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Siemens medica 1 ADIOLOGY ANO NCOLOGY Editorial office Radiologij and Oncology September 2003 Institute oj Oncologij Vol. 37 No. 3 Zaloška 2 Pages 141-211 Sl-1000 Ljubljana ISSN 1318-2099 Slovenia UDC 616-006 Phone: +386 1 5879 369 CODEN: RONCEM Phone/Fax: +386 1 5879 434 E-mail: gsersa@onko-i.si Aims and scope Radiology and Oncologij is a journal devoted to publication oj original contributions in diagnostic and interventional radiologij, computerized tomography, ultrasound, magnetic resonance, nuc/ear medicine, radiotherapy, clinical and experimental oncology, radiobiologij, radiophysics and radiation protection. Editor-in-Chief Editor-in-Chief Emeritus Gregor Serša Tomaž Benulic Ljubljana, Slovenia Ljubljana, Slovenia Executive Editor Editor Viljem Kovac Uroš Smrdel Ljubljana, Slovenia Ljubljana, Slovenia Editorial board Maja Osmak Marija Auersperg Valentin Fidler Zagreb, Croatia Ljubljana, Slovenia Ljubljana, Slovenia Branko Palcic Nada Bešenski Be1a Fornet Vancouver, Canada Zagreb, Croatia Budapest, Hungary /urica Papa Karl H. Bohuslavizki Tullio Giraldi Zagreb, Croatia Hamburg, Germany Trieste, ltaly Dušan Pavcnik Haris Boka Andrija Hebrang Portland, USA Zagreb, Croatia Zagreb, Croatia Stojan Plesnicar Nataša V. Budihna Ltiszl6 Horvtith Ljubljana, Slovenia Ljubljana, Slovenia Pecs, Hungary Ervin B. Podgoršak Marjan Budihna Berta Jereb Montreal, Canada Ljubljana, Slovenia Ljubljana, Slovenia Jan C. Roos Malte Clausen Vladimir Jevtic Amsterdam, Netherlands Hamburg, Germany Ljubljana, Slovenia Slavko Šimunic Christoph Clemm H. Dieter Kogelnik Zagreb. Croatia Miinchen, Germany Salzburg, Austria Lojze Smid Mario Corsi Jurij Lindtner Ljubljan_,a,Slovenia Udine, Italy Ljubljana, Slovenia Borut Stabuc Ljubomir Diankov Ivan Lovasic Ljubljana, Slovenia So jia, Bulgaria Rijeka, Croatia Andrea Veronesi Christian Dittrich Marijan Lovrencic Aviano, ltaly Vienna, Austria Zagreb, Croatia Živa Zupancic Ivan Drinkovic LukaMilas Ljubljana, Slovenia Zagreb, Croatia Houston, USA Gillian Duchesne Metka Milcinski Melbourne, Australia Ljubljana, Slovenia Publisher Association oj Radiology and Oncology Affiliated with Slovenian Medica/ Association -Slovenian Association oj Radiologtj, Nuclear Medicine Society, Slovenian Society far Radiotherapy and OncologtJ, and Slovenian Cancer Society Croatian Medica/ Association -Croatian Society oj Radiology Societas Radiologorum Hungarorum Friuli-Venezia Giulia regional groups oj S.I.R.M. (Italian Society oj Medica/ Radiology) Copyright © Radiology and Oncology. Ali rights reserved. Reader for English Mojca Cakš Key words Eva Klemencic Secretaries Milica Harisch Mira Klemencic Design Monika Fink-Serša Printed by Imprint d.o.o., Ljubljana, Slovenia Published quarterly in 700 copies Bank account number 02010-0090006751 Foreign currency account number 010-7100-900067 /4 NLB d.d., Podružnica Ljubljana Center, Ljubljana S. W.I.F. T. Code LJBASI2X Subscription fee far institutions EUR 100 (16000 SIT), individuals EUR 50 (5000 SIT) The publication oj this journal is subsidized by the Ministry oj Education, Science and Spori oj the Republic oj Slovenia. Indexed and abstracted by: BIOMEDICINA SLOVENICA CHEMICAL ABSTRACTS EMBASE / Excerpta Medica Sci Base This journal is printed on acid-free paper Radiologi; and OncologtJ is available on the internet at: http://www.onko-i.si/radiolog/rno.html ISSN 1581-3207 COLOGY Ljubljana, Slovenia ISSN 1318-2099 September 2003 UDC 616-006 Vol. 37 No. 3 CODEN: RONCEM CONTENTS Ten years of the journal Radiology and Oncology -some bibliometric evaluations Musek M, Oven M, Južnic P ULTRASOUND AND COMPUTED TOMOGRAPHY Unexpected diagnosis for preauricular swelling -two case reports Roic G, Posaric V, Marušic A, Boric I, Vlahovic T, Vrlicek K 155 Transrectal and transperineal sonography in the diagnosis of hydradenitis suppurativa Kotodziejczak M, Stefanski R, Sudol-Szopinska I, ]akubowski W 161 CLINICAL ONCOLOGY Pneumonia as a cause of death in patients with lung cancer Zi1;ba M, Baranowska A, Krawczyk M, Noweta K, Grzelewska-Rzymowska I, Kwiatkowska S 167 Radiotherapy for stage IAE non-Hodgkin' s lymphoma of the testicle -a case report Juretic A, Živkovic M, Gamulin M, Herceg T, Bagovic D, Kucan D, Zeijko Ž, Ajdukovic R 175 Long-term disease-free interval after irradiation for locally advanced lung cancer Haraguchi N, Satoh H, Homma T, Sekizawa K 183 EXPERIMENTAL ONCOLOGY The role of cyclooxygenase-2 in the malignant tissue and possible applicability of cyclooxygenase-2 inhibitors in the therapy of cancer Legan M 187 Survivin -an inhibitor of apoptosis and a new therapeutic target in cancer Pižem ], Car A 195 SLOVENIAN ABSTRACTS 203 NOTICES 209 Ten years of the journal Radiology and Oncology some bibliometric evaluations Matjai Musek1, Marjeta Oven1, Primoz Juinic2 1 Special Library for Oncology, Institute of Oncology Ljubljana; 2 Department of Library & Information Sciences and Book Studies, Faculty of Arts, University of Ljubljana, Slovenia Background. Bibliometrics and its methods are a useful set of tools for analysing a scientific journal's rel­ative position in the field. By measuring different quantitative data and comparing them with other journals in the field, certain decisions can be made as to the future of the journal. Objectives and methods. We thought as appropriate to take last ten years of Radiology and Oncology (1992-2001) and put that content to double scrutiny: first, by applying various quantitative measurements to the journal's content to get a more objective picture of the whole and of its development in the past ten years; then by additionally comparing it to another international journal from the field and of similar ori­entation, Neoplasma, to illustrate if differences and/ or similarities between the two are in favour of or detri­ment to Radiology and Oncology. Results and conclusion. Results show that Radiology and Oncology has been progressing in the right di­rection, but that extra efforts should be made by the editors and the editorial board to attract more articles per issue and to gradually increase the share of experimental articles to boost its impact in the field. Also, to improve its visibility, editors, reviewers and also authors that publish in Radiology and Oncology could con­sider citing the articles published in this journal, in the articles published elsewhere, when appropriate. Key words: radiology; medical oncology; periodicals; bibliometrics Received 5 September 2003 Accepted 15 September 2003 Correspondence to: Matjaz Musek, Special Library for Oncology, Institute of Oncology, P.O.Box 2217, SI­1001 Ljubljana, Slovenia; E-mail: mmusek@onko-i.si Introduction Rationale The aim of the study was to establish, and possibly define, the position of the scientific journal Radiology and Oncology and its relative importance in the field, by applying relevant bibliometric measurements. Bibliometrics has, for various reasons, been widely discussed in scientific circles re­cently,1'2 especially two of its best known Musek M et al. / Ten years of Radiology and Oncology methods, citation analysis and impact factor, a journal's relative weight in scientific com­munity. Both methods are in a way defining the position of a scientific journal in a highly competitive, if not sometimes controver­sial,3A market of published scientific commu­nication. The nature and importance of cita­tion analysis have not always been given equally welcome reception, since bibliomet­rics started its life as an independent scientif­ic discipline back in the 60s. However, the re­sults were always met with unhidden interest and due concern.5 Bibliometric methods -at least some -have been at times widely dis­puted as well as defended: bias in favour of scientifically important nations or countries and/or English language, overimportance giv­en to the tools provided by ISii, primarily its two important databases, SCI;; and JCRiii, which exclude most of the journals from non­English speaking world, and journals not published in English language, etc., to name just a few. 6 Still, all bibliometric methods can be used quite safely and effectively, bearing the only reproach which all other quantitative research methods are burdened with, so well epitomized by Disraeli'siv refering to the sta­tistics: »There are lies, bigger lies, and statis­tics!<< By analysing citations, i.e. bibliographic references or sources of information as they are sometimes called which appear at the end of articles, we may evaluate the importance of published articles, and consequently of the journals that publish them, and show their relative weight in peer circles, as well as measure their relevance in the process of ex­change of information among scientists.7 However, when comparing various larger en­vironments, like states or countries and re­search communications they generate, biblio­metric analysis must take into consideration many complex factors affecting such environ­ments, like fair comparison of the scientific development through time, local science pol­icy that does not always have positive impact on scientific community, the fact that scien­tific research has increasingly become inter­nationalized, with transborder cooperation involving many different scientists from dif­ferent cultural backgrounds, etc.5 To measure and evaluate the same for Slo­vene scientific journals is a much more com­plicated task, since until recentlyv no Slovene research journal had been included in SCI that regularly measures the relevance of se­lected scientific journals for, and their impact on, the research community worldwide. Ci­tation analysis data on Slovene medical jour­nals, for instance, would serve many purpos­es, not the least to establish in a more objec­tive way their position and role in the world­wide process of scientific communication ex­change.8 Comparing Slovene medical journals among themselves may be completly imprac­tical, if not downright impossible and would, in any case, require extreme caution to ex­clude the possibility of contents or disciplines being compared that can not be so. It is there­fore necessary to implement a certain level of precaution and to scale down the area of com­parison to possibly a very similar, if not the same, specific subject of research or activity. Since there are not many research centres in Slovenia that would be deeply involved in oncology research, let alone scientific jour­nals that would publish articles in this area, international comparisons are the obvious choice to establish the position of the journal in the field, like Radiology and Oncology. Actually, there was an attempt to assign im­pact factors to the medical journals published in Slovenia, based on recorded articles in the database BlOMEDICINA SLOVENICA.8 However, this was only an experimental en­terprise which brought some interesting and applicable solutions for further considera­tion. Genealogy The journal Radiology and Oncology represents a logical continuation of the now defunct sci- Musek M et al./ Tw years of Radiology and Oncology entific journal Radiologia lugoslavica, that was published by The Yugoslav Association of Radiology and The Yugoslav Association of Nuclear Medicine (later to merge into The Yugoslav Association of Radiology and Nuclear Medicine), appearing for the first time in 1964. Initially, it served the purposes of publishing proceedings or papers from var­ious national meetings and conferences in the field, but soon became more and more a sci­entific journal with its own set of articles. In the first few years the articles were written and published in various languages of the Yugoslav federation, but later accepted and published articles in all proposed languages. The Association's offices always were at the Institute of Oncology in Ljubljana, and the editorial board mostly comprised Slovene on­cologists: S.Plesnicar, T.Benulic, J.Skrk, P.Soklic, and B.Tavcar. In the first few years (1964-1968), the journal went through some difficult periods regarding financial support, as well as editorial and organizational mat­tersvi, however, after vol.4 (1969), the journal was well established and appeared regularly in one volume per annum, comprising 4 reg­ular issues and irregularly published supple­ments that in most cases brought proceedings from national and international conferences. This continued until vo1.25 (1991) when, on account of the break-up of Yugoslav federa­tion, the communications between members of the Association became very difficult or died out completly and the journal stopped being published. From among the member­ship a new editorial team grew up, which was more flexible, had new ideas and above all had experience with international journals as all editors regularly published elsewhere. In 1992 and with vol.26, the journal changed the name into Radiology and Oncology, the editors were the same as with the last volumes of Radiologia lugoslavica, however the design and looks of the journal were changed, though the numbering of volumes has been kept and ba­sic subject orientation was continued. The journal today does not resemble in any way its predecessor, except maybe in format which is still a book-size (the upper limit of what in the publishing industry used to be called octavo), a feature typical for many jour­nals with a Yugoslav pedigreevii. The design and looks are much more appealing, more graphics and photos accompany articles, the paper and print are of better quality (with one or two exceptions, perhaps). The journal is by now an official journal of the Association of Radiology and Oncology, affiliated with Slovenian Medical Association, Croatian Medical Association, Societas Radiologorum Hungarorum and Italian Society of Medical Radiology. The editorial policy is mostly run by T.Benulic, G.Sersa (who soon becomes the editor-in-chief), and V .Kovac. Later this group is joined by U.Smrdel. The offices of the journal remain in the Institute of Oncology in Ljubljana, Slovenia. The journal continues as a quarterly, with irregularly pub­lished supplements which in many cases are entirely in Slovene language, while the arti­cles in regular issues are now all in English, a clear indication that the journal intends to broaden or extend its authorship and reader­ship populations. The articles are grouped and published in rough subject categoriesviii and each issue also brings reports from meet­ings, conferences and/or symposia (these are not included into the analysis below), an­nouncements of future conferences, book or new journal reviews (also not included into analysis). The index of each volume (by au­thors and by subjects) is published in the last issue of the running volume and also includes supplementsix, while the names of participat­ing reviewers are given at the beginning of each index listing. In 1992, an entirely separate publication was published, entitled Advances in Radiology and Oncologtj (editors were G. Sersa, T. Benulic, V. Kovac), and though it re­sembled the then upcoming and still undis­closed new journal Radiology and Oncolog~; in almost all its outer features (paper and print quality, colour and graphic design), it did not have any direct link with the later journal it­self, nor was it its supplement. The publica­tion was issued to commemorate the 251h vol­ume of Radiologia Iugoslavica and brought to­gether, under one title, the papers from some of the best known world experts in oncologi­cal radiology, a kind of state-of-the-art at the time. This publication may, however, be to some extent considered as a link between the old journal with the old editorial policy, and the new journal with its new outlook (of which the publication is a precursor) and new and fresh editorial ideas. Methodology and types of analyses Bibliometric analyses of various features of publication were made, using three time probes, i.e. three different years, from the span of 10 years of publishing, i.e. 1992 being the first year under the new title, 1996, and 2001. Only professional articles were consid­ered, while meeting reports, book reviews and letters to the editor were excluded as al­ready mentioned above. Bibliometric meth­ods were applied with the aim to show the professional growth and the quality of arti­cles through time span of ten years and in some cases comparisons were made with Neoplasma, an international journal, similar in the subject orientation, that has already been included in !SI's SCI database and is also cov­ered by MEDLINE, the most important bio­medical bibliographic database. These are the two goals that Radiology and Oncology has yet to achieve, though international comparison might point to the set of very different rea­sons which may have little to do with contex­tual or subject quality levels but nevertheless seem to have an important impact on deci­sions as to who is Jet in (i.e. MEDLINE) and who remains waiting outside. Bibliometric analyses of articles Two important indicators were measured for both journals: the number of articles per vol­ume in a given period and their diversity ex­pressed by the type of article and article ori­entation. Since Neoplasma does not have the practice of assigning articles to specific sub­ject groupings within the journal while Radiology and Oncology does, articles from both journals were therefore grouped under their different types and orientations, based on the classes from the MeSH Thesaurusx. This analysis aimed to show the scientific ori­entation of the articles