+G/G) were not associated with the risk of CRC in overall subjects (OR = 0.81, CI = 0.56 to 1.19, P = 0.28, as well as in females (OR = 1.09, CI = 0.58 to 2.04, P = 0.79,) while it was associated in males (OR = 0.81, CI = 0.50 to 1.31, P < 0.01,). The relative risk (RR) for male was 2.2 times higher than for fe- male participants. The risk association of GSTP1 rs1138272 and CRC is shown in Table 4. Allele and genotype fre- quencies for GSTP1 rs1138272 in the population are shown in Figure 1, 2 respectively. In overall sub- jects, the T allele (35%) was more prevalent than C allele (32%). In overall subjects the presence of the genotype C/T+T/T (OR = 0.75, CI = (0.47 to 1.18), TABLE 3. Frequency of GSTP1 (rs1695) polymorphism and its association with colorectal cancer (CRC) risk Models/Genotype CRC Patients + Healthy Controls n (%) CRC Patients n (%) Healthy Controls n (%) OR P Value 95% CI RR Overall Subjects Codominant Model A/A 192 (43) 91 (46) 101 (40) Referent _ A/G 231 (51) 102 (51) 129 (52) 0.88 0.10 0.60–1.29 1.2 G/G 27 (6) 07 (4) 20 (8) 0.39 0.10 0.16–0.97 0.2 Dominant Model (A/G+G/G) 258 (57) 109 (54) 149 (60) 0.81 0.28 0.56–1.19 1.4 Recessive Model (A/A+A/G) 423 193 230 2.39 0.05* 0.99–5.79 - Over dominant Model (A/G) 231 (51) 102 (51) 129 (52) 1.02 0.89 0.70–1.48 - Male A/A 123 (42) 58 (48) 65 (38) Referent _ A/G 150 (52) 63 (52) 87 (51) 0.81 < 0.01* 0.50–1.31 1.3 G/G 18 (6) 01 (0.1) 17 (1) 0.07 < 0.01* 0.01–0.51 0.2 Dominant Model (A/G+G/G) 168 (58) 64 (52) 104 (52) 0.69 0.12 0.43–1.11 1.5 Female A/A 69 (43) 33 (42) 36 (44) Referent _ A/G 81 (51) 39 (50) 42 (52) 1.01 0.55 0.53–1.93 1.1 G/G 9 (6) 06 (8) 03 (4) 2.18 0.55 0.50–9.43 0.1 Dominant Model (A/G+G/G) 90 (57) 45 (58) 45 (56) 1.09 0.79 0.58–2.04 1.2 HWE (Genotype Frequencies) A2 0.46 0.50 0.436 - - - 2AG 0.43 0.41 0.449 - - - G2 0.10 0.08 0.116 - - - χ2total = 1 *Statistically significant associations (p ≤ 0.05), Logistic regression model adjusted by age, gender and smoking; CI = confidence interval; CRC = colorectal cancer; OR = odd ratio; RR = relative risk Radiol Oncol 2025; 59(1): 110-120. Shahwar D-e et al. / GSTP1 and PTEN polymorphism and risk of colorectal cancer114 A B FIGURE 1. GSTP1Alleles frequency distribution of the rs1695 A/G (A) and rs1138272 C/T (B). CRC = colorectal cancer FIGURE 2. GSTP1 genotypic count of the overall participants for rs1695 and rs1138272. The p-values and odds ratio (OR) displayed in the figure correspond to pairwise comparisons of genotypes in between the two groups. Lines typically represent trends or connections between data points and square dots mark data points or average. Genotype count means number of individuals with a specific genetic variation. CI = confidence interval P = 0.21) was not related to the risk of CRC and the relationship is not significant. Relative Risk for male and female is equal. Frequency of PTEN (rs701848) polymorphism and associated risk of CRC The allele frequencies of PTEN rs701848 in overall subjects were 0.78 for C and 0.22 for T. Representative images of genotyping are shown in Supplementary Figure 2 and random samples sequencing in Supplementary Figure 4. Among overall 450 subjects, the C allele was more preva- lent compared to T allele carriers. The presence of C/C genotype was significantly associated with a higher risk of CRC in overall subjects (OR = 3.9, CI = 1.86 to 8.23, P = 0.03 in males (OR = 8.02, P = 0.001, CI = 2.29 to 28.01) as well as in females (OR = 2.05, P = 0.14, CI = 0.77 to 5.48). The RR for females was 0.8 times higher than males. Frequency of PTEN (rs2735343) polymorphism and associated risk of CRC The risk association of CG rs2735343 polymor- phism and CRC is shown in Table 6. Similarly, in overall individuals, allele frequencies for PTEN rs2735343 were 0.65 and 0.35 for G and C alleles, respectively. In overall subjects, the G allele (C/ G+G/G) was more prevalent (52%) than the C/C genotype (48%). The combined heterozygous C/ G+G/G variant was observed to be 30% prevalent in healthy individuals and 80% in CRC partici- pants. The allele frequencies and genotype count for rs2735343 are presented in Figure 3,4. The presence of genotypes (C/G, GG &C/G+G/G) was positively correlated with a higher risk of CRC in overall subjects, males and females (OR = 3.6-17.0). The RR for males is 2.8 times greater than females. Radiol Oncol 2025; 59(1): 110-120. Shahwar D-e et al. / GSTP1 and PTEN polymorphism and risk of colorectal cancer 115 Association of GSTP1 and PTEN polymorphism with colon and rectum cancer cases The study analyzed CRC patients based on tumor location to assess the association of the GSTP1 and PTEN polymorphism and the link between the these polymorphisms and CRC was evaluated by sub-grouping the patients into those with colon and rectum cancers (Table 7). Of the 200 CRC pa- tients, 102 (51%) had colon cancer and 98 (49%) had rectal cancer. Heterozygous genotypes were significantly linked to increased risks of both co- lon and rectal cancer (p < 0.05) for GSTP1(rs1695, rs1138272) and PTEN (rs701848). Discussion CRC is a major global health issue influenced by various genetic factors. GSTP1, part of phase II de- toxification, conjugates glutathione to detoxify and remove harmful substances, promoting detoxifica- tion.21 Polymorphisms in these genes alter biologi- cal pathways and protein expression, contributing to tumor development.22 GSTP1 genotypes differ TABLE 4. Frequency of GSTP1(rs1138272) polymorphism and its association with colorectal cancer (CRC) risk Models/Genotype CRC Patients +Healthy Controls n (%) CRC Patients n (%) Healthy Controls n (%) OR P Value 95% CI RR Overall Subjects Codominant Model C/C 350 (78) 161(80) 189(76) Referent _ C/T 90 (20) 35(18) 55(22) 0.74 0.12 0.46-1.19 0.2 T/T 10 (2) 4(2) 6 (2) 0.78 0.70 0.21-2.82 0.03 Dominant Model C/T+T/T 100 (22) 39 (19) 61 (24) 0.75 0.21 0.47-1.18 0.3 Recessive Model (C/C+C/T) 440 196 244 1.20 0.77 0.33-4.32 - Over dominant Model (C/T) 90 (20) 35(18) 55(22) 0.75 0.23 0.46-1.20 - Male C/C 229(79) 98(80) 131(78) Referent - C/T 56(19) 20(17) 36(21) 0.74 0.33 0.40-1.36 0.2 T/T 6(2) 4(3) 02(1) 2.67 0.26 0.47-14.89 0.02 Dominant Model C/T+T/T 62(21) 24(20) 38(22) 0.84 0.56 0.47-1.49 0.2 Female C/C 121(76) 61(78) 60(74) Referent _ C/T 34(21) 15(19) 19(24) 0.77 0.51 0.36-1.66 0.3 T/T 4(3) 2(3) 02(2) 0.98 0.98 0.13-7.21 0.04 Dominant Model C/T+T/T 38(24) 17(22) 21(26) 0.88 0.74 0.43-1.82 0.3 HWE (Genotype Frequencies) C2 0.462 0.81 0.25 - - - - 2CT 0.435 0.18 0.5 - - - - T2 0.102 0.01 0.25 - - - - χ2total = 1 *Statistically significant associations (p ≤ 0.05), Logistic regression model adjusted by age, gender and smoking. CI = confidence interval; CRC = colorectal cancer; OR = odd ratio; RR = relative risk Radiol Oncol 2025; 59(1): 110-120. Shahwar D-e et al. / GSTP1 and PTEN polymorphism and risk of colorectal cancer116 A B FIGURE 3. PTEN Alleles frequency distribution of the rs701848 T/C (A) and rs2735343 C/G (B). CRC = colorectal cancer FIGURE 4. PTEN genotypic count of the overall participants for rs701848 and rs2735343. The p-values and odds ratio (OR) displayed in the figure correspond to pairwise comparisons of genotypes between the two groups in each of the bar graphs. Lines typically represent trends or connections between data points and square dots mark data points or average. Genotype count means number of individuals with a specific genetic variation. CI = confidence interval in their ability to detoxify toxic species, with en- zyme activity being significantly lower in individ- uals with Val instead of isoleucine at position 105 (rs1695).23 Research links GSTP1 Ile105Val (rs1695, A>G) and GSTP1 Ala114Val (rs1138272, C>T) muta- tions to various cancers, including breast, oral, and squamous cell carcinoma (SCC).24 GSTP1 Ile105Val (rs1695, A > G) is a missense mutation reducing enzyme activity. Santric found a significant asso- ciation between GSTP1 Ile105Val polymorphism and toxicity.25 showed that the Kudhair GSTP1 Ile105Val substitution increases lung cancer risk in Arab population. Watson et al. demonstrated that individuals with two GSTP1 valine alleles had low- er catalytic activity than those with two isoleucine alleles, with heterozygotes showing intermediate activity. Evidence on GST polymorphisms’ role in CRC susceptibility is mixed.26 GSTP1, highly ex- pressed in the colon and involved in heterocyclic amine deactivation, is a candidate susceptibility gene. GSTP1 SNPs, especially Ile105Val, are strong- ly associated with increased CRC risk and poorer prognosis. However, the association with rectal cancer is less robust than with colon cancer.27 The GSTP1 gene variants (rs1695, rs1138272) are unlikely to significantly increase CRC risk, al- though a minor effect cannot be excluded, aligning with Terrazzino27 and Osti’s findings.28 The GSTP1 105Val allele frequency in CRC patients was simi- lar to previous reports in healthy Caucasians and African-Americans.29 The frequency of both GSTP1 polymorphisms was comparable to Australian, English, and American Caucasians (34%, 33%, and 33% Val-105; 7%, 8%, and 9% Val-114, respec- tively).17 Khabaz in Saudi Arabia, and studies in Bulgaria and Kashmir populations also found no association between these genotypes and CRC risk.30 However, Gorukmez31 noted the GSTP1 Ile/ Radiol Oncol 2025; 59(1): 110-120. Shahwar D-e et al. / GSTP1 and PTEN polymorphism and risk of colorectal cancer 117 Ile genotype was more frequent in controls than patients, while Vlaykova32 reported a non-signif- icant protective role for the Val allele. A mild as- sociation of CRC with heterozygous and homozy- gous genotypes was observed compared to the wild type of GSTP1.30 Previous studies examining the Ile-1053Val and Ala-1143Val GSTP1 polymor- phisms in CRC reported no association, consistent with our findings.33,34 Phosphatase and TENsin homolog (PTEN) is also mutated in multiple advanced cancers and a tumor suppressor gene.35 PTEN is generally cyto- solic and regulates phosphatidylinositol 3,4,5-tris- phosphate (PIP3) levels; a small fraction of PTEN is recruited to the plasma membrane. PTEN reduces PIP3 levels, decreasing the mTOR/AKT signaling pathway critical for cancer cell growth, survival, and progression. Many SNPs and deletion poly- morphisms in PTEN have been reported in hu- man cancers.36 Both rs701848 and rs2735343 SNPs are located in the intron and non-coding region of the PTEN gene and increase cancer risk by prob- ably influencing splicing, protein expression, and cell cycle. The rs701848 polymorphism influences cancer susceptibility by altering PTEN expression and reducing PTEN mRNA stability. These func- TABLE 5. Frequency of PTEN (rs701848) polymorphism and its association with colorectal cancer (CRC) risk Models/Genotype CRC Patients +Healthy Controls n (%) CRC Patients n (%) Healthy Controls n (%) OR P Value 95% CI RR Overall Subjects Codominant Model T/T 293 (65) 136 (68) 157 (63) Referent _ T/C 113 (25) 30 (15) 83 (33) 0.41 0.03* 0.25–0.67 0.5 C/C 44 (10) 34 (17) 10 (4) 3.92 0.03* 1.86– 8.23 0.06 Dominant T/C+C/C 157 (35) 64 (32) 93 (37) 0.79 0.25 0.53–1.17 0.5 Recessive Model (T/T+T/C) 406 166 240 0.20 < 0.01* 0.09–0.42 - Over dominant Model (T/C) 113 (25) 30 (15) 83 (33) 0.35 < 0.01* 0.22–0.56 - Male T/T 197 (68) 86 (70) 111 (66) Referent T/C 71 (24) 17 (14) 54 (32) 0.40 0.04* 0.21–0.75 _ C/C 23 (8) 19 (16) 04 (2) 8.02 0.01* 2.29-28.01 0.04 Dominant T/C+C/C 94 (32) 36 (30) 58 (34) 0.81 0.42 0.49–1.35 0.5 Female T/T 96 (60) 50 (64) 46 (57) Referent _ T/C 42 (27) 13 (17) 29 (36) 0.41 0.02* 0.19–0.89 0.6 C/C 21 (13) 15 (19) 06 (7) 2.05 0.14 0.77-5.48 0.1 Dominant T/C+C/C 63 (40) 28 (36) 35 (43) 0.72 0.32 0.38–1.36 0.7 HWE (Genotype Frequencies) T2 0.04 0.04 0.03 - - - 2TC 0.34 0.32 0.29 - - - C2 0.60 0.64 0.67 - - - χ2total = 1 *Statistically significant associations (p < 0.05), Logistic regression model adjusted by age, gender, and smoking. CI = confidence interval; CRC = colorectal cancer; OR = odd ratio; RR = relative risk Radiol Oncol 2025; 59(1): 110-120. Shahwar D-e et al. / GSTP1 and PTEN polymorphism and risk of colorectal cancer118 tional genetic polymorphisms of PTEN are known to participate in tumorigenesis.30 Jang et al 37. and Xu et al.38 showed that the C allele of rs701848 was more susceptible than the T allele in developing esophageal squamous cell cancer (ESCC). The rs701848 is associated with an increased risk of breast cancer, renal cell cancer, CRC, and ESCC.31 GG genotype of rs2735343 is associated with an el- evated risk of ESCC while there is no association between rs2735343 (G/C) and the risk of endome- trial cancer. Moreover, Asian subjects carrying the TC/CC genotype or C allele of rs701848 were associated with an increased risk of esophageal squamous cell cancer.16 Studies have suggested a significant association between rs701848 and colon cancer risk, especially in populations with a fam- ily history of CRC. rs1903858 (G/A) and its specific association with colon, rectal, or CRC is still be- ing researched, it has been implicated in cancer susceptibility in various populations.39 Located in the promoter region of PTEN, some studies sug- gest rs2735343 plays a role in both colon and rectal cancers through its impact on PTEN expression.40 Our analyses demonstrated that CRC risk was associated with rs701848 in the C/C genotype and with rs2735343 in the GG and C/G genotypes and TABLE 6. Frequency of PTEN (rs2735343) polymorphism and its association with colorectal cancer (CRC) risk Models/Genotype CRC Patients +Healthy Controls n (%) CRC Patients n (%) Healthy Controls n (%) OR P Value 95% CI RR Overall Subjects Codominant Model C/C 215 (48) 40 (20) 175 (70) Referent _ C/G 77 (17) 35 (18) 42 (17) 3.6 < 0.01* 2.06–6.42 0.2 G/G 158 (35) 125 (62) 33 (13) 17.0 < 0.01* 10.0–28.0 0.1 Dominant C/G+G/G 235 (52) 160 (80) 75 (30) 9.5 < 0.01* 6.10–14.7 0.4 Recessive Model (C/C+C/G) 292 75 217 0.09 < 0.01* 0.05–0.14 - Over dominant Model (C/G) 77 (17) 35 (18) 42 (17) 1.09 0.71 0.67–1.79 - Male C/C 139 (48) 24 (20) 115 (68) Referent _ C/G 47 (16) 16 (13) 31 (18) 2.47 < 0.01* 1.17–5.22 0.2 G/G 105 (36) 82 (67) 23 (14) 17.08 < 0.01* 9.02–32.3 0.2 Dominant C/G+G/G 152 (52) 98 (80) 54 (32) 8.70 < 0.01* 5.01–15.0 0.4 Female C/C 76 (48) 16 (21) 60 (74) Referent _ C/G 30 (19) 19 (24) 11 (14) 6.48 < 0.01* 2.57–16.3 0.1 G/G 53 (33) 43 (55) 10 (12) 16.12 < 0.01* 6.68–38.9 0.1 Dominant C/G+G/G 83 (52) 62(79) 21 (26) 11.07 < 0.01* 5.28–23.3 0.3 HWE (Genotype Frequencies) C2 0.12 0.24 0.05 - - - 2CG 0.45 0.5 0.35 - - - G2 0.42 0.26 0.59 - - - χ2total = 1 *Statistically significant associations (p < 0.05), Logistic regression model adjusted by age, gender and smoking. CI = confidence interval; CRC = colorectal cancer; OR = od Ratio; RR = relative risk Radiol Oncol 2025; 59(1): 110-120. Shahwar D-e et al. / GSTP1 and PTEN polymorphism and risk of colorectal cancer 119 shown that these genotypes increased the risk of CRC in the Pashtun population which supports previous findings by Jang et al.37 The distribution of genotypes or alleles in cases at both genetic sites of PTEN was statistically different from those in controls. This study is limited by a small Pashtun sample, lack of population comparisons, and no meta-analyses. Future research should replicate these findings in larger, multi-ethnic cohorts to assess genetic links to CRC. Investigations should focus on the effects of rs701848 and rs2735343 poly- morphisms on PTEN expression and function to aid in developing targeted therapies. Conclusions The significant association of PTEN rs701848 and rs2735343 polymorphisms CRC suggests their potential role as genetic risk factors in the stud- ied population. The gender-specific association of GSTP1 rs1695 with CRC in males warrants further investigation to elucidate the underlying mecha- nisms. These findings contribute to the under- standing of genetic susceptibility to CRC and high- light the importance of personalized approaches in cancer prevention and treatment. Acknowledgments The authors would like to extend their special thanks to the volunteers who willingly participat- ed in this study. The authors extend their apprecia- tion to the Researchers Supporting Project number (RSP 2025R75), King Saudi University, Riyadh, Saudi Arabia for financial support. References 1. Xi Y, Xu P. Global colorectal cancer burden in 2020 and projections to 2040. Transl Oncol 2021; 14: 101174. doi: 10.1016/j.tranon.2021.101174 2. Huang P, Feng Z, Shu X, Wu A, Wang Z, Hu T, et al. 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Association of GSTP1 and PTEN polymorphism with colon and rectum cancer cases Gene/rs Genotype Colonn = 102 (%) Rectum n = 98 (49%) P Value GSTP1 rs1695 AA 62 (61.11) 26 (27.00) Referent AG 34 (33.33) 72 (73.33) < 0.01* GG 06 (5.65) - 0.25 GSTP1 rs1138272 CC 91 (89) 69 (69.5) Referent CT 13 (13.0) 17 (17.3) < 0.01* TT 17 (17.0) 17 (17.3) 0.27 PTEN rs701848 TT 72 (70.0) 64 (65.4) Referent TC 13 (13.0) 17 (17.3) < 0.01* CC 17 (17.0) 17 (17.3) 0.02 PTEN rs2735343 CC 20 (19.6) 20 (20.4) Referent CG 19 (18.6) 16 (16.3) 0.71 GG 63(61.8) 62 (63.3) 0.96 *Statistically significant associations (p < 0.05) Radiol Oncol 2025; 59(1): 110-120. Shahwar D-e et al. / GSTP1 and PTEN polymorphism and risk of colorectal cancer120 19. Welfare M, Monesola Adeokun A, Bassendine MF, Daly AK. Polymorphisms in GSTP1, GSTM1, and GSTT1 and susceptibility to colorectal cancer. Cancer Epidemiol Biomarkers Prev 1999, 8: 289-92. PMID: 10207630 20. Jang Y, Lu SA, Chen ZP, Ma J, Xu CQ, Zhang CZ, et al. Genetic polymorphisms of CCND1 and PTEN in progression of esophageal squamous carcinoma. Genet Mol Res 2013; 12: 6685-91. doi: 10.4238/2013 21. Potęga A. Glutathione-mediated conjugation of anticancer drugs: An overview of reaction mechanisms and biological significance for drug detoxification and bioactivation. Molecules 2022, 27: 5252. doi: 10.3390/ molecules27165252 22. Deng N, Zhou H, Fan H, Yuan Y. Single nucleotide polymorphisms and cancer susceptibility. Oncotarget 2017, 8: 110635. doi: 10.18632/oncotarget.22372 23. Deng X, Hou J, Deng Q, Zhong Z. Predictive value of clinical toxicities of chemotherapy with fluoropyrimidines and oxaliplatin in colorectal cancer by DPYD and GSTP1 gene polymorphisms. World J Surg Oncol 2020, 18: 1-10. doi: 10.1186/s12957-020-02103-3 24. Farmohammadi A, Arab-Yarmohammadi V, Ramzanpour R. Association analysis of rs1695 and rs1138272 variations in GSTP1 gene and breast cancer susceptibility. Asian Pac J Cancer Prev 2020; 21: 1167. doi: 10.31557/ APJCP.2020.21.4.1167 25. Kudhair BK, Abdulridha FM, Hussain GM, Lafta IJ, Alabid NN. The associa- tion of combined GSTM1, GSTT1, and GSTP1 genetic polymorphisms with lung cancer risk in male Iraqi Waterpipe Tobacco (Nargila) smokers. Cancer Epidemiol 2024; 93: 102689. doi: 10.1016/j.canep.2024.102689. 26. Watson MA, Stewart RK, Smith GB, Massey TE, Bell DA. Human glutathione S-transferase P1 polymorphisms: relationship to lung tissue enzyme activity and population frequency distribution. Carcinogenesis 1998; 19: 275-80. doi: 10.1093/carcin/19.2.275 27. Terrazzino S, La Mattina P, Masini L, Caltavuturo T, Gambaro G, Canonico PL, et al. Common variants of eNOS and XRCC1 genes may predict acute skin toxicity in breast cancer patients receiving radiotherapy after breast conserving surgery. Radiother Oncol 2012; 103: 199-205. doi: 10.1016/j. radonc.2011.12.002 28. Osti MF, Nicosia L, Agolli L, Gentile G, Falco T, Bracci S, et al. Potential role of single nucleotide polymorphisms of XRCC1, XRCC3, and RAD51 in predicting acute toxicity in rectal cancer patients treated with preopera- tive radiochemotherapy. Am J Clin Oncol 2017; 40: 535-42. doi: 10.1097/ COC.0000000000000182 29. Rodrigues-Fleming GH, Fernandes GMM, Russo A, Biselli-Chicote PM, Netinho JG, Pavarino É, et al. Molecular evaluation of glutathione S trans- ferase family genes in patients with sporadic colorectal cancer. World J Gastroenterol 2018; 24: 4462. doi: 10.3748/wjg.v24.i39.4462 30. Khabaz MN, Al-Maghrabi JA, Nedjadi T, Gar MA, Bakarman M, Gazzaz ZJ, et al. Does Val/Val genotype of GSTP1 enzyme affects susceptibility to colorectal cancer in Saudi Arabia. Neuro Endocrinol Lett 2016; 37: 46-52. PMID: 26994385 31. Gorukmez O, Yakut T, Gorukmez O, Sag SO, Topak A, Sahinturk S, et al. Glutathione S-transferase T1, M1 and P1 genetic polymorphisms and sus- ceptibility to colorectal cancer in Turkey. Asian Pac J Cancer Prev 2016; 17: 3855-9. PMID: 27644629 32. Vlaykova T, Miteva L, Gulubova M, Stanilova S. Ile 105 Val GSTP1 polymor- phism and susceptibility to colorectal carcinoma in Bulgarian population. Int J Colorectal Dis 2007; 22: 1209-15. doi: 10.1007/s00384-007-0305-z 33. Puerta-García E, Urbano-Pérez D, Carrasco-Campos MI, Pérez-Ramírez C, Segura-Pérez A, Calleja-Hernández, et al. Effect of DPYD, MTHFR, ABCB1, XRCC1, ERCC1 and GSTP1 on chemotherapy related toxicity in colorectal carcinoma. Surg Oncol 2020; 35: 388-98. doi: 10.1016/j.suronc.2020.09.016 34. Klusek J, Nasierowska-Guttmejer A, Kowalik A, Wawrzycka I, Lewitowicz P, Chrapek M, et al. GSTM1, GSTT1, and GSTP1 polymorphisms and colo- rectal cancer risk in Polish nonsmokers. Oncotarget 2018; 9: 21224. doi: 10.18632/oncotarget.25031 35. Liu J, Pan Y, Liu Y, Wei W, Hu X, Xin W, et al. The regulation of PTEN: Novel insights into functions as cancer biomarkers and therapeutic targets. J Cell Physiol 2023; 238: 1693-715. doi: 10.1002/jcp.31053 36. Papa A, Pandolfi P. The PTEN–PI3K axis in cancer. Biomolecules 2019; 9: 153. doi: 10.3390/biom9040153 37. Jang HY, Kim DH, Lee HJ, Kim WD, Kim SY, Hwang JJ, et al. Schedule- dependent synergistic effects of 5-fluorouracil and selumetinib in KRAS or BRAF mutant colon cancer models. Biochem Pharmacol 2019; 160: 110-20. doi: 10.1016/j.bcp.2018.12.017 38. Xu X, Chen G, Wu L, Liu L. Association of genetic polymorphisms in PTEN and additional gene–gene interaction with risk of esophageal squamous cell carcinoma in Chinese Han population. Dis Esophagus, 2016; 29: 944-9. doi: 10.1111/dote.12428 39. Hassan MH, Nassar AY, Meki AMA, Nasser SA, Bakri AH, Radwan E. Pharmacogenetic study of phosphatase and tensin homolog polymorphism (rs701848) in childhood epilepsy: relation to circulating Wnt signaling. Neurol Res 2024; 46: 99-110. doi: 10.1080/01616412.2023.2257465 40. Shek D, Read SA, Ahlenstiel G, Piatkov I. Pharmacogenetics of anticancer monoclonal antibodies. Cancer Drug Resistance 2019; 2: 69-81. doi: 10.20517/cdr.2018.20 Radiol Oncol 2025; 59(1): 121-131. doi: 10.2478/raon-2025-0013 121 research article Management of adrenocortical carcinoma in Slovenia: a real-life analysis of histopathologic markers, treatment patterns, prognostic factors, and survival Urska Bokal1, Jera Jeruc2, Tomaz Kocjan3,4, Metka Volavsek2, Janja Jerebic5, Matej Rakusa 3,4, Marina Mencinger1,4 1 Department of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia 2 Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 3 Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia 4 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 5 Department of Methodology, Faculty of Organizational Sciences, University of Maribor, Kranj, Slovenia Radiol Oncol 2025; 59(1): 121-131. Received 5 May 2024 Accepted 5 November 2024 Correspondence to: Assist. Marina Mencinger, M.D., Ph.D., Institute of Oncology Ljubljana, Zaloška 2, SI-1000 Ljubljana, Slovenia. E-mail: mmencinger@onko-i.si Disclosure: No potential conflicts of interest were disclosed. This is an open access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/). Background. Adrenocortical carcinoma (ACC) is a rare cancer that presents significant diagnostic and therapeutic challenges. We analyzed the management and estimated survival of ACC patients in Slovenia over a 17-year period. Patients and methods. Patients registered in the National Cancer Registry and treated from 2000 to 2017 were included. The survival and prognostic factors were assessed using the Kaplan-Meier method and Cox regression, respectively. Results. Forty-eight patients were included in our analysis. At the time of diagnosis, 6%, 42%, 25% and 27% had stage according European Network for the Study of Adrenal Tumors (ENSAT) I, II, III and IV, respectively. Adjuvant treatment with mitotane was assigned to 18 of 34 potentially eligible patients. High-risk patients treated with adjuvant mitotane showed a reduced probability of death, although the difference was not statistically significant. Relapses had numeri- cally higher rate of R1 resection and higher Ki67. Eleven patients underwent first-line therapy with etoposide, doxo- rubicin, cisplatin and mitotane (EDP-M). Their median progression-free survival was 4.4 months. The median overall survival of entire cohort was 28.9 and the median disease-specific survival (DSS) was 36.2 months. The 5-year DSS rate of ENSAT I, II, III and IV were 100%, 56%, 50% and 0%, respectively. The prognostic value of ENSAT stage and Helsinki score regarding overall survival was confirmed with the multivariate analysis. Conclusions. The 5-year DSS of our ENSAT II patients was worse than reported in contemporary cohorts. Suboptimal surgery and inconsistent adjuvant therapy with mitotane might have contributed to this outcome. Better outcomes of this rare disease might be accomplished with dedicated teams including various specialties, working towards optimal staging, diagnostic and therapeutic measures. Key words: adrenocortical carcinoma; Helsinki score; ENSAT stage; systemic treatment; survival; prognostic factors Introduction Adrenocortical carcinoma (ACC) is an aggressive orphan tumour. The annual incidence is around two cases per million people.1 The postoperative disease-free survival rate at five years is less than 50% and the 5-year survival rate for metastatic dis- ease worldwide remains dismal.2 About 50–60% of Radiol Oncol 2025; 59(1): 121-131. Bokal U et al. / Management of adrenocortical carcinoma in Slovenia122 patients with ACC have clinical hormone excess. In most cases, hypercortisolism (Cushing’s syn- drome) and/or virilisation syndrome due to andro- gen secretion are observed.3 As clinical, laboratory, and imaging features of ACC overlap with other benign and primary or secondary malignant adrenal tumours, the final diagnosis and malignant potential of an adrenal lesion depends largely on sophisticated histo- pathologic analysis of the surgical specimen. To fa- cilitate and standardize the diagnosis of ACC, sev- eral multiparametric scoring systems have been developed based on combined histopathological features, such as the Weiss score and the Helsinki score.4 The Weiss score considers nine histopatho- logic parameters and remains one of the most used scoring systems in clinical practice to classify con- ventional ACC in adults.5 A more recently devel- oped score, the Helsinki score, focuses on a combi- nation of the Ki67 proliferation index, mitotic rate, and the presence of necrosis. It can be used not on- ly for the diagnosis of conventional ACC, but also for oncocytic and myxoid variants.6 Two staging systems have been also proposed: TNM staging, which was revised in 2017 (AJCC cancer staging7), and the staging system by the European Network for the Study of Adrenal Tumors (ENSAT) in 2009.8 According to current clinical practice guide- lines, all patients with ACC and a high risk of re- currence after surgery (ENSAT stage III, R1 resec- tion or Ki67 >10%) should receive adjuvant treat- ment with mitotane.3 Recently published results of the ADIUVO trial did not support adjuvant treatment with mitotane in patients with low-in- termediate risk of recurrence (ENSAT stage I-III, R0 resection and Ki67 ≤ 10%).9 Only one phase III clinical trial (FIRM-ACT) was conducted in pa- tients with ACC. In this trial, etoposide, doxoru- bicin, and cisplatin (EDP) plus mitotane resulted in higher response rates and longer progression-free survival than streptozocin plus mitotane as first- line therapy, although there was no significant difference in overall survival.10 Recently, immune check point inhibitors and cabozantinib have been used successfully in some patients with ACC.11,12 Other treatment options are experimental at best.13 Locoregional therapies are recommended for slowly progressive oligometastatic disease or when a sustained response to systemic therapy has been achieved. In addition to surgery, there are other options such as radiotherapy, radiofrequency abla- tion and chemoembolization.3,14 We performed a retrospective analysis includ- ing histopathologic assessment of primary tu- mours and metastases, systemic treatment pat- terns, and outcomes of our patients with ACC over nearly two decades (2000-2017). In addition, we identified factors influencing survival. Patients and methods We conducted a retrospective cross-sectional study including all adult patients who were diagnosed with ACC from year 2000 to 2017 and were treated at the University Medical Centre Ljubljana and the Institute of Oncology Ljubljana. The patient list was taken from the National Cancer Registry. The study protocol was approved by the Review Board and Committee for the Medical Ethics of the Institute of Oncology in Ljubljana (ERIDEK - 0024/2020). A flowchart detailing the diagnostics and treatment decision-making process is shown in Figure 1. We used patients’ medical records to collect their demographic and clinical parameters, data on ENSAT stage at diagnosis, tumour size (defined as the largest diameter in axial plane), biochemically confirmed hormone hypersecretion, surgical treat- Endocrinology: hormonal work-up, imaging MTB: endocrinologist, radiotherapist, urologist, medical oncologist Clinical presentation or incidental imaging finding suggesting ACC Evaluation for adjuvant mitotane and radiotherapy, local surgery/ablative methods, systemic therapy Follow-up endocrinologist/medical oncologist MTB-multidisciplinary tumour Surgery Biopsy Histopathology Stage IV Stage I-III Primary or relapse M1 Locally advanced, high risk based on guidelines FIGURE 1. A patient flowchart describing the process of diagnostics and treatment decision-making. ACC = adrenocortical carcinoma; MTB = multidisciplinary tumour board; M1 = metastatic disease Radiol Oncol 2025; 59(1): 121-131. Bokal U et al. / Management of adrenocortical carcinoma in Slovenia 123 ment of the primary tumour, status of resection margins, adjuvant radiotherapy and adjuvant mi- totane treatment. We explored options for the first, the second and the third line of systemic treatment. Survival analyses and tests for prognostic factors were performed for the entire cohort. In accordance with our sample size, we chose to determine the prognostic significance of three variables: ENSAT stage (I and II versus III and IV), Helsinki score and hypercortisolism (present versus absent). The prognostic value of adjuvant mitotane treatment was analysed for the high-risk patients.3 In addi- tion, the prognostic value of the Ki67 index in me- tachronous metastasis or local recurrence (20 or more versus less than 20) was tested in univariate analysis. The cut-off value of 20 was used in anal- ogy to the cut-off values for primary tumours.15,16 Two additional assessments were carried out. First, data on local treatment options for meta- static/locally recurrent disease were analysed in detail. Several survival parameters were calcu- lated in patients who underwent surgery for local recurrence/oligometastatic disease. The median treatment-free interval (mTFI) was defined as the time from diagnosis of ACC to resection of the first metachronous metastasis. The median progres- sion-free survival (mPFS) was defined as the time from the local therapy of the first metastasis to the systemic disease progression or death. The median overall survival of this cohort (mOS) was defined as the time from diagnosis of ACC to death. Second, two experienced pathologists (MV and JJ) reviewed all available archival histologic tissue samples of primary tumours and metastases of the included patients. If multiple metastases or local recurrences were available, only the one that had been histologically analysed first was revised. The Weiss scoring system was used in all adrenalecto- my specimens except for the two patients with the oncocytic variant of ACC in which Weiss system tends to overdiagnose malignancy and Lin-Weiss- Bisceglia criteria are applied instead.17 The Weiss system was only used to evaluate adrenalectomy specimens, as it is not possible to perform the re- quired assessment of venous or capsular invasion in other types of specimens (e.g. needle biopsy, metastasis, excision of recurrent disease). The Helsinki index and the Ki67 proliferation index were determined using visual estimation method.18 Immunohistochemistry for Ki67 anti- gen (clone MIB-1, Dako, 1/50, UltraView) was per- formed using a Benchmark XT Ventana system according to manufacturer’s instructions. The cor- relation between the Weiss and the Helsinki score of the primary tumours was investigated. The Ki67 index and the Helsinki score of both specimens FIGURE 2. Our cohort according to European Network for the Study of Adrenal Tumors (ENSAT) stage, adjuvant mitotane treatment, relapses and different lines of systemic treatment. ACC = adrenocortical carcinoma; ST = systemic treatment Radiol Oncol 2025; 59(1): 121-131. Bokal U et al. / Management of adrenocortical carcinoma in Slovenia124 were compared in patients in whom the tissue from both, the primary tumour and the first local recurrence or metastasis was available. Statistical analyses Data for continuous variables were presented as median and range and for categorical data as fre- quencies and percentages. The cut-off date for the survival analysis was October 15, 2020. Survival outcomes were calculated using Kaplan-Meier method with 95% confidence intervals and pre- dictors of survival were calculated using Cox pro- portional hazards regression models. The p-values shown are two sided and the p-value < 0.05 was considered statistically significant. The calculations were performed using the statistic software pack- age IBM SPSS 28.0. Correlation between Weiss and Helsinki score