on one side, and of the journal as a whole on the other. Bibliometric analyses of authors The methods used in this type of analysis were applied to record the changes of and the variety in, the authors' population as one of the basic indicators of importance that the au­thors give to their publishing in a particular journal and in a particular field; of variety of their nationality or affiliation, and the level of cooperative writing as means of securing publishing of results of research as has re­cently been claimed in the literature from the field.9•10 Bibliometric analyses of citations Methodologies used here are among those that general public usually think of when bib­liometrics is mentioned and indeed, various types of citation analysis are sometimes taken almost as a synonym for bibliometrics. The aim here is to survey some classical attributes of bibliometric measurements that point to the professional level of articles in one jour­nal and compare them with general trends in similar journals elsewhere (in this case, with the bio-medical journals). This can be de­duced by analysing the age of citations, types of literature sources used in citations, the lan­guages in which citations were published, the extent of self citations being practised, etc. Bibliometric theory suggests that this last is also an indicator of the ambitions present in the editorial policy of the journal to boost the importance of the product and consequently be included into large and important data bas­es and information sources that are valued and frequently consulted by the peers in the profession, which in turn rewards the journal by new citations and consequently higher rat­ings in the field.11 Results and discussion Articles By analysing data in Table 1 we can see that Radiology & Oncology was fairly consistent in the number of articles published per year, i.e. the number is almost always between 40 and 50 (r = 48,4 article/year). There are two ex­ceptional years, 1994 with 62, and 1997 with 83 articles. Both were results of conferences, some articles of which found their way into the journal's regular issuesxi. Though Neoplasma is a bi-monthly and one would normally expect that it publishes more articles on account of its frequency, the clos­er look shows that the two additional issues per year can not be the main reason for such a difference but that evidently, every issue of Neoplasma brings more articles than Radiology Table 1. No. of articles per year and Oncology, an expectation that is con­firmed by comparing the total number of arti­cles published in the period 1992-2001 in Radiology and Oncology and the total number of articles published by Neoplasma only in the three compared years (1992; 1996; 2001): in the three years Neoplasma published almost half as much articles as Radiology and Oncology in ten years. Also by comparing the figures for the years chosen for analysis in both journals we can see that, for instance, in 1992 Radiology and Oncology published just above 10 articles/issue on average, while the same calculation for Neoplasma gives us good 11 articles. The difference of 1 article/issue remains steady also in 1996 (11 for Radiology and Oncology, 12 for Neoplasma), while it in­creases considerably in 2001 (less than 10 per issue for Radiology and Oncology, and over 14 per issue for Neoplasma). Radio/ Oncol Neoplasma Year Articles I year Articles I year 1992 41 68 1993 43 1994 62 1995 46 1996 44 72 1997 83 1998 44 1999 40 2000 42 2001 39 86 Total Radio/ Oncol 484 Total (92+96+01) 124 226 Is there a lesson to be learned? Very prob­ably -the figures for Radiology and Oncology for the years after the record high 1997 show a consistent decline in the number of pub­lished articles per annum which may point to several reasons: weak response by the au­thors to publish in the journal; the changes in the editorial team, or the change of the edito­rial policy which might not have been whole­heartedly accepted by potential authors. On the other hand it may also point to the old problem -the authors' population have ma­tured and the same individual researchers who got a chance to publish their research re­sults from their early enterprises in this jour­nal (which, by the way, has always been one of the important missions of the journal), have joined different teams and are now bound to publish together with their new team colleagues in other international jour­nals that expectedly have more impact on the profession, since publishing in high impact publications is favoured by the funding agen­cies and evaluators.9,12 One way of increasing journal's impact might be to increase the number of experi-mental articles. As Table 2 shows, Neoplasma has a significantly higher percentage of such articles than Radiology and Oncology. It seems that in the field of oncology, experimental ar­ticles tend to receive more citations than oth­er articles, which consequently boosts the im­pact factor of such journals. Therefore higher crop of original and experimental articles that compete for publishing space, higher quality of selected articles for publication, and con­sequently a stronger appeal for authors from other parts of the world to publish in the jour­nal. As soon as the journal gets accepted into important international data bases, it is signif­icantly more attractive to the authors. It would be therefore advisable for Radiology and Oncology to increase the number of arti­cles per issue and/or volume and at the same time to publish more experimental articles. Authors There is a general trend in STMxii category of journals towards expanded authorship, i.e. there are very few articles published in those journals nowadays that would be signed only by one or two authors. On one hand this rep­resents a healthy feature of the medicine as a discipline in itself, i.e. the convergence of sci­entific disciplines and interconnected team­work of many researchers from many fields towards the same goal; on the other, it may hide a much more mundane reason, i.e. being the result of planned response to the condi­tions put in place by the funding agencies: more researchers share authorship -more credibility the research work has, higher po­sition on the future priority lists for fund­ing.9,11·12 This may sometimes lead to exag­geration and consequently, hyperauthors­ hip.10,13 Still, recent studies show10·14 that the aver­age number of authors per article for the journals screened by SCI increased from 1,83 in 1995 to 3,9 in 1999 per article10·12, while an analysis made for the British Medical journal established that the articles published in that journal in the period 1975-1995 showed in­crease in the number of authors from 3,2 in 1975 to 4,7 in 1995.12,l3 As can be seen from Table 3, Radiology and Oncology very much experienced similar trends, with only 2,51 authors per article in 1992, increasing to 3,66 in 1996 and reaching almost 4,0 (3,92) in 2001. That such develop­ment is the result of the natural development of medicine, as was already explained above, is further witnessed by the results from Table 4: there is no trace of exaggerated authorship as most articles are shared by one, two or at most, seven authors. Table 2. Articles by type and orientation (based on MeSH classes) Type of article -Journal article -Review -Editorial -Letter to the editor -Case/Clinical trial -Other• By orientation -Diagnostic -Therapeutic -Experimental -Other•• RADIOL ONCOL NEOPLASMA 1992 1996 2001 1992 1996 2001 85,4% 77,3% 76,9% 98,5% 90,3% 82,6% 4,9% 9,1% 12,8% 5,5% 9,3% 9,7% 13,6% 10,3% 1,5% 4,2% 8,1% 1992 1996 2001 1992 1996 2001 53,7% 27,3% 38,5% 27,9% 30,6% 32,6% 19,5% 47,7% 41,0% 22,1% 25,0% 29,0% 9,7% 15,9% 15,4% 41,2% 31,9% 25,6% 17,1% 9,1% 5,1% 8,8% 12,5% 12,8% •reports, interviews, obituaries, patents, abstracts, etc. **etiological, epidemiological, prevention, incidence analyses, etc. Table 3. Number of authors per year and their average number per article Radio/ Onco/ Neoplasma Year au art 1992 103 41 1993 143 43 1994 226 62 1995 198 46 1996 161 44 1997 342 83 1998 173 44 1999 167 40 2000 133 42 2001 153 39 Total R & 0 1799 484 Total (92+96+01) 417 124 Hyperauthorship tends to include all kinds of junior staff or technicians which did their work as part of the daily routine and there­fore their share can not be equally assigned as 16 21 authorship15-, , or past research team mem­bers, which used to share their results with the others while still active. This is bogus and throws bad light on published research re­sults of serious teamwork endeavoursxiii_ It is very positive to see that the editors of Radiology and Oncology have not yielded to such trends. Addditional important feature to consider is the extent of internationalization of authors that publish in a scientific journal. With a few Table 4. Articles by the number of participating au­ thors Radio/ Onco/ Neoplasma 1992 1996 2001 1992 1996 2001 1 author 16 5 2 3 6 2 authors 10 14 8 15 10 8 3 2 5 8 16 10 17 4 7 5 9 16 17 9 5 4 8 3 8 15 12 6 1 2 7 3 8 13 7 1 1 0 7 4 8 8 0 3 0 2 2 3 9 0 0 2 3 0 4 10 or> 10 0 1 0 0 3 0 au art 2,51 293 68 4,31 3,32 3,65 4,30 3,66 325 72 4,51 4,12 3,93 4,18 3,17 3,92 426 86 4,95 3,72 3,36 1044 226 4,62 exceptions, most journals welcome the chance to have a colourful mixture of authors from all over the world. Still, in this process some institutes and as well as some re­searchers tend to develop stronger ties with each other, and consequently are more repre­sented in each other's publications. A fair spread of authors from various institutes and countries of affiliation shows a good editorial policy and is also an indicator that regardless of the all-important inclusion into as many in­ternational databases as possible, journals which are presently not contained in all of them are still fulfilling their mission and are selected by many authors from various cor­ners of the scientific arena to publish therein. This can certainly be said for Radiology and Oncologt;, as the results in Table 5 not only show a very even spread of international au­thors, but Table 6 also confirms, that mem­bers who are on the editorial team or mem­bers of the editorial board do not enjoy any advantages when being peer-reviewed for publishing or that the editors tend to form close circles of authors who have card blanche to publish in the journal, whenever and what­ever. Only one member of the editorial team was among the top 6 authors with highest number of articles published in 1996, while in 2001, there was none as there were only 2 au- Radio/ Onco/2003; 37(3): 141-53. Table 5. Authors by country of their affiliation (at the time of writing) Radial Onco/ Neoplasma 1992 1996 2001 1992 1996 2001 Australia 1 1 Austria 10 9 5 3 Belarus 1 Belgium 2 Bosnia and 11 Herzegovina Brazil 6 4 Bulgaria 9 1 9 Canada 9 2 1 China 5 Croatia 59 35 35 7 9 12 Czech Republic 6 *97 48 114 Denmark 2 Finland 2 France 2 6 Germany 5 34 17 6 4 1 Greece 7 4 Hungary 2 3 1 6 22 India 55 10 Israel 2 Italy 7 4 2 Japan 6 6 Kuwait 5 1 Macedonia FYRO 4 5 Poland 8 27 53 63 Romania 8 Russia 2 7 12 Slovak Republic 93 124 Slovenia 21 61 43 2 15 Spain 11 3 Sweden 1 3 Taiwan 12 20 Turkey 4 14 Ukraine 9 United Kingdom 4 5 1 United States 15 11 5 1 Yugoslavia** 1 20 19 21 *The number given contains both, data for Czech Republic and for Slovak Republic **The name used for FRY or what is now called Serbia thors that succeeded to publish more than 2 articles in the journal in that year. This also proves that the editorial team does the effort to allow equal representation to all classes of articles, though this may sometimes act against their ambition to be included in high­profiled international medical database, like MEDLINE. Similar features can be seen in Neoplasma, though the relative majority of au­thors from the Slovak or Czech institutes or/ and provinence does hint to, either a slight favouring of domestic authors as compared to Radiology and Oncology, or simply to the fact that authors from abroad were less keen to send their articles to be published in the jour­nal in the period reviewed. Citations There is a very strong opinion, supported by many empirical research, that citations are the very indicators and the key to evaluating the level of scientific significance of one jour­nal. Rennie16 quotes de Solla Price18 who pro­posed that the articles within each scientific discipline could be broadly classified as »Sci­entific« and »non-scientific<<, claiming that »ScientifiC<< articles are those that have 10 to 20 citations, and >>non-scientific < those with­out citations, while articles with more than 22 citations were to be treated more as further reading assistanceY As much as de Solla Price's theories were supported by empirical research18, there are actually many motives to be considered when investigating, why au­thors cite certain works and how many they choose to include into citations.9 A look at the results from the Table 7 shows that all articles published in Radiology and Oncologi; fulfil! the conditions proposed by the above theory. Actually, absolute num­bers showed that some articles did go into ex­cesive citing, but that majority still remain within the relative limits, which may be con­ and Montenegro strued that the journal as such falls into the category of »scientific<< in the field. By com­parison, Neoplasma seems to be overdoing Table 6. Top participating authors in articles (frequency >2) 1992 (frq) Fuckar, Zeljko (3) IvaniS, Nikola (3) Lovasic, !van (3) Lovrincevic, Antun (3) Peric, Relja (3) Rubinic, Milivoj (3) Radiology & Oncology 1996 (frq) 2001 (frq) Bohuslavizki, Karl H. (5) Bohuslavizki, Karl H. (3) Brenner, Winfried (5) MiklavCic, Damijan (3) Clausen, Malte (5) Henze, Eberhard (5) Kovac, ViJi• (3) Tinnemeyer, Stephan (3) Wolf, Heike (3) Zakotnik, Branko (3) • denotes that the author was on editorial board at the time of writing) Table 7. Number of citations per year and their average number (av) per article Radio/ Oncol Neoplasma Year cit art 1992 545 41 1993 772 43 1994 979 62 1995 898 46 1996 1141 44 1997 1098 83 1998 1083 44 1999 719 40 2000 827 42 2001 671 39 To tal R & 0 8733 484 Total (92+96+01) 2357 124 after 1996, when it was still within the values proposed by de Solla Price, while it overflows the limits towards 2001 when it reaches more than 31 citations per article on average. Besides the number, the age of citations represents another important indicator. It is well known that the aging of the information contained in the articles is directly related to the scientific field from which citations are taken.s,ll,l9 Researchers from STM group of journals, with the exception of taxonomy20, usually do not profusely cite older sources as it is believed that this would dicrease their us­ability and diminish the importance of the ar­ticle. Aging is therefore an important factor to consider and scientific disciplines that put 5 years or less as a half-life periodxiv are fast de­veloping and medicine is one of them. av cit art av 13,3 1441 68 21,2 18,0 15,8 19,5 25,9 1854 72 25,8 13,2 24,6 18,0 19,7 17,2 2702 86 31,4 18,0 19,0 5997 226 26,5 From the Table 8 it can be seen that the share of fresh research is being more and more prominent among the published articles in Radiology and Oncology. If in 1992, citations of up to 5 years of age were almost in equal proportion with those of 5-10 years of age, the proportion of fresh citations grows by rough­ly 6% every 5 years (36,2% in 1996 and 42,3% in 2001). Similar trend can be traced for Neoplasma, though the increase is not so dra­matic and shows also a negative trend, as ci­tations in the time frame 5-10 years increase towards 2001, which is quite opposite with Radiologtj and Oncologt;. The trend therefore is positive for Radiology and Oncology, also by analysing the languages of citations (Table 11), with English overpowering prevalence, especially in the last two test periods, when Radio/ Oncol 2003; 37(3): 141-53. Table 8. Citations by age span Radio/ Oncol Neoplasma Age span 1992 1996 2001 1992 1996 2001 0 -5 26,6% 36,2% 42,3% 32,7% 41,2% 44,1% 5 -10 24,8% 30,6% 28,3% 33,9% 29,3% 33,5% 10 -15 21,5% 17,4% 13,3% 16,3% 12,2% 12,1% 15-20 10,8% 8,0% 7,6% 7,9% 7,8% 5,2% > 20 16,3% 7,8% 8,5% 9,2% 9,5% 5,1% Table 9. Citations by types of bibliographic sources Radio/ Onco/ Neop/asma Type 1992 1996 2001 1992 1996 2001 Article 75,8% 89,4% 86,7% 90,6% 92,2% 95,5% Monograph 16,7% 8,7% 11,1% 8,5% 6,3% 4,0% Congress 3,8% 1,5% 1,6% 0,7% 1,3% 0,3% Gray lit. • 3,5% 0,2% 0,2% 0,1% 0,1% Other .. 