of primary tumours was investigat- ed with Spearman’s rank correlation coefficient test. To further explore the prognostic power of Helsinki score receiver operating characteristic (ROC) analysis was done. Area under the ROC curve (AUC) was calculated to assess the ability of Helsinki score to differentiate between “alive” versus “death” status. The cut-off value of Helsinki score to differentiate between different prognostic groups was determined based on maximizing the Youden index in the context of the ROC curve. Results Patients’ characteristics Forty-nine adult patients were diagnosed with ACC at our two centres during the studied period (2000–2017). During histologic revision one patient was diagnosed with adenoma instead of ACC and was excluded from the analysis. Characteristics of all analysed patients and of the 20 patients who re- lapsed after radical surgery are shown in Table 1. One patient with ENSAT stage III was not treated with radical surgery as the tumour was considered inoperable. Figure 2 shows our cohort according to ENSAT stage, adjuvant mitotane treatment, relapses and different lines of systemic treatment. Adjuvant mitotane treatment Thirty-four patients, who were classified as ENSAT stage I-III underwent surgical removal of the prima- ry tumour and could have been considered eligible for adjuvant mitotane. However, 12 patients (35.3%, median age 49.5 years; 7 females), including 6 pa- tients at high risk of recurrence after surgery (Ki67 >10%3); of whom three were classified as ENSAT stage II and three as stage III, were not started on this treatment. Relevant data was absent for further 4 patients (11.8%). The remaining 18 patients (52.9%, median age 63 years; 9 females,) received mitotane. Half of the treated subgroup (or 9 patients) were classified as ENSAT stage II, 38.9% (or 7) as stage III, and 11.1% (or 2) as stage I. Ki67 was > 10% in 14 of these patients (77.8%) with missing data for one patient in ENSAT stage III. Collectively, only two patients at low/intermediate risk of recurrence after surgery (R0, Ki67 ≤ 10%3; classified as ENSAT stage I and stage II), received mitotane. Two patients were followed at another institu- tion, so further data about mitotane treatment was available for 16 patients. Median time from sur- gery of primary tumour to start of adjuvant mito- tane was 26.5 (range 6–126) days, while median du- ration of treatment was 17.4 (3–73) months with the median daily mitotane dose of 2750 (500 – 7000) mg. All patients were on concurrent hydrocorti- sone replacement therapy with median daily dose of 40 (15–45) mg. Three patients (18.7%) progressed when on mitotane after median time of 30 (10–31) months of treatment and one patient died of meta- static breast cancer in the 11th month of adjuvant mitotane treatment. All discontinuations of mito- tane during adjuvant treatment were permanent. Reason for stopping were adverse effects: gastro- intestinal in 2 (25.0%), hepatic in 2 (25.0%) neuro- cognitive in 1 (12.5%) and other in 3 (37.5%) cases. Data on mitotane plasma concentrations were not obtainable for most patients, so they were not in- cluded in the analysis. High-risk patients that re- ceived adjuvant mitotane had lower risk of death (HR 0.614, 95% CI 0.207-1.820), but the difference was not statistically significant (p = 0.379). Adjuvant radiotherapy Thirty-four patients classified as ENSAT stage I-III underwent surgical removal of the primary tu- mour. Of these 34, 16 had either R1 resection or/ and ENSAT stage III disease. One of these 16 pa- tients had both ENSAT III and R1 resection, 11 had ENSAT III and 4 had R1. Finally, only three of them received adjuvant radiotherapy (RT): one with R1 resection, one with ENSAT III and one with both criteria. All other potential candidates from this group did not receive adjuvant RT (one of them due to treatment refusal); but two other patients without criteria did. Radiol Oncol 2025; 59(1): 121-131. Bokal U et al. / Management of adrenocortical carcinoma in Slovenia 125 Systemic treatment regimens for inoperable locally advanced or metastatic disease Thirty-four out of 48 patients had inoperable lo- cally advanced or metastatic disease, either at the time of the primary diagnosis or recurring after surgery. Nine patients were referred to palliative care only. First-line systemic treatment regimens for the remaining 25 patients are listed in Table 2. The median age of 11 patients who were treat- ed with standard first-line chemotherapy (EDP- mitotane) was 56 years (range 29–70). Their perfor- mance status was 0 in 6 patients (54%), 1 in 4 pa- tients (36%) and 2 in 1 patient (9%). Median number of cycles received was 5 (range 2–7). The mPFS was 4.4 months (95% CI 1.5–7.3) and the mOS was 15.8 months (95% CI 7.7–23.8). Two patients achieved partial response (PR), 6 patients had stable disease (SD), and 3 patients had progressive disease (PD). There were no complete responses. The patient who received treatment with dac- arbazine, cyclophosphamide and vincristine were initially diagnosed with pheochromocytoma, but histologic revision from a highly specialized cen- tre confirmed the diagnosis of ACC. All 25 patients treated with first-line therapy progressed during the therapy or follow-up pe- riod; among them, 9 (36%) received 2nd line sys- temic treatment, which is listed in Table 3 together with responses achieved. Five patients who received second line therapy with gemcitabine and capecitabine had median number of 2.5 cycles (range 2-5), median progres- sion free survival 2.3 months (95% CI 1.5-3.1) and median overall survival 10.0 months (95% CI 1.9– 18.1). Third line therapy was prescribed to 4 patients: reintroduction of gemcitabine - capecitabine, met- ronomic therapy with cyclophosphamide, tha- lidomide plus mitotane, all of whom progressed. One patient received radionuclide therapy with 131I-iodometomidate in a highly specialised centre in Würzburg, Germany, and had survived for 8 months after referral. Survival rate of ENSAT stage I, II, III and IV The 5-year overall survival (OS) of patients with ENSAT stage I, II, III and IV was 100%, 50%, 50% and 0%. If stages I/II and III/IV were grouped to- gether the 5-year OS was 56.5% and 24%. The 5-year disease specific survival (DSS) was 100%, TABLE 1. Characteristics of all analysed patients and of the patients with European Network for the Study of Adrenal Tumors (ENSAT) I-III that relapsed after surgery with curative intent Characteristics All included N = 48 (%) Relapsed N = 20 (%) Age: median (range); years 56.6 (21–82) 54.0 (21–72) Sex Male 21 (44) 11 (55) Female 27 (56) 9 (45) ENSAT stage at diagnosis I 3 (6) 0 II 20 (42) 12 (60) III 12 (25) 8 (40) IV 13 (27) N/R Tumour size: median (range), cm 12 (4–30) 12.5 (5–30) Unknown 6 2 Hormone secretion Yes – GC* 17 (35) 5 (25) Yes – O 8 (17) 4 (20) No 20 (42) 11 (55) Unknown 3 (6) / Weiss score (median, range) 6 (4–9) 7 (5–9) N/D+ 15 1 Ki67 score** (median, range) 20 (1–70) 24 (8–60) N/D° 9 1 Helsinki score** (median, range) 28 (1–78) 31 (16–68) N/D° 9 1 Resection margins of patients stage I –III treated with curative surgery R0 26 (76) 17 (85) R1 5 (15) 3 (15) Rx 3 (9) / GC = glucocorticoids; O = other; N/D = not determined; N/R = not relevant; * = isolated or in combination with other hormones; ** = of primary tumour; + due to oncocytic variant (2), unavailability of tissue samples (3): primary not operated - 1 patient; tissue not available at our institutions - 2 patients), only fine needle (6) or core needle biopsy (4) of primary tumour or metastases; ° due to unavailability of tissue samples (3) or only fine needle biopsy of primary tumour or metastases (6) TABLE 2. First-line systemic treatment regimens for inoperable locally advanced or metastatic disease Treatment regimen Patients (N) EDP-mitotane 11 mitotane (+/- local therapy) 11 etoposide + carboplatin 1 dacarbazine + cyclophosphamide + vincristine 1 tamoxifen 1 EDP = etoposide, doxorubicin and cisplatin 56%, 50% and 0%, respectively. The 5-year OS of patients with ENSAT stage I-III who were diag- nosed before year 2010 was 61.9% and of patients with ENSAT stage I-III who were diagnosed after the year 2010 was 42.9%; the difference was not Radiol Oncol 2025; 59(1): 121-131. Bokal U et al. / Management of adrenocortical carcinoma in Slovenia126 statistically significant (p = 0.132). The mOS of pa- tients with ENSAT stage IV who were diagnosed before and after year 2010 was 1.5 months (95% CI 0.00 – 3.89) and 8.6 months (95% CI 0.42 – 16.73), respectively. This difference was also not statisti- cally significant (p = 0.338). Survival analysis of the whole cohort and prognostic factors The median follow-up of the cohort was 30.0 months; 36 (75%) patients died. The mOS was 28.9 months (95% CI 10.25-47.51). Three patients died for other reasons (not ACC). Median DSS was 36.2 months (95% CI 11.8-60.6). In univariate analysis significant impact of ENSAT stage III/ IV versus I/II (HR 2.989; 95% CI 1.483-6.023; p = 0.002) and Helsinki score (HR for each additional unit of Helsinki score 1.02; 95% CI 1.003–1.042; p = 0.021) on OS was confirmed, but not of hypercor- tisolism (HR 1.523; 95% CI 0.772–3.006; p = 0.225). Multivariate analysis confirmed the prognostic value of the ENSAT stage (HR 2.796; CI 95% 1.258– 6.212; p = 0.012) and Helsinki score (HR 1.027; 95% CI: 1.005–1.049; p = 0.015). Kaplan-Meier curves of OS according to ENSAT stage groups are shown in Figure 3. Fourteen of 34 patients who were operated on ACC ENSAT stage I-III remained disease free. Two patients progressed more than 5 years after sur- gery on primary tumour: 10 years and 9 months with local recurrence treated with surgery and RT, being alive at the time of the data cut-off; 5 years and 7 months with inoperable local recurrence, later further systemic progression and death. To further explore the prognostic power of Helsinki score ROC analysis was performed which was statistically significant (overall model quality 0.55) with AUC 0.761 (95% CI 0.551-0.971). The cut- off value for Helsinki score determining two prog- nostically different groups was 19.5. Locoregional treatment for primary metastatic or relapsing disease Only 6 patients from our cohort were treated for local recurrence or metastatic disease with local treatment methods. As a rule, surgery was per- formed; which was combined with radiofrequen- cy ablation (RFA) in only one patient. Patients who received only palliative radiotherapy were not in- cluded in this subgroup analysis. Most patients (5 out of 6 or 83%) had metachronous metastases that had occurred three months or more after surgery for the primary tumour.19 One patient had solitary synchronous liver metastasis that was resected concomitantly with the primary tumour. In anoth- er patient, surgery was performed multiple times and combined in the third session with RFA of two liver metastases and one thoracic metastasis that had spread through the diaphragm. Overall, local recurrences were resected in three (50%) patients, liver metastases in two (33%) patients and lung and vertebral metastases in one (16%) patient. Four patients: two with local recur- rence, one with liver metastasis and one after right pneumonectomy of multiple lung metastases re- ceived RT after the local surgery. The mTFI was 32.1 months (95% CI 17.6–131.3). The mPFS was 7.29 months (95% CI 0.00-61.2) and mOS was 65.5 months (95% CI 9.4-121.55). The two patients who received RT after surgery for local recurrence both remained disease-free. TABLE 3. Second line treatment regimens Treatment Patients (N) Response gemcitabine + capecitabine +/- mitotane 5 SD: 1PD: 4 EDP-mitotane 1 PR pembrolizumab 1 SD dacarbazine + capecitabine + imatinib 1 PD vinblastine + interferon alpha-2a 1 PD EDP = etoposide, doxorubicin and cisplatin; SD = stable disease, PD = progressive disease, PR = partial response FIGURE 3. Kaplan-Meier curves of overall survival according to European Network for the Study of Adrenal Tumors (ENSAT) stage. Radiol Oncol 2025; 59(1): 121-131. Bokal U et al. / Management of adrenocortical carcinoma in Slovenia 127 Histopathologic features Histopathologic analysis was possible in 40 of our patients where the diagnosis was confirmed histo- logically by either resection or core needle biopsy of the primary tumour or metastases. In six pa- tients, the primary tumour or metastases were on- ly verified cytologically and in two patients adre- nalectomy was performed but no tissue was avail- able for analysis at our two institutions. Archival tissue blocks of formalin-fixed paraffin-embedded (FFPE) tissue for analysis were obtained after ad- renalectomy (35: from 34 patients ENSAT stage I– III and one patient ENSAT stage IV), core needle biopsy of primary tumours (4) or metastatic depos- its (2) and resection of the first local recurrences or metastases (10). Histologic variants of ACC in our cohort were as follows: 35 had conventional ACC, two patients had oncocytic variant, two myxoid (one of them partial myxoid and partial conventional type), and one sarcomatoid variant. Survival of patients with pure myxoid (3.9 months) and sarcomatoid (6.5 months) histologic variant was less than the medium overall survival of the whole cohort (28.9 months). Both patients with oncocytic variant and the patient with partial myxoid variant (ENSAT stage I) were progression-free at the time of the data cut-off. As far as primary tumours were concerned, Weiss score was determined in 33 patients and Ki67 proliferation index and Helsinki score in samples from 39 patients. These data are shown in Table 1. In 12 metastatic/recurrent samples, the median Ki67 index was 27.5 (range 11–60) and the median Helsinki score was 35.5 (range 19–68). There was no correlation between Weiss and Helsinki scores of primary tumours as the Spearman’s correlation coefficient was - 0.092 (p = 0.612). In 11 patients, the tissue from resected primary tumours as well as from the first metastasis/local recurrence was available for investigation. Table 4 shows the com- parison between their Ki67 index and Helsinki score. Patients from 1 to 9 had local recurrence or me- tachronous metastasis. In the univariate analysis of this cohort those with Ki67 index of the local recurrence/metastasis of 20 or more (N = 6) had a statistically significantly shorter survival from the diagnosis of being metastatic/recurrent than the others (N = 3), HR 1.12 (95% CI 1.01 – 1.25), p = 0.033. Multivariate analysis was not performed due to small sample size. Discussion We have confirmed the poor prognosis of patients with ACC treated in routine clinical practice. In al- most half of our patients, the tumour was confined to the adrenal gland and less than one third had primary metastatic disease, which differs from the stage distribution in historic reports. In an older series of 42 patients diagnosed with ACC at Roswell Park Memorial Institute between 1929 and 1977, only 7% of patients had tumour confined to the adrenal gland, while 41% had locally advanced disease and 52% had metastatic disease.20 Wooten et al. reviewed data on ACC patients described in the English literature between 1952 and 1992 and found that only 31.8% of 608 patients had tumours confined to the adrenal gland.21 However, in con- temporary reports from Portugal and Finland, stages were distributed similarly to our cohort, with 43% and 59% of tumours confined to the adrenal gland, respectively.22,23 The observed con- temporary shift in ENSAT staging is likely due to earlier ACC diagnosis, resulting from better avail- ability of radiologic imaging, often performed for unrelated reasons (adrenal incidentalomas).23 In our series oncocytic and myxoid variants accounted for five percent of ACCs, while sarco- matoid variant was detected in 2.5% of all ACC included in the histopathologic analysis. The relative frequency of the variant histology is con- sistent with previously published data.4 As ex- pected, the clinical behaviour of patients with myxoid and sarcomatoid variants of ACC was TABLE 4. Ki67 proliferation index and Helsinki score shown for primary tumour (P) and first metastasis/local recurrence (M) Patient Ki67 Helsinki score P M P M 1 16 40 24 48 2 20 16 23 24 3 15 25 23 33 4 20 20 28 23 5 30 30 38 38 6 40 30 48 38 7 15 11 18 19 8 30 20 38 28 9 10 11 18 19 10 40 50 48 50 11 25 50 29 58 Radiol Oncol 2025; 59(1): 121-131. Bokal U et al. / Management of adrenocortical carcinoma in Slovenia128 worse than in patients with the classic variant and the behaviour of oncocytic ACC was better. The patient with the partial myxoid variant who was progression-free at the time of the data cut- off, was diagnosed as ENSAT stage I, which was probably the most important factor for their good prognosis. Presumably, favourable stage distribu- tion and access to systemic treatments impacted the median OS of our entire cohort (28.9 months), which is longer than observed historically (14 months).20 Five-year overall survival rate of our ENSAT stage III (50%) and IV (0%) patients is com- parable to published series from Portugal22 (56%; 0%) and Finnland23 (stage III/IV 24% for our cohort vs. 26%). On the other hand, five-year survival rate of our ENSAT stage II patients is inferior to both Portuguese (stage I/II 56.5% vs. 67%) and especially to Finnish cohort (stage I/II 96%). Worse outcome can be at least partially explained by incomplete resections24 (four patients with ENSAT stage II had R1 resection), less than optimal surgical technique by non-expert surgeon, e.g. not performing con- comitant regional lymphadenectomy (four out of five patients operated by non-urologists relapsed), and lack of adjuvant mitotane therapy (three pa- tients with stage II should receive it due to high Ki67 but did not). In addition, some of our early ENSAT stage II patients might have been misclas- sified due to suboptimal staging, e.g. performing a chest X-ray instead of a CT. A higher percentage of stage I tumours in the Finnish cohort (19% versus 6% in our cohort) might have been also partially responsible for the difference. The five-year over- all survival of our ENSAT I-III patients diagnosed after 2010 was not better than before 2010. Less favourable stage distribution without any ENSAT stage I patients diagnosed after year 2010 might have contributed to the lack of improvement. This indicates that during our observed period 2000 – 2017 there was no trend in detecting disease ear- lier; this trend was only observed in comparison to historic cohorts as discussed previously. In the Finnish cohort, 79% of patients received adjuvant mitotane therapy, which was reported as a factor associated with better survival in this study.23 Mitotane was prescribed to everybody af- ter successful surgery except in cases with a very low risk for recurrence according to an expert opinion.25 No such straight-forward reasoning was present in our cohort. Only 52.9% of the patients started therapy with mitotane, therefore, 6 patients at high risk of recurrence after surgery3 might have been inappropriately excluded from this treat- ment. The main reason for this undertreatment was a lack of clinical practice guidelines on the management of ACC3 during the observed period causing not only uncertainties in the mitotane use, but also patients’ refusal of this treatment in some cases. Interestingly, similar inconsistency was also apparent in a recent Italian national cohort study where among 134 operated ACC patients selected just for surveillance 44.4% had Ki67 > 10%.26 On the positive side, only two of our patients who were started on mitotane were at low/intermediate risk of recurrence after surgery and might have been overtreated.9 Furthermore, most of our patients started with mitotane within the ideal 6 weeks after surgery. The drug was mostly administered for at least two years, but no longer than 5 years, as recommended.3 Some patients did not follow this pattern and there were 9 permanent discon- tinuations due to adverse effects like in other co- horts.22,23 Hydrocortisone supplementation was a uniform feature of all our patients on mitotane. However, our daily hydrocortisone replacement doses (median 40 mg, range 15–45 mg) might not have been entirely sufficient, as these patients typically require 50 mg or even up to 100 mg daily due to increased hydrocortisone clearance and in- creased cortisol-binding globulin.25,27 If our high- risk patients received adjuvant mitotane, they had better survival, as it was previously shown else- where.23 A lack of statistical significance could be attributed to small size of our cohort. The most frequent combined chemotherapy used for the first line treatment was EDP-M pro- tocol, which is the suggested treatment by the guidelines3,14 according to the results of FIRM-ACT trial.10 The outcomes of our patients who received the first line EDP-M treatment in real-life clini- cal practice were comparable to the results of that trial (mPFS 4.4 months (95% CI 1.5–7.3) versus 5.0 months (95% CI 3.5–6.9), mOS 15.8 months (95% CI 7.7-23.8) versus 14.8 months (95% CI 11.3–17.1), which probably reflects the fact that only patients with a good performance status were treated in such way (mostly WHO PS 0/1 and only 1 patient WHO PS 2). Monotherapy with mitotane was used as frequently for the first line therapy as the EDP-M protocol. Among reasons for the monotherapy with mitotane were poor performance status, co- morbidities and patients’ refusal of chemotherapy. No comparison between EDP-M protocol and mi- totane monotherapy could be made since patients in the latter group were in worse general health. Further lines of treatment were poorly effective, and few patients were able to receive them (36% of patients treated with the first line and 44% of Radiol Oncol 2025; 59(1): 121-131. Bokal U et al. / Management of adrenocortical carcinoma in Slovenia 129 patients treated with the second line therapy). In this setting, there is no proven systemic therapy showing improved survival in a randomised con- trolled trial. Accordingly, the selection of second- line treatment for our patients was based on small phase 2 trials or even case reports.28,29 The mOS of patients who received systemic treatment for advanced disease was 13.0 months (95% CI 5.1–20.8) which is less than the mOS of 18.7 months that was observed by the Ohio State University Comprehensive Cancer Centre be- tween years 1997 and 2016.30 In their cohort 64% of patients received the second line treatment and they also had the possibility to participate in clini- cal trials. This emphasizes the importance of col- laboration with international specialised centres when treating this rare disease.31 In our cohort the mOS of patients with ENSAT stage IV diagnosed after year 2010 is higher in comparison to those who were diagnosed until year 2010 which may reflect better systemic treatment options in the re- cent decade, although the difference is not statisti- cally significant. Two patients experienced relapse of the disease more than 5 years from surgery of the primary tumour, which supports the continu- ation of follow-up beyond 5 years as suggested by the clinical guidelines.3 Only six patients were treated with local ther- apy for relapsing/metastatic disease. Five patients had surgical resection of their solitary metastatic lesions according to the guidelines where routine use of surgery in widespread disease is not recom- mended.3 The remaining patient who underwent surgery despite several synchronous metastases died after only three months reflecting the futil- ity of the approach due to more aggressive disease. Contrary to that, the other 5 patients had a slowly progressive disease as indicated by mPFS that was 7.3 months and mTFI that was 31.1 months. Two patients had been disease-free for more than 10 years after surgery of local recurrence, which further dictates a tight follow up with an early detection of resectable local recurrence to benefit some patients. Both patients with long last- ing remission received also postoperative radia- tion. A large recent study in advanced ACC pro- vided evidence that RT can be effective.32 Importantly, only 3 out of our 5 patients who re- ceived adjuvant RT, were appropriately selected ac- cording to current guidelines. On the other hand, 9 of 13 patients classified as ENSAT stage III and/or having R1 resection were not offered adjuvant RT after surgery for a primary tumour. According to current guidelines adjuvant RT should be consid- ered on an individual basis (in addition to mito- tane) in patients with R1 or RX resection or/and in ENSAT stage III.3 Retrospective data showed that adjuvant RT can reduce the risk of local recurrence but does not prevent distant recurrences and, con- sequently, does not impact OS.32 Randomised data on the usefulness of RT after surgical resection of primary tumour and of metastases are needed. Only a single patient underwent RFA. Other locoregional methods such as stereotactic radia- tion or chemoembolization of metastases were not used. Contrary to our approach, it is currently rec- ommended to use several local therapeutic meas- ures on an individual basis in addition to surgery for advanced ACC.3 Furthermore, a recent retro- spective analysis of 106 patients supported the use of locoregional treatments to treat ACC recur- rence.33 It is reasonable to assume that close col- laboration with an interventional radiologist could have optimised palliation in a larger proportion of our patients with metastases amenable for local treatment. Not only the disease stage, but also margin- free (R0) resection, glucocorticoid excess and Ki67 proliferation marker were suggested as prognostic factors of survival.14 Due to small sample size only ENSAT stage, Helsinki score and hypercortisolism were tested as prognostic factors. In multivariant analysis, both ENSAT stage and Helsinki score predicted survival. Helsinki score was validated as a prognostic marker for ACC in several other stud- ies.6,34,35 Unlike ENSAT stage and Ki67, Helsinki score was not found to have prognostic value in a recent series of patients with ACC from Finland.23 Helsinki score includes two proliferation markers (Ki67 immunohistochemistry and mitotic count) and necrosis. While the prognostic value of prolif- eration has been validated in many studies on the Weiss parameter15,36,37,38,39, the presence of necrosis, on the other hand, has only recently been suggest- ed as the most powerful ominous factor and the best predictor of OS and DFS in ACC patients.40 No correlation between Helsinki and Weiss score was found in our cohort, which is different from the findings of another study showing strong positive correlation between these two scoring systems.41 In addition to low number of patients included in our calculation, technical issues with respect to Ki67 immunohistochemistry on archi- val samples not allowing optimal evaluation could partially explain these discrepancies. In our cohort, the cut-off value for the Helsinki score of 19.5 performed best in terms of prognos- tic stratification. In comparison, Pennanen et al. Radiol Oncol 2025; 59(1): 121-131. Bokal U et al. / Management of adrenocortical carcinoma in Slovenia130 proposed a lower cut-off value of 17 to distinguish tumours with prolonged survival from rapidly progressing tumours.34 Duregon et al. used the Helsinki scores of 13 and 19 to classify patients in- to three prognostically distinct groups.6 In a more recent study, the Helsinki score of 20 was identi- fied as one of the strongest independent predictors of death, being able to distinguish tumours with prolonged survival from those with rapid progres- sion.35 In our cohort, there were not enough pa- tients with low Helsinki scores to allow stratifica- tion into three groups. Several patients with a high Helsinki score had a favourable clinical course, possibly due to relatively small tumour size, com- plete surgical resection, and good response to treatment. Based on our and similar studies, there is probably no exact cut-off value for the Helsinki score to prognosticate disease, but rather a range between 17 and 20. We did not find a general tendency towards a higher Ki67 index in metastases compared to pri- mary tumours, as it was shown by study investi- gating the Ki67 index in primary breast cancer and corresponding metastases.42 Nevertheless, previ- ously published data for primary ACC tumours15,16 and our analysis of the Ki67 index of the first local recurrence/metachronous metastasis showed that a Ki67 index < 20 might correlate with a slower pro- gression compared to Ki67 ≥ 20. There is similarity to what was demonstrated in breast cancer, where a low Ki67 index in metastasis was associated with longer survival independently of primary tumour proliferation.43 Beside TFI indicating aggressive- ness of a disease course, analysis of Ki67 in a me- tastasis may be beneficial to indicate slowly pro- gressing disease as has already been suggested in breast cancer.43 However, more data are needed to draw any firm conclusions. Our study has some limitations due to its retro- spective methodology and incomplete information from patient charts. In addition, archived FFPE material of varying quality and age, originating from different institutions had to be re-examined. Importantly, patients treated with mitotane were not compared according to their mitotane plasma concentrations due to missing data. Small sample size allowed only few prognostic factors to be test- ed. The main strength of our study is the joint ef- fort of pathologists, endocrinologists and medi- cal oncologists to comprehensively review the management of ACC in Slovenia over the last two decades. We tried to highlight the available good practices while also exposing the shortcomings. In particular, the importance of the appropriate his- topathology diagnosis and strict adherence to the clinical guidelines if available were pointed out to improve all aspects of management from expert surgery and adjuvant mitotane treatment to lo- coregional therapies. Conclusions Research on ACC is partially hampered by the rar- ity of this type of cancer. Therefore, the presented real-world data might help the clinicians to im- prove the management of this rare and often fatal disease. A multidisciplinary approach, as high- lighted here, is of paramount importance, and has already been shown to impact survival.44 Acknowledgments We are indebted to Antonela Sabati Rajić, M.D. who started to systematically collect data about our patients with ACC. We also acknowledge the help of everybody else involved in the manage- ment of our patients with ACC. References 1. Kerkhofs TM, Verhoeven RH, Van der Zwan JM, Dieleman J, Kerstens MN, Links TP, et al. 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Ki67 meas- ured in metastatic tissue and prognosis in patients with advanced breast cancer. Breast Cancer Res Treat 2014; 147: 407-14. doi: 10.1007/s10549- 014-3096-2 44. Tizianel I, Caccese M, Torresan F, Lombardi G, Evangelista L, Crimì F, et al. The overall survival and progression-free survival in patients with advanced adrenocortical cancer is increased after the multidisciplinary team evalua- tion. Cancers 2022; 14: 3904. doi: 10.3390/cancers14163904 Radiol Oncol 2025; 59(1): 132-138. doi: 10.2478/raon-2025-0003 132 research article Effectiveness of tramadol or topic lidocaine compared to epidural or opioid analgesia on postoperative analgesia in laparoscopic colorectal tumor resection Alenka Spindler-Vesel1,2, Matej Jenko1,2, Ajsa Repar3, Iztok Potocnik2,3, Jasmina Markovic-Bozic1,2 1 Clinical Department of Anaesthesiology and Intensive Care Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia 2 Medical Faculty, University of Ljubljana, Slovenia 3 Department of Anaesthesiology and Intensive Care, Institute of Oncology Ljubljana, Slovenia Radiol Oncol 2025; 59(1): 132-138. Received 18 June 2024 Accepted 24 October 2024 Correspondence to: Assist. Prof. Jasmina Markovič Božič, M.D., Ph.D., Clinical Department of Anaesthesiology and Surgical Intensive Therapy. University Medical Centre Ljubljana, Zaloška c. 7, 1525 Ljubljana, Slovenia. E-mail: jasmina.markovic1@kclj.si Disclosure: No potential conflicts of interest were disclosed. This is an open access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/). Background. Chronic postoperative pain is the most common postoperative complication that impairs quality of life. Postoperative pain gradually develops into neuropathic pain. Multimodal analgesia targets multiple points in the pain pathway and influences the mechanisms of pain chronification. Patients and methods. We investigated whether a lidocaine patch at the wound site or an infusion of metamizole and tramadol can reduce opioid consumption during laparoscopic colorectal surgery and whether the results are comparable to those of epidural analgesia. Patients were randomly divided into four groups according to the type of postoperative analgesia. Group 1 consisted of 20 patients who received an infusion of piritramide. Group 2 consisted of 21 patients who received an infusion of metamizole and tramadol. Group 3 consisted of 20 patients who received patient-controlled epidural analgesia. Group 4 consisted of 22 patients who received piritramide together with a 5% lidocaine patch on the wound site. The occurrence of neuropathic pain was also investigated. Results. Piritramide consumption was significantly lowest in group 3 on the day of surgery and on the first and second day after surgery. Group 4 required significantly less piritramide than group 1 on the day of surgery and on the first and second day after surgery. The group with metamizole and tramadol required significantly less piritramide than groups 1 and 4 on the first and second day after surgery. On the day of surgery, this group required the highest amount of piritramide. Conclusions. Weak opioids such as tramadol in combination with non-opioids such as metamizole were as effective as epidural analgesia in terms of postoperative analgesia and opioid consumption. A lidocaine patch in combination with an infusion of piritramide have been able to reduce opioid consumption. Key words. laparoscopic surgery; colorectal tumor; postoperative analgesia; topical analgesia; epidural analgesia; opioid analgesia Introduction Chronic postoperative pain is one of the most common postoperative complications that se- verely impair patients’ quality of life. It occurs in about 10% of patients after major surgery and is a major health and economic problem. It typically starts as acute postoperative pain that is difficult Radiol Oncol 2025; 59(1): 132-138. Spindler-Vesel A et al. / Effectiveness of postoperative analgesia in laparoscopic colorectal tumor resection 133 to control and gradually turns into persistent neu- ropathic pain. Multimodal analgesics have the po- tential to reduce acute postoperative pain and tar- get multiple points in the pain pathway. For this reason, postoperative pain management should be multimodal and opioid sparing.1 Thoracic epi- dural analgesia could alleviate pain after laparo- scopic surgery.2-4 Although ERAS guidelines rec- ommend the use of less invasive techniques for pain relief5-8, opioids are frequently used periop- eratively despite their side effects.9-11 Non-opioids and 5% lidocaine patches applied topically could effectively reduce the use of opioids and their side effects.12,13 Indeed, efficient perioperative pain manage- ment is important to prevent late neuropathic pain, even after laparoscopic lower abdominal surgery. The incidence is generally low compared to open surgery.14 In comparison to epidural or opioid analge- sia, we wanted to investigate whether a lidocaine patch at the wound site or an infusion of metami- zole and tramadol can reduce opioid consumption in laparoscopic colorectal surgery and whether the results are comparable to those of epidural analge- sia. We also compared the incidence of postopera- tive neuropathic pain between the groups. The primary outcome of this study was opioid consumption (piritramide) during the postopera- tive period, measured at three time points (imme- diately after surgery, the first postoperative day, and the second postoperative day). Secondary out- comes included pain assessment (VAS scores) and the incidence of postoperative neuropathic pain. Patients and methods A prospective, randomised study with four paral- lel groups was conducted at the University Medical Centre (UMC) Ljubljana. The study included pa- tients from the Clinical Department of Abdominal Surgery who were categorised as high-risk ASA (American Society of Anaesthesiologists) class 2–3 surgical patients. Adult patients who had under- gone laparoscopic colorectal tumor resection were included in the study. Exclusion criteria included minors, pregnant women, patients undergoing laparotomy and patients undergoing palliative procedures. The study was approved by the Slovenian National Medical Ethics Committee (151/03/09, 220/03/09, 148/06/11) and registered with Clinical Trials under the ID number NCT04719884. Each patient was visited by a member of the re- search team one day prior to surgery to obtain in- formed consent and clarify any questions. Patients were randomised into four groups based on the type of postoperative analgesia. They were ran- domly assigned to one of four treatment groups using computer-generated random numbers. Randomization was performed prior to surgery by an independent statistician (simple randomisation was used), and allocation was concealed until the intervention was applied. Group 1 consisted of 20 patients who received an infusion of piritramide (patient-controlled anal- gesia, PCA). Group 2 consisted of 21 patients who received an infusion of metamizole and tramadol. FIGURE 1. Consort chart of the study. Thet diagram shows the flow of participants through each stage of a randomized trial. PCA = patient-controlled analgesia; PCEA = patient-controlled epidural analgesia Radiol Oncol 2025; 59(1): 132-138. Spindler-Vesel A et al. / Effectiveness of postoperative analgesia in laparoscopic colorectal tumor resection134 Group 3 consisted of 20 patients who received pa- tient-controlled epidural analgesia (PCEA). Group 4 consisted of 22 patients who received PCA to- gether with a 5% lidocaine patch on the wound site (Figure 1). Anaesthesia was performed by two anaes- thetists, with the technique being uniform in all groups. Standard monitoring was performed. On admission, intravenous access was established, and patients were premedicated with midazolam. In group 3, a thoracic epidural catheter was inserted at the level of Th 7–8 in the left lateral position before the procedure and tested with 3 ml of 2% lidocaine. Standard induction protocols were followed, in- cluding propofol (1–2 mg/kg) or etomidate (0.2 mg/ kg), fentanyl (3–5 μg/kg) and vecuronium (0.1 mg/ kg) or rocuronium (0.6 mg/kg). Anaesthesia was maintained with sevoflurane to keep the BIS value between 40 and 55. Analgesia was supplemented with fentanyl in groups 1, 2 and 4, while levobupiv- acaine 0.5% epidural was administered in group 2. Muscle relaxation was monitored and vecuro- nium (2–4 mg) or rocuronium (10–20 mg) was ad- ministered depending on the TOF values. At the end of the procedure, the volatile agents were dis- continued, and the muscle blockade was reversed with neostigmine (2.5 mg) and atropine (1 mg) or sugammadex (2 mg/kg). Postoperative analgesia began during wound closure: in group 1 with PCA (piritramide 0.5 mg/ ml; infusion 1.5 mg/h, bolus 1.5 mg, lockout 30 minutes), in group 2 with an infusion of tramadol 300 mg and metamizole 2.5 g (in 500 ml 0.9% NaCl, infusion rate 40 ml/h), in group 3 with PCEA (200 ml 0.125% levobupivacaine, 4 mg morphine, 0.075 mg clonidine; infusion 5 ml/h, bolus 5 ml, cut-off time 30 minutes) and in group 4 with PCA (piri- tramide 0.5 mg/ml; infusion 0.5 mg/h, bolus 1.5 mg, cut-off time 20 minutes) in combination with a 5% lidocaine patch on both sides of the wound. The plaster was removed after 12 hours and reap- plied after a 12-hour break. In all groups, paracet- TABLE 1. General patients’ and procedure characteristics Group 1 (PCA) Group 2 (tramadol- metamizole) Group 3 (PCEA) Group 4 (PCA and lidocaine) p Age (years) 59 65 60 59 0,394 Weight (kg) 76 75 79 76 0,833 Wound length (cm) 6,55 7,17 7,45 7,90 0,286 Duration of surgery (min) 139 133 117 112 0,024 Duration of hospitalization (days) 8 9 8 10 0,380 Day of first defecation 4 4 5 4 0,571 ANOVA test was used for comparison. p value of < 0.05 is statistically significant. PCA = patient-controlled analgesia; PCEA = patient-controlled epidural analgesia TABLE 2. Comparison of piritramide consumption between the group pairs Comparison P value (day 0) P value (day 1) P value (day 2) PCA PCEA 0.938 < 0.001 < 0.001 PCA tramadol-metamizole 0.083 < 0.001 < 0.001 PCA PCA + lidocaine 0.995 0.003 0.026 PCEA tramadol-metamizole 0.008 0.352 0.038 PCEA PCA + lidocaine 0.862 < 0 .001 < 0 .001 PCA + lidocaine tramadol-metamizole 0.030 < 0.001 < 0.001 Dwass-Steel-Critchlow-Fligner pairwise comparisons. p value of < 0.05 is statistically significant. PCA = patient-controlled analgesia; PCEA = patient-controlled epidural analgesia Radiol Oncol 2025; 59(1): 132-138. Spindler-Vesel A et al. / Effectiveness of postoperative analgesia in laparoscopic colorectal tumor resection 135 amol 1g/6–8hrs iv was administered regularly. In groups 1, 3 and 4, metamizole 2,5g/12hrs iv was also prescribed. The prescribed analgesia in all four groups was not changed during the study, as it would have made it more difficult to evaluate the difference in additional bolus consumption of piritramide. We monitored the side effects of the analgesics. Appropriate antiemetic therapy was planned, but our patients did not require it. No significant sedative effects were observed. After the operation, the patients were trans- ferred to the post-operative care unit (PACU) and later to the intensive care unit of the abdominal surgery department. They received additional bo- luses of piritramide (3 mg) if required. The dura- tion of the operation and the length of the wound were recorded intraoperatively. In the following two postoperative days, data such as visual ana- logue scale (VAS) scores, piritramide consump- tion, length of hospital stay and readmission to hospital were recorded. VAS was evaluated every six hours and when the additional piritramide bo- lus was needed. The DN4 (Douleur Neuropathique 4) and Pain Detect questionnaires were used to assess the oc- currence of neuropathic pain 30 days after surgery. Statistical analysis The results were analysed with R: A language and environment for statistical computing. (R Foundation for Statistical Computing, Vienna, Austria). The ANOVA test was used to determine differences between the study groups. Pairwise comparisons were performed using the Dwass- Steel-Critchlow-Fligner test. A p-value of < 0.05 was considered statistically significant. Power analysis A power analysis was performed to determine the appropriate sample size. Based on previous data from patients treated at our department and clinical relevance, we assumed a minimum effect size of 0.5 (Cohen’s d) for the reduction in opioid consumption between groups (based on previ- ous data, this corresponds to 3mg of piritramide). This effect size was considered clinically signifi- cant. To detect this effect with 80% power and a significance level of 0.05, a total of 80 patients (ap- proximately 20 per group) were required. The cal- culation was performed using standard formulas FIGURE 2. Piritramide consumption on day of surgery (day 0). FIGURE 3. Piritramide consumption on first postoperative day (day 1). PCA = patient-controlled analgesia; PCEA = patient-controlled epidural analgesia FIGURE 4. Piritramide consumption on second postoperative day (day 2). PCA = patient-controlled analgesia; PCEA = patient-controlled epidural analgesia Radiol Oncol 2025; 59(1): 132-138. Spindler-Vesel A et al. / Effectiveness of postoperative analgesia in laparoscopic colorectal tumor resection136 for comparing means in four independent groups (ANOVA). Results We analysed the data of 20 patients in group 1, 21 patients in group 2, 20 patients in group 3 and 22 patients in group 4 (Figure 1). The general patient characteristics, length of wound and duration of surgery are shown in Table 1. The duration of surgery was significantly shorter in the lidocaine group (p = 0.024). There was no statistically significant difference between the characteristics listed in Table 1 with regard to the gender or ASA status of the patients. In each group, patients were equally distributed in terms of gender. In group 1, there were 19 colon resections and 1 rectal resection. In group 2, there were 8 rectal re- sections and 12 colon resections. In group 3, there were 2 rectal resections and 18 colon resections, while in group 4, there were 3 rectal resections and 19 colon resections. All surgeries were lapa- roscopic. Patients in our study did not undergo ad- ditional anorectal excision during rectal surgeries. The duration of rectal surgeries and the length of postoperative wounds were comparable to bowel resections; therefore, we treated all surgeries as a group of laparoscopic colorectal resections. There was no statistically significant difference in VAS scores between the groups. The VAS scores were low (below 3). Figures 2–4 and Table 2 show the comparison of piritramide consumption on three consecutive postoperative days. After surgery, patients in group 3 (PCEA) re- quired less piritramide than patients in group 2 (tramadol-metamizole) (p < 0.08). There were no differences in piritramide consumption between patients in groups 2 and 3 on the first day after surgery, but on the second day after surgery, pa- tients in group 3 required less piritramide than those in group 2 (p < 0.038). Similarly, patients in group 4 (PCA + lidocaine) required less pirit- ramide than patients in group 2 (p < 0.03) on the day of the surgery. But on the first and second day after surgery, patients in groups 2 and 3 received statistically significantly less piritramide than patients in groups 1 and 4 (p < 0.001). Patients in group 4 required statistically significantly less pi- ritramide than patients in group 1 both on the first day (p < 0.003) and on the second day after surgery (p < 0.026). There were no significant differences between groups in Pain Detect or DN4 questionnaires scores using the Anova test (Table 3). Discussion Postoperative pain is managed in different ways in patients undergoing elective colorectal tumor resection, affecting patient outcomes and pain scores. The epidural catheter provides superior analge- sia for colorectal surgery, whether performed lapa- roscopically or with laparotomy.15 However, due to the frequent prolongation of the bowel recov- ery period and potential complications associated with catheter insertion, epidural analgesia is often replaced by other methods in minimally invasive procedures.2,4,5,16 Intravenous opioid-based patient- controlled analgesia (PCA) is a common method of postoperative analgesia, but peripheral analge- sics could also be used to attenuate the side effects of opioids.7,9,11 Therefore, group 2 in our study re- ceived an infusion of the weak opioid tramadol and metamizole. We found that the consumption of pi- ritramide was significantly reduced in this group on two consecutive days after surgery compared to group 1 (PCA) and group 4 (PCA + lidocaine). However, there was a significant requirement for additional opioids immediately after surgery. As expected, no additional analgesia was required in the epidural analgesia group. Pain scores measured using the VAS scale were low (below 3), indicating adequate postoperative analgesia in all groups. Several studies have shown that intravenous administration of lidocaine (for both laparoscopic and laparotomy procedures) improves postopera- tive analgesia in colorectal surgery, improves bow- el function and shortens hospital stay.6,17-22 Studies TABLE 3. The scores from Pain Detect and DN4 (Douleur Neuropathique 4) questionnaires in the study groups Group (No. of answers) Pain score (mean ± SD) DN4 (mean ± SD) PCA (12) 0 0 Tramadol and metamizole (12) 1.2 ±2.1 0.2 ± 0.4 PCEA (15) 0.1 ± 0.5 0.1 ± 0.4 Lidocaine (17) 0.06 ± 0.2 0 ANOVA test was used for comparison. p value of < 0.05 is statistically significant. DN4 = Douleur Neuropathique 4; PCA = patient-controlled analgesia; PCEA = patient- controlled epidural analgesia Radiol Oncol 2025; 59(1): 132-138. Spindler-Vesel A et al. / Effectiveness of postoperative analgesia in laparoscopic colorectal tumor resection 137 have also shown potential benefits in terms of long-term cancer outcomes.23 Patients receiving lidocaine reported low pain scores, but piritramide consumption was relatively high due to the additional PCA infusion. It is like- ly that total opioid consumption would have been significantly lower if only PCA bolus infusions had been programmed.22,24 The use of lidocaine patches did not result in lower opioid consumption after thoracotomy and sternotomy.25 In a study of 103 patients undergoing elective laparoscopic colorectal surgery, thoracic epidural anaesthesia, spinal diamorphine and PCA were compared. It was found that the use of patient-controlled analgesia was associated with significantly higher postoperative pain scores and higher pain intensity.26 Recovery of bowel function after laparoscopic colorectal surgery was similar in the epidural anal- gesia and intravenous lidocaine groups, although epidural analgesia provided better pain relief.27 In our study, topical lidocaine was applied to the wound site in group 4. Compared to the PCA group, topical lidocaine also reduced piritramide consumption but had no favourable effects on bow- el function, probably due to the local effect of lido- caine rather than systemic effects. No differences were observed in the postoperative recovery of bowel function in any of our groups. This finding is consistent with observations in another study of open colon resection, in which no differences were found between the epidural, intravenous opioid or intravenous lidocaine groups in terms of recovery of bowel function, length of hospital stay and post- operative pain control.28 67% of participants (56/83) completed pain ques- tionnaires and no neuropathic pain was noted 30 days after surgery, which is consistent with obser- vations from another study of laparoscopic colo- rectal surgery.29 The incidence of neuropathic pain is generally not expected in laparoscopic abdomi- nal surgery and does not exceed 5%.14 However, the reported incidence of chronic postoperative pain after laparoscopic colorectal surgery is 17%, similar to laparotomy.30 Conclusions In laparoscopic colorectal tumor surgery, weak opioid tramadol in combination with non-opioid metamizole could be as effective as patient-con- trolled epidural analgesia (PCEA) in terms of post- operative analgesia and opioid consumption. 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Eur J Anaesthesiol 2015; 32: 712-7. doi: 10.1097/EJA.0000000000000268 Radiol Oncol 2025; 59(1): 139-146. doi: 10.2478/raon-2025-0006 139 research article Interobserver and sequence variability in the delineation of pelvic organs at risk on magnetic resonance images Wanjia Zheng1,2, Xin Yang1,3,4, Zesen Cheng1,5, Jinxing Lian1,6, Enting Li1,7, Shaoling Mo1,8, Yimei Liu1, Sijuan Huang1,3,4 1 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong Province, China 2 Department of Radiation Oncology, Southern Theater Air Force Hospital of the People’s Liberation Army, Guangzhou, Guangdong Province, China 3 Guangdong Esophageal Cancer Institute, Guangzhou, Guangdong Province, China 4 United Laboratory of Frontier Radiotherapy Technology of Sun Yat-sen University & Chinese Academy of Sciences Ion Medical Technology Co., Ltd, Guangzhou, Guangdong Province, China 5 School of Electronic and Computer Engineering, Peking University, Shenzhen, Guangdong province, China 6 Department of Radiation Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong province, China 7 Department of Radiology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong province, China 8 Department of Radiation Oncology, The First People’s Hospital of Foshan, Foshan, Guangdong province, China Radiol Oncol 2025; 59(1): 139-146. Received 14 07 2024 Accepted 20 11 2024 Correspondence to: Sijuan Huang, Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, 651 Dongfeng East Road, Yue Xiu District, Guangzhou, P. R. China. E-mail: huangsj@sysucc.org.cn Wanjia Zheng and Xin Yang contributed equally to this work and should be considered co-first authors. Disclosure: No potential conflicts of interest were disclosed. This is an open access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/). Background. This study evaluates the contouring variability among observers using MR images reconstructed by dif- ferent sequences and quantifies the differences of automatic segmentation models for different sequences. Patients and methods. Eighty-three patients with pelvic tumors underwent T1-weighted image (T1WI), contrast enhanced Dixon T1-weighted (T1dixonc), and T2-weighted image (T2WI) MR imaging on a simulator. Two observers performed manual delineation of the bladder, anal canal, rectum, and femoral heads on all images. Contour differ- ences were used to analyze the interobserver and intersequence variability. A single-sequence automatic segmenta- tion network was established using the U-Net network, and the segmentation results were analyzed. Results. Variability analysis among observers showed that the bladder, rectum, and left femoral head on T1WI yielded the highest dice similarity coefficient (DSC) and the lowest 95% Hausdorff distance (HD) (all three sequences). Regarding sequence variability analysis for the same observer, the difference between T1WI and T2WI was the small- est. The DSC of the bladder, rectum, and femoral heads exceeded 0.88 for T1WI–T2WI. The differences between au- tomatic segmentations and manual delineations were minimal on T2WI. The averaged DSC of automatic and manual segmentation of all organs on T2WI exceeded 0.81, and the averaged 95% HD value was lower than 7 mm. Similarly, the sequence variability analysis of automatic segmentation indicates that the automatic segmentation differences between T2WI and T1WI are minimal. Conclusions. T1WI and T2WI yielded better results in manual delineation and automatic segmentation, respectively. The analysis of variability among three sequences indicates that the yielded good similarity outcomes between the T1WI and T2WI cases in manual and automatic segmentation. We infer that the T1WI and T2WI (or their combination) can be used for MR-only radiation therapy. Key words: MRI; multiple sequences; variability; automatic segmentation Radiol Oncol 2025; 59(1): 139-146. Zheng W et al. / Contouring variability among observers in MR images140 Introduction Adaptive radiotherapy (ART) is useful for detect- ing changes in the position, shape, size, and oth- er characteristics of the target and organs at risk (OARs) during radiotherapy. Appropriate adjust- ments to the treatment plan can improve the dose consistency and protect normal tissues.1,2 Accurate delineation of targets and OARs is a key aspect of the ART process. Compared with computed tomography (CT), magnetic resonance imaging (MRI) has the advantage of accurate soft- tissue contrast and does not produce additional ionizing radiation doses.3,4 Some studies5,6 have pointed out that compared with CT, the volumes of tumor targets and OARs delineated on mag- netic resonance imaging is significantly reduced such that the tumor can receive a higher dose. Simultaneously, the protection of normal tissues can be equivalent to or even better than CT.7,8 MR- enhanced soft tissue not only improves the posi- tioning accuracy of patients before radiotherapy but also improves the positioning of tumors and normal tissue during real-time imaging during treatment, thus making dose delivery more accu- rate.9,10 Vestergaard et al. found that re-optimized ART for MRI-guided bladder cancer treatment has considerable sparing potential for normal tissues.11 For lengthy MR scans, only one sequence is used for radiotherapy. Most studies have used T2- weighted and related sequences to delineate the tumor volume, but there is no consensus on which sequence should be used to delineate OARs.12 However, in some studies, experts recommended the use of the extended T2-weighted sequence to delineate the target and OARs.13 Therefore, in this study, we performed manual delineation of OARs on images reconstructed us- ing three sequences (T1-weighted image [T1WI], contrast enhanced Dixon T1-weighted [T1dixonc], T2-weighted image [T2WI]), which are commonly used in MRI simulators, to analyze interobserver and intersequence variability. Simultaneously, we automatically segmented the images obtained us- ing these three sequences to observe the stability of OARs in automatic segmentation. Patients and methods MR image acquisition This study enrolled 83 patients diagnosed with cervical cancer and treated at the SUSYCC Cancer Center between March 2017 and December 2018. The median age of patients at the time of scanning was 54 years (22–82 years). MR images collected from 54 patients were used as the training cohort to build a single-sequence, automatic segmenta- tion model, and images from the remaining 29 pa- tients were used to analyze the variability of the manual segmentation outcomes of the OARs. Patients were scanned in supine positions in a vacuum bag with their hands raised. MRI scans were conducted using a 70-cm bore Ingenia 3.0 T scanner (Philips, Netherlands), with a slice thick- ness of 3 mm. Three MRI sequences were selected and imported into the Monaco Planning System. The selected sequences and their respective param- eters were as follows: T1WI (repetition time [TR]: 710 ms; echo time [TE]: 15 ms), T1dixonc (TR: 5.5 ms; TE: 3.7 ms), and T2WI (TR: 6088 ms; TE: 105 ms). The basic data had been submitted to a public Research Data Deposit (RDD) platform (www.re- searchdata.org.cn), with an approval RDD number as RDDA2021001910. OAR contouring Due to the limited scanning range, this compara- tive study is limited to organs with complete con- tours within the image. According to the Radiation Therapy Oncology Group14 and based on the delin- eated guidelines and clinical requirements for the female’s normal pelvic tissue, bladder, rectum, anal canal, and femoral heads (left and right) were de- lineated on the three MRI sequences. Delineation of the rectum began at the junction of the third bone plane with the sigmoid colon and ended at the junction with the anal canal above the anorec- tal line. The delineation of the anal canal started at the anorectal line and ended at the anus. The bladder included all the bladder walls and their contents. Manual delineation of all organs were independently completed by two pelvic oncolo- gists (R1 and R2) with more than five experience of career and were handed over to the same more senior pelvic oncologist for independent valida- tion of all contours. Automatic segmentation There were two cohorts: a training cohort and a testing cohort. The training cohort includes 54 samples, and the testing cohort includes 29 sam- ples. All samples encompass three sequences and are annotated with contours for both R1 and R2. The training cohort was used for U-Net15 net- works for automatic segmentation, while the test- Radiol Oncol 2025; 59(1): 139-146. Zheng W et al. / Contouring variability among observers in MR images 141 ing cohort was used to evaluate the network’s au- tomatic segmentation performance. The contour of OARs includes the bladder, rec- tum, anal canal, and femoral heads (left and right). OAR evaluation The dice similarity coefficient (DSC) and Hausdorff distance (HD) are the commonly used evaluation indicators to quantify contouring differences.16 In this study, the DSC and 95% HD were used to as- sess volume- and distance-related differences, re- spectively. [1] where A and B represent two different contour volumes, and the DSC value ranges from zero to one. DSC values > 0.7 mean that the two contours coincide well17, and a DSC value of one indicates that the two contours coincide completely. The directed HD orientation from X to Y is the maximum distance from all the points on X to the closest point on Y. [2] The (undirected) HD is the maximum of the two directed Hausdorff measures. [3] The 95% HD value can be used to eliminate the influence associated with the elimination of a small part of an inaccurate segmentation on the overall segmentation quality evaluation.18 The un- directed 95% HD is defined as, [4] FIGURE 1. Delineation results on T1WI, T1dixonc, and T2WI performed by the two observers (magenta line: R1; blue line: R2). Radiol Oncol 2025; 59(1): 139-146. Zheng W et al. / Contouring variability among observers in MR images142 A lower 95% HD value indicates a smaller dif- ference between the two contours. All data were analyzed using SPSS (version 25.0; SPSS Inc., Chicago, Illinois, USA). The Wilcoxon rank-sum test was used to compare the results between the two observers. The intraclass corre- lation coefficient (ICC; two-way random method and absolute agreement for single measures) was used to measure the volume consistency between the two observers and among different sequences. A p-value of <0.05 was considered statistically sig- nificant. An ICC greater than 0.75 indicated a good correlation.19 Results Interobserver variability Figure 1 and Figure 2 shows example and results of the delineation performed by the two observers, re- spectively. All organs delineated by the two observ- ers yielded the smallest average volume differences on T1WI, except for the left and right femoral heads. The volume correlation outcomes for the bladder and femoral heads showed that T1WI yielded the maximum correlation (all ICC > 0.75). The ICC of the rectum (0.882) obtained by the two observers on T1dixonc was higher than those of the other se- A B C D E FIGURE 2. Summary boxplots of the contour volumes and interobserver variability. DSC = dice similarity coefficient; HD = Hausdorff distance; ICC = intraclass correlation coefficient Radiol Oncol 2025; 59(1): 139-146. Zheng W et al. / Contouring variability among observers in MR images 143 quences. The correlation coefficient analysis of the anal canal volume showed that the two observers yielded poor correlation for the anal canal, with ICC < 0.45 on all three sequences. A detailed statistical volume comparison is presented in Supplementary Table 1. Compared with T1dixonc and T2WI, the DSC and 95% HD of the bladder, rectum, and left femoral head were improved on T1WI. The DSC (0.714) and 95% HD (5.273 mm) of the anal canal delineated by the two observers on T1dixonc were better than those on the other sequences. The high- est DSC (0.903) and the lowest 95% HD (4.517 mm) of the right femoral head were observed on T2WI. In conclusion, the contours delineated by the two observers on T1WI yielded smaller variations in the most organs. Intersequence variability The volume analysis results of R2 for the contour delineations (images reconstructed Supplementary Table 1. No statistically significant differences were found in the volume variation of the rectum and right femoral head between T1WI and T2WI. However, there were significant differences be- tween the three sequences in the delineation of the bladder and left femoral head (all p < 0.001). In the comparison of ICCs between the sequenc- es Supplementary Table 2, T1WI–T2WI demon- strated an improvement in the correlation of vol- ume compared with the respective correlations of T1WI–T1dixonc and T1dixonc–T2WI (all p < 0.001). Except for the anal canal (ICC, 0.614; p < 0.001), the ICC between T1WI and T2WI was greater than 0.9 (all p < 0.001). The DSC was improved, and 95% HD was reduced in the T1WI–T2WI case compared with the respective values on T1WI–T1dixonc and T2WI–T1dixonc for all OARs. The DSC on T1WI– T2WI exceeded 0.88 for the bladder, rectum, and femoral heads, and the DSC of the anal canal ex- ceeded 0.75 (Table 1). A B C D E F G H I TABLE 1. The dice similarity coefficient (DSC) and 95% Hausdorff distance (HD) (mm) of OARs based on different MR sequences for R2 (mean ± SD) OARs T1WI–T1dixonc T1WI–T2WI T2WI–T1dixonc DSC Bladder 0.877 ± 0.079 0.920 ± 0.038 0.884 ± 0.073 Rectum 0.842 ± 0.064 0.883 ± 0.049 0.809 ± 0.050 Anal canal 0.705 ± 0.166 0.760 ± 0.077 0.733 ± 0.125 Femoral head _L 0.905 ± 0.062 0.952 ± 0.027 0.905 ± 0.055 Femoral head _R 0.904 ± 0.050 0.959 ± 0.026 0.906 ± 0.049 95% HD (mm) Bladder 6.427 ± 4.360 4.742 ± 1.574 7.092 ± 5.363 Rectum 5.260 ± 2.934 3.408 ± 1.484 5.953 ± 3.153 Anal canal 4.732 ± 2.398 4.076 ± 1.375 4.468 ± 2.144 Femoral head _L 3.811 ± 1.550 2.607 ± 1.405 3.994 ± 1.596 Femoral head _R 4.027 ± 1.275 1.181 ± 1.171 3.682 ± 1.654 L = left; OARs = organs at risk; R = right; T1dixonc = contrast enhanced Dixon T1-weighted; T1WI = T1-weighted; T2WI = T2-weighted FIGURE. 