0,2% 0,2% 0,4% 0,1% 0,2% 0,1% *Gray litetarure: project reports, internal doctrines, guidelines, expert opinions, reports of consultation meetings, memoirs, sketches of verbatim records, etc. • • Other: mostly electronic sources (excl. articles in e-journals or chapters in e-books), multimedia, graphic mate­rial, didactical aids, etc. citations in authors' local languages dramati­Clinical Oncology) are among those that are cally dicrease. most frequently chosen as sources for cita­ Concerning types of bibliographic sources tions by the authors of both journals, while all in citations (Table 9), it is quite clear that jour­others do not match. This may point to either nal articles represent the principal source of different research patterns and specializa­information to the authors of medical articles. tions of the authors that publish in the two That corresponds with the general trend of journals, or to a much lower level of similari­increased number of journal titles being pub­ty of content orientation between the two lished in STM group of disciplines and the journals compared. There may be one more rapid increase in the number of articles being reason for such a result: we already men­published annually in scientific journals. tioned that Neoplasma has a higher number of Journals are therefore the source of choice, experimental articles, which have a tendency while monographs, congress proceedings and to include higher number of citations, espe­gray literature represent only a fraction in cially those with very high impact factors. overall number of citations. Still, it seems Finally, there remains a question of self-ci­that the authors publishing in Neoplasma put tations. These may appear in two forms: ei­even more importance to journal articles as ther authors cite their own earlier work in principal information source as their share of their articles and such citations are not con­over 90% in all three control years is signifi­sidered as >>pure«, or the journal is being cit­cantly higher than in the same periods for ed in the articles it contains. It is that latter Radiology and Oncology. We therefore thought form that we decided to look into in our it interesting to see, how high is the level of analysis. A normal ambition of every editori­matching between most cited journals in both al team is to make their scientific journal im­publications: as can be seen from the Table portant among, and achieve recognition in, 10, only two journals (Cancer and journal of its own professional circles and be attractive Table 10. Scientific journals most frequently represented in citations in 2001 (with Impact Factors) Radio/ Oncol (2001) x-cit. IF lnt J Radiat Oncol Bioi Phys 33 3.327 Radiology 30 4.759 AJR Am J Roentgenol 22 1.998 J Clin Oncol 16 8.530 Med Phys 15 2.313 Cancer 14 3.909 Radiother Oncol 9 2.815 Eur J Cancer 8 3.460 Ann Surg 7 6.674 J Comput Assist Tomogr 7 1.302 Table 11. Citations by language Radio/ Oncol Neoplasma Year 1992 1996 2001 1992 1996 2001 Bulgarian 0 0 0 2 0 0 Croatian 56 17 0 0 0 0 Czech 1 0 3 7 11 0 English 399 1072 647 1409 1816 2693 French 20 5 0 0 5 0 German 35 33 13 10 9 9 Italian 1 1 0 0 0 0 Polish 0 0 0 0 3 0 Rumanian 0 0 0 1 0 0 Russian 0 0 0 3 0 0 Slovak 0 0 0 2 5 0 Slovene 33 13 8 0 0 0 Spanish 0 0 0 5 6 0 Swedish 0 0 0 1 0 0 Table 12. Self-citations Radio/ Oncol Neoplasma 1992 1996 2001 1992 1996 2001 NO. OF SELF-CIT. 10 9 7 52 57 40 IN% OFTOTAL 1,8% 0,8% 1,0% 3,6% 3,1% 1,5% for its peers to publish there. One of the man­ifestations of such importance is to be accept­ed into carefully groomed lists of journals that are processed by important international databases (MEDLINE, EMBASE, ISI's range of products, etc.). It will not come as a sur­prise then, that many editorial teams and re­viewers expect from the authors who propose articles for publishing to also cite the appro-priate articles from the journal they wish to publish in. Such an attitude and policy of the editors should not be considered as being against any moral standards or publishing culture, unless it develops into a condition for the authors, or a >>shortcut<<, to get accepted for publishing. It should be clear that a cer­tain level of self-citation is always present in every scientific journaJ.9 Neoplasma (2001) x-cit. IF Proc Natl Acad Sci USA 247 10,896 Cancer Res 113 8,302 Blood 81 9,273 J Bioi Chem 71 7,258 Cancer 61 3,909 Br J Cancer 55 3,942 Neoplasma 47 0,637 Mutat Res 44 4,556 Nature 43 27,955 J Clin Oncol 40 8,530 It is therefore customary in bibliometric analysis of journals to look into this matter as well. Data in Table 12 clearly shows that nei­ther of the two journals have any dramatic developments in that field. Actually, it would be advisable to stimulate the authors a bit more to cite their own published articles in Radiology and Oncology in their future works of related subject, regardless where they are accepted for publication. Though such an ad­vice may seem irrelevant at a first glance, it is actually not so, since an independent analy­sis12 of the citations in articles that are pub­lished in the journals with a high impact fac­tor by some of the authors represented in Radiology and Oncology showed, that these au­thors did not exhibit any bias in citation se­lection in favour of high impact journals and that the citations in the articles in such jour­nals did not significantly differ from the cita­tions in the articles the same authors got pub­lished in Radiology and Oncology. Self-ciations, as a dubious policy of the editors, are there­fore not an issue with Radiology and Oncology. Radio/ Onco/ 2003; 37(3): 141-53. Conclusions Results show that Radiology and Oncology is progressing in the right direction, but that ex­tra efforts should be made by the editors and the editorial board to attract more articles per issue and to increase the share of experimen­tal articles to raise its impact. Also, to im­prove the visibility of the journal, editors, re­viewers and also authors that publish in Radiology and Oncology could consider citing the articles published in this journal, in the articles published elsewhere, when appropri­ate. These are two features that stand out from the comparative data for Radiology and Oncology and Neoplasma. We also noted that there is not such a close similarity between the two journals, though both are from the same filed of medicine, both are originating from Central European publishing space, and both have a long tradition (if Radiologia Iugoslavica is taken into account as a precur­sor}. So called >>Scientifically marginal coun­tries«6 share the same fate of hardship with non-English scientific journals when trying to enter the all-important lists of journals being screened for inclusion into large databases. However, as recent developments show (see note v), the extra efforts invested in tying in­visible college network and editorial ambi­tions can be helpful in achieving such goals. References 1. Adam D. The counting house. Nah1re 2002; 415: 726-9. 2. Moed H.F. The impact-factor debate: the !SI's us­es and limits. Nahm 2002; 415: 730-1. 3. Check E. Sitting in judgement. Nature 2002; 419: 332-3. 4. Adam D. Publish, and be damned. Nature 2002; 419: 772-6. 5. Juznic P. Metodoloska osnova analize citirmrosli in njena uporaba v 5/oveniji: doktorska diserlacija. Ljubljana: [P.Juinic]; 1999. Radio/ Oncol 2003; 37(3): 141-53. 6. Ren S, Zu G, Wang H. Statistics hide impact of non-English journals. Nature; 415: 732. 7. Huber JC. A new method for analyzing scientific productivity. ]A SIST 2001; 52: 1089-99. 8. Adamic 5, Hristovski D, Rozic-Hristovski A, Dimec J. Citiranost biomedicinskih revij, ki izhaja­jo v Sloveniji. Zd rav vestn 1999; 68: 255-8. 9. Juznic P. Analiza citiranja in motivi za citiranje. Knjiinica 2000; 40: 33-50. 10. Cronin B. Hyperauthorship: a postmodern perver­sion or evidence of a structural shift in scholarly communication practices? JASIST 2001; 52: 558­69. 11. Musek M. Radiology and Oncology: nekaj bib­liometricnih kazalcev. Ljubljana: Filozofska fakulte­ta; 2000. 12. Oven M. Neznosna lahkotnost citiranja. Ljubljana: [M.Oven]; 2002 13. Drenth JPH. Multiple authorship : the contribu­tion of senior authors. ]AMA 1998; 280: 219-224 14. Flanagin A, Carey LA, Fontanarosa PB, Phillips SG, Pace BP, Lundberg GD, et al. Prevalence of ar­ticles with honorary authors and ghost authors in peer-reviewed medical journals. ]AMA 1998; 280: 222-4. 15. Slone RM. Coauthor's contributions to major pa­pers published in the AJR. American Journal of Roentgenology 1996; 167: 571-9. 16. Rennie D, Yank V, Emanuel L. When authorship fails: a proposal to make contributors accountable. ]AMA 1997; 278: 579-85. 17. Popovic M, Ambrozic M, Juinic P. Nekaj znacil­nosti razvoja slovenskega knjiznicarstva v novejsem obdobju. Knjiinica 1984; 28: 167-98. 18. Price DJ de Solla. Little science, big science. New York: Columbia University Press; 1963. 19. Egghe L. A noninformetric analysis of the rela­tionship between citation age and journal produc­tivity. ]ASIST 2001; 52: 371-7. 20. Krell F.-T. Why impact factors don't work for tax­onomy. Nature 2002; 415: 957. 21. Lawrence P A. Rank injustice : the misallocation of credit is endemic in science. Nah1re 2002; 415: 835­6. Notes Formerly, Institute of Scientific In formation, Philadelphia, now, with the new owners, just plain !SI ii Science Citation Index, comprising separate deriv­atives, SCI -Science Citation Index, SSCl -Social Science Citation Index, and AHCI -Arts and Humanities Citation Index iii Journal Citation Report iv Benjamin Disraeli (1804-1881), skilful diplomat and British Prime Minister during Queen Victoria's rulership v With 2002, Acta Chimicn Slovenica was included in­to the list of journals being screened by !SI for SCI and Web of Science vi First two volumes were published during 1964­1965, then nothing appeared in 1966; the journal got revived in 1967, then again nothing happened in 1968, until vol.4, when it became settled as a regular quarterly vu Due to Yugoslav OUS) standards for scientific journals that favoured book-size format viii Like Computerised Tomography, Diagnostic Radiology, Medical Oncology, Nuclear Medicine, History of ... etc. ix In the annual index, entries for articles from sup­plements arc given in bold x MeSH -Medical Subject Headings, the most au­thoritative and best known co-ordinated and con­trolled list of subject headings for bio-medical lit­erature; developed and maintained by the National Library of Medicine, Bethesda, USA xi Conference proceedings were otherwise pub­lished in yearly supplements (usually one or two) following the general policy and practice of med­ical journals. xii Science, Technology, and Medicine xiii That is why some important medical journals, i.e. New England Joumal of Medicin e, recently started the practice of requesting the authors to actually assign the portion of authorship share for each participating author signed under the article xiv Half-life denotes the time after which half or more of published material will not be cited again and is considered to be obsolete. Unexpected diagnosis for preauricular swelling ­two case reports Goran Roic1, Vesna Posaric1, Ante Marušic1, Igor Boric1, Tomislav Vlahovic2, Kristina Vrlicek3 1 Department of Paediatric Radiology, Children’s Hospital Zagreb, School of Medicine University of Zagreb; 2 Department of Paediatric Surgery, Children’s Hospital Zagreb, School of Medicine University of Zagreb; 3Pediatric Clinic, Zagreb Clinic Center, School of Medicine University of Zagreb, Zagreb, Croatia Background. Preauricular swelling in children may be associated with a wide range of pathology. The his­tory, clinical presentation and imaging features of such swellings may be non-specific. Sometimes it can be caused by underlying bone lesion. Case reports. We report about two children who were admitted to the hospital with swelling in the preau­ricular region and an unexpected final diagnosis. We found aneurismal bone cyst and central giant cell gran-uloma, respectively. Conclusions. Awareness of such lesions is important to avoid diagnostic errors and a potential misman­agement. These lesions are often difficult to differentiate on the basis of their radiographic features alone. A high-resolution US enables an accurate analysis of soft tissue and helps in the differential diagnosis. It also enables an accurate location of the lesion, which helps to avoid a wrong interpretation based on the clinical finding only. The CT-scan performed afterwards provides necessary information for the assessment of lo­cation, structure and size of the lesion. Key words: bone cysts, aneurismal - ultrasonography; granuloma, giant cell; tomography, X ray computed Received 7 July 2003 Accepted 10 August 2003 Correspondence to: Goran Roic, M.D., Department of Paediatric Radiology, Children’s Hospital Zagreb, School of Medicine University of Zagreb, Klaiceva 16, 10 000 Zagreb, Croatia; Phone: +385 1 4600 231; Fax: +385 1 4826053 / +385 1 4600169; e-mail: goran.roic@ zg.hinet.hr Introduction The aneurismal bone cyst (ABC) and central giant cell granuloma (CGCG) of the jaws are usually seen involving the posterior mandible.1-3 Due to their preauricular loca­tion they can be confused with other lesions presented as preauricular swelling such as lymphadenitis or parotitis. The imaging fea­tures, both the ultrasound (US) and comput­ed tomography (CT), of these mandibular le­sions are helpful in establishing a differential diagnosis, although microscopic tissue evalu­ation is generally necessary to accurately identify the lesion. Case 1 An 11-year old male child was admitted with signs of the swollen right preauricular region with light pain and leukocytosis. It was treat­ed as parotitis or lymphadenitis and antibi­otics were prescribed. After the therapy, the swollen area was still obvious; a fine needle aspiration biopsy (FNAB) was performed and it showed a mass of old and new erythrocytes, phagocytes, cy­tophages and some multinuclear histiocytes ­the differential diagnosis was cavernous hae­mangioma or hemorrhagic cyst of the parotid gland. FNAB was repeated two more times and each time the same findings were found. Two months later, when the swollen area showed no signs of the retreat, US and CT were preformed. US showed a complex mass containing anechoic areas separated by fibrous tissue (Figure 1). Precontrast CT (GE Sytec 3000) showed the expansive cystic mass of the processus condylaris of the mandible with multiple flu­id-fluid levels, suggesting the diagnosis of ABC. Contrast CT scans showed the enhance­ment of the septa, which helped to delineate them from the fluid they contain (Figure 2). The segmental resection of the jaw was fol­lowed by the orthodontic treatment. Case 2 A 9-year old boy complained of the pain and swelling of the right preauricular region, one week after a slap to the face. US examination showed the expansive soft-tissue mass of the processus condylaris of the mandible (Figure 3). Laboratory tests showed normal calcium, phosphorus, and alkaline phosphatase levels, a normal parathyroid hormone level (PTH), and no circulating PTH-related peptide (PTH­rP). Contrast-enhanced CT scans confirmed the presence of expanding soft-tissue mass replac­ing processus condylaris of the mandible with cor­tical expansion and thinning (Figure 4). A biopsy of the lesion confirmed the typi­cal histological appearance of a CGCG of the processus condylaris of the mandible. Although the parents of the child were familiar with the destructive nature of the tumour, they re­fused the operation, so the calcitonin treat­ment was commenced (100 IU or 0.5 mg of subcutaneous human calcitonin per day). Thirteen months after ceasing treatment there was no evidence of further growth. The lesion was filled with a soft, gritty bone. Discussion ABC is an erosive lesion of the bone, most commonly located in metaphysic of long bones and vertebral column in patients under the age of 30. Those that occur in jaws are rare, mostly involving the posterior part of mandible.2,3 The cause of ABC is not fully set­tled. The aetiology is thought to be secondary to the increased venous pressure with haem­orrhage that causes osteolysis. More often they are a reactive process, secondary to trau­ma or vascular lesion, caused by tumour or vascular malformation. Also ABC may repre­sent a primary bone abnormality.2 Patients often have a history of pain and swelling, usually of less than six months du­ration.2 CT scanning will define the lesion and is especially valuable for those lesions lo­cated in areas in which bony anatomy is com­plex, and which are not adequately evaluated by plain films.5-7 On the pathologic examination the underly­ing bone is replaced by cavities of various size filled with blood or/and proteinaceous materi­al. ABC can heal spontaneously after curettage and bone grafting, surgical removal or after se­lective arterial embolization.8-10 The removal of extensive mandibular and maxillary tu­mours is associated with the need of surgical tissue repair and prosthetic rehabilitation, and in young patients the surgical treatment must be followed by the orthodontic one.11,12 CGCG is a benign destructive bone lesion of the unknown ethiology. It represents 7% of benign lesions of joins, mostly involves parts of mandible and maxilla. It is of variable size and rate of progression, therefore some au­thors think that there is a spectrum of lesions that vary from the relatively benign CGCG of the jaws to the giant cell tumour of long bones, which may represent a low-grade sar­coma.13 The histological similarity of the CGCG to the »brown tumour« of hyperparathyroidism suggests the presence of an unidentified, cir­culating, PTH-like hormone. Microscopically, the lesion shows a collagenous stroma con­taining spindle cells and numerous multinu-cleated giant cells. An identical histological appearance can occur in the »brown tumour« of hyperparathyroidism, ABC and in cheru­bism. Due to the marked polymorphism a his­tological diagnosis of odontogenic tumours is often difficult, therefore, the correlation be­tween clinician, radiologist and pathologist is especially important. A number of the lesions did stabilize or decrease in size and, if they were explored, a fibrous tissue scar was found in many cases.14 However, it is gener­ally thought that most CGCG are not repara­tive and are in fact destructive and will progress if not treated. The treatment of the CGCG lesion is generally surgical and con­sists of curettage or resection, which may be associated with the loss of teeth and, by younger patients, the loss of dental germ.14 A resection is done by recurrent or more ag­gressive variants. Based on histological simi­larity between the CGCG and the »brown tu­mour« of hyperparathyroidism, Harris sug­gested that the CGCG might respond to cal-citonin, even though there was no biochemi­cal evidence of parathyroid disease.15,16 Although most commonly caused by parotitis or lymphadenitis, the swelling in the preauricular region in children may be a re­sult of mandibular lesion (posterior area of the mandible) as it was a case in our patients. It is our opinion that, to establish an early di­agnosis and begin with the treatment on time, an US examination of the preauricular swelling in all patients seems not only rea­sonable, but also necessary. A high-resolution US enables an accurate analysis of soft tissue and helps in the differential diagnosis. It also enables an accurate location of the lesion, which helps to avoid a wrong interpretation based on the clinical finding only. The CT-scan performed afterwards provides neces­sary information for the assessment of loca­tion, structure and size of the lesion. These le­sions are often difficult to differentiate on the basis of their radiographic features alone. References 1. Kaffe I, Ardekian L, Taicher S, Littner MM, Buchner A. Radiologic features of central giant cell granuloma of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996; 81(6): 720-6. 