3 Comparison example between automatic and manual segmentation results in the axial, coronal, and sagittal views on T1WI (A–C), T1dixonc (D–F), and T2WI (G–I). (Magenta line: R1; blue line: R2; and automatic segmentation: shaded green) Radiol Oncol 2025; 59(1): 139-146. Zheng W et al. / Contouring variability among observers in MR images144 The results summarized above show that when the same observer used different sequences for de- lineation, the similarities between T1WI and T2WI were more than those of other sequence combina- tions. Automatic segmentation Figure 3 shows example of the delineation per- formed by automatic and manual segmentation. The rectum volumes obtained from automatic segmentation and human observer delineation were significantly different among the three se- quences (R1-Auto: all p < 0.04; R2-Auto: all p < 0.03). On T2WI, the volume correlations between automatic and manual segmentations of the blad- der and right femoral head were 0.983 (T1WI = 0.933 and T1dixonc = 0.956) and 0.694 (T1WI = 0.673 and T1dixonc = 0.631), respectively Supplementary Table 3. Except for the rectum (T1WI = 0.739 and T2WI = 0.725), the best DSC outcomes of other organs on T2WI were obtained by R1 using auto- matic segmentation. The lowest 95% HD values of the bladder and right femoral head on T2WI were obtained by R1 using automatic segmentation, and the lowest 95% HD values of the rectum and left femoral head were found on T1dixonc. The best DSC and 95% HD outcomes of all organs were ob- tained by R2 and automatic segmentation on T2WI Supplementary Table 4. We analyzed the volume of OARs, volumetric ICC, DSC, and 95% HD to observe the variability in automatic segmentation results among different sequences. There were no significant differences in the volumes of the bladder, rectum, or anal canal among the three sequences. The volumet- ric ICC between T1WI and T2WI exceeded 0.8 in the bladder, rectum, and right femoral head cas- es. However, the highest ICC between T2WI and T1dixonc was observed for the anal canal and left femoral head Supplementary Table 5. The greatest DSC and lowest 95% HD values of the bladder and femoral heads were observed in the T1WI–T2WI case compared with those obtained in the T1WI– T1dixonc and T2WI–T1dixonc cases. Compared with T1WI–T2WI and T1WI–T1dixonc, the highest DSC and lowest 95% HD of the rectum and anal canal were found between T2WI and T1dixonc (Table 2). Discussion Although some reports have stated that various MR sequence imaging techniques should be used to assist the positioning or delineation of the tar- get and OARs, no study has identified the optimal sequence for pelvic tumor localization and deline- ation of the target and OARs. A previous report suggested that better anatomical definition can be achieved with T1-weighted images.20 The results of this study indicated that T1WI outperformed the other two sequences in terms of volumetric ICC, DSC, and 95% HD values of the bladder, rectum, and femoral heads, this suggests that the deline- ated of bladder by the two observers exhibited the least interobserver variability on T1WI. This may be attributed to signal differences in the different sequences of MR images of the bladder. The blad- der and urine yielded low signals on T1WI, where- as the surrounding muscles yielded high signals. Compared with T1-weighting, the bladder wall on T2WI without contrast imaging only yielded the muscular layer.21 Because of the bright urine ob- served on T2WI, the filled bladder demonstrated significant contrast with the surrounding muscles, which is beneficial for delineation.22 However, the bright urine signal obscured the signal from the TABLE 2. The dice similarity coefficient (DSC) and 95% Hausdorff distance (HD) (mm) for different MR sequences of automatic segmentation (mean ± SD) Bladder Rectum Anal canal Femoral head _L Femoral head _R DSC T1WI- T1dixonc 0.789±0.096 0.686±0.111 0.691±0.121 0.865±0.083 0.876±0.037 T1WI- T2WI 0.854±0.101 0.784±0.105 0.707±0.087 0.908±0.091 0.924±0.030 T2WI- T1dixonc 0.756±0.130 0.860±0.912 0.709±0.134 0.891±0.032 0.892±0.037 95% HD (mm) T1WI- T1dixonc 18.079±12.095 9.702±10.940 4.810±2.170 4.300±2.027 4.678±1.793 T1WI- T2WI 12.459±11.094 7.978±10.469 4.826±2.361 3.362±2.441 3.188±1.413 T2WI- T1dixonc 17.711±9.049 7.433±3.907 4.478±1.744 3.769±1.204 3.616±1.095 L = left; R = right; T1dixonc = contrast enhanced Dixon T1-weighted; T1WI = T1-weighted; T2WI = T2-weighted Radiol Oncol 2025; 59(1): 139-146. Zheng W et al. / Contouring variability among observers in MR images 145 urothelium and lamina propria and resulted in an inaccurate measurement of bladder thickness and tumor dimensions on T2-weighted MR images compared with T1-weighted MR images.21 The rec- tal wall had a uniformly low signal on T1WI; this yielded a significant contrast with the surround- ing fat layer and is beneficial for delineating the rectum.23 Similarly, in this study, the lowest vari- ability between the two observers was observed for the rectum delineated on T1WI (DSC = 0.849). For the delineation of femoral heads, T1WI showed a higher signal intensity than T1dixonc. We found that the interobserver variability in the delinea- tion of the femoral heads on T1WI were less than that on T1dixonc. In terms of variability between sequences, we compared the delineation results of different organs as assessed by a single observer and found that the results on T1WI and T2WI were the closest. When implementing MRI–ART, the acquisition time of MR images and the optimization of ra- diotherapy plans are extremely time-consuming. Accurate contour delineation is the most time-con- suming and essential step in radiotherapy plan- ning. Several studies have shown that automatic segmentation saves time in real-time planning and reduces inter- and intra–observer variability.24 Therefore, we investigated the differences among three sequences in automatic segmentation using MR images obtained from 29 patients as the test set and compared the results obtained using man- ual and automatic contouring. R1 and the automatic segmentation model ob- tained an optimal DSC and 95% HD on T2WI. Except for the anal canal, the DSC of the bladder, rectum, and femoral heads were greater than 0.7. The DSC of the anal canal on all three sequences were greater than 0.6, with the highest DSC ob- tained on T2WI (0.669). R2 obtained the best DSC and 95% HD values when compared with the auto- matic segmentation model for all organs on T2WI. For all organs on T1WI and T2WI (excluding the anal canal), the DSCs of R2 and the automatic seg- mentation model were both greater than 0.75. On the three sequences, the average DSC values of the observer and the automatic segmentation model were both greater than 0.78, with the highest DSC value (equal to 0.696) observed on T2WI. Therefore, we found T2WI to be the best sequence for auto- matic segmentation in this study; this result is con- sistent with the results of another study on MRI- based automatic segmentation of the pelvis.25 The sequence used for the automatic segmenta- tion of pelvic tumors in most studies is T2WI be- cause it yields better imaging results for the target area of pelvic tumors. In this study, we compared the automatic segmentation results among the tested sequences and found that T2WI and T1WI yielded the most similar results in the automatic segmentation model (highest DSC and lowest 95% HD). This suggests that T1WI may serve as a sub- stitute sequence for T2WI when using a single se- quence for model segmentation. Our results yield- ed a high similarity in manual delineation and au- tomatic segmentation models between T1WI and T2WI. This may indicate that T1WI can be used as a supplementary information input when con- structing automatic segmentation models, as also shown by Chi et al. who used a T2-weighted image and segmented the bladder outer wall boundary using a T1-weighted image.26 In this study, we analyzed the differences among the three MRI sequences used in radiotherapy and provided a reference for sequence selection in an MR-only workflow. Our research exhibits certain limitations. Initially, our investigation has been confined to assessing the delineation consistency of organs at risk across various imaging modali- ties. However, the contouring of the target volume is equally pivotal and warrants further exploration in terms of how imaging sequences may affect its delineation. Secondly, this study involved only two observers, which may have influenced the results. In clinical settings, there is inherent vari- ability among practitioners within the same spe- cialty, across different specialties, and even among institutions. To mitigate these biases and enhance the generalizability of our findings, future studies will incorporate a larger cohort of observers and multi-institutional collaborations, thereby aiming to deliver more equitable and evidence-based rec- ommendations. Conclusions In this study, we analyzed the variability in three MR sequences (T1WI, T2WI, and T1dixonc) based on the delineation of pelvic organs performed by human observers and automatic segmentation models. The results indicated that human observ- ers demonstrated better results on T1WI, whereas automatic segmentation models demonstrated bet- ter results on T2WI. The difference analysis results among the sequences in manual delineation and automatic segmentation indicated good similarity between T1WI and T2WI. Therefore, T1WI, T2WI, or a combination of T1WI and T2WI can be used Radiol Oncol 2025; 59(1): 139-146. Zheng W et al. / Contouring variability among observers in MR images146 for the planning of MR-only radiation therapy. To the best of our knowledge, there are few studies on interobserver variability based on pelvic MR multiple-sequence imaging. Acknowledgments This study was supported by Beijing Xisike Clinical Oncology Research Foundation (Y_Young2023-0156, Y-Young2024-0538), Scientific Research Cooperation Projects of UIH&SYSUCC (ZDZL-UIH-2022006) , and United Laboratory of Frontier Radiotherapy Tech-nology Fund (HT- 99982024-0350). References 1. Hardcastle N, Tomé WA, Cannon DM, Brouwer CL, Wittendorp PW, Dogan N, et al. A multi-institution evaluation of deformable image registration algorithms for automatic organ delineation in adaptive head and neck ra- diotherapy. Radiat Oncol 2012; 7: 90. doi: 10.1186/1748-717X-7-90 2. Burridge N, Amer A, Marchant T, Sykes J, Stratford J, Henry A, et al. Online adaptive radiotherapy of the bladder: small bowel irradiated-volume reduction. Int J Radiat Oncol Biol Phys 2006; 66: 892-7. doi: 10.1016/j. ijrobp.2006.07.013 3. Noel CE, Parikh PJ, Spencer CR, Green OL, Hu Y, Mutic S, et al. 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Proceedings of the 8th IEEE International Symposium on Biomedical Imaging: From Nano to Macro, Chicago, Illinois, USA 2011; 1653-6. doi: 10.1109/ISBI.2011.5872721 Radiol Oncol 2025; 59(1): 147-152. doi: 10.2478/raon-2025-0018 147 research article Bronchial bacterial colonization and the susceptibility of isolated bacteria in patients with lung malignancy Sabrina Petrovic1, Bojana Beovic2,3, Viktorija Tomic3,4, Marko Bitenc1, Mateja Marc Malovrh3,4, Vladimir Dimitric4, Dane Luznik4, Martina Miklavcic1, Tamara Bozic1, Tina Gabrovec1, Aleksander Sadikov5, Ales Rozman3,4 1 Surgery Bitenc, Medical Centre Ljubljana (MCL), Ljubljana, Slovenia 2 Clinic for Infectious Diseases and Fever Conditions, University Medical Centre Ljubljana, Ljubljana, Slovenia 3 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 4 University Clinic of Pulmonary and Allergic Diseases Golnik, Golnik, Slovenia 4 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 5 Faculty of Computer and Information Science, University of Ljubljana, Ljubljana, Slovenia Radiol Oncol 2025; 59(1): 147-152. Received 15 April 2024 Accepted 19 January 2025 Correspondence to: Sabrina Petrovic, M.D., Kirurgija Bitenc d.o.o., Medical Centre Ljubljana (MCL), Vilharjev podhod 1, 1000 Ljubljana, Slovenia. E-mail: sabrina.petrovic@surgery-bitenc.com Disclosure: No potential conflicts of interest were disclosed. This is an open access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/). Background. Postoperative pneumonia (POP) remains a leading cause of mortality following lung surgery. Recent studies have confirmed that the respiratory tract below the vocal cords is not sterile and often harbours potentially pathogenic microorganisms (PPMs), putting patients with lung malignancies at an increased risk for pulmonary infec- tions. Patients and methods. The study analysed 149 patients who underwent bronchoscopy for lung lesions suspected to be lung cancer. Protected specimen brush (PSB) samples were obtained during bronchoscopy prior to any specific treatment. Bacterial identification and antimicrobial susceptibility testing were conducted on the isolated strains. Results. Bacterial colonization was detected in 88.6% of patients, with 21.5% carrying PPMs. Notably, patients with type 2 diabetes exhibited a higher rate of PPM colonization compared to others. Antibiotic susceptibility testing showed no significant differences in efficacy between amoxicillin with clavulanic acid and first-generation cepha- losporin in both colonized patients and those with PPMs. Importantly, no multidrug-resistant bacteria were identified. Conclusions. Our findings indicate a slightly lower PPM colonization rate compared to previous studies, possibly due to the unique geographic characteristics of the study population. The absence of significant differences in bacterial susceptibility between the two tested antibiotics highlights the need for further research to refine perioperative infec- tion management strategies. Key words: bronchial bacterial colonization; potentially pathogenic microorganisms; antibiotic prophylaxis; lung cancer; bronchoscopy Introduction Postoperative pneumonia (POP) remains a sig- nificant contributor to postoperative mortality following lung surgery, with reported incidence rates ranging from 2% to 20%.1,2 Patients with lung malignancies are particularly susceptible to pul- monary infections due to factors such as immuno- suppression, impaired protective mechanisms, and localized inflammation caused by concurrent con- Radiol Oncol 2025; 59(1): 147-152. Petrovic S et al. Bacterial colonization in patients with lung malignancy148 ditions like bronchiectasis and chronic obstructive pulmonary disease (COPD).2 Recent studies have challenged the traditional belief that the respiratory tract below the vocal cords is sterile, highlighting the presence of mi- crobial colonization.3 However, limited research has focused on bronchial bacterial colonization (BBC) patterns in patients with lung malignan- cies. Existing studies report a wide range of BBC prevalence, from 10% to 83%, often involving po- tentially pathogenic microorganisms (PPMs) such as Haemophilus influenzae, Streptococcus pneumoniae, and Staphylococcus aureus.1,2,4,5 While the clinical significance of these microorganisms within the airways remains uncertain, their presence may influence the management and prognosis of lung cancer patients.3 Several risk factors, including age, gender, COPD, and smoking, have been asso- ciated with an increased likelihood of PPM colo- nization.1,2,4 Furthermore, studies have established a link between BBC and pneumonia in these pa- tients, though it remains unclear whether these bacteria contribute to postoperative infections af- ter lung surgery.1 Nevertheless, PPM colonization of the respiratory tract could elevate the risk of postoperative infections.2 The effectiveness of first-generation cephalo- sporins as perioperative antibiotic prophylaxis, as recommended by current guidelines, is under scrutiny due to the high incidence of postoperative pneumonia and the increasing prevalence of an- tibiotic-resistant bacteria among isolated strains.6-9 Addressing postoperative infections in patients with lung malignancies undergoing surgery is a critical clinical challenge, necessitating the identi- fication of effective prophylactic strategies. This study aims to prospectively evaluate the prevalence of PPM colonization in patients with lung malignancies, predominantly primary lung cancer, at the time of diagnosis before any specific treatment initiation. Additionally, it investigates antibiotic susceptibility among isolated bacteria to assess resistance rates and examines the potential association between PPM colonization and cancer stage. Patients and methods This prospective study was conducted from June 2021 to February 2023, focusing on patients pre- senting with lung lesions suspected to be primary lung cancer. During the initial outpatient evalu- ation, demographic and clinical data were col- lected, including age, gender, smoking history, and comorbidities. All patients were diagnosed following established guidelines for primary lung cancer diagnosis. TNM staging included chest, ab- dominal, and head CT scans, as well as PET-CT imaging. Flexible bronchoscopy was performed for all patients to obtain tumour tissue samples for histological diagnosis when possible. In addition, protected specimen brush (PSB) samples were col- lected during bronchoscopy prior to initiating any specific treatment. For cases where bronchoscopic tumour r access was not feasible, CT-guided needle biopsies were used to determine histological typ- ing. PSB samples were sent to the microbiology labo- ratory, where bacterial colonization was defined as the isolation of microorganisms at a threshold of ≥10³ CFU/mL. Antimicrobial susceptibility testing was performed on each bacterial isolate using the microbiology protocol tailored to the bacterial spe- cies. The study received approval from the National Medical Ethics Committee of the Republic of Slovenia (no. 0120-163/2021/3), and all participants provided written informed consent. TABLE 1. Baseline characteristics of patients Characteristics n % Patients 149 Male 90 60.4 Median age (years) 66 Smokers 50 33.6 Ex-smokers 71 47,7 Non-smokers 28 18,8 COPD 44 29.5 Diabetes type 2 13 8.7 Colonized patients 132 88.6 Colonized with PPMs 32 21.5 Multiple bacteria colonization 86 57.7 Adenocarcinoma 86 57.7 Squamous cell carcinoma 22 14.8 Small cell carcinoma, carcinoid or large cell carcinoma 11 7.4 Non-small cell carcinoma NOS* 17 11.4 Other, non-lung cancer malignancies (limfoma, methastases) 13 8,7 COPD = chronic obstructive pulmonary disease; NOS = not otherwise specified; PPMs = potentially pathogenic microorganisms Radiol Oncol 2025; 59(1): 147-152. Petrovic S et al. Bacterial colonization in patients with lung malignancy 149 Bronchoscopy Bronchoscopy was performed under moderate sedation, adhering to a strict no-suction policy prior to reaching the carina. Upon entering the trachea, topical lidocaine anaesthesia was admin- istered to the main and upper lobar bronchi. Sterile brushes (OLYMPUS disposable cytology brush BC-202D-210) were used to collect samples from the bronchi of the tumour-bearing lobe prior to di- agnostic sampling to detect bacterial colonization. Each sample was preserved in 1 mL of sterile saline solution and sent to the microbiology laboratory. Peripheral tumour sampling was conducted using various bronchoscopic techniques to determine tu- mour histological types. Microbiological analysis PSB samples were promptly processed in the mi- crobiology laboratory. Samples were vortexed, and slides were prepared before dilution and plating. Gram staining and microscopic examination as- sessed sample quality, bacterial morphology, and abundance. Samples were diluted to a final concen- tration of 10⁻³ and inoculated on various solid and liquid media, including blood agar, chocolate agar, Brucella blood agar, CHROMagar™ Orientation (CHROMagar, France), and thioglycollate broth. Plates were incubated aerobically and anaerobi- cally at 35°C and evaluated for growth at 24, 48, and 72 hours. Liquid medium subculturing onto the same solid media plates confirmed bacterial morphotypes and colony-forming units per milli- litre (CFU/mL). A threshold of ≥10³ CFU/mL was used to define positive culture results. Bacterial identification and antimicrobial sus- ceptibility testing were performed using the MALDI Biotyper® (Bruker Daltonics GmbH & Co, Germany) and the standardized EUCAST disc dif- fusion method. Bacteria were classified as PPMs (e.g., S. pneumoniae, H. influenzae, M. catarrhalis, S. aureus, P. aeruginosa, Enterobacterales) or non-PPMs (e.g., Streptococcus viridans group, Neisseria spp., Corynebacterium spp., coagulase-negative staphylo- cocci).5 Statistical analyses Descriptive statistics were presented as median (range) for continuous variables and as frequen- cies and proportions for categorical variables. Comparisons of bacterial colonization rates with respect to tumour stage and comorbidities, as well TABLE 2. Number and percentage of recovered bacteria RECOVERED BACTERIA No. of patients with isolated species % of patients with isolated species Streptococcus mitis 53 35,6% Streptococcus salivarius 36 24,2% Streptococcus oralis 27 18,1% Streptococcus parasanguinis 23 15,4% Streptococcus vestibularis 18 12,1% Veillonella atypica 13 8,7% Haemophilus influenzae 12 8,1% Streptococcus pneumoniae 11 7,4% Neisseria subflava 9 6,0% Actinomyces odontolyticus 9 6,0% Staphylococcus aureus 8 5,4% Haemophilus parahaemolyticus 8 5,4% Streptococcus gordonii 8 5,4% Rothia mucilaginosa 7 4,7% Escherichia coli 6 4,0% Staphylococcus epidermidis 6 4,0% Staphylococcus hominis 4 2,7% Streptococcus anginosus 4 2,7% Veillonella parvula 3 2,0% Fusobacterium periodonticum 3 2,0% Moraxella catarrhalis 2 1,3% Pseudomonas aeruginosa 2 1,3% Haemophilus parainfluenzae 2 1,3% Corynebacterium simulans 2 1,3% Prevotella nigrescens 2 1,3% Streptococcus constellatus 2 1,3% Gemella haemolysans 2 1,3% Serratia marcescens 2 1,3% Prevotella melaninogenica 2 1,3% Granulicatella adiacens 2 1,3% Streptococcus agalactiae 1 0,7% Staphylococcus capitis 1 0,7% Streptococcus cristatus 1 0,7% Neisseria macacae 1 0,7% Neisseria cinerea 1 0,7% Neisseria flavescens 1 0,7% Veillonella dispar 1 0,7% Prevotella jejuni 1 0,7% Campylobacter concisus 1 0,7% Citrobacter koseri 1 0,7% Prevotella pallens 1 0,7% Enterobacter bugandensis 1 0,7% Acinetobacter lwoffii 1 0,7% Moraxella nonliquefaciens 1 0,7% Radiol Oncol 2025; 59(1): 147-152. Petrovic S et al. Bacterial colonization in patients with lung malignancy150 as antibiotic susceptibility, were assessed using Pearson’s chi-squared test or Fisher’s exact test, as appropriate. A p-value < 0.05 was considered sta- tistically significant. All p-values are two-tailed. Statistical analyses were conducted using IBM SPSS (version 21, Chicago, IL, USA). Results The study included 149 consecutive patients with lung malignancies, with a median age of 66 years (20–84). Baseline characteristics of the participants are summarized in Table 1. Most patients (71.8%) were diagnosed with non-small cell lung cancer, primarily adenocarcinoma (57%). Respiratory tract colonization with at least one bacterial strain was confirmed in 132 patients (88.6%), with 86 patients (57.7%) harbouring multi- ple bacterial strains. Colonization with potentially pathogenic microorganisms (PPMs) was identi- fied in 32 patients (21.5%). Antibiotic sensitivity testing for amoxicillin with clavulanic acid and first-generation cephalosporins was performed in 120 patients. Sensitivity testing for amoxicillin with clavulanic acid and first-generation cephalo- sporins was not conducted for 12 patients due to colonization with bacteria requiring specific an- tibiotic panels (Rothia mucilaginosa, Streptococcus constellatus, Actinomyces odontolyticus, Streptococcus cristatus, and Fusobacterium periodonticum), none of which were classified as PPMs. The most frequently isolated PPMs were Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, and Escherichia coli (Table 2), while the most common non-PPMs included Streptococcus mitis and Streptococcus salivarius. Notably, 57.7% of patients exhibited colonization by multiple bacterial strains. No statistically significant differences in PPM colonization rates were observed across different cancer stages (Table 3). Similarly, no significant association was found between COPD and colo- nization with potentially pathogenic bacteria (p = 0.39) (Table 4). However, type 2 diabetes emerged as an independent risk factor for colonization with potentially pathogenic bacteria (p = 0.04) (Table 5). Antibiotic susceptibility testing revealed no significant differences in efficacy between amoxi- cillin with clavulanic acid and first-generation cephalosporin in both colonized patients and those colonized specifically by PPMs (Tables 6 and 7). TABLE 3. Relationship between cancer stage and colonization with potentially pathogenic microorganisms (PPMs) STAGE (8th TNM classification) PPMs Total no yes I 50 11 61 82.0% 18.0% 100.0% II 25 7 32 78.1% 21.9% 100.0% III 16 6 22 72.7% 27.3% 100.0% IV 11 2 13 84.6% 15.4% 100.0% Total 102 26 128* 79.7% 20.3% 100.0% *for patients, who didn’t have primary lung cancer, cTNM was not defined TABLE 4. Relationship between colonization with potentially pathogenic microorganisms (PPMs) and chronic obstructive pulmonary disease (COPD) COPD PPMs Total no yes no 83 21 104 79.8% 20.2% 100.0% yes 32 12 44 72.7% 27.3% 100.0% Total 115 33 148* 77.7% 22.3% 100.0% *for 1 patient, there was no comorbidity data TABLE 5. Relationship between colonization with potentially pathogenic microorganisms (PPMs) and diabetes type 2 DIABETES TYPE 2 PPMs Total no yes no 108 27 135 80.0% 20.0% 100.0% yes 7 6 13 53.8% 46.2% 100.0% Total 115 33 148* 77.7% 22.3% 100.0% *for 1 patient, there was no comorbidity data Radiol Oncol 2025; 59(1): 147-152. Petrovic S et al. Bacterial colonization in patients with lung malignancy 151 Discussion In this study, we conducted a prospective inves- tigation of BBC in patients suspected of primary lung cancer before initiating any treatment. Our methodology introduced a key distinction from previous studies by using sterile brush specimens to collect samples from the bronchi of the tumour- containing lobe. Additionally, we evaluated the an- tibiotic susceptibility of isolated bacteria to antibi- otics commonly used for perioperative prophylaxis in thoracic surgery. Our findings revealed a lower prevalence of colonization by PPMs (21.5%) compared to previ- ous studies. Only two patients harboured bacte- ria resistant to both amoxicillin with clavulanic acid and first-generation cephalosporin. In one in- stance, bacteria were resistant to amoxicillin with clavulanic acid but susceptible to first-generation cephalosporin, while the reverse was observed in another case. Importantly, there were no signifi- cant differences in susceptibility between the two antibiotics, and no multidrug-resistant bacteria were identified. In a similar study, Laroumagne et al. examined bronchial colonization at the time of lung cancer diagnosis. They reported a higher prevalence of PPM colonization (50%), likely due to non-sterile sampling conditions. Their findings suggested an association between bronchial colonization and lower survival rates, potentially linked to infec- tious complications.4 Ioanas et al. reported a PPM colonization rate of 41%, again using non-sterile sampling techniques. Their study demonstrated no resistance to con- ventional antibiotics, consistent with our findings. They also reported a low incidence of postopera- tive pulmonary infections (12%) and no pneumo- nia cases, likely attributable to effective prophy- laxis with first-generation cephalosporin adminis- tered perioperatively and for 48 hours postopera- tively. Similar complication rates were observed in colonized and non-colonized patients, although their study was limited to 41 patients.5 Dancewicz et al. also reported similar BBC rates and found no evidence of multidrug-resistant mi- croorganisms, aligning with our results.2 Boldt et al., however, reported a PPM colonization rate of 48% in patients undergoing lung surgery. They found that a single dose of sulbactam plus ampi- cillin was significantly more effective than first- generation cephalosporin in preventing infec- tions, suggesting alternative regimens for prophy- laxis.10 Radu et al. conducted a retrospective analysis of 312 cases, highlighting the inefficacy of first- generation cephalosporin in 84% of cases, raising concerns about current prophylactic guidelines.8 Schlusser et al. suggested that targeted antibiotic prophylaxis against bronchial colonizing bacteria could reduce postoperative pneumonia incidence. They observed a significant reduction when an- tibiotics were tailored to the identified bacteria, though their study was not randomized and war- rants further validation.6,7 Lastly, D’Journo et al.’s meta-analysis established a statistical correlation between preoperative BBC and postoperative respiratory complications, em- phasizing the clinical importance of preoperative colonization screening.1 Conclusions This study provides valuable insights into bron- chial bacterial colonization in patients with lung malignancies, predominantly primary lung cancer. The prevalence of PPM colonization and the low resistance to tested antibiotics characterize a pa- tient population primarily from central and west- ern Slovenia, differing from studies conducted in other geographical regions. While PPM coloniza- TABLE 6. Susceptibility among all colonized patients Amoxicillin with clavulanic acid First generation cephalosporin Total R S S/R R 2 2 0 4 S 2 101 1 104 S/R 0 6 6 12 Total 4 109 7 120 R = resistant; S = susceptible TABLE 7. Susceptibility among patients colonized by potentially pathogenic microorganisms (PPMs) Amoxicillin with clavulanic acid First generation cephalosporin Total R S S/R R 1 1 0 2 S 1 20 0 21 S/R 0 5 3 8 Total 2 26 3 31 R = resistant; S = susceptible Radiol Oncol 2025; 59(1): 147-152. Petrovic S et al. Bacterial colonization in patients with lung malignancy152 tion was not associated with lung cancer stage or COPD, a significantly higher prevalence was ob- served in patients with type 2 diabetes. The absence of significant differences in an- tibiotic susceptibility between amoxicillin with clavulanic acid and first-generation cephalosporin highlights the need for further research. Given the substantial rates of colonization and postoperative pneumonia, we recommend routine microbiologi- cal sampling during bronchoscopy for all patients suspected of primary lung cancer. This approach could enable targeted perioperative antibiotic prophylaxis in patients undergoing thoracic sur- gery. Future prospective studies comparing tar- geted versus standard prophylaxis are essential to establish best practices. References 1. D’Journo XB, Rolain JM, Doddoli C, Raoult D, Thomas PA. Airways coloniza- tions in patients undergoing lung cancer surgery. Eur J Cardiothorac Surg 2011; 40: 309-21. doi: 10.1016/j.ejcts.2010.11.036 2. Dancewicz M, Szymankiewicz M, Bella M, Sviniarska J, Kowalewski J. [Bronchial bacterial colonization in patients with lung cancer]. [Polish]. Pneumol Alergol Pol 2009; 77: 242-7. PMID: 9591094 3. Prat C, Lacoma A. Bacteria in the respiratory tract – how to treat? Or do not treat? Int J Infect Dis 2016; 51: 113-22. doi: 10.1016/j.ijid.2016.09.005 4. Laroumagne S, Lepage B, Hermant C, Plat G, Phelippeau M, Bigay-Game L, et al. Bronchial colonization in patients with lung cancer: a prospective study. Eur Respir J 2013; 42: 220-9. doi: 10.1183/09031936.00062212 5. Ioanas M, Angrill J, Baldo X, Arncibia F, Gonzalez J, Bauer T, et al. Bronchial bacterial colonization in patients with resectable lung carcinoma. Eur Respir J 2002; 19: 326-32. doi: 10.1183/09031936.02.00236402 6. Schlusser O, Dermine H, Alifano M, Casetta A, Coignard S, Roche N, et al. Should we change antibiotic prophylaxis for lung surgery? Postoperative pneumonia is the critical issue. Ann Thorac Surg 2008; 86: 1727-34. doi: 10.1016/j.athoracsur.2008.08.005 7. Schlusser O, Alifano M, Dermine H, Strano S, Casetta A, Sepulveda S, et al. Postoperative pneumonia after major lung resection. Am J Respir Crit Care Med 2006; 173: 1161-9. doi: 10.1164/rccm.200510-1556oc 8. Radu DM, Jaureguy F, Pharm D, Seguin A, Foulon C, Destable MD, et al. Postoperative pneumonia after major pulmonary resections: an unsolved problem in thoracic surgery. Ann Thorac Surg 2007; 84: 1669-74. doi: 10.1016/j.athoracsur.2007.05.059 9. Deguchi H, Tomoyasu M, Shygeeda W, Kaneko Y, Kanno H, Saito H. Influence of prophylactic antibiotic duration on postoperative pneumonia following pulmonary lobectomy for non-small cell lung cancer. J Thorac Dis 2019; 11: 1155-64. doi: 10.21037/jtd.2019.04.43 10. Boldt J, Piper S, Uphus D, Fussle R, Hempelmann G. Preoperative mi- crobiologic screening and antibiotic prophylaxis in pulmonary resection operations. Ann Thorac Surg 1999; 68: 108-11. doi: 10.1016/s0003- 4975(99)00400-2 11. Yamada Y, Sekine Y, Suzuki H, Iwata T, Chiyo M, Nakajima T, et al. Trends of bacterial colonisation and the risk of postoperative pneumonia in lung can- cer patients with chronic obstructive pulmonary disease. Eur J Cardiothorac Surg 2009; 37: 752-7. doi: 10.1016/j.ejcts.2009.05.039 Slovenian abstracts Radiol Oncol 2025; 59(1): I-XV. I Radiol Oncol 2025; 59(1): 1-22. doi: 10.2478/raon-2025-0011 Ablacija z električnim, pulznim poljem v medicini. Nepovratna elektroporacija in elektropermeabilizacija. Teorija in uporaba Jacobs EJ, Rubinksy B, Davalos RV Izhodišča. Tehnike lokalne ablacije so sestavni del kirurških posegov, pri katerih je potrebno čim bolj zmanjšati poškodbe okoliškega parenhima in kritičnih struktur. Irreverzibilna elektroporacija (IRE) in viso- kofrekvenčna IRE (angl. high-frequency irreversible electroporation, H-FIRE), ki jo pogovorno imenujemo pulzna ablacija (angl. pulsed-field ablation, PFA), uporabljata visokoamplitudna, nizkoenergijska pulzna električna polja (angl. pulsed electric fields, PEF) za netermično ablacijo mehkega tkiva. PEF povzročijo celično smrt s permeabilizacijo celične membrane, kar povzroči izgubo homeostaze. Posebnost neter- mične narava PFA je, da omogoča selektivno celično smrt ob minimalnem vplivu na okoliške beljakovin- ske strukture, kar omogoča zdravljenje v bližini občutljivih anatomskih struktur, kjer sta termična ablacija ali kirurška resekcija kontraindicirani. Poleg tega PFA uporabljamo za zdravljenje, kadar po kirurški resekciji ni pričakovati tumorja v predelu kirurških robov, kar imenujemo robno poudarjanje (angl. margin ac- centuatio). V preglednem članku obravnavamo teoretične temelje PFA, podrobno opisujemo, kako PEF povzroči destabilizacijo celične membrane in selektivno ablacijo tkiva, rezultate po zdravljenju ter klinične posledice v onkologiji in kardiologiji. Zaključki. Klinične izkušnje še vedno potekajo, vendar poročila kažejo, da PFA zmanjšuje zaplete, ki se pogosto pojavljajo pri tehnikah termične ablacije. Vse več onkoloških podatkov tudi potrjuje, da PFA stopnuje imunski odziv, ki lahko prepreči lokalne ponovitve in omili metastatsko bolezen. Kljub obetavnim rezultatom so potrebne nadaljnje raziskave izzivov, kot sta optimizacija aplikacije pulzneega električna polja in obravnavanje razlik v odzivu tkiva. Prihodnje usmeritve vključujejo izpopolnitev protokolov PFA in razširitev njene uporabe na druga terapevtska področja, kot sta benigna hiperplazija tkiva in kronični bronhitis. Focal ablation techniques are integral in the surgical intervention of diseased tissue, where it is necessary to minimize damage to the surrounding parenchyma and critical structures. IRreversible Electroporation (IRE) and High-Frequency IRE (H-FIRE), colloquially called Pulsed-Field Ablation (PFA), utilize high-amplitude, low-energy pulsed electric fields (PEFs) to nonthermally ablate soft tissue. PEFs in- duce cell death through permeabilization of the cellular membrane, leading to loss of homeostasis. The unique nonthermal nature of PFA allows for selective cell death while minimally affecting surrounding proteinaceous structures, permitting treatment near sensitive anatomy where thermal ablation or surgi- cal resection is contraindicated. Further, PFA is being used to treat tissue when tumor margins are not expected after surgical resection, termed margin accentuation. Clinical experience is still progressing, but reports have demonstrated that PFA reduces complications often seen with thermal ablation tech- niques. Mounting oncology data also support that PFA produces a robust immune response that may prevent local recurrences and attenuate metastatic disease. Despite promising outcomes, challenges such as optimizing field delivery and addressing variations in tissue response require further investigation. Future directions include refining PFA protocols and expanding its application to other therapeutic areas like benign tissue hyperplasia and chronic bronchitis. This review explores both the theoretical foundati- ons of PFA, detailing how PEFs induce cell membrane destabilization and selective tissue ablation, the outcomes following treatment, and its clinical implications across oncology and cardiology. Slovenian abstracts Radiol Oncol 2025; 59(1): I-XV. II Radiol Oncol 2025; 59(1): 23-30. doi: 10.2478/raon-2025-0010 Ponavljajoča respiratorna papilomatoza. Vloga bevacizumaba in cepljenja proti HPV. Pregled literature s predstavitvijo primerov Sporeni S, Rifaldi F, Lanzetta I, Imarisio I, Montagna B, Serra F, Agustoni F, Pedrazzoli P, Benazzo M, Bertino G Izhodišča. Ponavljajoča se respiratorna papilomatoza (angl. recurrent respiratory papillomatosis RRP) je bolezen, ki jo povzroča okužba s humanim papiloma virusom (HPV). Zdravljenja z namenom ozdravitve ni mogoče natančno opredeliti in je ohranitvena operacija pogosto najboljša možnost, da obdržimo dihalne funkcije. Doslej so monoklonska protitelesa veljala za izbiro zdravljenja z dobro učinkovitostjo in varnostnim profilom. Metode. Opravili smo spletno iskanje člankov v angleškem jeziku po podatkovnih bazah Medline/ PubMed, od leta 2000 do 2024. da bi našli članke, ki so vsebovali besede „respiratorna ali laringealna papilomatoza“ in „HPV respiratorna okužba, zdravljenje papilomatoze, cepljenje proti papilomatozi, sis- temsko zdravljenje papilomatoze“. Nato smo ročno pregledali reference iz izvirnih člankov, da bi odkrili dodatne raziskave. Izbrali smo 34 člankov. Rezultati. Od leta 2009 uporabljamo za zdravljenje RRP, ki se ne odziva na kirurško zdravljenje, sistem- sko aplikacijo bevacizumaba. Učinkovitost monoklonskega protitelesa proti vaskularnemu endotelnemu rastnemu dejavniku (angl. anti-vascular endothelial growth factor, anti-VEGF) pri spremembah RRP je lahko povezana z njihovo vaskularno naravo. Glavni izziv je ponovna rast papiloma ob prenehanju zdra- vljenja. Možna rešitev bi lahko bila sočasna uporaba imunoterapije, s katero bi zmanjšali breme preostale bolezni in hkrati aktivirali imunski sistem proti celicam, okuženim s HPV. Zaključki. Bevacizumab je varno zdravilo s kratkoročno lokalno zazdravitvijo HPV. Potrebne so nadaljnje prospektivne raziskave z dolgoročnim spremljanjem, da bi še bolje opredelili njegovo varnost in učinko- vitost proti ponovitvi bolezni. Glede na vlogo cepiva proti HPV, tako v preventivi okužbe kot pri dopolnil- nem zdravljenju, podatki kažejo potrebo po oceni njegove terapevtske učinkovitosti pri zdravljenju RRP. Slovenian abstracts Radiol Oncol 2025; 59(1): I-XV. III Radiol Oncol 2025; 59(1): 31-42. doi: 10.2478/raon-2025-0002 Finančno breme raka dojke. Sistematični pregled literature in prepoznavanje raziskovalnih izzivov Ratoša I, Bavdaž M, Došenović Bonča P, Zobec Logar HB, Perhavec A, Skubic M, Vöröš K, Mihor A, Zadnik V, Redek T Izhodišča. Rak dojk je eden najbolj pogostih rakov, ki je vse bolj prisoten tudi med delovno aktivnim prebivalstvom. Ne glede na starost ima rak dojk velike neposredne in posredne stroške za bolnike, družine in družbo. Namen raziskave je bil, da s pomočjo bibliometrične analize finančnega bremena raka dojk prepozna ključne vsebine v literaturi, glavne avtorje, osrednje revije ter odprta raziskovalna področja, ki predstavljajo izzive za prihodnje raziskave. Materiali in metode. Sistematični pregled literature je temeljil na uporabi več metod, analiza je združe- vala bibliometrične metode s standardnim pregledom/razpravo najpomembnejših prispevkov. Pri analizi smo uporabili programa Bibliometrics v R ter VosViewer. Rezultati. Navajamo ključne avtorje, revije in raziskovalne vsebine v literaturi pri proučevanju finanč- nega bremena raka dojke. Objavljeni članki, ki opisujejo finančna bremena zaradi raka dojk, kažejo na zgostitev tako avtorjev kot revij. Zaključki. Rezultati razkrivajo odsotnost celovitega pristopa pri preučevanju finančnega bremena ob raku dojke. Literatura se pogosto osredotoča le na enega ali nekaj izbranih vidikov finančnega breme- na, obravnavajo predvsem le nekaj držav. Poseben izziv z vidika primerjalne analize predstavljajo razlike v zdravstvenih sistemih. Slovenian abstracts Radiol Oncol 2025; 59(1): I-XV. IV Radiol Oncol 2025; 59(1): 43-53. doi: 10.2478/raon-2025-0014 Zgodnji 18F-FDG-PET/CT in drugi napovedni označevalci preživetja bolnikov z metastatskim melanomom, ki so prejemali imunoterapijo Hribernik N, Strašek K, Studen A, Zevnik K, Škalič K, Jeraj R, Reberšek M Izhodišča. Velik delež bolnikov z metastatskim melanomom se ne odzove na zaviralce imunskih nad- zornih točk, zaradi česar je potrebno razviti druge možne neinvazivne označevalce za prepoznavanje bolnikov že v obdobju zgodnjega zdravljenja, ki se na takšno imunoterapijo ne odzivajo. Namen priču- joče klinične raziskave je bil oceniti vlogo zgodnje [18F]2fluoro-2-deoksi-D-glukoza PET/CT (18F-FDG-PET/ CT) in drugih možnih napovednih označevalcev preživetja pri bolnikih z metastatskim melanomom, ki so prejemali zaviralce imunskih nadzornih točk, v četrtem tednu terapije (T4). Bolniki in metode. V prospektivni neintervencijski klinični raziskavi smo bolnike z metatstatskim mela- nomom, ki smo jih zdravili z zaviralci imunski nadzornih točk, redno spremljali z 18F-FDG PET/CT. Bolnikom smo naredili preiskavo 18F-FDG PET/CT pred zdravljenjem, zgodaj v četrtem tednu (T4) in šestnajstem tednu (T16) zdravljenja in nato vsakih 16 tednov. Odgovor na zaviralce imunskih nadzornih točk v T4 smo ocenili z uporabo prilagojenih meril Evropske organizacije za raziskave in zdravljenje raka (angl. European Organisation for Research and Treatment of Cancer, EORTC). Bolnike z napredovanjem bolezni smo razvrstili v skupino brez klinične dobrobiti, ostale odgovore na zdravljenje pa v skupino klinične dobro- biti. Primarni cilj raziskave je bil analiza preživetja na podlagi odgovora na zdravljenje, ugotovljenega z 18F-FDG PET/CT v T4. Sekundarni cilj je bila analiza preživetja na podlagi LDH, števila metastatskih lokali- zacij in imunsko pogojenih neželenih učinkov. Preživetja smo ocenili z uporabo Kaplan-Meierjeve metode in univariatne Coxove regresijske analize. Rezultati. Skupno smo v raziskavo vključili 71 bolnikov. Srednji čas sledenja bolnikov je bil 37,1 meseca (95 % interval zaupanja [IZ] = 30,1–38,0). Trije (4 %) bolniki so imeli pred 18F-FDG PET/CT v T4 le osnovni pregled zaradi hitrega napredovanja bolezni in smrti. 51 (72 %) bolnikov smo razvrstili v skupino klinične dobrobiti, 17 (24 %) pa v skupino brez klinične dobrobiti. Ugotovili smo statistično značilno razliko (p = 0,003) v srednjem celokupnem preživetju med skupino klinične dobrobiti (kjer srednje celokupno prežive- tje ni bilo doseženo [ND]; 95 % IZ = 17,8 meseca–ND) in skupino brez klinične dobrobiti (srednje celokupno preživetje 6,2 meseca; 95 % IZ = 4.6 meseca–ND; p = 0,003). Univariatna analiza po COX-u je pokazala razmerje obetov (RO) 0.4 (95 % IZ = 0.18–0.72; p = 0,004). Celokupno preživetje je bilo značilno daljše v skupini bolnikov z normalno serumsko vrednostjo LDH in v skupini z imunsko pogojenimi neželenimi učinki še posebej kožnimi. Zaključki. Zgodnja preiskava z 18F-FDG PET/CT v T4 lahko služi kot napovedni slikovni označevalec pri bolnikih z metastatskim melanomom, ki prejemajo imunoterapijo z zaviralci imunskih nadzornih točk. V raziskavi sta imela napovedno vrednost tudi normalna vrednost serumske LDH in pojav kožnih imunsko pogojenih neželenih učinkov. Slovenian abstracts Radiol Oncol 2025; 59(1): I-XV. V Radiol Oncol 2025; 59(1): 54-62. doi: 10.2478/raon-2025-0008 Razširjenost difuzne idiopatske skeletne hiperostoze in povezava s kalcifikacijami koronarnih arterij v Sloveniji Lesjak V, Hebar T, Pirnat M Izhodišča. Namen raziskave je bil ugotoviti prevalenco bolnikov z difuzno idiopatsko skeletno hipero- stozo (DISH) v Sloveniji, oceniti povezavo med atenuacijo epikardialnega maščevja (angl. epicardial adipose tissue, EAT) in stopnjo kalcifikacij koronarnih arterij (angl. coronary artery calcifications, CAC) pri bolnikih z in brez DISH ter preučiti dejavnike, ki vplivajo na te parametre. Bolniki in metode. V raziskavi smo obravnavali bolnike, ki so bili napoteni na koronarno CT angiografijo (CTA) zaradi kliničnega suma na koronarno arterijsko bolezen. DISH, CAC in atenuacijo EAT smo kvantifi- cirali s preiskavo CT brez kontrastnega sredstva. Diagnoza DISH je temeljila na Resnickovih kriterijih. S CTA smo ocenili prisotnost obstruktivne koronarne arterijske bolezni. Povezavo med DISH in obsegom CAC smo ugotavljali s korelacijsko analizo in multivariatno regresijo. Rezultati. V raziskavo smo vključili 219 bolnikov. Skupna prevalenca DISH je bila 7,8 %. Pri univariatni logistični regresiji so bili indeks telesne mase (razmerje obetov [RO] 1,133, p = 0,005), starost (RO 1,055, p = 0,032) in sladkorna bolezen (RO 3,840, p = 0,015) pomembno povezani s prisotnostjo DISH. Te povezave nismo dokazali pri multinomialni multivariatni analizi, kjer pa smo ugotovili, da so spol, starost, hipertenzija in atenuacija EAT značilno povezani z višjo stopnjo kalcifikacij koronark. Zaključek. Ugotovljena prevalenca DISH je primerljiva s predhodnimi objavami drugih raziskav. Med razširjenostjo DISH in CACS ni bilo neodvisne povezave. Naši podatki nakazujejo na bolj kompleksno in morda nevzročno povezavo med boleznijo koronarnih arterij in DISH. Slovenian abstracts Radiol Oncol 2025; 59(1): I-XV. VI Radiol Oncol 2025; 59(1): 63-68. doi: 10.2478/raon-2025-0006 Natančnost transtorakalnega ultrazvoka srca pri diagnostiki miksomov. Izkušnje največjega slovenskega terciarnega centra Kačar P, Pavšič N, Bervar M, Dolenc Stražar Z, Prokšelj K Izhodišča. Diferencialna diagnoza miksoma, najpogostejšega primarnega tumorja srca, je široka, zato je pred kirurškim zdravljenjem nujna natančna diagnostična obravnava za postavitev pravilne diagnoze. Transtorakalni ultrazvok srca (angl. transthoracic echocardiography, TTE) je najpogosteje prva preiskava izbora pri obravnavi bolnikov s sumom na miksom. Z raziskavo smo v želeli določiti natančnost, senzitivnost in specifičnost TTE pri diagnostiki miksoma ter določiti njihove ultrazvočne značilnosti. Bolniki in metode. Retrospektivno smo analizirali klinične, ehokardiografske in patohistološke izvide 73 bolnikov, ki so bili napoteni v največji slovenski terciarni center zaradi suma na miksom. Kirurško smo zdravili 53 (73 %) bolnikov. Rezultati. Na osnovi predoperativnega TTE smo bolnike razdelili v skupino z miksomom (n = 45, 85 %) in skupino z ne-miksomskim tumorjem. Od 53 perioperativnih patohistoloških vzorcev je bilo 39 (73 %) mi- ksomov. Senzitivnost predoperativnega TTE je bila 97 % in specifičnost 50 %. Skupna natančnost je bila 85 %. Vsi ne-miksomski tumorji so imeli atipično lokacijo in 72 % miksomov je imelo tipično lokacijo v levem preddvoru (p < 0.001). Ne-miksomski tumorji so bili značilno manjši od miksomov (24.3 ± 13.2 mm vs. 37.9 ± 18.3 mm; p = 0.017). Zaključki. Pričujoča raziskava je potrdila zadovoljivo natančnost TTE pri diagnostiki miksomov. Najpomembnejši ultrazvočni lastnosti za razlikovanje med miksomom in ne-miksomskim tumorjem sta lokacija in velikost tumorja. Manjši tumorji na atipični lokaciji so manj verjetno miksomi in v teh primerih je za postavitev pravilne diagnoze nemalokrat potrebna dodatna slikovna diagnostika. Slovenian abstracts Radiol Oncol 2025; 59(1): I-XV. VII Radiol Oncol 2025; 59(1): 69-78. doi: doi: 10.2478/raon-2025-0016 Primerjava 2D in 3D radiomskih značilnosti s konvencionalnimi značilnostmi, ki so temeljila na slikah CT s povečanim kontrastom pri predoperativnem napovedovanju tveganja za tumorje timusa Yuan YH, Zhang H, Xu WL, Dong D, Gao PH, Zhang CJ, Guo Y, Tong LL, Gong FC Izhodišča. Namen raziskave je bil razviti in potrditi dvodimenzionalne (2D) in tridimenzionalne (3D) radiomske znake, ki so temeljili na slikah računalniške tomografije (CT) s povečanim kontrastom pri pre- doperativnem napovedovanju tveganja za epitelne tumorje v timusu, pa tudi primerjati napovedno učinkovitost takšnega radiološke metode s slikami konvencionalne preiskave CT. Bolniki in metode. V raziskavo smo retrospektivno vključili 149 bolnikov z epitelnim tumorjem timusa od januarja 2016 do decembra 2018. Razdelili smo jih v skupino z visokim tveganjem (B2/B3/TCs, n = 103) in skupino z nizkim tveganjem (A/AB/B1, n = 46). Vse bolnike smo naključno razporedili v učni (n = 104) in testni (n = 45) niz. Zbrali smo 14 konvencionalnih značilnosti slik CT in 396 radioloških značilnosti, prido- bljenih iz 2D oziroma 3D slik CT s povečanim kontrastom. Z multivariatno logistično regresijsko analizo smo vzpostavili tri modele: konvencionalni model, 2D radiomski in 3D radiomski model. Različno učinkovitost modelov smo prikazali s krivuljami sprejemlivk operativnih karakteristik (ROC). Rezultati. Pri konvencionalnem modelu sta bili vrednosti območij pod krivuljo (AUC) v učnem in testnem nizu 0,863 in 0,853, občutljivost 78 % in 55 %, specifičnost pa 88 % in 100 %. Pri 2D-modelu sta bili vrednosti AUC 0,854 in 0,834, občutljivost 86 % in 77 %, specifičnost pa 72 % in 86 % v učnih in testnih nizih. Model 3D je pokazal AUC 0,902 in 0,906, občutljivost 75 % in 68 % ter specifičnost 94 % in 100 % v učnih in testnih nizih. Zaključki. Radiomske značilnosti, ki temeljijo na 3D-slikah, lahko razlikujejo med epitelnimi tumorji timusa z visokim in nizkim tveganjem ter zagotavljajo dopolnilne diagnostične informacije. Slovenian abstracts Radiol Oncol 2025; 59(1): I-XV. VIII Radiol Oncol 2025; 59(1): 79-90. doi: 10.2478/raon-2025-0012 Z MR srca ugotavljamo različno kardiotoksičnost, ki jo povzroča kemoterapija pri sarkomu in raku dojke Ibrahim ESH, Chaudhary L, Cheng YC, Sosa A, An D, Charlson J Izhodišča. V zadnjih nekaj desetletjih so se številne raziskave osredotočile na vpliv antraciklinov na srce (kardiotoksičnost) pri raku dojke, le nekaj pa na sarkom. V pričujoči raziskavi uporabljamo zmogljivosti naprednega slikanja z magnetno resonanco (MR) srca za opredelitev kardiotoksičnosti, ki jo povzročajo antraciklini pri sarkomu in rezultate primerjamo z rezultati pri bolnicah z rakom dojke. Bolniki in metode. Bolniki so opravili preiskavo z magnetno resonanco v treh časovnih točkah: v izho- dišču (pred zdravljenjem), po zdravljenju in po šestih mesecih. Rezultati. Izsledki preiskav so pokazali različen odziv srca na zdravljenje pri sarkomu, za katerega je bilo značilno povečanje mase levega prekata (angl. left ventricle, LV) in zmanjšanje iztisnega deleža desne- ga prekata (ang. right ventricular ejection fraction, RVEF). Pri vseh bolnikih je iztisni delež levega prekata (ang. left ventricular ejection fraction, LVEF) ostal > 50 % v vseh časovnih točkah. Deformacija miokarda je bila vedno nižja od običajnih mejnih vrednosti in je med različnimi časovnimi točkami kazala majhne spremembe. T2 miokarda in zunajcelični volumen (ECV) sta se pri sarkomu povečevala oziroma zmanj- ševala, kar je bilo nasprotno od vzorcev pri raku dojke. Medtem ko je T1 miokarda pri raku dojke pokazal naraščajoče vrednosti, se je T1 pri sarkomu po zdravljenju povečal in se nato zmanjšal ob 6-mesečnem spremljanju. Rezultati so pokazali obratno korelacijo med odmerkom in različnimi komponentami defor- macije pri sarkomu, kar pa ni veljalo za raka dojke. Nekateri segmenti srčne mišice so pokazali visoke koeficiente korelacije z odmerkom, kar lahko odseva njihovo večjo občutljivost na kardiotoksičnost. Zaključki. MR srca se je izkazala za dragoceno tehniko za ugotavljanje antraciklinskih sprememb srčne funkcije in sestave miokardnega tkiva pri sarkomu in kaže različno kardiotoksičnost, kot se pojavlja pri raku dojke po zdravljenju z antraciklini. Prav tako omogoča celovito oceno zdravja srca pred zdravljenjem, kar je pomembno za opredelitev tveganja. Slovenian abstracts Radiol Oncol 2025; 59(1): I-XV. IX Radiol Oncol 2025; 59(1): 91-99. doi: 10.2478/raon-2025-0004 Inovativne strategije za zmanjšanje tveganja hematoma pri biopsijah dojk, vodenih z magnetno resonanco Brönnimann MP, McMurray MT, Heverhagen JT, Christe A, Wyss C, Peters AA, Huber AT, Dammann F, Obmann VC Izhodišča. Namen raziskave je bil proučiti možnost zmanjšanja tveganja hematoma med biopsijami dojk, vodenimi z magnetno resonanco (MR). Ocenjevali smo parametre posega, ki so bili odvisni od položaja ter ovrednotili značilnosti biopsirane lezije. Bolniki in metode. Retrospektivno smo analizirali 252 perkutanih biopsij dojk, ki smo jih izvedli s pomo- čjo MR, opravljenih v terciarnem centru med januarjem 2013 in decembrom 2023. Glede na resnost nastanka relativnega hematoma (z uporabo mejne vrednosti ≤ 7,62 cm3 ali > 7,62 cm3) smo oblikovali dve skupini. Ocenili smo potencialne vplive spremenljivk, kot so bili bolničini demografski podatki, in- tervencijski parametri, povezani z anatomskimi podatki in značilnosti lezije. Za izračun statistične razlike med skupinami kategoričnih, dihotomnih in zveznih spremenljivk smo uporabili Fisherjev natančni test in Mann-Whitneyev U test. Za opredelitev najmočnejše povezave z relativnim nastankom hematoma smo uporabili multivariatno logistično regresijo. Rezultati. Univariatna analiza je pokazala, da so se relativno večji hematomi pojavili bistveno pogo- steje pri mlajših bolnicah (P = 0,002), kadar so bile primerljive razdalje od biopsirane lezije do bradavice (P = 0,001) in dostopnost poti (P = 0,001) večji ter kadar smo uporabili sistem za vakuumsko biopsijo v primerjavi s sistemom Spirotome® (P = 0,035). Tudi multivariatna logistična regresijska analiza je pokazala, da so bili ti dejavniki neodvisno povezani s pojavom relativno večjih hematomov. Epinefrin v lokalnem anestetiku, lokacija lezije, razvrščene po posameznih kvadrantih, in patohistološke ugotovitve niso vplivali na obseg hematoma. Zaključki. Ugotovitve raziskave poudarjajo pomen strateškega načrtovanja postopka za zmanjšanje pojava hematoma in za povečanje varnosti bolnikov med postopki biopsije dojk z MR. Slovenian abstracts Radiol Oncol 2025; 59(1): I-XV. X Radiol Oncol 2025; 59(1): 100-109. doi: 10.2478/raon-2025-0017 Primerjava selektivne intraarterijske in standardne intravenske aplikacije pri perkutani elektrokemoterapiji (pECT) jetrnih tumorjev Wilke T, Hussain E, Spallek H, de Terlizzi F, Mir LM, Bischoff P, Schäfer A, Bartmuß E, Cadossi M, Zanasi A, Pinkawa M, Kovács A Izhodišča. Elektrokemoterapija (ECT) je lokalno nekirurško učinkovito zdravljenje tumorjev, ki jo izvajamo tudi pri obravnavi bolnikov z jetrnimi tumorji ali metastazami. Namen raziskave je bil preveriti tehnično izvedljivost in varnost intraarterijske aplikacije bleomicina v primerjavi z uveljavljeno intravensko aplikacijo pri perkutani elektrokemoterapiji (pECT). Želeli smo tudi primerjati učinkovitost obeh načinov zdravljenja glede na lokalni odgovor na zdravljenje in preživetje brez napredovanja bolezni. Bolniki in metode. V raziskavo smo vključili 44 bolnikov, ki smo jih zdravili s pECT zaradi hepatocelular- nega karcinoma, holangiokarcinoma in jetrnih metastaz raka različnih izvorov. 18 bolnikom smo aplicirali bleomicin na standardni način intravenozno, 26 bolnikom pa intraarterijsko. Rezultati. Obe skupini sta si bili podobni po splošnih anagrafskih in po anamnestičnih podatkih ter po bolezenskih značilnostih. Zdravljenje smo lahko tehnično izvedli pri 95 % bolnikov z intravensko aplikacijo in pri 100 % bolnikov z intararterijsko. Kratkoročni lokalni odgovor na zdravljenje je bil v obeh skupinah bolnikov podoben, z nekoliko višjo stopnjo popolnega odgovora v skupini z intararterijsko aplikacijo. V skupini z intravensko aplikacijo bleomicina je bilo 61,9 % popolnih odgovorov; 23,8 % delnih in 4,8 % sta- gnacije bolezni, v skupini z intraarterijsko aplikacijo pa je bila lokalna kontrola bolezni glede na odgovor na zdravljenje 80,6 %; 12,9 % in 3,2 % (p = 0,3454). Enoletno preživetje brez napredovanja bolezni je bilo pri intravenski aplikaciji 60 % (I.Z. 33 % – 88 %), pri intararterijski pa 67 % (I.Z. 42 % – 91 %) (p = 0,5849). Zaključki. Rezultati raziskave potrjujejo varnost in izvedljivost superselektivne intraarterijske aplikacije bleomicina. Lokalni odgovor na zdravljenje in preživetja brez napredovanja bolezni sta v raziskavi po- kazala primerljivo učinkovitost intraarterijskega načina dovajanja bleomicina v primerjavi s standardnim intravenoznim pri zdravljenju primarnih in sekundarnih jetrnih malignomov s pECT. Slovenian abstracts Radiol Oncol 2025; 59(1): I-XV. XI Radiol Oncol 2025; 59(1): 110-120. doi: 10.2478/raon-2025-0001 Raziskava polimorfizmov genov GSTP1 in PTEN ter njihove povezave z dovzetnostjo za kolorektalni rak Shahwar D-e, Zubair H, Kashif Raza M, Khan Z, Mansour L, Ali A, Imran M Izhodišča. Preučevali smo povezavo enonukleotidnega polimorfizma (ang. Single-Nucleotide Polymorphism) v glutation S transferazi P1 (rs1695 in rs1138272) ter fosfatazi in homologu TENsin (rs701848 in rs2735343) s tveganjem za kolorektalni rak. Bolniki in metode. V raziskavo primerov in kontrol smo vključili 200 bolnikov s kolorektalnim rakom in 250 zdravih subjektov za kontrolo. Vsi preiskovanci so bili razdeljeni v 3 skupine: bolniki, zdravi subjekti za kontrolo ter skupna skupina (bolniki in kontrolni subjekti). Genotipizacijo smo naredili z verižno reakcijo s polimerazo in polimorfizmom dolžine restrikcijskih fragmentov. Zbrali smo demografske podatke, vključno s starostjo, spolom, mestom bolezni, kadilskim statusom, stadijem raka in prizadetostjo bezgavk. Rezultati. Pogostost alelov PTEN rs701848 pri vseh osebah je bila 0,78 za C in 0,22 za T. Podobno je bila pri vseh osebah pogostost alelov PTEN rs2735343 0,65 in 0,35 za alela G in C. Ugotovili smo, da sta bila genotip CC ali alel C rs701848 in genotip CG/GG rs2735343 dejavnika tveganja za kolorektalni rak. Pri vseh posameznikih smo opazili pomembno (p ≤ 0,05) povezavo med polimorfizmoma rs701848 in rs2735343 ter kolorektalnim rakom. Pogostosti alelov za rs1695 GSTP1 sta bili 0,68 oziroma 0,32 za alela A in G. Pogostosti alelov za GSTP1 rs113828 sta bili 0,68 oziroma 0,32 za alela C in T. Vendar smo za rs1695 ugotovili pomembno (p < 0,05) povezavo pri moških, medtem ko smo videli za porazdelitev vseh geno- tipov ali alelov pri GSTP1 (rs113828) nepomembno razliko. Zaključki. Oba enonukleotidna polimorfizma PTEN rs701848 in rs2735343 sta bila pomembno poveza- na s kolorektalnim rakom. Pri GSTP1 pa je bil rs1695 pomembno povezan s tveganjem za rak debelega črevesa in danke pri moških, med tem ko je rs113828 pokazal nepomembno povezavo s tveganjem za kolorektalni rak. Slovenian abstracts Radiol Oncol 2025; 59(1): I-XV. XII Radiol Oncol 2025; 59(1): 121-131. doi: 10.2478/raon-2025-0013 Obravnava karcinoma skorje nadledvične žleze v Sloveniji. Klinična analiza histopatoloških kazalcev, vzorcev zdravljenja, napovednih kazalcev in preživetja Bokal U, Jeruc J, Kocjan T, Volavšek M, Jerebic J, Rakuša M, Mencinger M Izhodišča. Karcinom skorje nadledvične žleze (angl. adrenocortical carcinoma, ACC) je redek rak, ki predstavlja izziv pri diagnosticiranju in zdravljenju. Preučili smo zdravljenje in preživetje bolnikov z ACC v Sloveniji v obdobju 17-ih let. Bolniki in metode. V raziskavo smo vključili bolnike, ki so bili vpisani v Register raka RS in smo jih zdravili od leta 2000 do 2017. Preživetje in napovedne dejavnike smo ocenili s Kaplan-Meierjevo metodo in Coxovo regresijo. Rezultati. Vključenih je bilo 48 bolnikov. Ob postavitvi diagnoze je 6 %, 42 %, 25 % oziroma 27 % bolni- kov imelo stadij bolezni glede na klasifikacijo Evropske zveze za raziskavo nadledvičnih tumorjev (angl. European Network for the Study of Adrenal Tumors, ENSAT) I, II, III oziroma IV. 18 od 34 potencialno pri- mernih bolnikov smo dopolnilno zdravili z mitotanom, Bolniki z visoko rizičnimi karcinomi, ki so bili dopolnil- no zdravljeni z mitotanom, so imeli nižje tveganje za smrt, čeprav razlika ni bila statistično značilna. Bolniki s ponovitvijo bolezni so imeli višji Ki67 in številčno bolj pogoste R1 resekcije. Enajst bolnikov je prejelo prvi red zdravljenja z etopozidom, doksorubicinom, cisplatinom in mitotanom (angl. EDP-M). Njihovo srednje preživetje brez napredovanja bolezni je bilo 4,4 meseca. Srednje celokupno preživetje celotne kohorte je bilo 28,9 in srednje specifično preživetje 36,2 meseca. Odstotek bolnikov s petletnim specifičnim preži- vetjem glede na stadij ENSAT I, II, III in IV je bil 100 %, 56 %, 50 % in 0 %. Stadij ENSAT in ocena po Helsinkih sta se izkazala kot napovedna dejavnika za preživetje v multivariantni analizi. Zaključki. Petletno specifično preživetje naših bolnikov s karcinomom skorje nadledvične žleze in sta- dijem ENSAT II je bilo manjše v primerjavi z nekaterimi drugimi sodobnimi kohortami. K temu sta lahko prispevala neoptimalno kirurško zdravljenje in nedoslednost pri izvedbi dopolnilnega zdravljenja z mito- tanom. Preživetje bolnikov s to redko boleznijo bi lahko izboljšali tudi z optimiziranjem diagnostičnih in zamejitvenih postopkov ter večjim poudarkom na multidisciplinarnosti pri načrtovanju zdravljenja. Slovenian abstracts Radiol Oncol 2025; 59(1): I-XV. XIII Radiol Oncol 2025; 59(1): 132-138. doi: 10.2478/raon-2025-0003 Učinkovitost tramadola ali topičnega lidokaina v primerjavi z epiduralno ali opioidno analgezijo na pooperativno analgezijo pri laparoskopski resekciji tumorjev debelega črevesa in danke Spindler-Vesel A, Jenko M, Repar A, Potočnik I, Markovič-Božič J Izhodišča. Kronična pooperativna bolečina poslabša kakovost življenja. Postopoma se razvije v nevro- patsko bolečino. Kombinirana analgezija vpliva na mehanizme nastanka kronične bolečine. Bolniki in metode. Raziskovali smo, ali lahko lidokainski obliž na mestu rane ali infuzija metamizola in tramadola zmanjšata porabo opioidov med laparoskopsko kolorektalno operacijo in ali so rezultati pri- merljivi z učinkovitostjo epiduralne analgezije. Bolnike smo naključno razdelili v štiri skupine. V prvo skupino smo vključili 20 bolnikov, ki so prejemali infuzijo piritramida, v drugo skupino pa 21 bolnikov, ki so prejemali infuzijo metamizola in tramadola. V tretji skupini je bilo 20 pacientov deležnih epiduralne analgezije, v četrti je 22 pacientov prejelo piritramid in 5 % lidokainski obliž na mestu rane. Raziskovali smo tudi pojav- nost nevropatske bolečine. Rezultati. Poraba piritramida je bila značilno najmanjša v tretji skupini na dan operacije ter prvi in drugi dan po operaciji. Četrta skupina je potrebovala bistveno manj piritramida kot prva na dan operacije ter prvi in drugi dan po operaciji. Skupina z metamizolom in tramadolom je prvi in drugi dan po operaciji potrebovala bistveno manj piritramida kot skupina 1 in 4 prvi in drugi dan po posegu. Na dan operacije je ta skupina potrebovala največjo količino piritramida. Zaključki. Za pooperativno analgezijo po laparoskopski resekciji kolorektalih tumorjev je bil tramadol v kombinaciji z metamizolom enako učinkovit kot epiduralna analgezija ali infuzija piritramida. Lidokainski obliž v kombinaciji z infuzijo piritramida je zmanjšal porabo opioidov. Slovenian abstracts Radiol Oncol 2025; 59(1): I-XV. XIV Radiol Oncol 2025; 59(1): 139-146. doi: 10.2478/raon-2025-0006 Različnost med opazovalci in zaporedij pri razmejitvi ogroženih medeničnih organov na slikah z magnetno resonanco Zheng W, Yang X, Cheng Z, Lian J, Li E, Mo S, Liu Y, Huang S Izhodišča. Raziskava ocenjuje različnost (variabilnost) oblikovanja kontur med opazovalci z uporabo slik magnetne resonance (MR), rekonstruiranih z različnimi zaporedji in kvantificira razlike med modeli samo- dejne segmentacije za različna zaporedja. Bolniki in metode. 83 bolnikov s tumorji medenice je na simulatorju opravilo magnetnoresonančna slikanja: T1 obteženo (angl. T1-weighted image, T1WI), kontrastno ojačano T1 Dixon obteženo (angl. contrast enhanced Dixon T1-weighted, T1dixonc) in T2 obteženo (angl. T2-weighted image, T2WI). Dva opazovalca sta na vseh posnetkih ročno razmejila mehur, analni kanal, danko in glave stegnenice. Za analizo različnosti med opazovalci in med zaporedji slikanja smo upoštevali razlike v konturah. S pomočjo omrežja U-Net smo vzpostavili mrežo za samodejno segmentacijo posamezne sekvence (angl. single- sequence segmentation), rezultate segmentacije pa smo analizirali. Rezultati. Analiza različnosti med opazovalci je pokazala, da so mehur, danka in glava levega stegne- nice pri T1WI pokazali najvišji koeficient podobnosti (angl. dice similarity coefficient, DSC) in najnižjo 95% Hausdorffovo razdaljo (angl. Hausdorff distance, HD), kar je bilo vidno pri vseh treh sekvencah. Pri analizi različnosti zaporedij za istega opazovalca je bila razlika med T1WI in T2WI najmanjša. DSC mehurja, dan- ke in stegneničnih glavic je pri sekvencah T1WI-T2WI presegel 0,88. Razlike med samodejnimi segmen- tacijami in ročnimi razmejitvami (delineacijami) so bile pri T2WI minimalne. Povprečje DSC samodejne in ročne segmentacije vseh organov na T2WI je preseglo 0,81, povprečna 95-odstotna vrednost HD pa je bila nižja od 7 mm. Podobno analiza različnosti zaporedja samodejne segmentacije je pokazala, da so bili razlike v samodejni segmentaciji med T2WI in T1WI minimalne. Zaključki. S T1WI in T2WI smo dosegli boljše rezultate pri ročni razmejitvi oziroma pri samodejni segmen- taciji. Prav tako je analiza različnost med tremi zaporedji pokazala, da smo dobili dobre rezultate podob- nosti med primeroma T1WI in T2WI pri ročni in samodejni segmentaciji. Sklepamo, da se lahko sekvence T1WI in T2WI (ali njuna kombinacija) uporabljajo za radioterapijo samo z MR. Slovenian abstracts Radiol Oncol 2025; 59(1): I-XV. XV Radiol Oncol 2025; 59(1): 147-152. doi: 10.2478/raon-2025-0018 Bronhialna bakterijska kolonizacija in občutljivost izoliranih bakterij pri bolnikih z rakom na pljučih Petrović S, Beović B, Tomič V, Bitenc M, Marc Malovrh M, Dimitrić V, Lužnik D, Miklavčič M, Božič T, Gabrovec T, Sadikov A, Rozman A Izhodišča. Pooperativna pljučnica ostaja pomemben vzrok smrtnosti po operaciji pljuč. Nedavne razi- skave so potrdile, da dihalne poti pod glasilkami niso sterilne in pogosto vključujejo potencialno patoge- ne mikroorganizme, zato se bolniki s pljučnimi malignimi boleznimi izpostavljeni povečanemu tveganju za pljučne okužbe. Bolniki in metode. V raziskavo smo vključili 149 bolnikov, pri katerih smo naredili bronhoskopijo zaradi za rak sumljivih sprememb na pljučih. Pri vsakem bolniku smo pred specifičnim zdravljenjem ob bronhosko- piji odvzeli vzorce z zaščitenim sterilnim katetrom. Vzorce smo poslali v mikrobiološki laboratorij, kjer smo identificirali izolirane bakterije in testirali njihovo občutljivost na protimikrobna zdravila. Rezultati. Bakterijsko kolonizacijo smo odkrili pri 88,6 % bolnikov, med njimi jih je 21,5 % imelo potenci- alno patogene mikroorganizme. Bolniki s sladkorno boleznijo tipa 2 so pokazali višjo stopnjo kolonizacije s potencialno patogenimi mikroorganizmi v primerjavi z drugimi bolniki v raziskavi. Testiranje občutljivosti ni pokazalo pomembne razlike med amoksicilinom s klavulansko kislino in cefalosporini prve generacije tako pri koloniziranih bolnikih kot pri tistih, ki so bili kolonizirani s potencialno patogenimi mikroorganizmi. Nismo pa našli bakterij, ki bi bile odporne na več zdravil. Zaključki. Rezultati v pričujoči raziskavi so pokazali nekoliko nižjo stopnjo kolonizacije s potencialno pa- togenimi mikroorganizmi v primerjavi z dosedanjimi raziskavami. Vzrok je verjetno edinstvena geografska značilnost obravnavane populacije. Odsotnost statistično pomembnih razlik v občutljivosti bakterij med obema testiranima antibiotikoma poudarja potrebo po nadaljnjih raziskavah za izboljšanje strategij peri- operativnega obvladovanja okužb. Pomembno: Predpisovanje in izdaja zdravila je le na recept zdravnika specialista ustreznega področja medicine ali od njega pooblaščenega zdravnika. Pred predpisovanjem zdravila Verzenios si preberite zadnji veljavni Povzetek glavnih značilnosti zdravil. Podrobne informacije o zdravilu so objavljene na spletni strani Evropske agencije za zdravila http://www.ema.europa.eu Reference: 1. Povzetek glavnih značilnosti zdravila Verzenios, zadnja odobrena verzija. Eli Lilly farmacevtska družba, d.o.o., Dunajska cesta 167, 1000 Ljub lja na, te le fon 01 / 580 00 10, faks 01 / 569 17 05 PP-AL-SI-0306, 24.9.2024. Samo za strokovno javnost. SKRAJŠAN POVZETEK GLAVNIH ZNAČILNOSTI ZDRAVILA IME ZDRAVILA: Verzenios 50 mg/100 mg/150 mg filmsko obložene tablete KAKOVOSTNA IN KOLIČINSKA SESTAVA: Ena filmsko obložena tableta vsebuje 50 mg/100 mg/150 mg abe- macikliba. Ena filmsko obložena tableta vsebuje 14 mg/28 mg/42 mg laktoze (v obliki monohidrata). Terapevtske indikacije: Zgodnji rak dojk: Zdravilo Verzenios je v kombinaciji z endokri- nim zdravljenjem indicirano za adjuvantno zdravljenje odraslih bolnikov z na hormonske receptorje (HR) pozitivnim, na receptorje humanega epidermalnega rastnega faktorja 2 (HER2) ne- gativnim zgodnjim rakom dojk s pozitivnimi bezgavkami, pri katerih obstaja veliko tveganje za ponovitev. Pri ženskah v pred- ali perimenopavzi je treba endokrino zdravljenje z zaviralcem aromataze kombinirati z agonistom gonadoliberina LHRH – luteinizing hormone–releasing hormone). Napredovali ali metastatski rak dojk: Zdravilo Verzenios je indicirano za zdravljenje žensk z lokalno napredovalim ali metastatskim, na hormonske receptorje (HR) pozitivnim in na receptorje humanega epidermalnega rastnega faktorja 2 (HER2) negativnim rakom dojk v kombinaciji z zaviralcem aromataze ali s fulvestrantom kot začetnim endokrinim zdravljenjem ali pri ženskah, ki so prejele predhodno endokrino zdravljenje. Pri ženskah v pred- ali perime- nopavzi je treba endokrino zdravljenje kombinirati z agonistom LHRH. Odmerjanje in način uporabe: Zdravljenje z zdravilom Verzenios mora uvesti in nadzorovati zdravnik, ki ima izkušnje z uporabo zdravil za zdravljenje rakavih bolezni. Priporočeni odmerek abemacikliba je 150 mg dvakrat na dan, kadar se uporablja v kombinaciji z endokrinim zdravljenjem. Zgodnji rak dojk: Zdravilo Verzenios je treba jemati neprekinjeno dve leti, ali do ponovitve bolezni ali pojava nesprejemljive toksičnosti. Napredovali ali metastatski rak dojk: Zdravilo Verzenios je treba jemati, dokler ima bolnica od zdravljenja klinično korist ali do pojava nesprejemljive toksičnosti. Če bolnica bruha ali izpusti odmerek zdravila Verzenios, ji je treba naročiti, da naj naslednji odmerek vzame ob predvidenem času; dodatnega odmerka ne sme vzeti. Obvladovanje nekaterih neželenih učinkov lahko zahteva prekinitev in/ali zmanjšanje odmerka. Zdravljenje z