2. Laor T, Jaramillo D, Oestrich AE. Musculoskeletal system in practical paediatric imaging. Philadelphia: Lippincott-Raven; 1998. 3. Stavropoulos F, Katz J. Central giant cell granulo-mas: a systemic review of the radiografic charac­teristics with the addition of 20 new cases. Dentomaxillofac Radiol 2002; 31: 213-7. 4. Onerci M, Ergin NT. Aneurysmal bone cyst of the mandible. Laryngorhinootologie 1996; 75(5): 306-8. 5. Kransdorf MJ, Sweet DE. Aneurysmal bone cyst: concept, controversy, clinical presentation and im­aging. Am J Roentgenol 1995; 164(3): 573-80. 6. Scholl RJ, Kellett HM, Neumann DP, Lurie AG. Cysts and cystic lesions of the mandible: clinical and radiologic-histopathologic review. Radiograp­hics 1999; 19(5): 1107-24. 7. Matsura S, Tahara T, Ro T, Masumi T, Kasuya H, Yokota T. Aneurysmal bone cyst of the coronoid process of the mandible. Dentomaxillofac Radiol 1999; 28: 167-72. 8. Freiberg AA, Loder RT, Heidelberger KP, Hensinger RN. Aneurysmal bone cyst in young children. J Pediatr Orthop 1994; 14:86-91. 9. De Cristofaro R, Biagini R, Boriani S, Ricci S, Ruggieri P, Rossi G, et al. Selective arterial em- bolization in the treatment of aneurysmal bone cyst and angioma of the bone. Skeletal Radiol 1992; 21(8): 523-7. 10. Sheikh BY. Cranial aneurysmal bone cyst »with special emphasis on endovascular management«. Acta Neurochir 1999; 141(6): 601-11. 11. Stypulkowska J. Odontogenic tumors and neo­plastic-like changes of the jaw bone. Clinical study and evaluation of treatment results. Folia Med Cracov 1998; 39(1-2): 35-141. 12. Martin JP, Unkel JH, Fordjour I. Preservation of the dentition following removal of a central cell granuloma: a case presentation. J Clin Pediatr Dent 1999; 24(1): 35-7. 13. Stern M, Eisenbud L. Management of giant cell le­sions of the jaws. Oral Maxillofac Surg Clin North Am 1991; 3: 165-7. 14. De Lange J, Rosenberg AJ, van den Akker HP, Koole R, Wirds JJ, van den Berg H. Treatment of central giant cell granuloma of the jaw with calci­tonin. Int J Oral Maxillofac Surg 1999; 28(5): 372-6. 15. Harris M. Central giant cell granuloma of the jaws regress with calcitonin therapy. GBr J Iral Maxillofac Surg 1993; 31: 89-94. 16. Porgel MA, Regezi JA, Harris ST, Goldring SR. Calcitonin treatment for central giant cell granulo-mas of the mandible: report of two cases. J Oral Maxillofac Surg 1999; 57: 848-53. Transrectal and transperineal sonography in the diagnosis of hydradenitis suppurativa Malgorzata Kolodziejczak1, Robert Stefanski2, Iwona Sudol-Szopinska3, Wieslaw Jakubowski3 1Department of Proctology, Warsaw County Hospital; 2Department of Gastroenterology, Ss Elzbietanek Hospital; 3Department of Diagnostic Imaging, Second Faculty of Medicine, Warsaw, Poland Background. The aim of this paper is to present the application of transrectal and transperineal sonogra­phies in the differential diagnosis of the hydradenitis suppurativa with the anal fistula. Patients and methods. Transrectal and transperineal sonographies were performed in 8 patients with a clinical diagnosis of the anal fistula (6 patients) and the hydradenitis suppurativa (2 patients) in order to de­fine precisely the relation of the inflammatory changes to the anal canal. Results. In all patients the endosonography showed the preserved structures of the anal canal and the transperineal approach proved the superficial location of lesions. Conclusions. Transrectal and transperineal sonographies are helpful in the differentiation between the hy­dradenitis purulenta and the anal fistula. The use of both methods enables a correct diagnosis. Key words: hidradenitis suppurativa - ultrasonography; rectal fistula Introduction The hydradenitis suppurativa (HS) or Verneuil disease is a chronic purulent inflam­mation of the skin and subcutaneous tissue. This entity affects apocrine glands, which are located in axillas, groins, around breasts and anus. Apocrine glands in these regions differ Received 26 June 2003 Accepted 24 July 2003 Correspondence to: Iwona Sudol-Szopinska, MD, PhD, Zaklad Diagnostyki Ultrasonograficznej, Wojewódzki Szpital Bródnowski, 03 285 Warszawa, ul. Kondratowicza 8; Fax +48 22 326 5991; Mobile Phone 0048 501 716 407; E-mail: mdyvonne@wp.pl from glands situated in other regions of the body. They are usually located more deeply and are larger. According to the latest data the HS is genetically determined as an auto-somal dominant disease, and also results from the elevated level of androgens.1 Frequently the HS is misdiagnosed as an anal fistula. It is because the symptoms of the HS most frequently observed in the area of the anus or perineum include the inflammatory changes of the skin and subcutaneous tissue that, by the proctologic examination, very fre­quently resemble the anal fistula. The inflam­mation of the apocrine glands involves, how­ever, superficial tissues and has no connec­tion with the anal canal. Decisive examina­tions for a differential diagnosis are anoscopy, both transrectal and transperineal sonographies which confirm the superficial location. The treatment of the Verneuil dis­ease is alike as for the anal fistula and in­volves the resection of the inflamed skin and subcutaneous tissue. If the area of the inflam­mation is very extensive, a few steps proce­dures are performed, and more than once, if necessary, a skin graft is desirable to cover the wound. Some use an ozone therapy or a local radiotherapy for recurrent inflammatory changes. The aim of the study was to present the ap­plication of transrectal and transperineal sonographies in the differential diagnosis of the hydradenitis suppurativa with the anal fistula. Patients and methods Eight patients (2 women and 6 men, aged be­tween 27-62 years; mean age 54,5 years) with the clinical diagnosis of the anal fistula (6 pa­tients) and the hydradenitis suppurativa (2 patient) were examined. All patients suffered from the recurrent purulent inflammation of the skin and subcutaneous tissue around the anus. They were all sent for a consultation to the proctologist. A proctologic examination together with a rectoscopy did not prove the relationship of these changes with the anal canal. To confirm this diagnosis transrectal and transperineal sonographies were also performed in 2 co-operating diagnostic de­partments. For this purpose Siemens Sonoline SI-450 with transrectal multiplane sector probe 7,5MHz (in 5 patients) and Bruel & Kjarer 3535 with 10MHz transducer (in 3 patients) were used, and a transperineal sonography was performed with the linear 7,5MHz probe. The patients were examined in the left lateral position. No preparation was required before the examination. Results In all patients superficial inflammatory changes of the mixed echogenicity, mostly hipoechoic, were visualised in the transper­ineal sonography. Tubular forms were repre­senting superficial fistulas, round or oval rep­resented superficial perianal abscesses (Figure 1) and uniform hipoechoic areas were seen in the areas of the inflamed skin and subcutaneous tissue (Figures 2a, 2b). A transperineal approach precisely defined the range of inflammation and correlated it with skin changes. The transrectal sonography was decisive in the precise assessment of the relation of these lesions to the anal canal. In all studied cases the preserved structures of the anal canal were shown (Figure 3). A tran­srectal approach was useful in 2 patients who had relatively deep located abscesses and so it was difficult to define their relation to the anal canal. The final diagnosis was made after the confrontation of both approaches. Discussion Although the inflammation of the apocrini glands of the perianal area is not common its tendency to recur and involve the extensive area of skin causes a serious therapeutic problem. A prompt diagnosis is requisite for a successful treatment. As skin changes re­semble the anal abscess or external openings of the anal fistula the HS is rarely recognised. An anal endosonography is currently one of the most widely used imaging techniques in the diagnosis of anal canal diseases.2-9 A ma­jor role of the endosonography, as well as other imaging modalities, is to establish the relation of the fistula and the anal abscess to the anal sphincters. This simple and well tol­erated examination allows in many cases for a precise and definitive diagnosis of the fistu­la and the abscess as well for the follow-up of these patients after the surgery. The accuracy of the anal endosonography in diagnostics of anal fistulas is up to 70%.10.,11 The inflamma­tion of the apocrini glands involves superfi­cial tissues with the creation of small shallow abscesses and fistulas. A transperineal sonog­raphy is a satisfactory imaging examination to confirm this location. A transrectal sonog­raphy is rarely necessary in patients with the HS. Limitations of the endoanal sonography resulting from incomplete coupling of the probe to anal walls at the level of the anal verge are well known.12 Air between the transducer and the anal wall produces arte-facts, which obscure the image of the anal canal. In such cases a transperineal approach Figure 2a. Hipoechoic inflammed subcutaneous tissue in the right perianal area. Figure 2b. Normal echogenicity on the left side. facilitates the diagnosis. Superficial abscess­es, fistulas and the inflammation of the skin are better visualised using the linear probe with a large amount of gel for better coupling and stand-off (Figures 1,2,3).12-16 The main in­dication for the endosonography is to exclude the communication of the perianal lesion with the anal canal. In 2 of the presented group of 8 patients it was difficult to define with the transperineal sonography if the very superficial abscess had the communication with the anal canal or not. The transrectal sonography showed a normal anal canal. Some reports proved a high accuracy of the transperineal approach not only in the visual-isation of anal tumours and local recurrence, especially following the abdomino-perineal resection of rectal or anal tumours, but also in the diagnosis of anal abscesses and fistulas, and sphincters trauma involving a distal part of the anal canal. The quality of the image in the transperineal sonography is, however, not as high as in the transrectal endosonogra­phy; thereby its role is only additional. It may be very helpful in patients with the anal fis­tula or the abscess in whom, because of the strong pain, it will be impossible to introduce the probe into the anal canal. Under the con­trol of the perineal probe, a drainage of the abscess may also be done, and a biopsy of any solid lesion or a differentiation between cyst, haematoma or abscess can be undertaken. In patients with the HP a transperineal ap­proach is also very helpful. In 6 out of 8 pre­sented cases with the initial diagnosis of the anal fistula superficial changes, typical for the HP were shown. In two others, deep ab­scesses were also visible; however, the reli­able diagnosis was possible after the con­frontation with the endosonography. Still, it must be stressed that in this presented entity a proctologic examination remains the most crucial for the diagnosis. Imaging techniques are also very helpful in the differential diag­nosis, which is important in deciding on the choice of the surgical procedure. Conclusions Transrectal and transperineal sonography are helpful in differentiation Verneuil disease from anal fistula. The use of both these meth­ods enables correct diagnosis. References 1. Fitzimmons JS, Guilbert PR. A family study of hy­dradenitis suppurativa J Med Genet 1985; 22: 367­73. 2. Bartram CI, DeLancey JOL. Imaging pelvic floor dis­orders. Berlin: Springer Verlag; 2003. 3. Bartram CI, Frudinger A. Handbook of anal en-dosonography. Petersfield, Bristol: Wrightson Biomedical Publishing LTD; 1997. 4. Deen KI, Williams JG, Hutchinson R, Keighley MRB, Kumar D. Fistulas in ano: endoanal ultra-sonographic assessment assists decision making for surgery. Gut 1994; 35: 391-4. 5. Halligan S. Imaging fistula-in-ano. Clinical Radiol 1998; 53: 85.-95 6. Cataldo PA, Senagore A, Luchtefeld MA. Intrarectal ultrasound in the evaluation of perirec­tal abscess. Dis Colon Rectum 1993; 36: 554-8. 7. Kumar A, Scholefield JH. Endosonography of the anal canal and rectum. World J Surg 2000; 24: 208­15. 8. Law PJ, Talbot RW, Bartram CI, Northover JMA. Anal endosonography in the evaluation of peri-anal sepsis and fistula in ano. Br J Surg 1989; 76: 752-5. 9. Grant TH, Eisenstein MM, Brandt T, Leland J. Supralevator abscess: evaluation with transrectal sonography. Gastrointest Radiol 1989; 14: 354-6. 10. Stoker J, Rociu E, Wiersma TG, Lameris JS. Imaging of anorectal disorders. Br J Surg 2000; 87: 10-27. 11. Poen AC, Felt-Bersma RJ, Eijsbouts QA, Cuesta MA, Meuwissen SG. Hydrogen peroxide-en­hanced transanal ultrasound in the assessment of fistula-in-ano. Dis Colon Rectum 1998; 41: 1147-52. 12. Choen S, Burnett S, Bartram CI, Nicholls RJ. Comparison between anal endosonography and digital examination in the evaluation of anal fistu­lae. Br J Surg 1991; 78: 445-7 13. Kleinubing H, Jannini JF, Malafaia O, Brenner S, Pinho M. Transperineal ultrasonography. New method to image the anorectal region. Dis Colon Rectum 2000; 43: 1572-4. 14. Roche B, Deleaval J, Fransioli A, Marti MC. Comparison of transanal and external perineal ul­trasonography. Eur Radiol 2001; 11: 1165-70. 15. Rubens DJ, Strang JG, Bogineni-Misra S, Wexler IE. Transperineal sonography of the rectum: anatomy and pathology revealed by sonography compared with CT and MR imaging. Am J Roentgenol. 1998; 170: 637-42. 