abemaciklibom prekinite v primeru povišanja vrednosti AST in/ali ALT >3 x ZMN SKUPAJ s celokupnim bilirubinom > 2,0 x ZMN v odsotnosti holestaze ter pri bolnicah z intersticijsko pljučno boleznijo (ILD)/ pnevmonitis stopnje 3 ali 4. Sočasni uporabi močnih zaviralcev CYP3A4 se je treba izogibati. Če se uporabi močnih zaviralcev CYP3A4 ni mogoče izogniti, je treba odmerek abemacikliba znižati na 100 mg dvakrat na dan. Pri bolnicah, pri katerih je bil odmerek znižan na 100 mg abemacikliba dvakrat na dan in pri katerih se sočasnemu dajanju močnega zaviralca CYP3A4 ni mogoče izogniti, je treba odmerek abemacikliba dodatno znižati na 50 mg dvakrat na dan. Pri bolnicah, pri katerih je bil odmerek znižan na 50 mg abemacikliba dvakrat na dan in pri katerih se sočasnemu dajanju močnega zaviralca CYP3A4 ni mogoče izogniti, je mogoče z odmerkom abemacikliba nadaljevati ob natančnem spremljanju znakov toksičnosti. Alternativno je mo- goče odmerek abemacikliba znižati na 50 mg enkrat na dan ali prekiniti dajanje abemacikliba. Če je uporaba zaviralca CYP3A4 prekinjena, je treba odmerek abemacikliba povečati na od- merek, kakršen je bil pred uvedbo zaviralca CYP3A4 (po 3–5 razpolovnih časih zaviralca CYP3A4). Prilagajanje odmerka glede na starost in pri bolnicah z blago ali zmerno ledvično okvaro ter z blago (Child Pugh A) ali zmerno (Child Pugh B) jetrno okvaro ni potrebno. Pri dajanju abemacikliba bolnicam s hudo ledvično okvaro sta potrebna previdnost in skrbno spremljanje glede znakov toksičnosti. Način uporabe: Zdravilo Verzenios je namenjeno za peroralno uporabo. Odmerek se lahko vzame s hrano ali brez nje. Zdravila se ne sme jemati z grenivko ali grenivkinim sokom. Bolnice naj odmerke vzamejo vsak dan ob približno istem času. Tableto je treba pogoltniti celo (bolnice tablet pred zaužitjem ne smejo gristi, drobiti ali deliti). Kontrain- dikacije: Preobčutljivost na učinkovino ali katero koli pomožno snov. Posebna opozorila in previdnostni ukrepi: Pri bolnicah, ki so prejemale abemaciklib, so poročali o nevtropeniji, o večji pogostnosti okužb kot pri bolnicah, zdravljenih s placebom in endokrinim zdravljenjem, o povečanih vrednostih ALT in AST. Pri bolnicah, pri katerih se pojavi nevtropenija stopnje 3 ali 4, je priporočljivo prilagoditi odmerek. Do primerov nevtropenične sepse s smrtnim izidom je prišlo pri < 1 % bolnic z metastatskim rakom dojk. Bolnicam je treba naročiti, naj o vsaki epizodi povišane telesne temperature poročajo zdravstvenemu delavcu. Bolnice je treba spremljati za znake in simptome globoke venske tromboze (VTE) in pljučne embolije ter jih zdraviti, kot je medicinsko utemeljeno. Glede na stopnjo VTE bo morda treba spremeniti odmerek abemacikliba. Pri bolnikih, pri katerih se pojavi resni arterijski trombembolični dogodek (ATE), je treba oceniti koristi in tveganja nadaljnjega zdravljenja z abemaciklibom. Glede na povečanje vrednosti ALT ali AST je mogoče potrebna prilagoditev odmerka. Driska je najpogostejši neželeni učinek. Bolnice je treba ob prvem znaku tekočega blata začeti zdraviti z antidiaroiki, kot je loperamid, povečati vnos peroralnih tekočin in obvestiti zdravnika. Sočasni uporabi induktorjev CYP3A4 se je treba izogibati zaradi tveganja za zmanjšano učinkovitost abemacikliba. Bolnice z redkimi dednimi motnjami, kot so intoleranca za galaktozo, popolno pomanjkanje laktaze ali malapsorpcija glukoze/galaktoze, tega zdravila ne smejo jemati. Bolnice je treba spremljati glede pljučnih simptomov, ki kažejo na ILD/pnevmonitis, in jih ustrezno zdraviti. Glede na stopnjo ILD/pnevmonitisa je morda potrebno prilagajanje odmerka abemacikliba. Medsebojno delovanje z drugimi zdravili in druge oblike interakcij: Abemaciklib se primarno presnavlja s CY- P3A4. Sočasna uporaba abemacikliba in zaviralcev CYP3A4 lahko poveča plazemsko koncentracijo abemacikliba. Uporabi močnih zaviralcev CYP3A4 sočasno z abemaciklibom se je treba izogibati. Če je močne zaviralce CYP3A4 treba dajati sočasno, je treba odmerek abemacikliba zmanjšati, nato pa bolnico skrbno spremljati glede toksičnosti. Pri bolnicah, zdravljenih z zmernimi ali šibkimi zaviralci CYP3A4, ni potrebno prilagajanje odmerka, vendar jih je treba skrbno spremljati za znake toksičnosti. Sočasni uporabi močnih induktorjev CYP3A4 (vključno, vendar ne omejeno na: karbamazepin, fenitoin, rifampicin in šentjanževko) se je treba izogibati zaradi tveganja za zmanjšano učinkovitost abemacikliba. Abemaciklib in njegovi glavni aktiv- ni presnovki zavirajo prenašalce v ledvicah, in sicer kationski organski prenašalec 2 (OCT2) ter prenašalca MATE1. In vivo lahko pride do medsebojnega delovanja abemacikliba in klinično pomembnih substratov teh prenašalcev, kot je dofelitid ali kreatinin. Trenutno ni znano, ali lahko abemaciklib zmanjša učinkovitost sistemskih hormonskih kontraceptivov, zato se ženskam, ki uporabljajo sistemske hormonske kontraceptive, svetuje, da hkrati uporabljajo tudi mehansko metodo. Neželeni učinki: Najpogostejši neželeni učinki so driska, okužbe, nevtropenija, levkopenija, anemija, utrujenost, navzea, bruhanje in zmanjšanje apetita. Zelo pogosti: okužbe, nevtropenija, levkopenija, anemija, trombocitopenija, limfopenija, zmanjšanje apetita, glavo- bol, disgevzija, omotica, driska, bruhanje, navzea, stomatitis, alopecija, pruritus, izpuščaj, pireksija, utrujenost, povečana vrednost alanin-aminotransferaze, povečana vrednost aspartat-ami- notransferaze Pogosti: povečano solzenje, venska trombembolija, ILD/pnevmonitis, dispepsija, spremembe na nohtih, suha koža, mišična šibkost Občasni: febrilna nevtropenija, fotopsija Rok uporabnosti: 3 leta Posebna navodila za shranjevanje Za shranjevanje zdravila niso potrebna posebna navodila. Imetnik dovoljenja za promet z zdravilom: Eli Lilly Nederland B.V., Pa- pendorpseweg 83, 3528BJ, Utrecht, Nizozemska. Datum prve odobritve dovoljenja za promet: 27. september 2018. Datum zadnjega podaljšanja: 23. junij 2023. Datum zadnje revizije besedila: 4. 7. 2024 Režim izdaje: Rp/Spec - Predpisovanje in izdaja zdravila je le na recept zdravnika specialista ustreznega področja medicine ali od njega pooblaščenega zdravnika. abemaciklib DAJTE JI VEČ KOT UPANJE Za lajšanje bolečine in oteklin v ustni in žrelu, ki so posledica radiomukozitisa Sestava: 1,5 mg/ml: 1 ml raztopine vsebuje 1,5 mg benzidaminijevega klorida, kar ustreza 1,34 mg benzidamina. V enem razpršku je 0,17 ml raztopine. En razpršek vsebuje 0,255 mg benzidaminijevega klorida, kar ustreza 0,2278 mg benzidamina. Sestava 3 mg/ml: 1 ml raztopine vsebuje 3 mg benzidaminijevega klorida, kar ustreza 2,68 mg benzidamina. V enem razpršku je 0,17 ml raztopine. En razpršek vsebuje 0,51 mg benzidaminijevega klorida, kar ustreza 0,4556 mg benzidamina. Terapevtske indikacije: Samozdravljenje: Lajšanje bolečine in oteklin pri vnetju v ustni votlini in žrelu, ki so lahko posledica okužb in stanj po operaciji. Po nasvetu in navodilu zdravnika: Lajšanje bolečine in oteklin v ustni votlini in žrelu, ki so posledica radiomukozitisa. Odmerjanje in način uporabe: Uporaba: 2- do 6-krat na dan (vsake 1,5 do 3 ure). Odmerjanje 1,5 mg/ml: Odrasli: 4 do 8 razprškov 2- do 6-krat na dan. Pediatrična populacija: Mladostniki, stari od 12 do 18 let: 4-8 razprškov 2- do 6-krat na dan. Otroci od 6 do 12 let: 4 razprški 2- do 6-krat na dan. Otroci, mlajši od 6 let: 1 razpršek na 4 kg telesne mase; do največ 4 razprške 2- do 6-krat na dan. Odmerjanje 3 mg/ml: Odrasli: 2 do 4 razprški 2- do 6-krat na dan. Pediatrična populacija: Mladostniki, stari od 12 do 18 let: 2 do 4 razprški 2- do 6-krat na dan. Otroci od 6 do 12 let: 2 razprška 2- do 6-krat na dan. Otroci, mlajši od 6 let: 1 razpršek na 8 kg telesne mase; do največ 2 razprška 2- do 6-krat na dan. Starejši bolniki, bolniki z jetrno okvaro in bolniki z ledvično okvaro: niso potrebni posebni previdnostni ukrepi. Trajanje zdravljenja ne sme biti daljše od 7 dni. Način uporabe: Za orofaringealno uporabo. Zdravilo se razprši v usta in žrelo. Kontraindikacije: Preobčutljivost na učinkovino ali katero koli pomožno snov. Posebna opozorila in previdnostni ukrepi: Pri nekaterih bolnikih lahko resne bolezni povzročijo ustne/žrelne ulceracije. Če se simptomi v treh dneh ne izboljšajo, se mora bolnik posvetovati z zdravnikom ali zobozdravnikom, kot je primerno. Uporaba benzid- amina ni priporočljiva za bolnike s preobčutljivostjo na salicilno kislino ali druga nesteroidna protivnetna zdravila. Pri bolnikih, ki imajo ali so imeli bronhialno astmo, lahko pride do bronhospazma. Pri takih bolnikih je potrebna previdnost. To zdravilo vsebuje 13,6 mg alkohola (etanola) v enem razpršku (0,17 ml), kar ustreza manj kot 0,34 ml piva oziroma 0,14 ml vina. Majhna količina alkohola v zdravilu ne bo imela nobenih opaznih učinkov. To zdravilo vsebuje metilparahidroksibenzoat (E218). Lahko povzroči alergijske reakcije (lahko zapoznele). To zdravilo vsebuje manj kot 1 mmol (23 mg) natrija v enem razpršku (0,17 ml), kar v bistvu pomeni ‘brez natrija’. Zdravilo vsebuje aromo poprove mete z benzilalkoholom, cinamilalkoholom, citralom, citronelolom, geraniolom, izoevgenolom, linalolom, evgenolom in D-limonen, ki lahko povzročijo alergijske reakcije. Zdravilo z jakostjo 3 mg/ml vsebuje makrogolglicerol hidroksistearat 40. Lahko povzroči želodčne težave in drisko. Medsebojno delovanje z drugimi zdravili in druge oblike interakcij: Študij medsebojnega delovanja niso izvedli. Nosečnost in dojenje: O uporabi benzidamina pri nosečnicah in doječih ženskah ni zadostnih podatkov. Uporaba zdravila med nosečnostjo in dojenjem ni priporočljiva. Vpliv na sposobnost vožnje in upravljanja strojev: Zdravilo v priporočenem odmerku nima vpliva na sposobnost vožnje in upravljanja strojev. Neželeni učinki: Neznana pogostnost (ni mogoče oceniti iz razpoložljivih podatkov): anafilaktične reakcije, preobčutljivostne reakcije, odrevenelost, laringospazem, suha usta, navzea in bruhanje, oralna hipestezija, angioedem, fotosenzitivnost, pekoč občutek v ustih. Neposredno po uporabi se lahko pojavi občutek odrevenelosti v ustih in v žrelu. Ta učinek se pojavi zaradi načina delovanja zdravila in po kratkem času izgine. Način in režim izdaje zdravila: BRp-Izdaja zdravila je brez recepta v lekarnah in specializiranih prodajalnah. Imetnik dovoljenja za promet: Aziende Chimiche Riunite Angelini Francesco – A.C.R.A.F. S.p.A., Viale Amelia 70, 00181 Rim, Italija Datum zadnje revizije besedila: 05. 04. 2022 Pred svetovanjem ali izdajo preberite celoten Povzetek glavnih značilnosti zdravila. Samo za strokovno javnost. Datum priprave informacije: julij 2024 Odgovoren za trženje: Bonifar d.o.o. PR /B SI /B EN /2 02 4/ 00 8 Bistvene informacije iz Povzetka glavnih značilnosti zdravila Tantum Verde 1,5 mg/ml oralno pršilo, raztopina Tantum Verde 3 mg/ml oralno pršilo, raztopina SI- 47 49 SKRAJŠAN POVZETEK GLAVNIH ZNAČILNOSTI ZDRAVILA TAGRISSO 40 mg filmsko obložene tablete / TAGRISSO 80 mg filmsko obložene tablete SESTAVA: Ena filmsko obložena tableta vsebuje 40 ali 80 mg osimertiniba. INDIKACIJE: Zdravilo Tagrisso je kot monoterapija indicirano za: adjuvantno zdravljenje po popolni resekciji tumorja pri odraslih bolnikih z nedrobnoceličnim rakom pljuč v stadiju IB-IIIA (NSCLC - non-small cell lung cancer), pri katerem ima tumorski receptor za epidermalni rastni faktor (EGFR - epidermal growth factor receptor) delecije eksona 19 ali substitucije eksona 21 (L858R). • prvo linijo zdravljenja odraslih bolnikov z lokalno napredovalim ali metastatskim nedrobnoceličnim rakom pljuč (NSCLC – “non-small-cell lung cancer”), katerega receptor za epidermalni rastni faktor (EGFR – “epidermal growth factor receptor”) ima aktivirajoče mutacije. • zdravljenje odraslih bolnikov z lokalno napredovalim ali metastatskim NSCLC, pozitivnim za mutacijo T790M EGFR. • zdravljenje odraslih bolnikov z lokalno napredovalim, neoperabilnim NSCLC, katerih tumorji imajo delecije eksona 19 ali substitucijske mutacije eksona 21 (L858R) EGFR in jim bolezen med kemoradioterapijo na podlagi platine ali po njej ni napredovala. Zdravilo Tagrisso je indicirano v kombinaciji s: pemetreksedom in kemoterapijo na podlagi platine za prvo linijo zdravljenja odraslih bolnikov z napredovalim NSCLC, ki imajo tumorje z delecijo eksona 19 EGFR ali substitucijsko mutacijo eksona 21 (L858R) EGFR. ODMERJANJE IN NAČIN UPORABE: Zdravljenje z zdravilom Tagrisso mora uvesti zdravnik, ki ima izkušnje z zdravili za zdravljenje raka. Pri odločanju o uporabi zdravila Tagrisso je treba določiti stanje mutacije EGFR (v vzorcih tumorja pri adjuvantnem zdravljenju ali za zdravljenje lokalno napredovalih, neoperabilnih tumorjev in v vzorcih tumorja ali plazme pri lokalno napredovalem ali metastatskem raku) z uporabo validirane testne metode. Odmerjanje: Priporočeni odmerek je 80 mg osimertiniba enkrat na dan. Bolniki na adjuvantnem zdravljenju morajo zdravilo jemati do ponovitve bolezni ali nesprejemljivih toksičnih učinkov. Zdravljenja, daljšega od 3 let, niso preučili. Bolniki z lokalno napredovalim ali metastatskim rakom pljuč morajo zdravilo jemati do napredovanja bolezni ali nesprejemljivih toksičnih učinkov. Če bolnik izpusti odmerek zdravila Tagrisso, ga mora vzeti, razen če je do naslednjega odmerka že manj kot 12 ur. Zdravilo Tagrisso je mogoče vzeti s hrano ali brez nje, vsak dan ob istem času. Med uporabo s pemetreksedom in kemoterapijo na podlagi platine je priporočeni odmerek zdravila Tagrisso 80 mg osimertiniba enkrat na dan. Prilagoditve odmerka: Glede na varnost in prenašanje pri posameznem bolniku je lahko potrebna prekinitev odmerjanja in/ali zmanjšanje odmerka. V primeru potrebe po zmanjšanju odmerka je treba odmerek zmanjšati na 40 mg enkrat na dan. Smernice za zmanjšanje odmerka v primeru neželenih učinkov/toksičnosti so navedene v preglednici v Povzetku glavnih značilnosti zdravila. To zdravilo je namenjeno za peroralno uporabo. Tableto je treba zaužiti celo z vodo in se je ne sme drobiti, lomiti ali gristi. Odmerek pemetrekseda, cisplatina ali karboplatina je treba prilagoditi v skladu z navodili v ustreznih povzetkih glavnih značilnosti zdravil. Cisplatin in/ali karboplatin je treba uporabljati do 4 cikle. KONTRAINDIKACIJE: Preobčutljivost na učinkovino ali katerokoli pomožno snov. Šentjanževke se ne sme uporabljati skupaj z zdravilom Tagrisso. OPOZORILA IN PREVIDNOSTNI UKREPI: Pri odločanju o uporabi zdravila TAGRISSO pri bolnikih z lokalno napredovalim, neoperabilnim NSCLC, ki jim bolezen ni napredovala med kemoradioterapijo na podlagi platine ali po njej, za adjuvantno zdravljenje bolnikov z NSCLC po popolni resekciji tumorja ali če je zdravilo TAGRISSO uporabljeno v kombinaciji s pemetreksedom in kemoterapijo na podlagi platine za prvo linijo zdravljenj je pomembno določiti prisotnost mutacije EGFR (delecije eksona 19 (Ex19del) ali substitucije eksona 21 (L858R)). V kliničnem laboratoriju je treba opraviti validirano preiskavo tumorske DNK iz vzorca tkiva, pridobljenega z biopsijo ali kirurškim posegom. Pri odločanju o uporabi zdravila Tagrisso za zdravljenje lokalno napredovalega ali metastatskega NSCLC je pomembno določiti stanje mutacije T790M EGFR. Opraviti je treba validirano preiskavo tumorske DNK, dobljene iz vzorca tkiva, ali tumorske DNK v obtoku (ctDNA – circulating tumor DNA), dobljene iz vzorca plazme. Določitev prisotne mutacije EGFR (aktivirajoče mutacije EGFR pri prvi liniji zdravljenja ali mutacije T790M po napredovanju bolezni med zdravljenjem ali po zdravljenju z zaviralcem tirozin kinaze receptorja za epidermalni rastni faktor) v vzorcu tkiva ali plazme pomeni, da je bolnik primeren za zdravljenje z zdravilom TAGRISSO. A če je uporabljena preiskava za ctDNA iz plazme in je izvid negativen, je priporočljivo opraviti še preiskavo tkivnega vzorca, če je le mogoče. Pri preiskavah vzorcev plazme namreč obstaja možnost lažno negativnih rezultatov. Uporabiti se sme le robustne, zanesljive in občutljive preiskave z dokazano uporabnostjo za določanje stanja mutacije EGFR v tumorski DNK (iz vzorca tkiva ali plazme). O intersticijski bolezni pljuč (IBP) ali neželenih učinkih, podobnih IBP, so poročali pri 4,3 % od 1956 bolnikov, ki so v študijah ADAURA, FLAURA, FLAURA2, AURA in LAURA prejemali zdravilo Tagrisso. Poročali so o 8 dogodkih s smrtnim izidom. Pri adjuvantnem zdravljenju niso poročali o smrtnih primerih. Pojavnost IBP je bila pri bolnikih japonske etnične pripadnosti 10,4 %, pri bolnikih azijske etnične pripadnosti 2,8 % in pri neazijskih bolnikih 3,2 %. Vse bolnike z akutnim nastankom in/ali nepojasnjenim poslabšanjem pljučnih simptomov (dispneja, kašelj, zvišana telesna temperatura) je treba skrbno pregledati, da bi izključili IBP. V času preiskovanja teh simptomov je treba zdravljenje s tem zdravilom prekiniti. Če je diagnosticirana IBP, je treba ukiniti zdravljenje z zdravilom Tagrisso in uvesti ustrezno zdravljenje, kot je potrebno. Ponovna uvedba zdravila Tagrisso pride v poštev le po skrbnem pretehtanju koristi in tveganj pri posameznem bolniku. Radiacijski pnevmonitis: V študiji LAURA so po definitivni kemoradioterapiji na podlagi platine o radiacijskem pnevmonitisu poročali pri 48 % od 143 bolnikov, ki so prejemali zdravilo TAGRISSO in pri 38 % od 73 bolnikov, ki so prejemali placebo.V skupini z zdravilom TAGRISSO so imeli učinke 3. stopnje trije bolniki (2,1 %), v nobeni skupini pa niso poročali o učinkih 4. ali 5. stopnje. Mediani čas od prvega odmerka do pojava radiacijskega pnevmonitisa je bil v skupini z zdravilom TAGRISSO 1,7 meseca in v skupini s placebom 1,8 meseca. Mediani čas od zadnjega odmerka radioterapije do pojava radiacijskega pnevmonitisa je bil v skupini z zdravilom TAGRISSO 2,5 meseca in v skupini s placebom 2,6 meseca. Hudi kožni neželeni učinki (SCARs - Severe Cutaneous Adverse Reactions): V povezavi z zdravljenjem z zdravilom TAGRISSO so poročali o primerih Stevens-Johnsonovega sindroma (SJS), s kategorijo pogostnosti redko in o primerih toksične epidermalne nekrolize (TEN) s kategorijo pogostnosti neznano. Pred uvedbo zdravljenja je treba bolnike seznaniti z znaki in simptomi SJS in TEN. Če se pojavijo znaki ali simptomi, ki nakazujejo SJS ali TEN, je treba zdravljenje z zdravilom TAGRISSO prekiniti. Če se diagnosticira SJS ali TEN se mora zdravljenje z zdravilom TAGRISSO nemudoma ukiniti. Podaljšanje intervala QTc: Bolnikom, zdravljenim z zdravilom Tagrisso, se pojavi podaljšanje intervala QTc. Takšno podaljšanje lahko poveča tveganje za ventrikularne tahiaritmije (npr. torsade de pointes) ali nenadno smrt. V študijah ADAURA, LAURA, FLAURA, FLAURA2 ali AURA niso poročali o motnjah srčnega ritma, povezanih s QTc. Uporabi zdravila Tagrisso se je treba pri bolnikih s prirojenim sindromom dolgega intervala QT izogniti, če je le mogoče. O rednih kontrolah elektrokardiograma (EKG) in elektrolitov je treba razmisliti pri bolnikih s kongestivnim srčnim popuščanjem, elektrolitskimi motnjami in prejemnikih zdravil, za katera je znano, da podaljšajo interval QTc. Prekinite uporabo pri bolnikih, ki se jim interval QTc podaljša preko 500 msec na vsaj 2 ločenih posnetkih EKG, in ga ne uporabljajte, dokler ni interval QTc manj kot 481 msec oziroma do njegove vrnitve na izhodiščno vrednost, če je izhodiščni interval QTc 481 msec ali več. Potem začnite zdravilo Tagrisso znova uporabljati v manjšem odmerku. Trajno ukinite zdravljenje z zdravilom Tagrisso, če se bolniku pojavi podaljšanje intervala QTc v kombinaciji s čimer koli od naslednjega: torsade de pointes, polimorfna ventrikularna tahikardija, znaki/ simptomi resne motnje srčnega ritma. Spremembe v krčljivosti srca: V kliničnih preskušanjih se je zmanjšanje iztisnega deleža levega prekata (LVEF “left ventricular ejection fraction”) za ≥ 10 odstotnih točk ali na manj kot 50 % pojavilo pri 4,2 % (65/1557) bolnikov, zdravljenih z monoterapijo z zdravilom TAGRISSO, ki so imeli LVEF izmerjen izhodiščno in vsaj še enkrat med obdobjem spremljanja. Pri bolnikih s srčnimi dejavniki tveganja in bolnikih s stanji, ki prizadenejo LVEF, je treba razmisliti o nadziranju delovanja srca, vključno z ocenjevanjem LVEF izhodiščno in med zdravljenjem. Pri bolnikih, ki se jim med zdravljenjem pojavijo pomembni srčni znaki ali simptomi, je treba razmisliti o nadziranju delovanja srca, vključno z ocenjevanjem LVEF. V s placebom nadzorovanem preskušanju adjuvantnega zdravljenja (ADAURA) se je zmanjšanje LVEF za ≥ 10 odstotnih točk ali na manj kot 50 % pojavilo pri 1,5 % (5/335) bolnikov, zdravljenih z zdravilom TAGRISSO, in 1,5 % (5/331) bolnikov, zdravljenih s placebom. V študiji LAURA se je med bolniki, ki so imeli izhodiščno in poizhodiščno oceno LVEF, po kemoradioterapiji na podlagi platine pojavilo zmanjšanje LVEF za 10 odstotnih točk ali več ter za manj kot 50 % po kemoradioterapiji na podlagi platine pojavilo pri 3,0 % (4/135) prejemnikov zdravila TAGRISSO in pri nobenem prejemniku placeba. V študiji FLAURA2 se je LVEF zmanjšal za 10 odstotnih točk ali več oziroma je upadel na manj kot 50 % pri 8,0 % (21/262) bolnikov, ki so prejemali zdravilo TAGRISSO v kombinaciji s pemetreksedom in kemoterapijo na podlagi platine ter so imeli LVEF izmerjen izhodiščno in vsaj še enkrat med obdobjem spremljanja. Keratitis: O keratitisu so poročali pri 0,6 % bolnikov, zdravljenih z zdravilom Tagrisso v študijah ADAURA, FLAURA, FLAURA2, LAURA in AURA. Bolnike z znaki in simptomi, ki nakazujejo keratitis (na primer vnetje očesa, solzenje, občutljivost na svetlobo, zamegljen vid, bolečine v očesu in/ali pordelost očesa), je treba nemudoma napotiti k specialistu oftalmologu. Aplastična anemija: V povezavi z zdravljenjem z zdravilom Tagrisso so poročali o redkih primerih aplastične anemije, vključno s smrtnimi primeri. Pred uvedbo zdravljenja je treba bolnike seznaniti z znaki in simptomi aplastične anemije, ki vključujejo, a niso omejeni le na dolgotrajno zvišano telesno temperaturo, podplutbe, krvavitve, bledico, okužbe in utrujenost. Če se pojavijo znaki in simptomi, ki kažejo na aplastično anemijo, je treba razmisliti o natančnem nadziranju bolnika ter o prekinitvi ali prenehanju zdravljenja z zdravilom Tagrisso. Pri bolnikih s potrjeno aplastično anemijo je treba zdravljenje z zdravilom Tagrisso ukiniti. Starost in telesna masa: Pri bolnikih starih nad 65 let ali bolnikih z telesno maso pod 50 kg je lahko prisotno povečano tveganje za pojav neželenih učinkov 3. ali višje stopnje. Pri teh bolnikih je priporočeno skrbno spremljanje. MEDSEBOJNO DELOVANJE Z DRUGIMI ZDRAVILI: Močni induktorji CYP3A lahko zmanjšajo izpostavljenost osimertinibu. Osimertinib lahko poveča izpostavljenost substratom BCRP in P-glikoproteina (P-gp). Študije in vitro so pokazale, da poteka presnova I. faze osimertiniba pretežno s CYP3A4 in CYP3A5. Podatki iz klinične farmakokinetične študije so pokazali, da ni verjetno, da bi zaviralci CYP3A4 vplivali na izpostavljenost osimertinibu. Dodatnih katalizacijskih encimov niso odkrili. Podatki klinične farmakokinetične študije o sočasni uporabi z rifampicinom kažejo, da se je sočasni uporabi močnih induktorjev CYP3A (npr. fenitoina, rifampicina, karbamazepina) in zdravila Tagrisso priporočljivo izogniti. Izpostavljenost osimertinibu lahko zmanjšajo tudi zmerni induktorji CYP3A4 (npr. bosentan, efavirenz, etravirin, modafinil), zato jih je treba uporabljati previdno oziroma se jim je treba izogniti, če je mogoče. Kliničnih podatkov, ki bi omogočali priporočilo za prilagoditev odmerka zdravila Tagrisso, ni na voljo. Sočasna uporaba šentjanževke je kontraindicirana. Glede na podatke klinične farmakokinetične študije je pri sočasni uporabi zdravila Tagrisso in rosuvastatina ter ostalih zdravil, katerih odstranjevanje je odvisno od BCRP in imajo ozek terapevtski indeks, treba bolnike skrbno spremljati glede znakov spremenjenega prenašanja zaradi večje izpostavljenosti sočasnemu zdravilu med prejemanjem zdravila Tagrisso. Tveganja za manjšo izpostavljenost hormonskim kontraceptivom ni mogoče izključiti. Bolnike, ki sočasno jemljejo zdravila, katerih odstranjevanje je odvisno od P-gp in imajo ozek terapevtski indeks (npr. digoksin, dabigatran, in aliskiren), je treba skrbno spremljati glede znakov spremenjenega prenašanja zaradi večje izpostavljenosti sočasnemu zdravilu v času prejemanja zdravila Tagrisso. NEŽELENI UČINKI: Podatki iz petih randomiziranih študij lll. faze (ADAURA – adjuvantno zdravljenje, FLAURA in FLAURA2 (skupina z monoterapijo) – prva linija LAURA (po kemoradioterapiji na podlagi platine) in AURA3 – le druga linija) in iz dveh študij z eno samo skupino (AURAex in AURA2 – druga linija ali več) in eni študiji l. faze (AURA1 – prva linija ali več) povzemajo izpostavljenost zdravilu Tagrisso pri 1956 bolnikih z nedrobnoceličnim rakom pljuč in pozitivno mutacijo EGFR. Večina neželenih učinkov je bila glede na resnost 1. ali 2. stopnje. Najpogostejši neželeni učinki zdravila so bili driska (46 %), izpuščaj (45 %), paronihija (33 %), suha koža (31 %) in stomatitis (23 %). V vseh študijah skupaj je bilo neželenih učinkov 3. stopnje 11 % in 4. stopnje 0,2 %. Med bolniki, ki so prejemali zdravilo Tagrisso 80 mg enkrat na dan, so zaradi neželenih učinkov odmerek zmanjšali 3,4 % bolnikom. Ukinitev uporabe zdravila zaradi neželenih učinkov je bilo 5,5 %. Varnost zdravila TAGRISSO v kombinaciji s pemetreksedom in kemoterapijo na podlagi platine temelji na podatkih 276 bolnikov z NSCLC in pozitivno mutacijo EGFR in se sklada z varnostjo monoterapije z zdravilom TAGRISSO in znanimi varnostnimi značilnostmi pemetrekseda in kemoterapije na podlagi platine. Najpogosteje poročani neželeni učinki med uporabo zdravila TAGRISSO v kombinaciji s pemetreksedom in kemoterapijo na osnovi platine, so bili izpuščaj (49 %), driska (43 %), zmanjšan apetit (31 %), stomatitis (31 %), paronihija (27 %) in suha koža (24 %). Zelo pogosti neželeni učinki: zmanjšan apetit, driska, stomatitis, izpuščaj, suha koža, paronihija, srbenje ter zmanjšano število levkocitov, limfocitov, trombocitov in nevtrofilcev. Pogosti neželeni učniki: epistaksa, intersticijska bolezen pljuč, alopecija, urtikarija, sindrom palmarno-plantarne eritrodizestezije, zvišanje ravni kreatinina v krvi, zvišanje ravni kreatin fosfokinaze v krvi, zmanjšan iztisni delež levega prekata. VRSTA IN VSEBINA OVOJNINE: Al/Al perforirani pretisni omoti za enkratni odmerek. Škatle z 28 x 1 tableto (4 pretisni omoti). NAČIN IZDAJANJA ZDRAVILA: samo na recept DATUM REVIZIJE BESEDILA: 19.12.2024. (SI-3575) IMETNIK DOVOLJENJA ZA PROMET: AstraZeneca AB, S-151 85, Sodertalje, Švedska Pred predpisovanjem, prosimo, preberite celoten povzetek glavnih značilnosti zdravila. Dodatne informacije so na voljo pri družbi AstraZeneca UK Limited, Podružnica v Sloveniji, Verovškova 55, Ljubljana, telefon +386 1 51 35 600. NSCLC... nedrobnocelični rak pljuč, ROg...razmerje ogroženosti, IZ...interval zaupanja, OS...celokupno preživetje, PFS...preživetje brez napredovanja bolezni 1.Povzetek glavnih značilnosti zdravila Tagrisso. 2. Tsuboi M, Wu YL, Grohe C, et al. Osimertinib as adjuvant therapy in patients with resected EGFRm stage IB-IIIA NSCLC: updated results from ADAURA. Presented at: ESMO Congress 2022; September 9-13, 2022; Paris, France. 3.Vansteenkiste J, Planchard D, et al; FLAURA Investigators. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):41-50. 4. FLAURA-2 5. LAURA, 4. Ramalingam SS, Vansteenkiste J, Planchard D, et al; FLAURA Investigators. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):41-50. 5. Planchard D et al. Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC. N Engl J Med. 2023 Nov 23;389(21):1935-1948. Samo za strkovno javnost. Informacija pripravljena januarja 2025. NADGRAJUJEMO ZDRAVLJENJE PLJUČNEGA RAKA Resektabilni EGFRm NSCLC (stadiji IB-IIIA), katerega EGFR ima Del19 ali L858R 51% manjša verjetnost za smrt v primerjavi s placebom v celokupni populaciji ROg=0,62 ROg = 0,49 (95% IZ: 034, 0,70; p<0,001) 2 Lokalno napredovali neresektabilni EGFRm NSCLC 39,1 vs 5,6 mesecev mediano PFS v primerjavi s placebom ROg=0,16 (95% IZ: 0,10, 0,24); p<0.001) 5 Ocenjeno s slepim, neodvisnim centralnim pregledom (BICR) Lokalno napredovali ali metastatski NSCLC, katerega EGFR ima aktivirajoče mutacije 38,6 vs 31,8 mediano OS v primerjavi z gefitinib/erlotinib ROg: 0,80 (95,05% IZ: 0,641, 0,997; p<0,001) 3 Lokalno napredovali ali metastatski NSCLC, katerega EGFR ima aktivirajoče mutacije 29,9 vs 19,4 mesecev mediano PFS zdravilo Tagrisso v kombinaciji s kemoterapijo v primerjavi z monoterapijo ROg=0,62 (95% IZ; 0,48, 0,80) 4 Ocenjeno s slepim, neodvisnim centralnim pregledom (BICR) LAURA FLAURA 2 ADAURA FLAURA Oglas TAGRISSO NOV 2025 RADIOLOGY Oncology_210x280 _jan 2025.indd 1 5. 2. 25 09:43 SKRAJŠAN POVZETEK GLAVNIH ZNAČILNOSTI ZDRAVILA LYNPARZA 100 mg filmsko obložene tablete / LYNPARZA 150 mg filmsko obložene tablete SESTAVA: Ena filmsko obložena tableta vsebuje 100 mg olapariba ali 150 mg olapariba. INDIKACIJE: Rak jajčnikov: 1) zdravilo Lynparza je indicirano kot monoterapija za: • vzdrževalno zdravljenje odraslih bolnic z napredovalim (stadij III in IV po FIGO) epitelijskim rakom visokega gradusa jajčnikov, jajcevodov ali primarnim peritonealnim rakom z mutacijo gena BRCA1/2 (germinalno in/ali somatsko), ki so v odzivu (popolnem ali delnem) po zaključeni prvi liniji kemoterapije na osnovi platine. • vzdrževalno zdravljenje odraslih bolnic, pri katerih je prišlo do ponovitve epitelijskega raka visokega gradusa jajčnikov, jajcevodov ali primarnega peritonealnega raka, občutljivega na platino, ki so v popolnem ali delnem odzivu na kemoterapijo na osnovi platine. 2) zdravilo Lynparza je v kombinaciji z bevacizumabom indicirano za: • vzdrževalno zdravljenje odraslih bolnic z napredovalim (stadij III in IV po FIGO) epitelijskim rakom visokega gradusa jajčnikov, jajcevodov ali primarnim peritonealnim rakom, ki so v popolnem ali delnem odzivu po zaključeni prvi liniji kemoterapije na osnovi platine v kombinaciji z bevacizumabom, pri katerih je rak povezan s pozitivnim stanjem pomanjkanja homologne rekombinacije (HRD – homologous recombination deficiency), opredeljenim z mutacijo gena BRCA1/2 in/ali genomsko nestabilnostjo. Rak dojk: zdravilo Lynparza je indicirano kot: • monoterapija ali v kombinaciji z endokrinim zdravljenjem za adjuvantno zdravljenje odraslih bolnikov z germinalnimi mutacijami gena BRCA1/2, ki imajo HER2‑negativnega zgodnjega raka dojk z velikim tveganjem in so bili predhodno zdravljeni z neoadjuvantno ali adjuvantno kemoterapijo. • monoterapija za zdravljenje odraslih bolnikov z germinalno mutacijo gena BRCA1/2, ki imajo HER2‑negativnega lokalno napredovalega ali metastatskega raka dojk. Bolniki morajo biti predhodno zdravljeni z antraciklinom in taksanom v okviru (neo)adjuvantnega zdravljenja ali zdravljenja metastatske bolezni, razen če za ti zdravljenji niso primerni. Pri bolnikih, ki imajo raka dojk s pozitivnimi hormonskimi receptorji (HR), je morala bolezen prav tako napredovati med predhodnim hormonskim zdravljenjem ali po njem, ali morajo bolniki veljati za neprimerne za hormonsko zdravljenje. Adenokarcinom trebušne slinavke: zdravilo Lynparza je kot monoterapija indicirano za vzdrževalno zdravljenje odraslih bolnikov z germinalno mutacijo gena BRCA1/2, ki imajo metastatski adenokarcinom trebušne slinavke in njihova bolezen ni napredovala po najmanj 16 tednih zdravljenja s platino v shemi prve linije kemoterapije. Rak prostate: zdravilo Lynparza je indicirano: • kot monoterapija za zdravljenje odraslih bolnikov z metastatskim, na kastracijo odpornim rakom prostate (mKORP) in mutacijami gena BRCA1/2 (germinalnimi in/ali somatskimi), pri katerih je bolezen napredovala po predhodni terapiji, ki je vsebovala novo hormonsko zdravilo. • v kombinaciji z abirateronom in prednizonom ali prednizolonom za zdravljenje odraslih bolnikov z mKORP, pri katerih kemoterapija ni klinično indicirana. Rak endometrija: Zdravilo Lynparza je v kombinaciji z durvalumabom indicirano za vzdrževalno zdravljenje odraslih bolnic s primarno napredovalim ali ponovljenim rakom endometrija, ki nimajo okvare popravljanja neujemanja pri podvojevanju DNA (pMMR), bolezen pa jim ni napredovala med zdravljenjem prve linije z durvalumabom v kombinaciji s karboplatinom in paklitakselom. ODMERJANJE IN NAČIN UPORABE: Priporočeni odmerek zdravila Lynparza pri monoterapiji ali v kombinaciji z drugimi zdravili je 300 mg (dve 150 mg tableti) dvakrat na dan; to ustreza celotnemu dnevnemu odmerku 600 mg. 100 mg tablete so na voljo za zmanjšanje odmerka. Bolnice s ponovitvijo raka jajčnikov morajo začeti zdravljenje z zdravilom Lynparza najpozneje v 8 tednih po zadnjem odmerku sheme zdravljenja na osnovi platine. Če je zdravilo Lynparza uporabljeno v kombinaciji z bevacizumabom za prvo linijo vzdrževalnega zdravljenja po dokončanju prve linije zdravljenja na osnovi platine in z bevacizumabom, je odmerek bevacizumaba 15 mg/kg enkrat na 3 tedne. Glejte celotne informacije o zdravilu za bevacizumab. Za priporočeno odmerjanje partnerskega zdravila/partnerskih zdravil (zaviralec aromataze/antiestrogen in/ali LHRH) v kombinaciji endokrinega zdravljenja glejte celotne informacije o zadevnem zdravilu. Če je zdravilo Lynparza uporabljeno v kombinaciji z abirateronom za zdravljenje bolnikov z mKORP, je odmerek abiraterona 1000 mg peroralno enkrat na dan. Abirateron je treba dajati s 5 mg prednizona ali prednizolona peroralno dvakrat na dan. Glejte celotne informacije o zdravilu za abirateron. Če je zdravilo Lynparza uporabljeno v kombinaciji z durvalumabom za vzdrževalno zdravljenje odraslih bolnic s primarno napredovalim ali ponovljenim rakom endometrija brez okvare MMR (pMMR), ki jim bolezen ni napredovala med zdravljenjem prve linije z durvalumabom v kombinaciji s karboplatinom in paklitakselom, je odmerek durvalumaba 1500 mg na 4 tedne. Glejte celotne informacije o zdravilu za durvalumab. Prvo linijo vzdrževalnega zdravljenja napredovalega raka jajčnikov z mutacijo gena BRCA in prvo linijo vzdrževalnega zdravljenja HRD‑pozitivnega napredovalega raka jajčnikov v kombinaciji z bevacizumabom je priporočljivo nadaljevati do radiološkega napredovanja bolezni ali nesprejemljive toksičnosti ali do največ 2 leti, če po 2 letih ni radioloških znakov bolezni. V primeru znakov bolezni po 2 letih, se lahko zdravljenje nadaljuje, če bi le to po mnenju zdravnika bilo koristno za bolnico. Glejte informacije o zdravilu bevacizumab za priporočeno celotno trajanje zdravljenja največ 15 mesecev, vključno z obdobji v kombinaciji s kemoterapijo in kot vzdrževalno zdravljenje. Pri adjuvantnem zdravljenju zgodnjega raka dojk je prporočljivo, da bolniki prejemajo zdravljenje do 1 leto ali do ponovitve bolezni ali do nesprejemljive toksičnosti, kar od tega se zgodi najprej. Zdravljenje ponovitve raka jajčnikov, raka dojk, adenokarcinoma trebušne slinavke,raka prostate in napredovalega ali ponovljenega raka endometrija je priporočljivo nadaljevati do napredovanja osnovne bolezni ali nesprejemljive toksičnosti. Učinkovitost in varnost ponovnega vzdrževalnega zdravljenja z zdravilom Lynparza po prvi ali poznejši ponovitvi bolezni pri bolnicah z rakom jajčnikov nista bili dokazani. Podatkov o učinkovitosti in varnosti ponovnega zdravljenja pri bolnicah z rakom dojk ni. Pri raku prostate je treba pri bolnikih, ki niso bili kirurško kastrirani, nadaljevati z medicinsko kastracijo z analogom luteinizirajočega hormona sproščajočega hormona. Če je zdravilo Lynparza uporabljeno v kombinaciji z abirateronom in prednizonom ali prednizolonom, je zdravljenje priporočljivo nadaljevati do napredovanja osnovne bolezni ali do nesprejemljivih toksičnih učinkov. Pri vseh bolnikih je treba med zdravljenjem še naprej uporabljati analoge GnRH (gonadotropin sproščajočega hormona) ali pa morajo bolniki pred tem opraviti obojestransko orhidektomijo. Glejte informacije o zdravilu za abirateron. Podatkov o učinkovitosti ali varnosti ponovnega zdravljenja z zdravilom Lynparza pri bolnikih z rakom prostate ni. Če je zdravilo uporabljeno v prvi liniji vzdrževalnega zdravljenja napredovalega ali ponovljenegaraka endometrija, ki nima okvare MMR (pMMR), v kombinaciji z durvalumabom je zdravljenje je priporočljivo nadaljevati do napredovanja osnovne bolezni ali do nesprejemljivih toksičnih učinkov. Glejte informacije o zdravilu za durvalumab. V primeru potrebe po zmanjšanju odmerka zaradi neželenih učinkov je priporočeno zmanjšanje odmerka na 250 mg dvakrat na dan (to ustreza celotnemu dnevnemu odmerku 500 mg). Če je potrebno še dodatno zmanjšanje odmerka, je priporočljivo zmanjšanje odmerka na 200 mg dvakrat na dan (to ustreza celotnemu dnevnemu odmerku 400 mg). Zdravljenje z zdravilom Lynparza mora uvesti in nadzorovati zdravnik, ki ima izkušnje z uporabo zdravil proti raku. Mutacijsko stanje BRCA in/ali genomsko nestabilnost morajo imeti bolniki potrjeno z validiranim testom. Pred uporabo zdravila Lynparza v kombinaciji z abirateronom in prednizonom ali prednizolonom za zdravljenje bolnikov z mKORP genomsko testiranje ni potrebno. Pri zdravljenju v prvi liniji vzdrževalnega zdravljenja napredovalega ali ponovljenega raka endometrija, ki nima okvare MMR (pMMR), v kombinaciji z durvalumabom je pred uvedbo zdravljenja treba z validiranim testom potrditi, da ima bolnica stanje tumorja brez okvare MMR (pMMR). Genetsko svetovanje bolnikom z mutacijami BRCA je treba opraviti v skladu z lokalnimi predpisi. Zdravilo Lynparza se lahko pri bolnikih z blago okvaro ledvic (očistek kreatinina 51 do 80 ml/min) uporablja brez prilagoditve odmerka. Pri bolnikih z zmerno okvaro ledvic (očistek kreatinina 31 do 50 ml/min) je priporočen odmerek 200 mg dvakrat na dan. Uporaba zdravila se pri bolnikih s hudo okvaro ali končno odpovedjo ledvic (očistek kreatinina ≤ 30 ml/min) ne priporoča, ker varnost in farmakokinetika pri tej skupini bolnikov nista bili raziskani. Zdravilo Lynparza se lahko daje bolnikom z blago ali zmerno okvaro jeter (klasifikacija Child‑Pugh A ali B) brez prilagoditve odmerka. Uporabe zdravila Lynparza se ne priporoča pri bolnikih s hudo okvaro jeter (klasifikacija Child‑Pugh C), ker varnost in farmakokinetika pri tej skupini bolnikov nista bili raziskani. Zdravilo Lynparza je za peroralno uporabo. Tablete zdravila Lynparza je treba pogoltniti cele in se jih ne sme gristi, drobiti, raztapljati ali lomiti. Lahko se jih jemlje ne glede na obroke. KONTRAINDIKACIJE: Preobčutljivost na učinkovino ali katero koli pomožno snov. Dojenje med zdravljenjem in en mesec po zadnjem odmerku. POSEBNA OPOZORILA IN PREVIDNOSTNI UKREPI: Hematološki toksični učinki: Pri bolnikih, zdravljenih z zdravilom Lynparza, so bili opisani hematološki toksični učinki, vključno s klinično diagnozo in/ali laboratorijskimi izsledki, na splošno blage ali zmerne (stopnja 1 ali 2 po CTCAE) anemije, nevtropenije, trombocitopenije in limfopenije. Če je bilo zdravilo Lynparza uporabljeno v kombinaciji z durvalumabom, so poročali o čisti aplaziji rdečih krvnih celic (PRCA) in/ali o avtoimunski hemolitični anemiji (AIHA). Bolniki ne smejo začeti zdravljenja z zdravilom Lynparza, dokler ne okrevajo po hematoloških toksičnih učinkih predhodnega zdravljenja proti raku. Preiskava celotne krvne slike je priporočljiva na začetku zdravljenja, potem vsak mesec prvih 12 mesecev zdravljenja in pozneje redno. Če se pri bolniku pojavijo hudi hematološki toksični učinki ali je odvisen od transfuzij krvi, je treba zdravljenje z zdravilom Lynparza prekiniti in uvesti ustrezno hematološko testiranje. Če krvne vrednosti ostanejo klinično nenormalne še 4 tedne po prekinitvi uporabe zdravila Lynparza, je priporočljivo opraviti preiskavo kostnega mozga in/ali krvno citogenetsko analizo. Če je PRCA ali AIHA potrjena, je treba zdravljenje z zdravilom Lynparza in durvalumabom prenehati. Mielodisplastični sindrom/akutna mieloična levkemija (MDS/AML): Celokupna pojavnost MDS/AML je bila pri bolnikih, ki so v kliničnih preizkušanjih prejemali monoterapijo z zdravilom Lynparza, vključno v obdobju dolgoročnega spremljanja preživetja, < 1,5 %, z večjo pojavnostjo pri bolnicah z BRCAm, pri katerih je prišlo do ponovitve na platino občutljivega raka jajčnikov, ki so predhodno prejele vsaj dve liniji kemoterapije s platino in so jih spremljali 5 let. Večina teh primerov je bila s smrtnim izidom. Če obstaja sum na MDS/AML, je potrebno bolnico napotiti na nadaljnje preiskave k hematologu, vključno z analizo kostnega mozga in odvzemom krvi za citogenetiko. Če se po preiskavi dolgotrajne hematološke toksičnosti potrdi MDS/AML, je treba uporabo zdravila Lynparza prekiniti in bolnico ustrezno zdraviti. Venski trombembolični dogodki: Med zdravljenjem z zdravilom Lynparza so poročali o venskih trombemboličnih dogodkih, predvsem o pljučni emboliji, vendar ti dogodki niso imeli kakšnega doslednega kliničnega vzorca. V primerjavi z drugimi odobrenimi indikacijami so opažali večjo pojavnost pri bolnikih z metastatskim, na kastracijo odpornim rakom prostate, ki so prejemali tudi androgeno deprivacijsko zdravljenje. Bolnike spremljajte glede kliničnih znakov in simptomov venske tromboze in pljučne embolije, ter jih zdravite kot je medicinsko ustrezno. Bolniki z anamnezo VTE imajo morda večje tveganje za njeno ponovitev in jih je treba ustrezno spremljati. Pnevmonitis: V kliničnih študijah je bil pnevmonitis, vključno s smrtnim izidom, opisan pri < 1,0 % bolnikov, ki so prejemali zdravilo Lynparza, spremljali pa so jih številni predispozicijski dejavniki. Če se pri bolniku pojavijo novi ali poslabšajo obstoječi dihalni simptomi, npr. dispneja, kašelj in zvišana telesna temperatura, ali je ugotovljen nenormalen radiološki izvid prsnih organov, je treba zdravljenje z zdravilom Lynparza prekiniti in takoj opraviti preiskave. Če je pnevmonitis potrjen, je treba zdravljenje z zdravilom Lynparza prekiniti in bolnika ustrezno zdraviti. Hepatotoksičnost: Če se pojavijo klinični simptomi ali znaki, ki kažejo na razvoj hepatotoksičnosti, je treba takoj izvesti klinično oceno bolnika in preiskave delovanja jeter. V primeru suma na z zdravilom povzročeno okvaro jeter (DILI ‑ drug‑induced liver injury) je treba zdravljenje prekiniti. V primeru hude DILI je treba razmisliti o ukinitvi zdravljenja, kot je klinično primerno. MEDSEBOJNO DELOVANJE Z DRUGIMI ZDRAVILI IN DRUGE OBLIKE INTERAKCIJ: Zdravilo Lynparza se uporablja kot monoterapija in ni primerno za uporabo v kombinaciji z mielosupresivnimi zdravili proti raku, vključno z zdravili, ki poškodujejo DNA. Sočasna uporaba olapariba s cepivi ali imunosupresivnimi zdravili ni raziskana. Za presnovni očistek olapariba so pretežno odgovorni izoencimi CYP3A4/5. Sočasna uporaba zdravila Lynparza z znanimi močnimi ali zmernimi zaviralci tega izoencima ni priporočljiva. Če je treba sočasno uporabiti močne ali zmerne zaviralce CYP3A, je treba odmerek zdravila Lynparza zmanjšati. Prav tako med zdravljenjem z zdravilom Lynparza ni priporočljivo pitje grenivkinega soka. Prav tako olapariba ni priporočljivo uporabljati z znanimi močnimi ali zmernimi do močnimi induktorji tega izoencima, ker obstaja možnost, da se učinkovitost zdravila Lynparza bistveno zmanjša. Olaparib in vitro zavira CYP3A4 ter in vivo predvidoma blago zavira CYP3A. Zato je potrebna previdnost pri sočasni uporabi olapariba z občutljivimi substrati CYP3A4 ali substrati, ki imajo ozko terapevtsko okno. Bolnike, ki sočasno z olaparibom prejemajo substrate CYP3A z ozkim terapevtskim oknom, je priporočljivo ustrezno klinično spremljati. In vitro so ugotovili indukcijo CYP1A2, 2B6 in 3A4, prav tako ni mogoče izključiti možnosti, da olaparib inducira CYP2C9, CYP2C19 in P‑gp, zato lahko olaparib po sočasni uporabi zmanjša izpostavljenost substratom teh presnovnih encimov in prenašalne beljakovine. Učinkovitost nekaterih hormonskih kontraceptivov se lahko zmanjša, če so uporabljeni sočasno z olaparibom. In vitro olaparib zavira efluksni prenašaleca P‑gp, zato je potrebno bolnike, ki sočasno prejemajo substrate P‑gp, ustrezno klinično spremljati. In vitro olaparib zavira BCRP, OATP1B1, OCT1, OCT2, OAT3, MATE1 in MATE2K. Ni mogoče izključiti možnosti, da olaparib poveča izpostavljenost BCRP, OATP1B1, OCT1, OCT2, OAT3, MATE1 in MATE2K. Še zlasti je previdnost potrebna, če se olaparib uporablja v kombinaciji s katerim koli statinom. Izvedli so klinično študijo za oceno kombinacije olapariba z anastrozolom, letrozolom in tamoksifenom, vendar klinično pomembnih medsebojnih delovanj niso opazili. NEŽELENI UČINKI: Zdravilo Lynparza je bilo povezano z neželenimi učinki, ki so bili na splošno blage ali zmerne resnosti (stopnja po CTCAE  1 ali 2) in na splošno niso zahtevali prekinitve zdravljenja. Če je zdravilo Lynparza uporabljeno v kombinaciji z bevacizumabom pri raku jajčnikov, v kombinaciji z abirateronom in prednizonom ali prednizolonom pri raku prostate, ali v kombinaciji z durvalumabom po zdravljenju z durvalumabom v kombinaciji s kemoterapijo na osnovi platine za raka endometrija, se varnostni profil na splošno sklada z varnostnim profilom vsakega posameznega zdravila. Varnostni profil temelji na kumulativnih podatkih 4499  bolnikov s solidnimi tumorji, ki so bili v kliničnih preskušanjih zdravljeni z monoterapijo z zdravilom Lynparza v priporočenem odmerku. Zelo pogosti neželeni učinki: anemija, nevtropenija, levkopenija, zmanjšanje apetita, omotica, glavobol, spremenjen okus, kašelj, dispneja, bruhanje, driska, navzea, dispepsija in utrujenost (vključno z astenijo). Pogosti neželeni učinki: limfopenija, trombocitopenija, zvišanje transaminaz, stomatitis, bolečine v zgornjem delu trebuha, izpuščaj, zvišanje kreatinina v krvi in venska trombembolija. Pri bolnicah, ki so prejemale zdravilo Lynparza v kombinaciji z durvalumabom po zdravljenju z durvalumabom v kombinaciji s kemoterapijo na osnovi platine, so se z večjo pogostnostjo pojavili neželeni učinki: trombocitopenija in izpuščaj (zelo pogosti) ter preobčutljivost (pogosti). Ugotovili so tudi dodatni neželeni učinek čiste aplazije rdečih krvnih celic. PLODNOST, NOSEČNOST IN DOJENJE: Ženske v rodni dobi ne smejo biti noseče na začetku zdravljenja z zdravilom Lynparza in ne smejo zanositi med zdravljenjem in še 6 mesecev po prejetju zadnjega odmerka. Pri vseh ženskah v rodni dobi je potrebno pred zdravljenjem opraviti test nosečnosti in ga redno izvajati med celotnim zdravljenjem. Priporočljivi sta dve visoko učinkoviti in komplementarni obliki kontracepcije. Zaradi možnega medsebojnega delovanja olapariba s hormonsko kontracepcijo je treba razmisliti o dodatni nehormonski kontracepciji. Pri ženskah s hormonsko odvisnim rakom je treba razmisliti o dveh nehormonskih načinih kontracepcije. Zdravilo Lynparza je kontraindicirano med obdobjem dojenja in še en mesec po prejetju zadnjega odmerka. Moški bolniki morajo med zdravljenjem in še 3 mesece po prejetju zadnjega odmerka zdravila Lynparza med spolnimi odnosi z nosečo žensko ali žensko v rodni dobi uporabljati kondom. Tudi partnerke moških bolnikov morajo uporabljati visoko učinkovito kontracepcijo, če so v rodni dobi. Moški bolniki med zdravljenjem z zdravilom Lynparza in še 3 mesece po zadnjem odmerku tega zdravila ne smejo darovati sperme. REŽIM PREDPISOVANJA IN IZDAJE ZDRAVILA: Rp/Spec. DATUM ZADNJE REVIZIJE BESEDILA: 12.8.2024 (SI‑4324) IMETNIK DOVOLJENJA ZA PROMET: AstraZeneca AB, SE‑151 85 Södertälje, Švedska. Dodatne informacije so na voljo pri podjetju AstraZeneca UK Limited, Podružnica v Sloveniji, Verovškova 55, 1000 Ljubljana, telefon: 01/51 35 600. Pred predpisovanjem, prosimo, preberite celoten povzetek glavnih značilnosti zdravila. Literatura: 1. Povzetek glavnih značilnosti zdravila Lynparza, 12.8.2024, 2. https://www.ema.europa.eu/en/medicines/human/EPAR/rubraca, dostopano 1.9.2024, 3. https://www.ema.europa.eu/en/medicines/human/EPAR/zejula, dostopano 1.9.2024, 4. https://www.ema.europa.eu/en/medicines/human/EPAR/talzenna, dostopano 1.9.2024, 5. https://www.ema.europa.eu/en/news/lynparza‑recommended‑approval‑ovarian‑cancer, dostopano 1.9.2024 AstraZeneca UK Limited, Podružnica v Sloveniji, Verovškova 55, 1000 Ljubljana, tel: 01/51 35 600 Samo za strokovno javnost. Datum priprave gradiva: september 2024 SI‑4341 PARP – poli (ADP‑riboza) polimeraza, 1L – v prvem redu zdravljenja, 2L – v drugem redu zdravljenja, HRD – pomanjkanje homologne rekombinacije, KORP – na kastracijo odporen rak prostate *Zdravili Lynparza in durvalumab za zdravljenje raka endometrija še nista razvrščeni na listo zdravil ZZZS DOVOLI SI VERJETI Prvi in edini zaviralec PARP odobren za 5 različnih lokalizacij tumorjev1-5* RAK ENDOMETRIJA Prvi in edini zaviralec PARP odobren za vzdrževalno zdravljenje odraslih bolnic s primarno napredovalim ali ponovljenim rakom endometrija v kombinaciji z durvalumabom za bolnice, ki nimajo okvare popravljanja neujemanja pri podvojevanju DNA (pMMR), bolezen pa jim ni napredovala med zdravljenjem prve linije z durvalumabom v kombinaciji s karboplatinom in paklitakselom.1-4,* RAK PROSTATE Edini zaviralec PARP odobren za zdravljenje bolnikov z razsejanim KORP v monoterapiji za bolnike z mutacijami gena BRCA1/2, ki jim je bolezen napredovala po zdravljenju z novim hormonskim zdravilom, in v kombinaciji z abirateronom ne glede na status mutacij.1-4 RAK DOJK Prvi zaviralec PARP odobren za zdravljenje, pri bolnikih z zarodno mutacijo gena BRCA1/2, ki imajo HER2- negativni zgodnji, lokalno napredovali ali razsejan rak dojk.1-2, 4 RAK TREBUŠNE SLINAVKE Edini zaviralec PARP odobren za vzdrževalno zdravljenje bolnikov z zarodno mutacijo gena BRCA1/2, ki imajo razsejani adenokarcinom trebušne slinavke in jim bolezen ni napredovala po najmanj 16 tednih prvega reda zdravljenja s kemoterapijo na osnovi platine.1-4 RAK JAJČNIKOV Prvi zaviralec PARP odobren za vzdrževalno zdravljenje napredovalega raka jajčnikov v monoterapiji (v 1L pri bolnicah z mutacijo gena BRCA1/2 in 2L) ali kombinaciji z bevacizumabom (pri bolnicah s HRD).1-3, 5 5 NA NOVO razvrščenih indikacij:1 (pembrolizumab, MSD) Skenirajte QR kodo in izvedite več o osredotočenosti družbe MSD na zdravljenje raka. Okrajšave: 1L - prva linija; CPS - kombinirana pozitivna ocena ; NDPR – nedrobnocelični pljučni rak; PD-L1 - ligand programirane celične smrti 1; RMV – rak materničnega vratu Referenci: 1. ZZZS. E-gradiva. Spremembe seznama B. Dostopano 16.12.2024 na https://www.zzzs. si/?id=126&detail=F641B38F0189A2BFC1257B2D0047239C 2. Povzetek glavnih značilnosti zdravila KEYTRUDA SKRAJŠAN POVZETEK GLAVNIH ZNAČILNOSTI ZDRAVILA • Pred predpisovanjem, prosimo, preberite celoten Povzetek glavnih značilnosti zdravila! • Ime zdravila: KEYTRUDA 25 mg/ml koncentrat za raztopino za infundiranje vsebuje pembrolizumab. • Terapevtske indikacije: Zdravilo KEYTRUDA je kot samostojno zdravljenje indicirano za zdravljenje: odraslih in mladostnikov, starih 12 let ali več, z napredovalim (neoperabilnim ali metastatskim) melanomom; za adjuvantno zdravljenje odraslih in mladostnikov, starih 12 let ali več, z melanomom v stadiju IIB, IIC ali III, in sicer po popolni kirurški odstranitvi; za adjuvantno zdravljenje odraslih z nedrobnoceličnim pljučnim rakom, ki imajo visoko tveganje za ponovitev bolezni po popolni kirurški odstranitvi in kemoterapiji na osnovi platine; metastatskega nedrobnoceličnega pljučnega raka (NSCLC) v prvi liniji zdravljenja pri odraslih, ki imajo tumorje z ≥ 50 % izraženostjo PD-L1 (TPS) in brez pozitivnih tumorskih mutacij EGFR ali ALK; lokalno napredovalega ali metastatskega NSCLC pri odraslih, ki imajo tumorje z ≥ 1 % izraženostjo PD-L1 (TPS) in so bili predhodno zdravljeni z vsaj eno shemo kemoterapije, bolniki s pozitivnimi tumorskimi mutacijami EGFR ali ALK so pred prejemom zdravila KEYTRUDA morali prejeti tudi tarčno zdravljenje; odraslih in pediatričnih bolnikov, starih 3 leta ali več, s ponovljenim ali neodzivnim klasičnim Hodgkinovim limfomom (cHL), pri katerih avtologna presaditev matičnih celic (ASCT) ni bila uspešna, ali po najmanj dveh predhodnih zdravljenjih kadar ASCT ne pride v poštev kot možnost zdravljenja; lokalno napredovalega ali metastatskega urotelijskega raka pri odraslih, predhodno zdravljenih s kemoterapijo, ki je vključevala platino; lokalno napredovalega ali metastatskega urotelijskega raka pri odraslih, ki niso primerni za zdravljenje s kemoterapijo, ki vsebuje cisplatin in imajo tumorje z izraženostjo PD-L1 ≥ 10, ocenjeno s kombinirano pozitivno oceno (CPS); ponovljenega ali metastatskega ploščatoceličnega raka glave in vratu (HNSCC) pri odraslih, ki imajo tumorje z ≥ 50 % izraženostjo PD-L1 (TPS), in pri katerih je bolezen napredovala med zdravljenjem ali po zdravljenju s kemoterapijo, ki je vključevala platino; za adjuvantno zdravljenje odraslih z rakom ledvičnih celic s povišanim tveganjem za ponovitev bolezni po nefrektomiji, ali po nefrektomiji in kirurški odstranitvi metastatskih lezij, za zdravljenje odraslih z MSI-H (microsatellite instability-high) ali dMMR (mismatch repair de cient) kolorektalnim rakom v naslednjih terapevtskih okoliščinah: prva linija zdravljenja metastatskega kolorektalnega raka; zdravljenje neoperabilnega ali metastatskega kolorektalnega raka po predhodnem kombiniranem zdravljenju, ki je temeljilo na  uoropirimidinu; in za zdravljenje MSI-H ali dMMR tumorjev pri odraslih z: napredovalim ali ponovljenim rakom endometrija, pri katerih je bolezen napredovala med ali po predhodnem zdravljenju, ki je vključevalo platino, v katerih koli terapevtskih okoliščinah, in ki niso kandidati za kurativno operacijo ali obsevanje; neoperabilnim ali metastatskim rakom želodca, tankega črevesa ali biliarnega trakta, pri katerih je bolezen napredovala med ali po vsaj enem predhodnem zdravljenju. Zdravilo KEYTRUDA je kot samostojno zdravljenje ali v kombinaciji s kemoterapijo s platino in 5- uorouracilom (5-FU) indicirano za prvo linijo zdravljenja metastatskega ali neoperabilnega ponovljenega ploščatoceličnega raka glave in vratu pri odraslih, ki imajo tumorje z izraženostjo PD-L1 s CPS ≥ 1. Zdravilo KEYTRUDA je v kombinaciji s kemoterapijo, ki vključuje platino, indicirano za neoadjuvantno zdravljenje, in v nadaljevanju kot samostojno zdravljenje za adjuvantno zdravljenje odraslih z operabilnim nedrobnoceličnim pljučnim rakom, ki imajo visoko tveganje za ponovitev bolezni; v kombinaciji s pemetreksedom in kemoterapijo na osnovi platine je indicirano za prvo linijo zdravljenja metastatskega neploščatoceličnega NSCLC pri odraslih, pri katerih tumorji nimajo pozitivnih mutacij EGFR ali ALK; v kombinaciji s karboplatinom in bodisi paklitakselom bodisi nab- paklitakselom je indicirano za prvo linijo zdravljenja metastatskega ploščatoceličnega NSCLC pri odraslih; v kombinaciji z enfortumab vedotinom je indicirano za prvo linijo zdravljenja neoperabilnega ali metastatskega urotelijskega raka pri odraslih; v kombinaciji z aksitinibom ali v kombinaciji z lenvatinibom je indicirano za prvo linijo zdravljenja napredovalega raka ledvičnih celic (RCC) pri odraslih; v kombinaciji s kemoterapijo s platino in  uoropirimidinom je indicirano za prvo linijo zdravljenja lokalno napredovalega neoperabilnega ali metastatskega raka požiralnika pri odraslih, ki imajo tumorje z izraženostjo PD-L1 s CPS ≥ 10; v kombinaciji s kemoterapijo za neoadjuvantno zdravljenje, in v nadaljevanju kot samostojno adjuvantno zdravljenje po kirurškem posegu, je indicirano za zdravljenje odraslih z lokalno napredovalim trojno negativnim rakom dojk ali trojno negativnim rakom dojk v zgodnjem stadiju z visokim tveganjem za ponovitev bolezni; v kombinaciji s kemoterapijo je indicirano za zdravljenje lokalno ponovljenega neoperabilnega ali metastatskega trojno negativnega raka dojk pri odraslih, ki imajo tumorje z izraženostjo PD-L1 s CPS ≥ 10 in predhodno niso prejeli kemoterapije za metastatsko bolezen; v kombinaciji s karboplatinom in paklitakselom je indicirano za prvo linijo zdravljenja primarno napredovalega ali ponovljenega raka endometrija (EC) pri odraslih, ki so kandidati za sistemsko zdravljenje; v kombinaciji z lenvatinibom je indicirano za zdravljenje napredovalega ali ponovljenega raka endometrija pri odraslih z napredovalo boleznijo med ali po predhodnem zdravljenju s kemoterapijo, ki je vključevala platino, v katerih koli terapevtskih okoliščinah, in ki niso kandidati za kurativno operacijo ali obsevanje; v kombinaciji s kemoradioterapijo (zdravljenje z zunanjim obsevanjem, ki mu sledi brahiterapija) je indicirano za zdravljenje lokalno napredovalega raka materničnega vratu v stadiju III - IVA po FIGO 2014 pri odraslih, ki niso prejeli predhodne de nitivne terapije; v kombinaciji s kemoterapijo, z bevacizumabom ali brez njega, je indicirano za zdravljenje persistentnega, ponovljenega ali metastatskega raka materničnega vratu pri odraslih bolnicah, ki imajo tumorje z izraženostjo PD-L1 s CPS ≥ 1; v kombinaciji s trastuzumabom,  uoropirimidinom in kemoterapijo, ki vključuje platino, je indicirano za prvo linijo zdravljenja lokalno napredovalega neoperabilnega ali metastatskega HER2-pozitivnega adenokarcinoma želodca ali gastroezofagealnega prehoda pri odraslih, ki imajo tumorje z izraženostjo PD-L1 s CPS ≥ 1; v kombinaciji s  uoropirimidinom in kemoterapijo, ki vključuje platino, je indicirano za prvo linijo zdravljenja lokalno napredovalega neoperabilnega ali metastatskega HER2-negativnega adenokarcinoma želodca ali gastroezofagealnega prehoda pri odraslih, ki imajo tumorje z izraženostjo PD-L1 s CPS ≥ 1; v kombinaciji z gemcitabinom in cisplatinom je indicirano za prvo linijo zdravljenja lokalno napredovalega neoperabilnega ali metastatskega raka biliarnega trakta pri odraslih. • Odmerjanje in način uporabe: Testiranje PD-L1: Če je navedeno v indikaciji, je treba izbiro bolnika za zdravljenje z zdravilom KEYTRUDA na podlagi izraženosti PD-L1 tumorja potrditi z validirano preiskavo. Testiranje MSI/MMR: Če je navedeno v indikaciji, je treba izbiro bolnika za zdravljenje z zdravilom KEYTRUDA na podlagi MSI-H/dMMR statusa tumorja potrditi z validirano preiskavo. Odmerjanje: Priporočeni odmerek zdravila KEYTRUDA pri odraslih je bodisi 200 mg na 3 tedne ali 400 mg na 6 tednov, apliciran z intravensko infuzijo v 30 minutah. Priporočeni odmerek zdravila KEYTRUDA za samostojno zdravljenje pri pediatričnih bolnikih s cHL, starih 3 leta ali več, ali bolnikih z melanomom, starih 12 let ali več, je 2 mg/kg telesne mase (do največ 200 mg) na 3 tedne, apliciran z intravensko infuzijo v 30 minutah. Za uporabo v kombinaciji glejte povzetke glavnih značilnosti zdravil sočasno uporabljenih zdravil. Če se zdravilo KEYTRUDA uporablja kot del kombiniranega zdravljenja skupaj z intravensko kemoterapijo, je treba zdravilo KEYTRUDA aplicirati prvo. Če se zdravilo KEYTRUDA uporablja kot del kombiniranega zdravljenja skupaj z enfortumab vedotinom, je treba zdravilo KEYTRUDA aplicirati po enfortumab vedotinu, kadar sta uporabljena na isti dan. Bolnike je treba zdraviti do napredovanja bolezni ali nesprejemljivih toksičnih učinkov (in do maksimalnega trajanja zdravljenja, če je le to določeno za indikacijo). Pri adjuvantnem zdravljenju melanoma, NSCLC ali RCC je treba zdravilo uporabljati do ponovitve bolezni, pojava nesprejemljivih toksičnih učinkov oziroma mora zdravljenje trajati do enega leta. Za neoadjuvantno in adjuvantno zdravljenje operabilnega NSCLC morajo bolniki neoadjuvantno prejeti zdravilo KEYTRUDA v kombinaciji s kemoterapijo, in sicer 4 odmerke po 200 mg na 3 tedne ali 2 odmerka po 400 mg na 6 tednov ali do napredovanja bolezni, ki izključuje de nitivni kirurški poseg, ali do pojava nesprejemljivih toksičnih učinkov, čemur sledi adjuvantno zdravljenje z zdravilom KEYTRUDA kot samostojnim zdravljenjem, in sicer 13 odmerkov po 200 mg na 3 tedne ali 7 odmerkov po 400 mg na 6 tednov ali do ponovitve bolezni ali do pojava nesprejemljivih toksičnih učinkov. Bolniki, pri katerih pride do napredovanja bolezni, ki izključuje de nitivni kirurški poseg, ali do nesprejemljivih toksičnih učinkov, povezanih z zdravilom KEYTRUDA kot neoadjuvantnim zdravljenjem v kombinaciji s kemoterapijo, ne smejo prejeti zdravila KEYTRUDA kot samostojnega zdravljenja za adjuvantno zdravljenje. Za neoadjuvantno in adjuvantno zdravljenje TNBC morajo bolniki neoadjuvantno prejeti zdravilo KEYTRUDA v kombinaciji s kemoterapijo, in sicer 8 odmerkov po 200 mg na 3 tedne ali 4 odmerke po 400 mg na 6 tednov, ali do napredovanja bolezni, ki izključuje de nitivni kirurški poseg, ali do pojava nesprejemljivih toksičnih učinkov, čemur sledi adjuvantno zdravljenje z zdravilom KEYTRUDA kot samostojnim zdravljenjem, in sicer 9 odmerkov po 200 mg na 3 tedne ali 5 odmerkov po 400 mg na 6 tednov ali do ponovitve bolezni ali pojava nesprejemljivih toksičnih učinkov. Bolniki, pri katerih pride do napredovanja bolezni, ki izključuje de nitivni kirurški poseg, ali do nesprejemljivih toksičnih učinkov povezanih z zdravilom KEYTRUDA kot neoadjuvantnim zdravljenjem v kombinaciji s kemoterapijo, ne smejo prejeti zdravila KEYTRUDA kot samostojnega zdravljenja za adjuvantno zdravljenje. Za lokalno napredovalega raka materničnega vratu morajo bolnice prejeti zdravilo KEYTRUDA sočasno s kemoradioterapijo, čemur sledi samostojno zdravljenje z zdravilom KEYTRUDA. Zdravilo KEYTRUDA se lahko daje v odmerku 200 mg na 3 tedne ali 400 mg na 6 tednov do napredovanja bolezni, pojava nesprejemljivih toksičnih učinkov ali do 24 mesecev. Če je aksitinib uporabljen v kombinaciji s pembrolizumabom, se lahko razmisli o povečanju odmerka aksitiniba nad začetnih 5 mg v presledkih šest tednov ali več. V primeru uporabe v kombinaciji z lenvatinibom je treba zdravljenje z enim ali obema zdraviloma prekiniti, kot je primerno. Uporabo lenvatiniba je treba zadržati, odmerek zmanjšati ali prenehati z uporabo, v skladu z navodili v povzetku glavnih značilnosti zdravila za lenvatinib, in sicer za kombinacijo s pembrolizumabom. Pri bolnikih starih ≥ 65 let, bolnikih z blago do zmerno okvaro ledvic, bolnikih z blago ali zmerno okvaro jeter prilagoditev odmerka ni potrebna. Odložitev odmerka ali ukinitev zdravljenja: Zmanjšanje odmerka zdravila KEYTRUDA ni priporočljivo. Za obvladovanje neželenih učinkov je treba uporabo zdravila KEYTRUDA zadržati ali ukiniti, prosimo, glejte celoten Povzetek glavnih značilnosti zdravila. • Kontraindikacije: Preobčutljivost na učinkovino ali katero koli pomožno snov. • Povzetek posebnih opozoril, previdnostnih ukrepov, interakcij in neželenih učinkov: Imunsko pogojeni neželeni učinki (pnevmonitis, kolitis, hepatitis, nefritis, endokrinopatije, neželeni učinki na kožo in drugi): Pri bolnikih, ki so prejemali pembrolizumab, so se pojavili imunsko pogojeni neželeni učinki, vključno s hudimi in smrtnimi primeri. Večina imunsko pogojenih neželenih učinkov, ki so se pojavili med zdravljenjem s pembrolizumabom, je bila reverzibilnih in so jih obvladali s prekinitvami uporabe pembrolizumaba, uporabo kortikosteroidov in/ali podporno oskrbo. Pojavijo se lahko tudi po zadnjem odmerku pembrolizumaba in hkrati prizadanejo več organskih sistemov. V primeru suma na imunsko pogojene neželene učinke je treba poskrbeti za ustrezno oceno za potrditev etiologije oziroma izključitev drugih vzrokov. Glede na izrazitost neželenega učinka je treba zadržati uporabo pembrolizumaba in uporabiti kortikosteroide – za natančna navodila, prosimo, glejte Povzetek glavnih značilnosti zdravila Keytruda. Zdravljenje s pembrolizumabom lahko poveča tveganje za zavrnitev pri prejemnikih presadkov čvrstih organov. Pri bolnikih, ki so prejemali pembrolizumab, so poročali o hudih z infuzijo povezanih reakcijah, vključno s preobčutljivostjo in ana laksijo. Pembrolizumab se iz obtoka odstrani s katabolizmom, zato presnovnih medsebojnih delovanj zdravil ni pričakovati. Uporabi sistemskih kortikosteroidov ali imunosupresivov pred uvedbo pembrolizumaba se je treba izogibati, ker lahko vplivajo na farmakodinamično aktivnost in učinkovitost pembrolizumaba. Vendar pa je kortikosteroide ali druge imunosupresive mogoče uporabiti za zdravljenje imunsko pogojenih neželenih učinkov. Kortikosteroide je mogoče uporabiti tudi kot premedikacijo, če je pembrolizumab uporabljen v kombinaciji s kemoterapijo, kot antiemetično pro lakso in/ali za ublažitev neželenih učinkov, povezanih s kemoterapijo. Ženske v rodni dobi morajo med zdravljenjem s pembrolizumabom in vsaj še 4 mesece po zadnjem odmerku pembrolizumaba uporabljati učinkovito kontracepcijo, med nosečnostjo in dojenjem se ga ne sme uporabljati. Varnost pembrolizumaba pri samostojnem zdravljenju so v kliničnih študijah ocenili pri 7631 bolnikih, ki so imeli različne vrste raka, s štirimi odmerki (2 mg/kg telesne mase na 3 tedne, 200 mg na 3 tedne in 10 mg/kg telesne mase na 2 ali 3 tedne). V tej populaciji bolnikov je mediani čas opazovanja znašal 8,5 meseca (v razponu od 1 dneva do 39 mesecev), najpogostejši neželeni učinki zdravljenja s pembrolizumabom pa so bili utrujenost (31 %), diareja (22 %) in navzea (20 %). Večina poročanih neželenih učinkov pri samostojnem zdravljenju je bila po izrazitosti 1. ali 2. stopnje. Najresnejši neželeni učinki so bili imunsko pogojeni neželeni učinki in hude z infuzijo povezane reakcije. Pojavnost imunsko pogojenih neželenih učinkov pri uporabi pembrolizumaba samega za adjuvantno zdravljenje je znašala 37 % za vse stopnje in 9 % od 3. do 5. stopnje, pri metastatski bolezni pa 25 % za vse stopnje in 6 % od 3. do 5. stopnje. Pri adjuvantnem zdravljenju niso zaznali nobenih novih imunsko pogojenih neželenih učinkov. Varnost pembrolizumaba pri kombiniranem zdravljenju s kemoterapijo ali kemoradioterapijo (CRT) so ocenili pri 6093 bolnikih z različnimi vrstami raka, ki so v kliničnih študijah prejemali pembrolizumab v odmerkih 200 mg, 2 mg/kg telesne mase ali 10 mg/kg telesne mase na vsake 3 tedne. V tej populaciji bolnikov so bili najpogostejši neželeni učinki naslednji: anemija (53 %), navzea (52 %), diareja (36 %), utrujenost (35 %), zaprtost (32 %), bruhanje (28 %), zmanjšano število nevtro lcev (28 %) in zmanjšanje apetita (27 %). Pojavnost neželenih učinkov 3. do 5. stopnje je pri bolnikih z NSCLC pri kombiniranem zdravljenju s pembrolizumabom znašala 69 % in pri zdravljenju samo s kemoterapijo 61 %, pri bolnikih s HNSCC pri kombiniranem zdravljenju s pembrolizumabom 85 % in pri zdravljenju s kemoterapijo v kombinaciji s cetuksimabom 84 %, pri bolnikih z rakom požiralnika pri kombiniranem zdravljenju s pembrolizumabom 86 % in pri zdravljenju samo s kemoterapijo 83 %, pri bolnikih s TNBC pri kombiniranem zdravljenju s pembrolizumabom 80 % in pri zdravljenju samo s kemoterapijo 77 %, pri bolnicah z rakom materničnega vratu pri kombiniranem zdravljenju s pembrolizumabom (kemoterapija z ali brez bevacizumaba ali v kombinaciji s CRT) 77 % in pri zdravljenju s kemoterapijo z ali brez bevacizumaba ali samostojno s CRT 71 %, pri bolnikih z rakom želodca pri kombiniranem zdravljenju s pembrolizumabom (kemoterapija z ali brez trastuzumaba) 74 % in pri kemoterapiji v kombinaciji z ali brez trastuzumaba 68 %, pri bolnikih z rakom biliarnega trakta pri kombiniranem zdravljenju s pembrolizumabom 85 % in pri samostojni kemoterapiji 84 %, in pri bolnicah z EC pri kombiniranem zdravljenju s pembrolizumabom 59 % in pri samostojni kemoterapiji 46 %. Varnost pembrolizumaba v kombinaciji z aksitinibom ali lenvatinibom pri napredovalem RCC in v kombinaciji z lenvatinibom pri napredovalem EC so ocenili pri skupno 1456 bolnikih z napredovalim RCC ali napredovalim EC, ki so v kliničnih študijah prejemali 200 mg pembrolizumaba na 3 tedne skupaj s 5 mg aksitiniba dvakrat na dan ali z 20 mg lenvatiniba enkrat na dan, kot je bilo ustrezno. V teh populacijah bolnikov so bili najpogostejši neželeni učinki diareja (58 %), hipertenzija (54 %), hipotiroidizem (46 %), utrujenost (41 %), zmanjšan apetit (40 %), navzea (40 %), artralgija (30 %), bruhanje (28 %), zmanjšanje telesne mase (28 %), disfonija (28 %), bolečine v trebuhu (28 %), proteinurija (27 %), sindrom palmarno-plantarne eritrodizestezije (26 %), izpuščaj (26 %), stomatitis (25 %), zaprtost (25 %), mišično- skeletna bolečina (23 %), glavobol (23 %) in kašelj (21 %). Neželenih učinkov od 3. do 5. stopnje je bilo pri bolnikih z RCC med uporabo pembrolizumaba v kombinaciji z aksitinibom ali lenvatinibom 80 % in med uporabo sunitiniba samega 71 %. Pri bolnicah z EC je bilo neželenih učinkov od 3. do 5. stopnje med uporabo pembrolizumaba v kombinaciji z lenvatinibom 89 % in med uporabo kemoterapije same 73 %. Varnost pembrolizumaba v kombinaciji z enfortumab vedotinom so ocenili pri 564 bolnikih z neoperabilnim ali metastatskim urotelijskim rakom, ki so prejemali 200 mg pembrolizumaba 1. dan in 1,25 mg/kg enfortumab vedotina 1. in 8. dan vsakega 21-dnevnega ciklusa. Na splošno so opazili, da je bila pojavnost neželenih učinkov za pembrolizumab v kombinaciji z enfortumab vedotinom višja kot pri samostojnem zdravljenju s pembrolizumabom, kar odraža prispevek enfortumab vedotina in daljšega trajanja kombiniranega zdravljenja. Neželeni učinki so bili na splošno podobni neželenim učinkom, ki so jih opazili pri bolnikih, ki so prejemali pembrolizumab ali enfortumab vedotin kot samostojno zdravljenje. Pojavnost makulopapuloznega izpuščaja vseh stopenj je bila 36 % (10 % od 3. do 4. stopnje), kar je višje, kot je bilo opaženo pri samostojnem zdravljenju s pembrolizumabom. Na splošno so bile pogostnosti neželenih učinkov višje pri bolnikih, starih ≥ 65 let, v primerjavi z bolniki, starimi < 65 let, predvsem za resne neželene učinke (56,3 % pri bolnikih, starih ≥ 65 let, in 35,3 % pri bolnikih, starih < 65 let) in učinke ≥ 3. stopnje (80,3 % pri bolnikih, starih ≥ 65 let, in 64,2 % pri bolnikih, starih < 65 let), podobno kot opažanja pri primerjalni kemoterapiji. Za celoten seznam neželenih učinkov, prosimo, glejte celoten Povzetek glavnih značilnosti zdravila. Za dodatne informacije o varnosti v primeru uporabe pembrolizumaba v kombinaciji glejte povzetke glavnih značilnosti zdravila za posamezne komponente kombiniranega zdravljenja. • Način in režim izdaje zdravila: H – Predpisovanje in izdaja zdravila je le na recept, zdravilo se uporablja samo v bolnišnicah. • Imetnik dovoljenja za promet z zdravilom: Merck Sharp & Dohme B.V. , Waarderweg 39, 2031 BN Haarlem, Nizozemska. Merck Sharp & Dohme inovativna zdravila d.o.o. Ameriška ulica 2, 1000 Ljubljana, Slovenija; Telefon: 01/ 520 42 01, faks: 01/ 520 43 50 Veeva code: SI-KEY-00735; Pripravljeno v Sloveniji, 01/2025. Vse pravice pridržane. Copyright ©2025 Merck & Co., Inc., Rahway, NJ, USA and its a liates. All rights reserved. Samo za strokovno javnost H - Predpisovanje in izdaja zdravila je le na recept, zdravilo pa se uporablja samo v bolnišnicah. Pred predpisovanjem, prosimo, preberite celoten Povzetek glavnih značilnosti zdravila Keytruda, ki je na voljo pri naših strokovnih sodelavcih ali na lokalnem sedežu družbe. NEDROBNOCELIČNI PLJUČNI RAK: > samostojno adjuvantno zdravljenje odraslih z visokim tveganjem za ponovitev bolezni po popolni kirurški odstranitvi in kemoterapiji na osnovi platine2 > neoadjuvantno zdravljenje v kombinaciji s kemoterapijo, ki vključuje platino in v nadaljevanju samostojno adjuvantno zdravljenje odraslih z operabilnim NDPR z visokim tveganjem za ponovitev bolezni2 ADENOKARCINOM ŽELODCA ali GASTROEZOFAGEALNEGA PREHODA: > lokalno napredovali neoperabilni ali metastatski HER2-pozitiven rak: 1L zdravljenja v kombinaciji s trastuzumabom,  uoropirimidinom in kemoterapijo, ki vključuje platino, pri odraslih s tumorsko izraženostjo PD-L1 s CPS ≥ 12 > lokalno napredovali neoperabilni ali metastatski HER2-negativen rak: 1L zdravljenja v kombinaciji s  uoropirimidinom in kemoterapijo, ki vključuje platino, pri odraslih s tumorsko izraženostjo PD-L1 s CPS ≥ 12 RAK MATERNIČNEGA VRATU: > v kombinaciji s kemoterapijo, z bevacizumabom ali brez njega, za zdravljenje persistentnega, ponovljenega ali metastatskega RMV, pri odraslih bolnicah s tumorsko izraženostjo PD-L1 s CPS ≥ 12 85 % bolnikov daje prednost zdravilu PHESGO v primerjavi z intravenskima oblikama pertuzumaba in trastuzumaba1 Moj čas.Moja izbira.2 DODATNE INFORMACIJE SO NA VOLJO PRI: Roche farmacevtska družba d.o.o., Stegne 13G, Ljubljana Datum priprave informacije: oktober 2024 M-SI-00001285 (v1.0) Za to zdravilo se izvaja dodatno spremljanje varnosti. Tako bodo hitreje na voljo nove informacije o njegovi varnosti. Zdravstvene delavce naprošamo, da poročajo o katerem koli domnevnem neželenem učinku zdravila. Kako poročati o neželenih učinkih, si poglejte v povzetku glavnih značilnosti zdravila pod poglavjem ‘’Poročanje o domnevnih neželenih učinkih’’ Če bolnica med zdravljenjem z zdravilom Phesgo ali v 7 mesecih po prejemu zadnjega odmerka zdravila Phesgo zanosi, vas prosimo, da nosečnost takoj poročate podjetju Roche farmacevtska družba d.o.o. (na e-naslov: slovenia.drugsafety@roche.com ali po telefonu na številko 01 3602 606). Prosili vas bomo za dodatne informacije med izpostavljenostjo zdravilu Phesgo v času nosečnosti in v prvem letu otrokovega življenja. S tem bomo v družbi Roche bolje razumeli varnost zdravila Phesgo in zagotovili ustrezne informacije zdravstvenim oblastem, zdravstvenim delavcem in bolnikom. Za dodatne informacije glejte Povzetek glavnih značilnosti zdravila Phesgo. Referenci: 1. O´Shaughnessy J, Sousa S, Cruz J, et al., Preference for the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer (PHranceSCa): A randomised, open-label phase II study, European Journal of Cancer 2021; 152: 223 – 232. 