16. Stewart LK, McGee J, Wilson SR. Transperineal and transvaginal sonography of perianal inflam­matory disease. Am J Roentgenol 2001; 177: 627-32. Pneumonia as a cause of death in patients with lung cancer Marek Zieba, Agnieszka Baranowska, Michal Krawczyk, Krzysztof Noweta, Iwona Grzelewska-Rzymowska, Sylwia Kwiatkowska Department of Tuberculosis and Pulmonary Diseases, Medical University of Lódz, Poland Background. Lung cancer is a very serious clinical problem in departments of pulmonary diseases. In many patients with lung cancer pneumonia is a secondary cause of death, which is caused not only by the pro­gression of the disease but also by the applied treatment negatively influencing the immunity of human or­ganism. Clinical and radiological symptoms of the infection can frequently suggest the progression of neo­plastic disease. That is why in each case of deterioration of the state of patients with lung cancer the pro­per diagnosis of the cause should be endeavoured in order to implement the right therapeutic procedures. Patients and methods. We have retrospectively evaluated 70 patients who died in the period between 1997and 1999 in our Department due to lung cancer. Both clinical and bacteriological analyses of deaths were performed and a particular interest in pneumonia as a cause of deat was taken. Results. Pneumonia was diagnosed in 41 patients with lung cancer (58.5%) and Streptococcus pneumoni­ae was the main etiological factor of pulmonary infection. In patients with SCLC, the extent of inflamma­tory changes on chest X-ray and white blood cell count correlated negatively with the period of hospitalisa­tion (R = -0.6 and R = -0.54; p<0.05, respectively). Conclusions. Lung cancer was the main cause of death in patients died in the Department of Tuberculosis and Pulmonary Diseases, Medical University of Lódz. Pneumonia was diagnosed in 58.5 % as a secondary cause of death in lung cancer patients. Key words: lung neoplasms; pneumonia - mortality Introduction Lung cancer is the most common malignant tumour in men in Poland, with the morbidity Received 7 May 2003 Accepted 21 May 2003 Correspondence to: Marek Zieba, M.D., Department of Tuberculosis and Pulmonary Diseases, Medical University of Lódz, Okólna 181, 90-520 Lódz, Poland; Phone/Fax: + 48 42 659 00 16 This work was supported by grant 502 11 572 (135) from Medical Academy of Lódz. index of about 50 in 100,000, and in women it is the fourth most common in respect of the frequency of occurrence (the morbidity index is about 8 in 100,000). All together every year about 20,000 new cases of the disease are recorded, and at the same time about 18,000 people die of lung cancer (in 1990 the number of deaths amounted to 19,301, and in 1998 to about 17,000 with the average death rate of 44.2).1,2 The main causes of death in patients with lung cancer are local progression of the dis­ease, metastases to remote organs and the respiratory system infections.3,4 Infections are the most frequent complications that break out by the treatment in this group of patients. The occurrence of infections is relat­ed to the immunological disorders connected with neoplasmatic disease, its location and progression as well to antineoplasmatic treat­ment. Among the factors favouring the respi­ratory system infections are mainly the ones, which are evoked by the presence of neo­plasm in the respiratory system and its metastases to other organs. The microorganisms responsible for infec­tions in lung cancer patients may be bacteria, viruses, fungi and protozoa.2,5 There have even been recorded some cases of infection caused by nemathelminthes. A patient with impaired immunity is primarily (by neoplas­matic disease) and secondarily (by the treat­ment) is exposed to the infection with pathogens and also with saprophytes (oppor­tunistic infections).6,7 The aim of this research was a retrospec­tive clinical and bacteriological analysis of deaths in lung cancer patients treated in the period between 1997 and 1999 in the Department of Tuberculosis and Pulmonary Diseases at the Medical University of Lódz, taking a particular interest in pneumonia as a cause of death. Material and methods The extent of the advancement of neoplas­matic disease was estimated on the basis of the physical examination, chest radiographs, chest and brain computed tomography, bron­chofibroscopy and ultrasonographic exami­nation of the abdominal cavity. Pneumonia was diagnosed on the basis of the following criteria: increased cough, purulent sputum, dyspnoea, increase in body temperature, rise in WBC (white blood cell count) and the oc­currence of new infiltrates in chest radi­ographs. A microbiological examination of the spu­tum was performed according to the Mulder-Lanyi method.8,9 The sputum was collected into the Petri container in the morning, after washing of the mouth with water. This mate­rial was immediately sent to the Laboratory Department. Before the examination the spu­tum is 3-5 times washed by sterile 0.9% NaCl and the pus flakes are separated. Two prepa­rations were made: Pappenheim for the cyto-logical examination and Gram for the bacte­rioscopic one. Then the culture was per­formed and antibiotic sensitivity was denot­ed. The criteria of the infection covered: cyto-logical examination, contents of eosinophils, Gram stain and culture. Patient’s characteristics The total of 116 patients who died in the Department of Tuberculosis and Pulmonary Diseases at the Medical University of Lódz in the period between 1997 and 1999 were ex­amined retrospectively. The primary cause of death in 70 of them (60%) was lung cancer (23 women, 47 men). As for the rest of patients the cause of death was COPD (25%), and a few others, such as tuberculosis, pulmonary fibrosis, pulmonary embolism, circulatory failure (15%). Fifty-one patients (73%) with lung tumour were diagnosed histologically: small cell lung cancer (SCLC) was diagnosed in 15 patients (6 women, 9 men), and non-small cell lung cancer (NSCLC) in 36 (5 women, 31 men). In 19 patients (12 women, 7 men) the type of neoplasm was not deter­mined, and the diagnosis was given on the basis of the cytological examination of the sputum or bronchoscopic specimens (diagno­sis: neoplasmatic cells). The average age of patients was 64.8 ± 11.8 years (SCLC: 62.8 ± 11.5; NSCLC: 63 ± 11.4). The extended dis­ease (ED) was diagnosed in 13 (87%) patients with SCLC, the limited disease (LD) in 2 (13%). In the group with NSCLC the occur­rence of metastases was detected in 12 pa­tients (33%): clinical stage IV, and the rest of patients were classified as stage III B. The mean disease period was 8.9 ± 4.6 months (median: 9 months) (SCLC: 8.6 ± 3.7 vs. NSCLC: 10.4 ± 4.8; p>0.05) and the average hospitalisation period was 7.8 ± 4.6 days (SCLC: 7.1 ± 4.3; NSCLC: 8.4 ± 4.8). All pa­tients were smokers and the mean cumulated cigarette consumption was 40.9 ± 18.8 pack-years (SCLC: 37.0 ± 23.0; NSCLC: 41.6 ± 19.7). The basic method of the treatment in pa­tients with SCLC is chemotherapy. PE (cis­platin and ethoposide in six 3-day courses every 21 days) was the most often applied scheme among the examined patients (n=7). Not all the patients were given the full scheme (n=5) considering the lack of re­sponse or fairly large intensification of side effects. Alternatively the scheme CAV (cy­clophosphamide, adriblastine and vin­cristine) was applied (n=2). In LD SCLC pa­tients chemotherapy was supplemented with radiotherapy. The patients with NSCLC were covered by the palliative care. All patients re­ceived glucocorticoids (prednisone 20 mg/day). Statistical analysis The results were presented as an average val­ue ± a standard deviation. Statistical differ­ences were determined with the t-test or Kolmogorov-Smirnov test. Survival curves were constructed according to the Kaplan-Meier method and differences in the survival were compared with the log-rank test. Correlations were expressed as Pearson’s or Spearman’s coefficient depending on data distribution. A p value of < 0.05 was consid­ered significant. Results Pneumonia was diagnosed as the secondary cause of death in 41 patients (58.5%). In the radiographs inflammatory changes occupy 3.4 ± 1.4 lung fields on average. In the blood examination no considerable changes were observed except the increased WBC (Table 1). There were no differences between measured routine panel blood parameters in SCLC and NSCLC patients. The bacteriological diagnosis was given only in 6 patients (all with NSCLC) with pneumonia (8.5%) and Streptococcus was the most common evoking factor (Table 2). All the patients with a diagnosed infection were subjected to the antibiotic therapy. The most frequently applied drugs were cephalosporins of II and III generation (n=15; 36.6%) and amoxicillin with clavulanic acid (n=6; 21.9%). The autopsy was conducted in 4 patients (5.7%). In each case pneumonia was con­firmed as a secondary cause of death. Table 2. Bacteriological examination in patients with lung cancer and pneumonia Etiologic agent Number of patients (%) Streptococcus sp. 3 50 Proteus sp. 2 33 M. tuberculosis 1 17 Total 6 100 Table 1. Blood examination in patients with lung cancer and pneumonia Lung cancer (mean) NSCLC SCLC Erythrocytes (106/µl) 4.4 ±0.9 4.5 ±0.9 3.9 ±0.9 Hb (g/dl) 12.4 ±2.6 12.5 ±2.8 11.6 ±2.8 Htc (%) 38.2 ±7.8 38.5 ±8.5 35.5 ±8.3 MCHC (g/dl) 32.4 ±0.9 32.4 ±0.9 32.5 ±1.1 Leucocytes (103/µl) 12.2 ±7.0 13.1 ±6.9 12.2 ±8.4 Thrombocytes (103/µl) 294.5 ±168.5 332.5 ±180.0 236.8 ±141.9 The survival median in the examined group was 9 months (Figure 1). For patients with SCLC it was 8 months, and with NSCLC 12 months (p>0.05). The correlation analysis of the examined parameters indicated that in the group of patients with SCLC the period of hospitalisation correlated negatively to WBC (R = -0.54; p<0.05) and the extent of inflam­matory changes on radiological pictures (R = ­0.6; p<0.05) (Figure 2). In the same group of patients the positive correlation between the extent of inflammatory changes on chest x-ray and WBC was found (R = 0.68; p<0.05). The local progression of lung cancer (n=20) or the circulatory failure (n=9) were the cause of death in the rest of the patients. Discussion During the examined period in the Department of Tuberculosis and Pulmonary Diseases of the Medical University of Lódz the most common primary cause of death was the lung cancer (60%). It is estimated that about 75-80% of all patients with lung cancer are patients with the diagnosis of NSCLC, while 20-25% are patients with SCLC.1,3 Similarly, in the examined group of patients the microcellular form of cancer was diag­nosed in 21.4% of patients, while the non-mi­crocellular form -in 51.4%. In the remaining patients (27.2%) the histopathological diagno­sis was not made. The reason was often the short observation time of patients. In the examined group of patients pneu­monia was the main or accessory cause of death in 41 patients (58.5%). The conducted autopsy examinations in each case confirmed the clinical diagnosis. According to Remiszewski et al. in a group of patients with SCLC the infections of the respiratory system were the main cause of death only in 4.6% of patients, and the accessory cause in 9.1%.6 In examinations conducted by Putinati et al. the frequency of occurrence of infections in lung cancer patients was estimated on the grounds of the results of the bacteriological examina­tion of the broncho-alveolar lavage fluid (BALF), the presence of the infectious agent was indicated in 34.3% of patients. This result is probably underestimated because in some patients showing clinical symptoms of the respiratory system infections etiological agent was not discovered (sampling was con­ducted during the antibiotic therapy.10 In Japanese examinations the group of patients with lung cancer was divided into three sub­groups depending on the method of treat­ment and the frequency of the inferior respi­ratory tracts was estimated at 41.7-60.5%. Most often infections appeared in the group of patients receiving cytostatics and glucocor­ticoids.11 In patients with granulocytopoenia, apart from the typical for the respiratory system in­fections caused by alpha-haemolysing Streptococcus, Streptococcus from the D group, Staphylococcus aureus and epider-midis, Haemophilus influenzae, the impor­tant role is played by Gram-negative bacteria: Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacter, Proteus. Subjects with the cell-mediated im­munity disorders are exposed to infections caused by: Listeria monocytogenes, Salmonella, Mycobacterium, Nocardia aster-oides and Legionella.12,13 The most frequently occurring virus infec­tions include the ones caused by: Varicella­zoster, Herpes simplex, Cytomegalovirus and Ebstein-Barr virus.13,14 Other severe infections are the ones caused by fungi: Pneumocystis carinii, Cryptococcus neoformans, Aspergillus fumi­gatus, Candida albicans, Candida krusei, Histoplasma capsulatum, Candida glabrata, protozoa (Toxoplasma gondii). Infections caused by Strongyloides stercoralis were also observed.7,15-18 The conducted bacteriological examina­tions showed that the etiological agents of pneumonia in the examined group were bac­teria of Streptococcus and Proteus species as well as Mycobacterium tuberculosis. Putinati et al. indicated Gram-negative rods as the most frequent cause of infections (most often Haemophilus sp.) - 45.2%, Gram-positive coc­ci (most often Staphylococcus aureus) ­33.3%, Pneumocystis carinii and Chlamydia trachomatis - 16.7% as well as Gram-negative cocci - 4.8%.8 In the Japanese examinations cited before cases of pneumonia were caused by Gram-positive bacteria in 38.4%, Gram-negative bacteria in 30.8%, and mixed bacter­ial flora in 30.8%.11 Remiszewski et al. showed that the most frequent etiological agents of the infections causing death of patients with lung cancer were Gram-negative bacteria (Klebsiella sp., Pseudomonas sp., Escherichia coli). Gram-positive bacteria (Staphylococcus sp., Streptococcus sp.) were isolated more sparsely. In some patients infections were caused by fungi: Aspergillus sp., Candida sp., Pneumocystis carinii and Mycobacterium tuberculosis.2,5,6,15 It is difficult to compare these data with our results because of small number of bacteriological confirmations of the pulmonary infection (8.5%). Due to the limited accessibility of microbi­ological tests and the possibility of rapid out­come of the infection in patients with lung cancer the empirical treatment is recom­mended.19 Patients with neutropoenia below 500/µL are conventionally treated with aminoglycoside and ß-lactamic antibiotic (amoxicillin + claevulanic acid or cephalosporins of II/III generation). In case of leucopoenia above 500/µl aminoglycoside and cephalosporin of III generation or cephalosporin of III generation and macrolid are administered. In patients with neutropoe­nia and fever cephalosporin of III generation and clindamycin are applied. In the lack of re­sults of this treatment after 5 days a different etiology must be considered. In case of pneu­monia caused by Pneumocystis carinii (PCP) trimetoprim-sulfametoxasol is usually ap­plied.13,18 In cases of infections caused by fungi patients are treated with amphotericin B.2,7,20,21 In the examined group cephalosporins of II/III generation, amoxi­cillin with claevulanic acid and aminoglyco-sides were most frequently applied. Severe pulmonary infections in lung can­cer patients may develop due to local or sys­temic immunological disorders. Systemic im­munological disturbances occur relatively early in patients with lung cancer. Irregularities concern mainly the cellular type of immunity.6,22 What is advantageous to in­fections is also permeability disorder of bronchus caused by helophytic or intramural increase of the neoplasm or by the pressure to a bronchus wall caused by the mass of the tu­mour or enlarged lymph nodes. These phe-nomena are intensified by the impaired cough reflex which may take place against the background of applied therapy (narcotics, psychotropic) or as a result of neoplasmatic metastases to brain.23 Moreover, metastases to bone marrow may lead to leucopoenia and anaemia.2,6,24 It seems that in our patients the main causes of pneumonia were atelectasis and dysfunction of phagocytes and lympho­cytes (with normal or increased WBC), espe­cially in NSCLC. Another group of factors predisposing to the occurrence of the respiratory system in­fection includes those connected with the rad­ical and palliative treatment for lung cancer. Most of drugs applied in the antineoplasmat­ic therapy have a suppressive effect on the function of the immune system. Alkalising drugs, antimethabolites of purines, pirim­idines and folic acid produce the stronger im­munosuppressive effect.22,25 Almost all cyto-statics create disorders of proliferation and function of granulocytes with a temporary shortage of these cells in the peripheral blood. In SCLC group of patients 60% received chemotherapy with cisplatin, etoposide or cy­clophosphamide, adriblastine and vincristine and all of patients were treated with glicocor­ticosteroids. The risk of the infection increas­es considerably in patients whose number of neutrophils does not exceed 500/µl and is es­pecially high in the case of neutropoenia be­low 100/µl.10,25 Glucocorticoids are often used as supportive drugs in lung cancer patients. By the suppressive influence on the cellular immunity they contribute to the increase of susceptibility to infections.12 The syndrome produced by radiotherapy depends on the size of irradiated area and the amount of a total dose. Developing inflam­matory changes in lungs may be responsible for the occurrence of respiratory failure and the patients’ death, especially with this state being often complicated by the respiratory system infection.2,3,26 It is estimated that over 80% of patients do not survive the first year since the diagnosis, and only few per cent survive 5 years.1,10 Similarly in the examined group the median of the patients’ survival was 9 months (NSCLC: 12 months; SCLC: 8 months). Our results indicated additionally that the high in­tensity of pulmonary inflammation measured by WBC and the extent of radiological changes are connected with a poor prognosis and short period of hospitalisation. This was confirmed by our previous studies. The nega­tive correlation between the serum concentra­tion of lipid hydroperoxides and radiological regression was observed in patients with pneumonia after 14-days therapy.27 Moreover, in patients with tuberculosis, the serum con­centration of other inflammatory indicators such as conjugated dienes, thiobarbituric acid-reactive substances,28 soluble tumour necrosis factor receptor I, and intercellular ad­hesion molecule-1 were significantly higher in the radiologically advanced disease.29 Conclusions (1) Lung cancer was the main cause of death among our patients; (2) Pneumonia was diag­nosed in 58.5% as a secondary cause of death in lung cancer patients; (3) In patients with SCLC, the extent of inflammatory changes on chest X-ray and WBC correlated negatively with the period of hospitalisation. References 1. Jassem J, Paplinski Z. Lung cancer. Warszawa: PZWL; 1994. 2. Remiszewski P. Supporting care in lung cancer. Nowa Klinika 1999; 6: 324-28. 3. Spiro SG. Lung cancer. Eur Respir Monogr 2001; 17: 22-48. 4. Brown BW, Brauner C, Minnotte MC. Noncancer deaths in white adult cancer patients. J Natl Cancer Inst 1993; 85: 979-87. 5. Zych J, Szymanska D, Drozd I, Slupek A, Rowinska-Zakrzewska E. Infections as a cause of death in patients with lung cancer. Pneumonol Pol 1984; 52: 11-7. 6. Remiszewski P, Slodkowska J, Wiatr E, Zych J, Zaleska J, Radzikowska E, et al. Infections as a main and additional cause of death in patients treated due to small cell lung cancer. Pneumonol Alergol Pol 1999; 67: 347-53. 7. Varthalitis I, Aoun M, Daneau D, Meunier F. Pneumocystis carinii Pneumonia in patients with cancer. Cancer 1993; 71: 481-5. 8. Mulder J. Haemophilus influenzae as an ubiqui­tous cause of common acute and chronic purulent bronchitis. Acta Med Scand 1938; 43: 94-8. 9. Lanyi M. Uber den begriff des bakteriellen bronchialinfektes. Dtsch Med Wschr 1968; 49: 2390-93. 10. Putinati S, Trevisani L, Gualandi M, Guerra G, Rossi MR, Sartori S, et al. Pulmonary infections in lung cancer patients at diagnosis. Lung Cancer 1994; 11: 243-9. 11. Nagata N, Nikaido Y, Kido M, Ishibashi T, Sueishi K. Terminal pulmonary infections in patients with lung cancer. Chest 1993; 103: 1739-42. 12. Maschmeyer G, Link H, Hiddemann W, Meyer P, Helmerking H, Eisenmann E, et al. Pulmonary Infiltrations in Febrile Patients with Neutropenia. Cancer 1994; 73: 2296-304. 13. Masur H, Shelhamer J, Parrillo JE. The manage­ment of pneumonias in immunocompromised pa­tients. JAMA 1985; 235: 1769-73. 14. Tamm M, Traenkle P, Grilli B, Soler M, Bollinger CT, Dalquen P, et al. Pulmonary cytomegalovirus infection in immunocompromised patients. Chest 2001; 119: 838-43. 15. Remiszewski P, Slodkowska J, Wiatr E, Szczepek B, Radomski P, Rowinska-Zakrzewska E. Mycosis and pneumocystis carini pneumonia as a cause of death in patients treated due to small cell lung cancer. Pneumonol Alergol Pol 1998; 66 (Suppl 2): S173. 16. Kuan-Yu C, Shiann-Chin K, Po-Ren H, Kwen-Tay L, Pan- Chyr Y. Pulmonary fungal infection, em­phasis on microbiological spectra, patient out­come and prognostic factors. Chest 2001; 120: 177­84. 17. Kanda Y, Yamamoto R, Chizuka A, Hamaki T, Suguro M, Arai Ch, et al. Prophylactic action of oral fluconazole against fungal infection in neu­tropenic patients. A meta-analysis of 16 random­ized controlled trials. Cancer 2000; 89: 1611-25. 18. Fossieck BE, Spagnolo SV. Pneumocystis carinii pneumonitis in patients with lung cancer. Chest 1980; 78: 721-2. 19. Talcott JA, Siegel RD, Finberg R, Goldmann L. Risk assessment in cancer patients with fever and neutropenia: A prospective, two-centre validation of a prediction rule. J Clin Oncol 1992; 10: 316-22. 20. Jarvis WR. Epidemiology of nosocomial fungal in­fections with emphasis of Candida species. Clin Infect Dis 1995; 20: 1526-30. 21. Rubenstein EB, Rolston K, Benjamin RS, Loewy J, Escalante C, Manzullo E, et al. Outpatient treat­ment of febrile episodes in low-risk neutropenic patients with cancer. Cancer 1993; 71: 3640-6. 22. van Meerten E, Verweij J, Schellens JHM. Antineoplastic agents. Drug interaction of clinical significance. Drug Staf 1995; 12: 168-82. 23. Law A, Karp DD, Dipetrillo T, Daly BT. Emergence of increased cerebral metastasis after high dose preoperative radiotherapy with chemiotherapy in patients with locally advanced nonsmall cell lung carcinoma. Cancer 2001; 92: 160-4. 24. Remiszewski P, Slodkowska J, Szczepek B, Zwolska Z, Radomski P, Byszewska D, et al. Etiology of infection as a main and additional cause of death in patients treated due to small cell lung cancer. Pneumonol Alergol Pol 1999; 67: 354­61. 25. Earle CC, Stewart DJ, Cormier Y, Evans WK, Gertler SZ, Mihalcioiu C, et al. A phase I study of gemcitabine/ cisplatin/ etoposid in the treatment of small-cell lung cancer. Lung Cancer 1998; 22: 235-41. 26. Ali MA, Kraut MJ, Valdivieso M, Merskovic AM, Du W, Kalemkerian GP. Phase II study of hiper-fractionated radiotherapy and concurrent weekly alternating chemiotherapy in limited-stage small cell lung cancer. Lung Cancer 1998; 22: 39-44. 27. Nowak D, Zieba M, Zawiasa D, RoNniecki J, Król M. Changes of serum concentration of lipid per-oxidation products in patients with pneumonia. Monaldi Arch Chest Dis 1996; 51: 188-93. 28. Kwiatkowska S, Piasecka G, Zieba M, Piotrowski W, Nowak D. Increased serum concentration of conjugated dienes and malondialdehyde in pa­tients with pulmonary tuberculosis. Respir Med 1999; 93: 272-6. 29. Kwiatkowska S, Kuzminska B, Zieba M, Kroczynska-Bednarek J, Kuna P. Enhanced con­centration of cerculating ICAM-1 and TNF recep­tor I in patients with pulmonary tuberculosis. Current Pneumology 1999; 3: 225-30. Radiotherapy for stage IAE non-Hodgkin' s lymphoma of the testicle-a case report Antonio }uretic-1.·, Mirko Zivkovic-1.-t Marija Gamulin~", Tonko Herceg1, Davorin Bagovic-1., Damir Kucan2, Zarko Zeljko2··, Radmila Ajdukovie 1 Department of Radiotherapy, University Hospital for Tumors; 2Department of Urology, Clinical Hospital »Merkur«; 3Department of Hematology, Clinical Hospital »Dubrava«, Zagreb, Croatia Background. The aim of this report is to present the irradiation technique applied to a patient with primary testicular non-Hodgkin's (NHL) lymphoma stage IEA, histologically CD20 positive NHL -diffuse follicular center cell (FCC) lymphoma grade Ill. Since primary NHLs of the testis are rather rare, no uniform radio­therapy approach to their treatment has been developed to date. Testicular NHLs are relatively often of ag~ gressive biological characteristics, so that the disease relapse is not uncommon even in patients in an early stage of the disease (stage I and ll), who received seemingly optimal therapy (orchiectomy of the diseased testicle, polychemotherapy and irradiation). Case report. In this report the applied radiation treatment field is shown. The disease was diagnosed in June 2001 after the inguinal orchiectomy. Afterwards, the patient received 6 courses of polychemotherapy (CHOP) plus intrathecal methotrexate therapy. The irradiation was conducted with one direct 6 megavolt (MV) energy photon beam. The irradiation field encompassed the contralateral testicle (scrotum) and in­guina-femora/lymph nodes. The radiotherapy dose was 30 Gy applied in 15 fractions calculated at the depth of 4 cm. The radiotherapy finished in December 2001. The patient has regular check-ups (last in May 2003) and has been in remission since then. Conclusions. Relapse sites are quite often extranodal, not in the regional lymph nodes. Therefore, consid­ering the radiation treatment fields there are no definitive recommendations. Key words: testicular neoplasms; Lymphoma, non-hodgkin Received 7 June 2003 Introduction Accepted 21 June 2003 Primary lymphoma of the testis is a rather Present addresses: •clinics for Oncology, Clinical rare disease. It accounts for around 1% of all Hospital Center »Zagreb«, Zagreb, Croatia; .. Department of Urology, Clinical Hospital NHL's, 2% of extranodallymphoma and less •Dubrava«, Zagreb, Croatia than 10% of all testicular neoplasms. Correspondence to: Prof. Antonio Juretic, MD, PhD, However, in men over 60, it is the most com­ Radiation Oncologist, Clinics for Oncology, Clinical mon malignancy of the testis. The prognosis Hospital Center •Zagreb«, Kispaticeva 12, HR-10000 Zagreb, Croatia; E-mail: antonio.juretic@zg.hinet.hr of testicular lymphoma is relatively poor corn­ pared to other nodal and extranodal lym­phomas. Median survival is 12 to 24 months.I-3 Because this entity is relatively rare, much of the literature includes reports on a limited number of patients (usually between 10 to 30) 417 collected over a span of many years.­Accordingly, one can find differences in both lymphoma classifications and treatment ap­proaches. Recently, two publications includ­ing a much larger number of patients have al­so appeared due to the multicentric or inter­national nature of data collection and study.15,17 Due to their relatively larger num­ber of patients, these recent publications al­low us to better define the specific clinical features at presentation, prognostically im­portant clinical variables, a response to thera­py, and patterns of failure. Most of primary testicular lymphomas are of B-cell origin, and overall diffuse large B-cell lymphomas as well as diffuse small non­cleaved cell lymphoma appear to be the most common type. Follicular lymphomas and oth­er histologic subtypes are less frequently rep­resented.1-3 Inguinal orchiectomy is univer­sally recommended as an initial therapy for patients with localized disease. Although the long-term disease-free survival has been de­scribed after the orchiectomy alone, the vast majority of the patients relapse, so this can­not be considered an adequate therapy, not even for patients with lE disease. Further­more, relapse rates exceeding 50% have been observed in the majority of reports in which the adjuvant radiotherapy (RT) was used fol­lowing the orchiectomy. Relapses often occur in extranodal sites, such as in the central nervous system (CNS), Waldeyer's ring, skin and lung. In field failures were reported in patients who received adjuvant locoregional radiation at doses lower than 30 to 35 Gy. Such clinical course suggests that testicular NHL is usually a systemic disease, even when it initially presents as a localized disease. Accordingly, combined chemotherapy and Radio/ Oncol 2003; 37(3): 175-81. radiation therapy have been the accepted treatment modality for stage IE and HE ag­gressive nodal lymphomas. The chemothera­py is usually doxorubicin based (for example, CHOP, cyclophosphamide, doxorubicin, vin­cristine, prednisone) accompanied with con­comitant CNS prophylaxis (4-6 injection of methotrexate intrathecally). The radiothera­py, if any, is usually applied in a form of in­volved-field, encompassing the contralateral testis (scrotum) or scrotal, iliac and possibly para-aortic regions. A routine use of irradia­tion to the paraaortic lymphnodes is not rec­ommended because of the unpredictable metastatic pathway of the primary NHL lym­phomas. The irradiation of the contralateral testis is with a prophylactic intention since the relapse rate in case of nonirradiation, is approximately 8% to 35%.1-3 On the other hand, there are also reports where the irradi­ation of the contralateral testis was either not performed5'7'9'11 or performed only in a por­tion of patients reported.4,12,15,17 Regarding radiotherapy, these reports sur­prisingly include very few details about the target volume and techniques.4-17 Concerning the radiation dose, they regularly mention the total dose. The target volume and irradiation technique is usually not precisely described. In a sentence or two it is mentioned that the involved field or involved-region irradiation was administered, or that scrotum and pelvic (iliac) lymphnodes ± paraaortic lymphnodes were irradiated. Therefore, we present the ir­radiation treatment we applied to a patient with stage lEA primary testicular NHL lym­phoma. Case report The presented patient was born in 1937. Due to the enlargement of the left testis he was ex­amined at the Department of Urology, Clinical Hospital >>Merkur<<, Zagreb, Croatia. A diagnostic examination, which included a!­ so the computerized tomography (CT} of the abdomen and pelvis, did not reveal or indi­cate a disease spreadout outside of the left testicule. In June 2001, the patient underwent the left inguinal orchiectomy. The pathologic diagnosis was >>CD20 positive NHL -diffuse follicular center cell (FCC) lymphoma grade TIT<< (Diffuse large B-cell lymphoma according to the revised European-American classifica­tion of lymphoid neoplasms (REAL)-World Health Organization (WHO) classification).3 The patient was thereafter referred to a hematologist at another hospital (Department of Hematology, Clinical Hospital »Dubrava«, Zagreb). There he underwent an additional extended staging procedure that also includ­ed CT of the head and neck, thorax and ab­domen and pelvis again as well as the bone marrow examination. These examinations did not show any evidence of the disseminat­ed disease and/or regional lymph node in­volvement. Accordingly, the patient was di­agnosed with primary NHL of the testicle, stage TAE. Moreover, according to the International Prognostic Index (IPI), he could be classified among low risk patients. His age was a risk factor (>60), while other four pa­rameters did not indicate the elevated risk (serum lactate dehydrogenase was within normal limits, performance status -ECOG score = 0, stage of the disease I, one extran­ 18 odal site involved).3· He was treated thereafter with six cycles of CHOP polychemotherapy (cyclophos­phamide, 750 mglm2 i.v. on day 1; doxoru­bicin, 50 mg!m2 i.v. on day 1; vincristine, 1,4 mglm2 i.v. on day 1; prednisone, 40 mg!m2 p.o. on days 1 to 5) and intrathecally with methotrexate (15 mg on the first day of each CHOP chemotherapy cycle). Cycles of CHOP polychemotherapy were administered at 3­week intervals. When the patient completed the chemo­therapy treatment he had a control examina­tion. No signs which could indicate the dis­ease relapse or the development of distant metastasis were found. After that, he was re­ferred to radiation oncologists at the University Hospital for Tumors in Zagreb for the further radiotherapy treatment. Taking into account patient's previous treatments, the possible clinical course of the disease and the patient's overall good condition (ECOG score 0), it was decided that he should receive the consolidation radiotherapy, to be applied to the contralateral testis (scrotum) and the neighboring inguino-femoral lymph nodes and subcutaneous lymph-vessels (>>involved­field«). The total tumor dose was 30 Gy in 15 fractions.1•2•19 Radiation details Since the scrotum and the inguino-femoral lymphnodes are located superficially, the rac diotherapy was performed by a single »di­rect<< beam. Moreover, the region was encom­passed by a single radiation field. The radia­tion was planned as nonisocentrical, using a single 6 MV photon beam from the linear ac­celerator, having a focus to skin distance (FSD) of 100 cm, with the gantry angle of 0 de­gree (antero-posterior direction), respectively. The radiation field was determined during the simulation process by using a treatment­planning simulator. The patient was placed supine on the simulator table with his arms crossed over his chest (Figure 1). Consequently, for the radiotherapy the pa­tient was always identically positioned. By means of simulator x-rays, the radiation field was tailored so to encompass the scrotum and inguino-femorallymph nodes (Figure 1). The size of the treatment radiation field was 25 x 17.5 cm (Figure 1). After the appropriate subtractions of the shielded surfaces, the size of the radiation field approximated 18 x 18 cm. At the central axis the patient's antero­posterior diameter was 21.5 cm. The total tu­mor dose of 30 Gy, or single irradiation frac­tions of 2 Gy were calculated at the 4 cm depth. The isodose plan is shown in Figure 2. To obtain a comparably homogenous dose Figure 2. Two-dimensional presentation of the dose distribution ratio by depth delivered by 6 MV pho­tons. (isodose curves, i.e., isodose plan). Centimeter scale is shown on the left and at the bottom. Point »A« in the isodose plan denotes the depth of 4 cm -a dose of 2 Gy per fraction. Radio/ On col 2003; 3 7(3): 175-81. Figure 1. Presentation of the irradiation field. Figures la and lb show different parts of the same radiation field, i.e., x-ray images taken on a simulator during ra­diotherapy planning. Irradiation of the contralateral testicle, scrotum and of inguino-femoral lymph nodes is achieved. The position of shielding blocks for the penis and lateral parts of thighs can be observed. Figure le shows the radiation field on the patient body. Plexiglass located shielding blocks enable pro­tection of the penis (fixed by an adhesive plaster tape) and lateral part of thighs. distribution within the depth of the first 4 cm, tissue bolus in equivalency of 6 mm of water is used during the irradiation. Finally, after having all calculations done, reviewed and approved, irradiation was carried out. The ra­diotherapy was conducted in December 2001. Discussion This case report is aimed at pointing out the difficulty a radiation oncologist may en­counter in planning the radiotherapy for a disease with primary tumors being surgically removed and a propensity for primarily dis­tant metastasis, the disease with no strict rec­ommendations for the radiotherapy due to its rarity. For example, in the publication from Zucca et a/17 which includes 373 patients, the authors admit that among the patients receiv­ing radiotherapy (n=196, as primary or as combined with chemotherapy) there is a wide range of radiotherapy doses {from 18 to 50 Gy) and fields (from only scrotal to a variety of extended fields with or without inclusion of the contralateral testis). When considering the total tumor dose and the target volume we took into account the possible pattern of relapse, patient's stage of the disease, previous treatments, and his overall good condition. Moreover, the ra­diosensitivity of the testicular NHL cells, pos­sible existence of microscopic residual NHL cells in both the contralateral testis and in­guino-femoral lymph nodes, normal tissue tolerance and possible side effects of irradia­tion to normal tissues were also taken into ac­count.1·3,19 The irradiation could be per­formed also by a photon beam from a cobalt­60 machine, but due to the fact that the pa­tient was obese with a substantial slope dif­ference between the upper and lower field portions, 6 MV photons were given advan­tage. We have also been considering the us­age of 20 MeV electrons, but the field size was a problem, as well as the patient's con­tour slope and especially the construction of a penis-shielding block. Megavolt electron beams show the advantage in the deeper body structures receiving much less of the ra­diation energy. If the irradiation has to be ap­plied only to the scrotum, then the megavolt electrons are satisfactory. At the total tumor dose of 30 Gy in 15 fractions one does not ex­pect an intensive painful skin reaction (irra­diation dermatitis) of the scrotum by using megavolt electrons. The radiation therapy was well tolerated by the patient. The standard routine control examination was 6 weeks after the irradiation had been completed. The patient was well and felt well in the postirradiation period. No skin reaction (irradiation dermatitis) was ob­served. At examination, his locoregional sta­tus was in order. Standard laboratory test re­sults were also normal. Since then, the pa­tient has regular check-ups every three to four months (last in May 2003.) and is in re­mission since then. Considering the treatment strategy for non-Hodgkin's lymphoma (NHL) it is largely determined by the histologic sub-type, stage at diagnosis and by the patient's overall con­dition.l-3.20 The treatment of localized (stages I, lE, non-bulky TT and liE) aggressive histolo­gies of non-Hodgkin's lymphoma has been evolving over the past 20 years. These dis­eases could be locally controlled with the ra­diotherapy, but systemic relapses and deaths are common. Cure rates for the intermediate­and high-grade localized NHL improved dra­matically with the addition of doxorubicin­containing chemotherapy. In the 1990s, two large randomized, prospective trials demon­strate that initial chemotherapy followed by the radiation therapy (combined modality therapy) gives the best results; so, such com­bined treatment might be considered as the best available current treatment strategy. 