2. Povzetek glavnih značilnosti zdravila Phesgo https://ec.europa.eu/health/documents/community-register/2020/20201221150167/anx_150167_sl.pdf (dostopano septembra 2024). Ime zdravila: Phesgo 600 mg/600 mg in 1200 mg/600 mg raztopina za injiciranje Kakovostna in količinska sestava: Ena viala z 10 ml raztopine vsebuje 600 mg pertuzumaba in 600 mg trastuzumaba. En ml raztopine vsebuje 60 mg pertuzumaba in 60 mg trastuzumaba (Phesgo 600 mg/600 mg). Ena viala s 15 ml raztopine vsebuje 1200 mg pertuzumaba in 600 mg trastuzumaba. En ml raztopine vsebuje 80 mg pertuzumaba in 40 mg trastuzumaba (Phesgo 1200 mg/600 mg). Terapevtske indikacije: Zgodnji rak dojk: Zdravilo Phesgo je v kombinaciji s kemoterapijo indicirano za neoadjuvantno zdravljenje odraslih bolnikov s HER2-pozitivnim, lokalno napredovalim, vnetnim ali zgodnjim rakom dojk z visokim tveganjem za ponovitev in adjuvantno zdravljenje odraslih bolnikov s HER2- pozitivnim zgodnjim rakom dojk z visokim tveganjem za ponovitev. Razsejani rak dojk: Zdravilo Phesgo je v kombinaciji z docetakselom indicirano za zdravljenje odraslih bolnikov s HER2-pozitivnim, razsejanim ali lokalno ponovljenim neoperabilnim rakom dojk, ki pred tem še niso prejeli anti-HER2 terapije ali kemoterapije za razsejano bolezen. Odmerjanje in način uporabe: Zdravilo Phesgo je lahko uvedeno le pod nadzorom zdravnika, ki ima izkušnje z uporabo zdravil proti raku. Zdravilo Phesgo mora dajati zdravstveni delavec, ki je usposobljen za obvladovanje anafilaksije, in v okolju, kjer je takoj na voljo celotna oprema za oživljanje. Bolniki, ki trenutno prejemajo pertuzumab in trastuzumab intravensko, lahko preidejo na zdravilo Phesgo. Odmerjanje: Bolniki, zdravljeni z zdravilom Phesgo, morajo imeti HER2-pozitivni tumor, imunohistokemijsko opredeljen kot 3+ in/ali razmerje pri ISH > 2,0. Bolniki, ki prejemajo taksan, morajo zdravilo Phesgo dobiti pred taksanom. Kadar se zdravilo Phesgo uporablja sočasno z docetakselom, je priporočeni začetni odmerek docetaksela 75 mg/m2, nato pa se ga poveča na 100 mg/m2 glede na izbrano shemo in prenašanje začetnega odmerka. Druga možnost je odmerek docetaksela 100 mg/m2 po 3-tedenskem razporedu že od začetka, ponovno glede na izbrano shemo. Če se uporablja shemo, ki temelji na karboplatinu, je priporočeni odmerek docetaksela ves čas 75 mg/m2. Kadar se zdravilo Phesgo uporablja sočasno s paklitakselom v adjuvantnem zdravljenju, je priporočeni odmerek paklitaksela 80 mg/m2 enkrat na teden v 12-tedenskih ciklih. Bolniki, ki prejemajo shemo na osnovi antraciklina, morajo zdravilo Phesgo dobiti po koncu celotne sheme na osnovi antraciklina. Razsejani rak dojk: Zdravilo Phesgo je treba uporabljati v kombinaciji z docetakselom. Zdravljenje z zdravilom Phesgo se lahko nadaljuje do napredovanja bolezni ali pojava neobvladljivih toksičnih učinkov, tudi če se zdravljenje z docetakselom ukine. Zgodnji rak dojk: Pri neoadjuvantnem zdravljenju, ki predstavlja del celostnega zdravljenja zgodnjega raka dojk, je treba zdravilo Phesgo dajati 3 do 6 ciklov v kombinaciji. V okviru adjuvantnega zdravljenja je treba zdravilo Phesgo uporabljati v skupnem trajanju eno leto, ki predstavlja del celostnega zdravljenja zgodnjega raka dojk in ne glede na čas operacije. Zdravljenje mora vključevati standardno kemoterapijo na osnovi antraciklina in/ali taksana. Zdravilo Phesgo naj se začne uporabljati 1. dan prvega cikla, ki vsebuje taksan, in ga je treba uporabljati še naprej, tudi če se kemoterapija ukine. Zamujeni ali izpuščeni odmerki: Če je čas med dvema zaporednima injiciranjema: krajši od 6 tednov: vzdrževalni odmerek zdravila Phesgo 600 mg/600 mg je treba dati čimprej. Nato nadaljujte s 3-tedenskim režimom. 6 tednov ali več: ponovno je treba dati polnilni odmerek zdravila Phesgo 1200 mg/600 mg, sledi pa mu vzdrževalni odmerek zdravila Phesgo 600 mg/600 mg na vsake 3 tedne. Prilagoditev odmerka: Za zdravilo Phesgo ni priporočljivo zmanjševanje odmerka. Po presoji zdravnika bo morda potrebna prekinitev zdravljenja z zdravilom Phesgo. Prehod z intravenskega pertuzumaba in trastuzumaba na zdravilo Phesgo: Bolnikom, ki so zadnji odmerek intravenskega pertuzumaba in trastuzumaba prejeli pred manj kot 6 tedni, je treba dati vzdrževalni odmerek zdravila Phesgo 600 mg pertuzumaba/600 mg trastuzumaba in ta odmerek uporabljati tudi za nadaljnje aplikacije na vsake 3 tedne. Bolnikom, ki so zadnji odmerek intravenskega pertuzumaba in trastuzumaba prejeli pred 6 tedni ali več, je treba dati polnilni odmerek zdravila Phesgo 1200 mg pertuzumaba/600 mg trastuzumaba, ki mu sledi vzdrževalni odmerek 600 mg pertuzumaba/600 mg trastuzumaba na vsake 3 tedne. Način dajanja: Zdravilo Phesgo moramo dajati le kot subkutano injekcijo. Zdravilo Phesgo ni namenjeno intravenskemu dajanju. Mesto injiciranja je treba izmenjevati le med levim in desnim stegnom. Polnilni odmerek je treba dati v 8 minutah, vzdrževalni odmerek pa v 5 minutah. Zaradi z injiciranjem povezanih reakcij je priporočljiv čas opazovanja 30 minut po danem polnilnem odmerku in 15 minut po zaključku vzdrževalnega odmerka zdravila Phesgo. Kontraindikacije: Preobčutljivost na učinkovino ali katero koli pomožno snov. Posebna opozorila in previdnostni ukrepi: Disfunkcija levega prekata (vključno s kongestivnim srčnim popuščanjem): Med uporabo zdravil, ki zavirajo aktivnost HER2, so poročali o zmanjšanju LVEF. Večino primerov simptomatskega srčnega popuščanja v okviru adjuvantnega zdravljenja so zabeležili pri bolnikih, zdravljenih s kemoterapijo na osnovi antraciklina. Bolniki, predhodno zdravljeni z antraciklini ali obsevanjem v predelu prsnega koša, imajo lahko večje tveganje za zmanjšanje LVEF glede na študije z intravenskim pertuzumabom v kombinaciji s trastuzumabom in kemoterapijo. Pred uvedbo zdravila Phesgo je treba oceniti vrednost LVEF in jo nato med zdravljenjem tudi redno spremljati ter zagotoviti, da LVEF ostaja znotraj normalnih vrednosti. Če se LVEF poslabša in se ob naslednjem merjenju ne izboljša ali se še dodatno poslabša, je treba resno razmisliti o prenehanju zdravljenja z zdravilom Phesgo, razen če koristi za posameznega bolnika odtehtajo tveganja. Pred uporabo zdravila Phesgo skupaj z antraciklinom je treba skrbno razmisliti o kardiološkem tveganju in ga pretehtati glede na zdravstvene potrebe posameznega bolnika. Z upoštevajnjem farmakološkega delovanja zdravil, usmerjenih proti HER2, in antraciklinov je med sočasno uporabo zdravila Phesgo in antraciklinov mogoče pričakovati večje tveganje za kardiotoksičnost kot med zaporedno uporabo. Z injiciranjem povezane reakcije/z infundiranjem povezane reakcije: Uporabo zdravila Phesgo so spremljale z injiciranjem povezane reakcije. Opredeljene so bile kot katera koli sistemska reakcija s simptomi, kot so zvišana telesna temperatura, mrzlica, glavobol, najverjetneje zaradi sproščanja citokinov, ki se je pojavilo v 24 urah po dajanju zdravila Phesgo. Priporoča se skrbno opazovanje bolnika med dajanjem polnilnega odmerka in še 30 minut po njem ter med dajanjem vzdrževalnega odmerka zdravila Phesgo in še 15 minut po njem. Če se pojavi pomembna z injiciranjem povezana reakcija, injiciranje upočasnimo ali prekinemo ter nudimo ustrezno zdravljenje. Oceniti je treba stanje bolnika in ga skrbno spremljati, dokler znaki in simptomi popolnoma ne izzvenijo. Pri bolnikih s hudo reakcijo je treba razmisliti o dokončni prekinitvi zdravljenja. Klinična ocena mora temeljiti na tem, kako huda je bila prejšnja reakcija, in na odzivu na zdravljenje neželenega učinka. Preobčutljivostne reakcije/anafilaksija: Bolnike je treba skrbno opazovati glede preobčutljivostnih reakcij. Pri pertuzumabu v kombinaciji s trastuzumabom in kemoterapijo so opazili hude reakcije preobčutljivosti, vključno z anafilaksijo in dogodki s smrtnim izidom. Zdravilo Phesgo je treba dokončno ukiniti v primeru preobčutljivostne reakcije 4. stopnje po merilih NCI-CTCAE, bronhospazma ali akutnega respiratornega distresnega sindroma. Febrilna nevtropenija: Pri bolnikih, ki se zdravijo z zdravilom Phesgo v kombinaciji s taksanom, obstaja večje tveganje za nastanek febrilne nevtropenije. Pri bolnikih, ki se zdravijo z intravenskim pertuzumabom v kombinaciji s trastuzumabom in docetakselom, obstaja večje tveganje za nastanek febrilne nevtropenije v primerjavi z bolniki, ki se zdravijo s placebom, trastuzumabom in docetakselom, še posebej med prvimi 3 cikli zdravljenja. Driska: Zdravilo Phesgo lahko izzove hudo drisko. Driska je najpogostejša med sočasnim prejemanjem terapije s taksanom. Starejši bolniki (≥ 65 let) imajo večje tveganje za drisko v primerjavi z mlajšimi bolniki (< 65 let). Zlasti pri starejših bolnikih in v primeru hude ali dolgotrajne driske je treba razmisliti o zgodnjem zdravljenju z loperamidom in nadomeščanju tekočin ter elektrolitov. Razmisliti je treba o prekinitvi zdravljenja z zdravilom Phesgo, če ne dosežemo izboljšanja bolnikovega stanja. Pljučni dogodki: Pri uporabi trastuzumaba so v obdobju po prihodu zdravila na trg poročali o hudih pljučnih dogodkih. Ti dogodki so bili občasno smrtni. Poleg tega so poročali o primerih intersticijske pljučne bolezni, vključno s pljučnimi infiltrati, sindromom akutne respiratorne stiske, pljučnico, pnevmonitisom, plevralnim izlivom, dihalno stisko, akutnim pljučnim edemom in respiratorno insuficienco. Dejavniki tveganja, povezani z intersticijsko pljučno boleznijo, vključujejo predhodno ali sočasno zdravljenje z drugimi antineoplastičnimi terapijami, za katere je znano, da so z njo povezane, kot so taksani, gemcitabin, vinorelbin in radioterapija. Ti dogodki se lahko pojavijo kot del z infuzijo povezane reakcije ali imajo zapoznel nastop. Bolniki z dispnejo v mirovanju zaradi zapletov napredovale maligne bolezni in sočasnih bolezni imajo lahko večje tveganje za pljučne dogodke. Zato teh bolnikov ne smemo zdraviti z zdravilom Phesgo. Pri pnevmonitisu je potrebna previdnost, zlasti pri bolnikih, ki se sočasno zdravijo s taksani. Medsebojno delovanje z drugimi zdravili in druge oblike interakcij: Formalnih študij medsebojnega delovanja niso izvedli. Neželeni učinki: Najpogostejši neželeni učinki zdravila (≥ 30%), o katerih so poročali pri bolnikih, zdravljenih z zdravilom Phesgo ali intravenskim pertuzumabom v kombinaciji s trastuzumabom in kemoterapijo, so bili alopecija, driska, navzea, anemija, astenija in artralgija. Najpogostejši resni neželeni dogodki (≥ 1 %), o katerih so poročali pri bolnikih, zdravljenih z zdravilom Phesgo ali intravenskim pertuzumabom v kombinaciji s trastuzumabom, so bili febrilna nevtropenija, srčno popuščanje, zvišana telesna temperatura, nevtropenija, nevtropenična sepsa, zmanjšanje števila nevtrofilcev in pljučnica. Poročanje o domnevnih neželenih učinkih: Poročanje o domnevnih neželenih učinkih zdravila po izdaji dovoljenja za promet je pomembno. Omogoča namreč stalno spremljanje razmerja med koristmi in tveganji zdravila. Od zdravstvenih delavcev se zahteva, da poročajo o katerem koli domnevnem neželenem učinku zdravila na: Javna agencija Republike Slovenije za zdravila in medicinske pripomočke, Sektor za farmakovigilanco, Nacionalni center za farmakovigilanco, Slovenčeva ulica 22, SI-1000 Ljubljana, Tel: +386 (0)8 2000 500, Faks: +386 (0)8 2000 510, e-pošta: h-farmakovigilanca@jazmp.si, spletna stran: www.jazmp.si. Za zagotavljanje sledljivosti zdravila je pomembno, da pri izpolnjevanju obrazca o domnevnih neželenih učinkih zdravila navedete številko serije biološkega zdravila. Režim izdaje zdravila: H. Imetnik dovoljenja za promet: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Nemčija Za podrobnejše informacije glejte celoten Povzetek glavnih značilnosti zdravila. Verzija: 1.0/24 SKRAJŠAN POVZETEK GLAVNIH ZNAČILNOSTI ZDRAVILA Onivyde pegylated liposomal 4,3 mg/ml SESTAVA*: Onivyde pegylated liposomal 4,3 mg/ml koncentrat za disperzijo za infundiranje: ena viala z 10 ml koncentrata vsebuje 43 mg brezvodnega irinotekana (v obliki irinotekanijeve soli saharoznega oktasulfata v pegilirani liposomski formulaciji). TERAPEVTSKE INDIKACIJE*: Zdravilo Onivyde pegylated liposomal je v kombinaciji z oksaliplatinom, 5-fluorouracilom (5-FU) in levkovorinom (LV) indicirano za prvo izbiro zdravljenja metastatskega adenokarcinoma trebušne slinavke pri odraslih bolniki in v kombinaciji s 5-FU in LV za zdravljenje metastatskega adenokarcinoma trebušne slinavke pri odraslih bolnikih, pri katerih je bolezen po zdravljenju na osnovi gemcitabina napredovala. ODMERJANJE IN NAČIN UPORABE*: Onivyde pegylated liposomal smejo bolnikom predpisati in dajati samo zdravstveni delavci, ki imajo izkušnje pri uporabi zdravil za zdravljenje raka. Zdravilo Onivyde pegylated liposomal ni enakovredno drugim neliposomskim formulacijam irinotekana, zato jih ne smemo zamenjevati. Zdravilo Onivyde pegylated liposomal se ne daje kot samostojno zdravilo. Z zdravljenjem je treba nadaljevati, dokler bolezen ne napreduje ali bolnik zdravljenja z zdravilom ne prenaša več. Priporočeni odmerek zdravila Onivyde pegylated liposomal v kombinaciji z oksaliplatinom, LV in 5-FU je 50 mg/m2 v obliki 90-minutne intravenske infuzije, ki ji sledi 120-minutna intravenska infuzija oksaliplatina v odmerku 60 mg/m2, nato 30-minutna intravenska infuzija LV v odmerku 400 mg/m2 in zatem 46-urna intravenska infuzija 5-FU v odmerku 2400 mg/m2, vsaka 2 tedna. Priporočeni začetni odmerek zdravila Onivyde pegylated liposomal pri bolnikih z znano homozigotnostjo za alel UGT1A1*28 je nespremenjen. Priporočeni odmerek in režim odmerjanja zdravila Onivyde pegylated liposomal v kombinaciji s 5-FU in LV je 70 mg/m2 intravensko 90 minut, čemur sledi LV 400 mg/m2 intravensko 30 minut in nato 5 FU 2400 mg/m2 intravensko 46 ur, vsaka 2 tedna. Pri bolnikih z znano homozigotnostjo za alel UGT1A1*28 je treba razmisliti o manjšem začetnem odmerku zdravila Onivyde pegylated liposomal 50 mg/m2. Če zdravilo bolniki dobro prenašajo, lahko v naslednjih ciklih razmislimo o odmerku zdravila Onivyde pegylated liposomal 70 mg/m2. Prilagajanje odmerka se priporoča za obvladovanje toksičnosti, povezane z zdravilom Onivyde pegylated liposomal. KONTRAINDIKACIJE*: Anamneza hude preobčutljivosti na irinotekan ali katero koli pomožno snov. Dojenje. OPOZORILA*: Mielosupresija/nevtropenija: Med zdravljenjem z zdravilom Onivyde pegylated liposomal se priporoča nadziranje celotne krvne slike. Bolniki se morajo zavedati tveganja za nevtropenijo in pomena povišane telesne temperature. Febrilno nevtropenijo je treba nujno zdraviti v bolnišnici s širokospektralnimi intravenskimi antibiotiki. Pri bolnikih, ki doživijo hude hematološke neželene učinke, se priporoča zmanjšanje odmerka ali prekinitev zdravljenja. Bolnikov s hudo odpovedjo kostnega mozga ne smemo zdraviti z zdravilom Onivyde pegylated liposomal. Anamneza predhodnega obsevanja trebuha poveča tveganje za hudo nevtropenijo in febrilno nevtropenijo po zdravljenju z zdravilom Onivyde pegylated liposomal. Pri bolnikih, ki hkrati prejemajo zdravilo Onivyde pegylated liposomal in so obsevani, je potrebna previdnost. Bolniki s pomanjkljivo glukuronidacijo bilirubina, kot so bolniki z Gilbertovim sindromom, imajo med zdravljenjem z zdravilom Onivyde pegylated liposomal lahko večje tveganje za mielosupresijo. Imunosupresivni učinki in cepiva: Dajanje živih ali atenuiranih cepiv bolnikom z oslabljenim imunskim sistemom lahko povzroči resne ali smrtne okužbe. Interakcije z močnimi induktorji encima CYP3A4, močnimi zaviralci encima CYP3A4 in močnimi zaviralci encima UGT1A1: Zdravila Onivyde pegylated liposomal ne smemo dajati skupaj z močnimi induktorji encima CYP3A4, močnimi zaviralci encima CYP3A4 ali z močnimi zaviralci encima UGT1A1, razen če ni drugih terapevtskih možnosti. Zdravljenje z močnimi zaviralci encima CYP3A4 moramo prekiniti vsaj 1 teden pred začetkom zdravljenja z zdravilom Onivyde pegylated liposomal. Driska: Zdravilo Onivyde pegylated liposomal lahko povzroči hudo in smrtno nevarno drisko. Zdravila Onivyde pegylated liposomal se ne sme dajati bolnikom s črevesno obstrukcijo in kronično vnetno črevesno boleznijo.Pri bolnikih, ki doživijo zgodnji pojav driske (v ≤ 24 urah po začetku zdravljenja z zdravilom Onivyde pegylated liposomal) ali holinergične simptome, je treba razmisliti o terapevtskem in profilaktičnem zdravljenju z atropinom, razen če je kontraindicirano. Bolnike je treba opozoriti na tveganje za zapoznelo drisko (> 24 ur), ki je izčrpavajoča in v redkih primerih tudi življenjsko nevarna. Loperamid je treba uvesti ob prvem pojavu neoblikovanega ali mehkega blata ali takoj, ko odvajanje blata postane pogostejše kot običajno. Loperamid je treba dajati, dokler bolnik ni brez driske vsaj 12 ur. Da bi se izognili hudi driski, opustite vse izdelke, ki vsebujejo laktozo, ohranjajte hidracijo in uživajte dieto z nizko vsebnostjo maščob. Če driska traja tudi, ko bolnik prejema loperamid več kot 24 ur, je treba razmisliti o dodatni peroralni antibiotični podpori. Loperamida zaradi tveganja za paralitični ileus ne smemo uporabljati več kot 48 ur zaporedoma. Nov cikel zdravljenja se ne sme pričeti, dokler se driska ne umiri do ≤ 1. stopnje (2–3 odvajanja/dan več kot pred zdravljenjem). Holinergične reakcije: Zgodnjo drisko lahko spremljajo rinitis, povečano slinjenje, zardevanje, diaforeza, bradikardija, mioza in hiperperistaltika. Pri bolnikih s holinergičnimi simptomi moramo uporabiti atropin. Preobčutljivostne reakcije, vključno z akutnimi infuzijskimi reakcijami: V primeru hudih preobčutljivostnih reakcij je treba zdravljenje z zdravilom Onivyde pegylated liposomal prekiniti. Predhodna Whipplova operacija: Večje tveganje za resne okužbe. Bolnike je treba spremljati glede znakov okužbe. Žilne bolezni: Zdravilo Onivyde pegylated liposomal je bilo povezano s trombemboličnimi dogodki, kot so pljučna embolija, venska tromboza in arterijska trombembolija. Treba je pridobiti podrobno zdravstveno anamnezo, da bi prepoznali bolnike z več dejavniki tveganja poleg osnovne neoplazme. Bolnike je treba obvestiti o znakih in simptomih trombembolije in jim svetovati, da se v primeru katerega od teh znakov ali simptomov takoj obrnejo na svojega zdravnika ali medicinsko sestro. Pljučna toksičnost: Pri bolnikih, ki so prejemali neliposomski irinotekan, so se pojavili dogodki, podobni intersticijski pljučni bolezni (IPB), ki so vodili do smrtnih primerov. Pri bolnikih z dejavniki tveganja (obstoječo pljučno boleznijo, uporabo pnevmotoksičnih zdravil, kolonije stimulirajočimi dejavniki ali predhodnim zdravljenjem z obsevanjem) je treba pred zdravljenjem z zdravilom Onivyde pegylated liposomal in po njem skrbno nadzirati respiratorne simptome. Dokler ni opravljena diagnostična ocena, je treba ob pojavu nove ali napredovale dispneje, kašlja in povišane telesne temperature zdravljenje z zdravilom Onivyde pegylated liposomal začasno prekiniti. Pri bolnikih s potrjeno diagnozo IPB moramo zdravljenje z zdravilom Onivyde pegylated liposomal dokončno prekiniti. Jetrna okvara: Bolniki s hiperbilirubinemijo so imeli povišane koncentracije skupnega SN-38, zato je tveganje za nevtropenijo povečano. Pri bolnikih z vrednostjo skupnega bilirubina 1,0–2,0 mg/dl je treba redno nadzirati celotno krvno sliko. Previdnost je potrebna pri bolnikih z jetrno okvaro (bilirubin > 2-kratna zgornja meja normalnih vrednosti [ULN]; aminotransferaze > 5-kratna ULN). Previdnost je potrebna, če zdravilo Onivyde pegylated liposomal dajemo v kombinaciji z drugimi hepatotoksičnimi zdravili. Bolniki s premajhno telesno maso (indeks telesne mase < 18,5 kg/m2): Potrebna je previdnost. Pomožne snovi: To zdravilo vsebuje 33,1 mg natrija na vialo, kar je enako 1,65 % največjega dnevnega vnosa natrija za odrasle osebe, ki ga priporoča SZO in znaša 2 g. En mililiter zdravila Onivyde pegylated liposomal vsebuje 0,144 mmol (3,31 mg) natrija. INTERAKCIJE*: Previdnostni ukrepi: Sočasno dajanje z induktorji encima CYP3A4 (npr. antikonvulzivi, rifampicin, rifabutin in šentjanževka) lahko zmanjša sistemsko izpostavljenost zdravilu Onivyde pegylated liposomal. Sočasno dajanje z zaviralci encima CYP3A4 (npr. grenivkinim sokom, klaritromicinom, indinavirjem, itrakonazolom, lopinavirjem, nefazodonom, nelfinavirjem, ritonavirjem, sakvinavirjem, telaprevirjem, vorikonazolom) ali encima UGT1A1 (npr. atazanavirja, gemfibrozila, indinavirja, regorafeniba) lahko poveča sistemsko izpostavljenost zdravilu Onivyde pegylated liposomal. Sočasna uporaba z zdravili z delovanjem na novotvorbe (flucitozinom) lahko poslabša neželene učinke zdravila Onivyde pegylated liposomal. PLODNOST*: Pred začetkom zdravljenja z zdravilom Onivyde pegylated liposomal premislite o svetovanju bolnikom glede shranjevanja spolnih celic. NOSEČNOST*: Uporaba ni priporočljiva. DOJENJE*: Zdravilo je kontraindicirano. KONTRACEPCIJA*: Ženske v rodni dobi morajo med zdravljenjem in še 7 mesecev po zdravljenju z zdravilom Onivyde pegylated liposomal uporabljati učinkovito kontracepcijo. Moški morajo med zdravljenjem z zdravilom Onivyde pegylated liposomal in 4 mesece po zdravljenju uporabljati kondome. VPLIV NA SPOSOBNOST VOŽNJE IN UPRAVLJANJA STROJEV*: Bolniki morajo biti med zdravljenjem pri vožnji in upravljanju strojev previdni. NEŽELENI UČINKI*: Zdravilo Onivyde pegylated liposomal v kombinaciji z oksaliplatinom, 5-fluorouracilom in levkovorinom: Zelo pogosti: anemija, nevtropenija, trombocitopenija, hipokaliemija, zmanjšan apetit, periferna nevropatija, disgevzija, parestezija, driska, navzea, bruhanje, bolečine/nelagodje v trebuhu, stomatitis, alopecija, astenija, vnetje sluznic, zmanjšana telesna masa. Pogosti: sepsa, infekcija urinarnega trakta, okužba s kandido, nazofaringitis, febrilna nevtropenija, levkopenija, limfopenija, dehidracija, hiponatriemija, hipofosfatemija, hipomagneziemija, hipoalbuminemija, hipokalciemija, tremor, nevrotoksičnost, disestezija, holinergični sindrom, glavobol, omotica, zamegljen vid, tahikardija, hipotenzija, trombembolični dogodki, pljučna embolija, kolcanje, dispneja, epistaksa, kolitis, enterokolitis, zaprtje, suha usta, napenjanje, napihnjenost trebuha, dispepsija, gastroezofagealna refluksna bolezen, hemoroidi, disfagija, hiperbilirubinemija, suha koža, sindrom palmarno-plantarne eritrodizestezije, izpuščaj, hiperpigmentacija kože, mišična šibkost, mialgija, mišični krči, akutna poškodba ledvic, pireksija, edem, mrzlica, zvišana raven transaminaz (ALT in AST), zvišana raven alkalne fosfataze v krvi, zvišana raven gama-glutamil transferaze, zvišana raven kreatinina v krvi, z infuzijo povezana reakcija. Občasni: divertikulitis, pljučnica, analni absces, febrilna okužba, gastroenteritis, okužba sluznice, oralna glivična okužba, okužba s Clostridium difficile, konjuktivitis, furunkel, herpes simpleks, laringitis, parodontitis, pustulozni izpuščaj, sinusitis, okužba zob, vulvovaginalna glivična okužba, peritumoralni edem, pancitopenija, hemolitična anemija, elektrolitsko neravnovesje, hiperkalciemija, celična smrt, hipokloremija, protin, hiperglikemija, hiperkaliemija, pomanjkanje železa, podhranjenost, nespečnost, zmedenost, depresija, nevroza, napadi, možganska krvavitev, možganska ishemija, ishemična možganska kap, anozmija, agevzija, motnje ravnotežja, hipersomnija, hipestezija, motnje v duševnem razvoju, letargija, motnje spomina, presinkopa, sinkopa, prehodni ishemični napad, draženje oči, zmanjšana ostrina vida, vrtoglavica, angina pektoris, akutni miokardni infarkt, palpitacije, hipertenzija, periferna hladnost, hematom, flebitis, orofaringealna bolečina, kašelj, hiperoksija, vnetje nosu, atelektaza, disfonija, pnevmonitis, gastrointestinalna toksičnost, obstrukcija dvanajstnika, analna inkontinenca, afta, oralna disestezija, bolečina v ustni votlini, motnje jezika, analna razpoka, angularni heilitis, dishezija, oralna parestezija, zobni karies, eruktacija, želodčne motnje, gastritis, motnje dlesni, boleče dlesni, hematohezija, hiperestezija zob, paralitični ileus, otekanje ustnic, razjede v ustih, spazem požiralnika, parodontalna bolezen, rektalna krvavitev, holangitis, toksični hepatitis, holestaza, hepatična citoliza, pruritus, hiperhidroza, bulozni dermatitis, generalizirani eksfoliativni dermatitis, eritem, toksičnost za nohte, papule, petehije, luskavica, občutljiva koža, luščenje kože, kožna lezija, teleangiektazija, urtikarija, artralgija, bolečine v hrbtu, bolečine v kosteh, bolečine v okončinah, poliartritis, okvara ledvic, odpoved ledvic, disurija, proteinurija, vulvovaginalna suhost, slabo počutje, splošno poslabšanje telesnega zdravja, vnetje, sindrom večorganske disfunkcije, gripi podobna bolezen, nesrčna bolečina v prsnem košu, aksilarna bolečina, bolečina v prsnem košu, hipotermija, bolečina, otekel obraz, temperaturna intoleranca, kseroza, zvišano mednarodno umerjeno razmerje, znižana raven celokupnih beljakovin, zmanjšan ledvični očistek kreatinina, podaljšan QT interval na elektrokardiogramu, povečano število monocitov, zvišana raven troponina I. Zdravilo Onivyde pegylated liposomal v kombinaciji s 5-fluorouracilom in levkovorinom: Zelo pogosti: nevtropenija, levkopenija, anemija, trombocitopenija, hipokaliemija, hipomagneziemija, dehidracija, zmanjšan apetit, omotica, driska, bruhanje, navzea, bolečine v trebuhu, stomatitis, alopecija, pireksija, periferni edem, vnetje sluznic, utrujenost, astenija, zmanjšana telesna masa. Pogosti: septični šok, sepsa, pljučnica, febrilna nevtropenija, gastroenteritis, oralna kandidoza, limfopenija, hipoglikemija, hiponatriemija, hipofosfatemija, nespečnost, holinergični sindrom, dizgevzija, hipotenzija, pljučna embolija, trombembolični dogodki, dispneja, disfonija, kolitis, hemoroidi, hipoalbuminemija, pruritus, akutna ledvična odpoved, z infuzijo povezana reakcija, edem, zvišana raven bilirubina, zvišana raven transaminaz (ALT in AST), zvišano mednarodno umerjeno razmerje. Občasni: biliarna sepsa, preobčutljivost, hipoksija, ezofagitis, proktitis, urtikarija, izpuščaj, obarvanje nohtov. Neznana pogostnost: anafilaktična/anafilaktoidna reakcija, angioedem, eritem. PREVELIKO ODMERJANJE*: Za preveliko odmerjanje zdravila ni znanega antidota. Treba je uvesti maksimalno podporno nego, s katero preprečimo dehidracijo zaradi driske in zdravimo zaplete zaradi okužb. FARMAKODINAMIČNE LASTNOSTI*: Irinotekan (zaviralec topoizomeraze I), inkapsuliran v vezikel z lipidnim dvoslojem oziroma liposom. Irinotekan je derivat kamptotecina. Kamptotecini delujejo kot specifični zaviralci encima DNA-topoizomeraza I. Irinotekan in njegov aktivni presnovek SN-38 se reverzibilno vežeta na kompleks topoizomeraze I in DNA ter sprožita poškodbe v enoverižni DNA, kar zaustavi replikacijske vilice pri podvajanju DNA in povzroča citotoksičnost. Irinotekan se presnavlja s karboksilesterazo do SN-38. SN-38 je približno 1.000-krat močnejši kot irinotekan kot zaviralec topoizomeraze I, očiščene iz tumorskih celičnih linij človeka in glodavcev. PAKIRANJE*: Pakiranje vsebuje eno vialo z 10 ml koncentrata. NAČIN PREDPISOVANJA IN IZDAJE ZDRAVILA: H - Predpisovanje in izdaja zdravila je le na recept, zdravilo pa se uporablja samo v bolnišnicah. DATUM ZADNJE REVIZIJE BESEDILA: 04. 2024. Imetnik dovoljenja za promet: Les Laboratoires Servier, 50, rue Carnot, 92284 Suresnes cedex, Francija. *Pred predpisovanjem preberite celoten povzetek glavnih značilnosti zdravila. Celoten povzetek glavnih značilnosti zdravila in podrobnejše informacije so na voljo pri: Servier Pharma d. o. o., Podmilščakova ulica 24, 1000 Ljubljana, www.servier.si. Zdravilo je na slovenskem trgu na voljo v tuji ovojnini. Za uporabnika so informacije v slovenskem jeziku dostopne na uradni spletni strani www.cbz.si. Navodila za uporabo v slovenskem jeziku so na voljo tudi na https://servier-pro.si/. UTIRA NOVO POT NA PODLAGI TRDNIH DOKAZOV Z zdravilom ONIVYDE v režimu NALIRIFOX lahko bolnikom z mPaCa ponudite učinkovito zdravljenje z obvladljivim varnostnim profilom in omogočite, da se njihova kakovost življenja ohrani.1, 2 Zdravilo ONIVYDE pegylated liposomal je indicirano: • v kombinaciji z oksaliplatinom, 5-fluorouracilom (5-FU) in levkovorinom (LV) za prvo izbiro zdravljenja metastatskega adenokarcinoma trebušne slinavke pri odraslih bolnikih, • v kombinaciji s 5-FU in LV za zdravljenje metastatskega adenokarcinoma trebušne slinavke pri odraslih bolnikih, pri katerih je bolezen po zdravljenju na osnovi gemcitabina napredovala. Zdravilo ni bilo preizkušano pri otrocih, mlajših od 18 let, in je indicirano le za odrasle.1 ONIVYDE® pegylated liposomal V REŽIMU NALIRIFOX ODOBREN V PRVI LINIJI ZDRAVLJENJA mPaCa ON I A D1 C 1 20 24 -2 5. S am o za s tro ko vn o ja vn os t. Da tu m p rip ra ve in fo rm ac ije : a vg us t 2 02 4. Kratice in literatura: NALIRIFOX: liposomski irinotekan v kombinaciji z oksaliplatinom, 5-fluorouracilom in levkovorinom; mPaCa: metastatski rak trebušne slinavke; mOS: mediana celokupnega preživetja; mPFS: mediana preživetja brez napredovanja bolezni; ORR: skupna stopnja odziva. 1. Povzetek glavnih značilnosti zdravila ONIVYDE pegylated liposomal, april 2024. 2. Melisi D et al. Annals of Oncology. 2023;34:S896-S897. The editorial policy Radiology and Oncology is a multidisciplinary journal devoted to the publishing original and high-quality scientific papers and review articles, pertinent to oncologic imaging, interventional radiology, nuclear medicine, radiotherapy, clinical and experimental oncology, radiobiology, medical physics, and radiation protection. Papers on more general aspects of interest to the radiologists and oncologists are also published (no case reports). 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