18~ 21 Within the group of aggressive NHLs the prognosis of testicular lymphoma is relatively poor compared to other nodal and extranodal 815~17~22 aggressive lymphomas1 ·3 , , . The sur­gery, i.e. orchiectomy, has an important role in the diagnosis, but its usefulness, unless the disease is really limited to the testis, is re­stricted. As mentioned, available data suggest that in the majority of stage lE patients sys­temic occult metastases are already present. Accordingly, the radiotherapy usually has al­so a limited role. The goal of RT in the treat­ment of localized aggressive NHL is to deliv­er an adequate dose to the disease site and margin. The radiation is generally given after the initial chemotherapy treatment. Factors determining the dose of radiation, aside from normal tissue tolerance, include bulk of dis­ease and performance status. In case of tes­ticular lymphoma, the affected organ has usu- Radio/ 011col 2003; 37(3): 175-81. ally been already removed by orchiectomy. Due to an unpredictable metastatic pattern of the testicular NHL, the question is what to ir­radiate. The irradiation is applied on the as­sumption that the probable site of the initial relapse will be in the pelvic or para-aortic lymph nodes or in the contralateral testis. Distant extranodal failures, especially in the CNS, remain a major problem, even in pa­tients who receive a full course of doxoru­bicin-based chemotherapy accompanied with the intrathecal CNS prophylaxis with methotrexate alone or combined with cytara­bine.16·17 In the cases of CNS relapses it may be important to distinguish intraparenchymal failures from the lepromeningeal ones since for the prevention of intraparenchymal fail­ures more effective CNS prophylaxis, such as low-dose whole-brain irradiation or high-dose methotrexate must be prospectively ex­plored.11.16 The recent multicentric prospec­tive studies with a relatively high number of patients indicate that, because of the poor prognosis, an aggressive treatment approach, if possible, is warranted.16•17 For example, the results from the Zucca's study17 indicate that among the prognostic factors that were statis­tically significant at the multivariate analysis, IPI. B symptoms, anthracycline-containing chemotherapy, and prophylactic scrotal irra­diation retained statistical significance with the overall survival (OS), cause-specific sur­vival and progression-free survival. Patients receiving radiotherapy have a significantly longer OS, but most of them have a favorable IPI score. Among patients receiving radio­therapy locoregional to the primary testicular site of involvement, the OS was longer for those receiving an irradiation dose of at least 30 Gy. On the other hand, testicular lym­phoma is predominantly a disease of older men who often have limited ability to tolerate aggressive treatment. The rarity of the disease makes randomized trials virtually impossible. Hence, an international collaboration is cru­cial to properly address the management of Radio/ Oncol 2003; 37(3): 175-81. testicular lymphoma. The improved under­standing of the genetic and molecular charac­teristics of testicular lymphoma may help identify patients at risk of CNS failure and apply a patient-tailored treatment in the fu­ture.1 5,17 Acknowledgement This work was partially supported by the Ministry of Science and Technology of the Republic of Croatia (grant no. 0074004 to AJ). Refferences 1. Shabab N, Doll DC. Testicular lymphoma. Semin Onco/ 1999; 26: 259-69. 2. Armitage JO, Mauch PM, Harris NL, Bierman P. Non-Hodgkin's lymphomas. In: DeVita Jr. VT, Hellman S, Rosenberg SA, editors. Cancer: princi­ples and practice of oncology. 6'h Edit. Philadelphia: Lippincot Willimas and Wilkins; 2001. p. 2256­316. 3. National Cancer Institute. Adult non-Hodgkin's lymphoma. CancerNet, PDQ -treatment -health professionals, date last modified 0211912003, pages 53. Available: http: 11 www.nci.nih.gov I cancer info I pdq I treatment I adult non -Hodgkin's lymphoma I health professional/. Date of access May 61h, 2003. 4. Duncan PR, Checa F, Gowing NFC, McElwain TJ, Peckham MJ. Extranodal non-Hodgkin's lym­phoma presenting in the testicle: a clinical and pathological study of 24 cases. Cancer 1980; 45: 1578-84. 5. Martenson JA, Buskirk SJ, Tlstrup OM, Banks PM, Evans RG, Calgan JP, et al. Patterns of failure in primary testicular non-Hodgkin's lymphoma. J Clin Onco/ 1988; 6: 297-302. 6. Connors JM, Klimo P, V ass N, Fairey RN, Jakson S. Testicular lymphoma: improved outcome with early brief chemotherapy. ] Clin Onco/ 1988; 6: 776-81. 7. Crellin AM, Hudson BV, Bennett MH, Harland S, Hudson GV. Non-Hodgkin's lymphoma of the testis. Radio/her Onco/1993; 27: 99-106. 8. Touroutouglou N, Dimopoulos MA. Younes A. Hess M, Pugh W, Cox J, et al. Testicular lym­phoma: late relapses and poor outcome despite doxorubicin-based therapy.] Clin Onco/1995; 13: 1361-7. 9. Zietman AL, Coen JJ, Ferry JA, Scully RE, Kaufman OS, McGovern FG. The managment and outcome of stage IAE nonhodgkin's lymphoma of the testis. ] Uro/1996; 155: 943-6. 10. Niitsu N, Umeda M. Clinical features of testicular non-Hodgkin's lymphoma. Focus on treatment strategy. Acta Onco/ 1998; 37: 677-80. 11. Tondini C, Ferreri AJ, Siracusano L, Valagussa P, Giardini R, Rampinelli I, et al. Diffuse large-cell lymphoma of the testis. J Clin Oncol 1999; 17: 2854-8. 12. Fonseca R, Haberman TM, Colgan JP, O'Neill BP, White WL, Witzg TE, et al. Testicular lymphoma is associated with a high incidence of extranodal re­currence. Cancer 2000; 88: 154-61 . 13. Lote K, Holte H, Nome 0, Langholm R, Kvaloy S. Stage I high-grade non-Hodgkin's lymphoma. Acta Oncol 2000; 39: 865-72. 14. Pectasides 0, Economopoulos T, Kouvatseas G, Antoniou A, Zoumbos Z, Aravantinos G, et al. Anthracycline-based chemotherapy of primary non-Hodgkin's lymphoma of the testis: the Hellenic Cooperative Oncology Group experience. Oncology 2000; 58: 286-92. 15. Lagrange JL, Ramaioli A, Theodore CH, Terrier­Lacombe MJ, Beckendorf V, Biron P, et al. Non­Hodgkin's lymphoma of the testis: a retrospective study of 84 patients treated in the French anti­cancer centres. Ann Oncol 2001; 12: 1313-9. 16. Zouhair A, Weber 0, Belkacemi Y, Ketterer N, Dietrich PY, Villa S, et al. Outcome and patterns of failure in testicular lymphoma: a multicenter Rare Cancer Network study. Tnt J Radiat Oncol Bioi Phys 2002; 52: 652-6. 17. Zucca E, Conconi A, Mughal TI, Sarris AH, Seymour JF, Vitolo U, et al. Patterns of outcome and prognostic factors in primary large-cell lym­phoma of the testis in a survey by the International Extranodal Lymphoma Study Group.] Clin Onco/ 2003; 21: 20-7. 18. Miller TP, Dahlberg S, Cassady JR, Adelstein DJ, Spier CM, Grogan TM, et al. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate-and high-grade non­Hodgkin's lymphoma. N Engl J Med 1998; 339: 21­ 6. 19. Tsang RW, Gospodarowicz MK. Non-Hodgkin's lymphoma. In: Gunderson LL, Tepper JE, editors. Clinical radiation oncology. New York: Churchill Livingstone; 2000. p. 1158-88. 20. Briggs JH, Miller TP. Combined chemotherapy plus radiotherapy for treatment of early-stage in­termediate-and high-grade non-Hodgkin's lym­phoma. Curr Oncol Rep 2000; 2: 176-81. 21. Glick JH, Kim K, Earle J, O'Connell MJ. An ECOG randomized phase Ill trial of CHOP vs. CHOP plus radiotherapy for intermediate grade early stage non-Hodgkin's lymphoma (abstract). Proc ASCO 1995; 14: 391a. 22. Shenkier TN, Voss N, Fairey R, Gascoyne RD, Hoskins P, Klasa R, et al. Brief chemotherapy and involved-region irradiation for limited-stage dif­fuse large-cell lymphoma: an 18-year experience from the British Columbia Cancer Agency. j Clin Onco/2002; 20: 197-204. case report Long-term disease-free interval after irradiation for locally advanced lung cancer Norihiro Haraguchi, Hiroaki Satoh, Toshiaki Homma, Kiyohisa Sekizawa Division of Respiratory Medicine, Institute of Clinical Medicine, University of Tsukuba, Japan Background. The purpose of the report is to describe a patient with the lung cancer who had long-term dis-ease-free interval after the irradiation therapy. Case report. The patient was a 58-year-old woman with large cell lung carcinoma with neck lymph node metastasis, which was treated with radical radiotherapy. Within a 9-year disease-free interval, the patient developed loco-regional recurrence and distant metastases. Conclusions. Despite a long-term disease-free interval, non-small cell lung cancer represents a life-long threat to some patients and requires constant vigilance by medical practitioners. Key words: lung neoplasms - radiotherapy; carcinoma, non-small-cell lung; disease free survival Introduction Case report Locally advanced non-small cell carcinoma of the lung is one of the good candidates for ir­radiation therapy because of its anatomical location. Despite radical radiation therapy, lo­cal recurrence is observed in 20 - 60 % of pa­tients with non-small cell lung cancer and the majority of all recurrences develop within 2 years after radiation therapy.1-3 We report a case of recurrence within a 9­year disease-free interval of the first course of irradiation therapy. Received 3 September 2003 Accepted 10 September 2003 Correspondence to: Hiroaki Satoh, M.D., Division of Respiratory Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba-city, Ibaraki, 305 8575, Japan; Phone: +81-29-853-3210; Fax: 81-29-853­3320; E-mail: hirosato@md.tsukuba.ac.jp In February 1991, a 58-year-old woman was admitted to our hospital with cervical lymph node swelling which she noticed three months prior to the presentation. She was ba­sically healthy without significant past med­ical history. Her physical examination re­vealed cervical lymph node adenopathy on the right. Bulkily swollen right mediastinal lymph nodes with a tumour of the right upper lobe, which was adjacent to the swollen lymph nodes, were observed on chest X-ray and CT scan on admission (Figure 1). Biopsy from the cervical lymph node revealed metastatic large cell carcinoma of the lung. A brain MRI and an ultrasound echogram of the abdomen and a bone scintigram revealed no metastasis, therefore we treated her as pa­tients with locally advanced disease in spite of there were proven metastases in the cervi­cal lymph nodes. However, we clinically di­agnosed this patient as large cell carcinoma of the lung of right upper lobe; clinical T3N2M1, stage IV. Thereafter, she received external ra­diation therapy to the primary lesion, medi­astinal and supraclavicular lymph nodes and right cervical lymph nodes with a total dose of 60 Gy in 30 fractions over 47 days. The re­sponse was evaluated as partial response; the patient then received one course of chemotherapy consisted of cisplatin, vin­desin, and ifosphamide. The patient was dis­charged from the hospital and followed up regularly. She was free of any signs of recur­rence until February 2001, when she devel­oped dry cough and dysarthria. Chest CT scan revealed loco-regional re­currence of the right upper lobe of the lung (Figure 2), and brain MRI shown multiple nodular metastases to the cerebrum (Figure 3). We also observed multiple uptakes on bone scintigram (Figure 4). The patient did not want to receive additional intensive ther­apy and she died of the disease one month af­ter the diagnosis of loco-regional recurrence and distant metastasis. Post-mortem exami­nation was not permitted. Discussion Radiotherapy is one the choice of treatment for locally advanced non-small cell lung can­cer owing to an anatomical restriction. Despite radical radiotherapy, a relatively high incidence of loco-regional recurrences has been observed.1-3 Although the majority of all loco-regional recurrences develop outside or at the margin of the treatment portal within 2 years after radiation therapy, some recur­rences have been observed after a long latent period.4-7 Most of the distant metastases also occur within 2 years after treatment and the common sites of distant metastases are the bones and/or lungs.3 Our patient developed recurrence inside the irradiation field and dis­tant metastases within a 9-year disease-free interval of the first course of radiation thera­py for the primary lesion and cervical lymph node metastasis. Many recent investigators have recom­mended chemotherapy with taxan for recur­rent non-small cell carcinoma.8,9 Very recent­ly, Gefitinib, an oral selective inhibitor of the epidermal growth factor receptor (EGFR) ty­rosine kinase, has been reported to be a safe agent, although some toxic effects, such as in­terstitial pneumonia, diarrhea and skin rash have been recognized.10-12 But our patient did not want to receive any additional intensive treatment. Moreover, the patient’s condition got worse very rapidly and she died of the dis­ease only one month after the diagnosis of re­currence. A general belief in the treatment of cancers has it that a cure is present if the disease-free interval is longer than five years. This con­cept may apply to the majority of cases of lung cancer, but rare cases do recur after many years of disease-free survival. Most of these patients who had long-term of disease-free interval were those with lung adenocar­cinoma.4-7 Therefore, a recurrence of large cell carcinoma of the lung within 9 years after irradiation is almost unique. Although the pa­tient had developed loco-regional recurrence and distant metastases, we had some hope for her additional long-term survival, because the patient had a long disease-free interval from the initial therapy to the recurrences and because there has been no deterioration in her performance status for more than 9 years after the completion of the radiation therapy. This observation suggests either a long period of dormancy of residual large cell carcinoma cells prior to re-initiation of prolif­erative activity or the presence of a more slowly growing population of residual cells. Certain clues of mechanism of the late re­currence might have existed in the clinoco-pathological information; but, at present, we are not able to detect the clues. Whatever mechanism was involved, it is clear that radi­cal radiation therapy did not provide certain cure in our patient. Despite a long-term dis-ease-free interval, large cell carcinoma of the lung represents a life-long threat to some pa­tients, and it requires constant vigilance by medical practitioners. Acknowledgement The authors special thank to Dr. Kiyoshi Ohara for his helpful advices. References 1. Cox JD, Eisert DR, Komaki R, Mietlowski W, Petrovich Z. Patterns of failure following treat­ment of apparently localized carcinoma of the lung. In: Muggia FM, Rozencweig M, editors. Lung Cancer: progress in therapeutic research. Vol 11. New York: Raven Press; 1979. p. 279-88. 2. Eisert DR, Cox JD, Komaki R. Irradiation for bronchial carcinoma: Reasons for failure. Cancer 1976; 37: 2665-70. 3. Perez CA, Pajak TF, Rubin P, Simpson JR, Mohiuddin M, Brady LW, et al. Long-term obser­vation of the patterns of failure in patients with unresectable non-oat cell carcinoma of the lung treated with definitive radiotherapy. Cancer 1987; 59: 1874-81. 4. Munnell ER, Dilling E, Grantham RN, Harkey MR, Mohr JA. Reappraisal of solitary bronchiolar (alve­olar cell) carcinoma of the lung. Ann Thorac Surg 1978; 25: 289-97. 5. Martini N, Bains MS, Burt ME, Zokowski MF, McCormack P, Rusch VW, et al. Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 1995; 109: 120-9. 6. Lenner R, Teirstein AS, Krellenstein DJ. Metachronous cancers or late recurrences after re­section of stage I lung cancer. Ann Thorac Surg 1999; 67: 548-9. 7. Kikuchi N, Satoh H, Sekizawa K, Ishikawa S. Late recurrence after resection of stage I lung adeno-carcinoma. Ann Thorac Surg 2003; 75: 1069-70. 8. Fossella FV, Lynch T, Shepherd FA. Second line chemotherapy for NSCLC: establishing a gold standard. Lung Cancer 2002; 38(Suppl 4): 5-12. 9. Lilenbaum RC, Schwartz MA, Seigel L, Belette F, Blaustein A, Wittlin FN, et al. Phase II trial of weekly docetaxel in second-line therapy for non-small cell lung carcinoma. Cancer 2001; 92: 2158­63. 10. Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, et al. Multi-institution­al randomized phase II trial of gefitinib for previ­ously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 2003; 21: 2237-46. 11. Pallis G, Mavroudis D, Androulakis N, Souglakos J, Kouroussis C, Bozionelou V, et al. ZD1839, a novel, oral epidermal growth factor receptor-tyro­sine kinase inhibitor, as salvage treatment in pa­tients with advanced non-small cell lung cancer. Experience from a single center participating a compassionate use program. Lung Cancer 2003; 40: 301-7. 12. Inoue A, Saijo Y, Maemondo M, Gomi K, Tokue Y, Kimura Y, et al. Severe acute interstitial pneumo­nia and gefitinib. Lancet 2003; 361: 137-9. review The role of cyclooxygenase-2 in the malignant tissue and possible applicability of cyclooxygenase-2 inhibitors in the therapy of cancer Mateja Legan Institute of Histology & Embryology, Medical Faculty, Ljubljana, Slovenia Cyclooxygenase-2 (COX-2), an inducible prostaglandin (PG) synthase, is elevated in many types of malig­nant and pre-malignant tissues. This enzyme is localized in neoplastic (epithelial) cells, microvascular en­dothelial cells, and stromal fibroblasts. Through the released PG it enhances carcinogenesis with increasing angiogenesis, inhibiting apoptosis, activating matrix metalloproteinases, suppressing of cell mediated anti-tumor immune response and protection against damage by cytotoxic agents. Evidences from in vitro stud­ies, studies on animal models as well as first clinical outcomes suggest that the inhibition of COX-2 may suppress carcinogenesis by affecting a number of pathways: inhibiting angiogenesis, invasiveness of tumors and promoting apoptosis. References forecast that COX-2 inhibitors, mostly COX-2 selective inhibitors, may get a role in the therapy of cancer as an adjuvant therapy or as an co-chemotherapeutic agent. The purpose of the present article is to summarize the most important facts about the role of COX-2 in the malignant tis­sue and discuss possible ways for potential therapeutic place of COX-2 inhibitors in clinical practice. Key words: neoplasms - drug therapy - physiology; cyclooxygenase inhibitors; apoptosis About cyclooxygenase Cyclooxygenase (COX) enzyme is a prostag­landin (PG) H synthase that catalyzes the rate limiting step in the production of PG and tromboxanes. It mediates the insertion of mo­lecular oxygen into arachidonic acid that is liberated from membrane glycerophospho- Received 25 July 2003 Accepted 11 August 2003 Correspondence to: Mateja Legan, M.D., Ph.D., Institute of Histology & Embryology, Medical Faculty, University of Ljubljana, Korytkova 2, SI-1000 Ljubljana, Slovenia; E-mail: mateja.legan@mf.uni-lj.si lipids and forms unstable intermediate PGG2 that is rapidly converted to PGH2 by the per­oxidase activity of COX. Specific isomerases then convert PGH2 into biologically active PGs, such as PGF2 alpha, PGE2, PGD2, PGI2, and thromboxane (TX) A2. PGs have important function in almost every organ sys­tem; they regulate diverse physiological processes, such as immunity, reproduction, maintenance of vascular integrity and tone, nerve growth and development and bone me­tabolism. PGs act as autocrine and paracrine mediators to signal changes within the imme­diate environment.1,2 There are two isoforms of COX: COX-1 and COX-2. They are encoded by different genes and express cell-specific regulation. COX-1 is constitutively expressed in most mammalian tissues and is responsible for normal kidney and platelet function and for the maintenance of gastrointestinal mucosa.3 On the other hand, COX-2 is not detected in most of normal tissues. It is induced by mito­genic and inflammatory stimuli, which re­sults in an enhanced synthesis of PGs in neo­plastic and inflamed tissues.4 COX-2 is overexpressed in several premalignant and malignant conditions There are growing evidences that COX-2 is commonly overexpressed in malignant tis­sue. Eberhart et al.5 first noted that COX-2 is upgraded in colorectal cancer. Till today, COX-2 overexpression was found in the colon adenoma and adenocarcinoma, stomac meta-plasia and adenocarcinoma, in Barrett’s esophagus and carcinoma of the esophagus, chronic hepatitis, hepatocellular carcinoma, cholangiocarcinoma, bill duct hyperplasia, adenocarcinoma and squamous cell carcino­ma of the lung, actinic keratose and squa­mous cell carcinoma of the skin, malignan­cies and premalignancies of the breast, blad­der, pancreas, head and neck.6-11 An enhanced expression of COX-2 is the result of increased transcription and stability of COX-2 mRNA12 due to oncogenes, growth factors, cytokines, chemotherapy and tumor promoters. COX-2 is expressed as an early re­sponse13 due to these factors. One possible mechanism of increased transcription of the COX-2 mRNA is the loss of wild-type p53, an inhibitor of transcription of COX-2 gene.14 In oral mucosal lesions, the expression of COX-2 protein increases from hyperplasia to dysplasia and is the highest in squamous-cell carcinoma.15 Chan et al.11 quantified the lev­els of COX-2 mRNA by RT-PCR and found that, in comparison to normal controls, COX­2 mRNA was increased 150-fold in the head and neck squamous-cell carcinoma and 50­fold in a normal appearing epithelium adja­cent to cancer. What are the precise COX-2 signaling pathways that promote tumorigenesis COX-2 in carcinogenesis may include multi­ple mechanisms that may act at different stages of malignant disease. PGs, especially of the E series, induce cell proliferation, an-giogenesis, invasion and metastases. Probably the most important role of COX-2 in tumorigenicity is enhancing angiogenesis of the tumor cells.2 Angiogenesis is the prereq­uisite for tumor development and metastasis. Hypoxia, like in-growing tumor tissue, in­duces in vitro COX-2 expression, thereby also increasing the expression of the proangio­genic growth factor VEGF - vascular endothe­lial growth factor.16 Studies by Cianchi et al.17 on 31 surgical specimens of colorectal carcinoma suggest that VEGF should be considered as one of the most important factors involved in the stimu­lation of tumor angiogenesis promoted by COX-2 activity in colorectal cancer. These in­vestigators found a significant correlation be­tween COX-2 and VEGF mRNA levels as well as VEGF protein levels in the colorectal spec­imens. Gallo18 showed that the COX-2 activa­tion in epidermal tumor cell lines causes a rapid induction of VEGF mRNA and VEGF production in the neoplastic cells. COX-2 can also directly stimulate endothelial cell migra­tion and growth factor induced angiogenesis with the production of eicosanoid products like TXA2, PGE2 and PGI2. Each of them is capable to stimulate the endothelial cell mi­gration, tube formation, and induction of growth factors.2 COX-2 also inhibits endothelial cell apop­tosis.3 The pathogenetic pathway is the stim­ulation of Bcl-2 transcription.3 Human mi-crovascular endothelial cells that overexpress Bcl-2 are refractory to the apoptotic and an-giosuppressive properties, and participate in more vigorous and sustained angiogenetic re­sponse.19 There are several studies on animal models that demonstrate these pathogenetic mecha­nisms. However, the recent clinical studies, where COX-2 expression was examined by immunohistochemistry, and correlated to clinicopathological features, are the most ex­pressive. Tomozawa et al.20 showed that COX­2 overexpression correlated with tumor re­currence and haematogenous metastasizing in colorectal cancer. In the study on esophageal squamous cell carcinomas by Kase et al.21 COX-2 expression was associated with an increased intratumoral microvessel density and suppressed tumor cell apoptosis. In the study on renal cell carcinomas of 131 patients by Miyata et al.,22 COX-2 immuno-histochemical expression was significantly associated with various clinicopathological features (like high T, N, M stage in high tu­mor grade), with microvessel density and metalloproteinase-2 expression, but not with the apoptotic index (p= 0.054). In multivariate analysis, COX-2 expression was not a signifi­cant prognostic factor for survival; the dis­ease stage stays the most significant determi­nant of patient’s survival. The same signifi­cant positive correlations between COX-2 ex­pression and lymph node metastases as well as histologic grade and tumor size were proved in the patients with breast carcino­ma.23 COX-2 is also involved in the suppression of cell-mediated anti-tumor immune re­sponse. PGE2, probably the most damaging final products of COX-2 enzymatic action, in­hibits, in vitro the production of tumor necro­sis factor alpha and induces the production of interleukin-10,24 a cytokine with immunosup­pressive effects. COX-2 also induces matrix metallopro­teinase production via PGE2.13 Matrix metal-loproteinase enzymes degrade the type IV collagen of basement membrane and thus in­crease the invasiveness of tumor cells. COX-2 may enhance the activation of pro-carcinogenesis - it can activate several classes of chemical carcinogens (aromatic and hete­rocyclic amines).25 Use of nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2 selective inhibitors in human cancers In the early 1990s, Thun et al.26 showed in their study that regular aspirin use at low dos­es may reduce the risk of colon cancer. They speculated that this could be mediated through the inhibition of PG synthesis. Several studies were then performed on the use of other nonsteroidal anti-inflammatory drugs (NSAIDs), which are among the oldest and most widely used drugs. They reported about a 50-percent lower risk of colorectal cancer in people who are continuously taking these drugs.27-29 Recent epidemiological stud­ies found a significant inverse association be-tween the intake of NSAIDs and the risk of breast cancer.30,31 Meta-analysis of 14 epi­demiological studies, analyzing the reduction of the risk for breast carcinoma with the use of NSAIDs was studied, showed that the reg­ular use of NSAIDs was associated signifi­cantly with an 18-percent reduction in breast carcinoma.32 Seven patients with head and neck squamous cell carcinoma (stages III and IV) were treated with different doses of in-domethacin for 2 to 7 weeks.33 Five of 7 pa­tients demonstrated tumor regression; in 3 of them, it was significant. The patients who did not receive indomethacin showed no de­tectable response. The studies led to the iden­tification of a molecular target, COX-2, in­volved in tumor promotion during colorectal cancer progression.34-36 It was also discovered that NSAIDs did not suppress COX-2 expres­sion or COX-2 protein level, but reduced its activity and inhibited PGE2 production.37 Encouraging results have now also been obtained with selective COX-2 inhibitors. Two different COX-2-selective inhibitors - ro­fecoxib and celecoxib - are currently avail­able. Reddy et al.34 reported that the adminis­tration of celecoxib to rats (male F344 rats with azoxymethane-induced colon carcino-genesis) during either stage of tumorigenesis inhibited the incidence as well as multiplicity of adenocarcinomas of the colon in a dose-de­pendent manner. It also suppressed colon tu­mor volume. This study provides the first ev­idence that celecoxib is very effective if given in the promotion or progression stage of colon carcinogenesis, indicating that chemo-preventive efficacy is achieved during the lat­er stages of colon tumor development. Also, the study on mice35 showed that selective COX-2 inhibitor prevented hematogenous metastases of colon cancer. In addition to studies on colorectal carcinomas, the selec­tive COX-2 inhibitor was used on human oral squamous cell carcinoma cell line (KB cells) implanted on the oral cavity of nude mice.38 The significant reduction of tumor growth was observed and the number of microves­sels, peripheral to the side of the tumor, was reduced. The study of Leahy et al.39 on FGF-2 treated rodent corneas showed that the use of celecoxib at a dose of 30 mg/kg/day per os inhibited angiogenesis by 79%, and PGE2 production by 73%. A 65-percent decrease of proliferation and a 2.5-percent increase of apoptosis were observed. The treatment with selective COX-2 in­hibitors inhibited the COX-2 enzyme selec­tively and did not lower the gastrointestinal PG levels associated with mucosal protection. Celecoxib 400 mg twice daily effectively de­creased the number and size of colon polyps in familial adenomatous polyposis with as lit­tle as 6 months of treatment;40 however the dose of celecoxib 100 mg twice daily was not associated with significant regression in the size and number of polyps. Clinical evidence indicates that COX-2 selective inhibitors offer the therapeutic benefits of traditional NSAIDs with less of the associated toxicity. Future directions Recent studies in humans indicate that the therapy with specific COX-2 inhibitors might be an effective approach to cancer prevention and treatment. As the treatment with com­monly used NSAIDs inhibit COX-1 and COX­2, the use of these agents may be limited by normal tissue toxicity, particularly that of gastrointestinal tract. Selective COX-2 in­hibitors exert potent antiinflammatory activi­ty but cause fewer undesired side effects. In both, the prevention of carcinogenesis and cancer therapy they may be more suitable as anticancer agents than standard NSAIDs. Based on the results of the study by Steinbach et al.,40 US Food and Drug Administration ap­proved celecoxib as adjuvant therapy for the patients with familial adenomatous polyposis (FAP). Similiarities between the biology of FAP and sporadic colorectal cancer suggest that the strategies effective in FAP might be applicable also in the patients with colorectal adenoma. Several clinical studies are already under way to assess the efficacy of selective COX-2 inhibitors (celecoxib and rofecoxib) in preventing sporadic colorectal adenomas in large population. Since COX-2 inhibitors protect against the formation of multiple tumor types in experi­mental animals, the potential utility on vari­ous target organs is also being examined. Therefore, cohorts of patients with Barrett’s dysplasia, premalignant oral lesions, bronchial metaplasia, basal cell nevi and ac­tinic keratosis are being treated.1 COX-2 in­hibitors could play a role in the chemopre­vention of epithelial cancers.13 COX-2 in­hibitors could have an additive role also in the treatment of some breast tumors. In the breast cancer tissue, aromatase activity for the production of estrogens is enhanced via the increased expression of the aromatase CYP19 gene by PGE2,41,42 which is increased by overexpression of COX-2 in neoplastic breast cells. The discovery that a selective COX-2 inhibitor suppresses aromatase activi­ty would be very important since a large num­ber of postmenopausal women who are at risk of breast cancer chronically use selective COX-2 inhibitors to treat artritis; thus an epi­demiologic study should not be problemati­cal. In preclinical models, a selective inhibitor of COX-2 potentiated the beneficial antitu­mor effects of ionizing radiation with no in­crease in normal tissue antitoxicity.43 A selec­tive COX-2-inhibitor-induced enhancement of tumor radioresponse was associated with a decrease in PGE2 levels, inhibition of neoan­giogenesis; however, there was no effect on radiation-induced apoptosis. This opens the possibility for the use of these drugs for the chemoprotection during the courses of ioniz­ing radiotherapy. Recent evidence indicates that COX-2 also increases multidrug resist­ance protein1 (also known as P-glycoprotein), an efflux pump for chemotherapeutic agents.44 This effect was prevented by the treatment with a selective COX-2 inhibitor.44 Although much work is required to establish the clinical significance of this interaction, it is appealing to speculate that selective COX-2 inhibitors will enhance the antitumor activity of cancer chemotherapy by reducing mul­tidrug resistance.1 Mohan and Epstein13 discussed the use of COX-2 inhibitors in the head and neck squa-mous-cell carcinoma and proposed that this drug may represent a strategy for the preven­tion of displasia and cancer. Although, the prevention and treatment with celecoxib seem promising, there are many obstacles that must not be overlooked. Selective COX-2 inhibitors have an excellent safety profile regarding gastrointestinal tract, but concerns have risen about cardiovascular safety.45 The incidence of myocardial infarc­tion has increased in the groups treated with Vioxx (rofecoxib) comparing with naproxen. By now, it is not certain whether this is a chance event, a pro-thrombotic effect of rofe­coxib or a cardioprotective effect of naprox-en. Further studies are needed. Most likely, selective COX-2 inhibitors could become promising adjuvant therapy in the prevention and treatment of certain carci­noma, next to radiation and/or chemothera­py. It is most promising, too, that COX-2 in­hibitor will be added to antiangiogenic chemotherapy. That clinical evaluation is ur­gently warranted. A possible indication for selective COX-2 inhibitor may also include secondary prevention of recurrent disease. Conclusions Combining the evidence from many studies, it may be concluded that the inhibition of COX-2 is a viable approach to cancer preven­tion and treatment. Despite these successes, many questions remain unanswered. Clearly, research on COX-2 offers more hope of find­ing new approaches to the treatment of can­cer. Acknowledgement Author would like to thank Prof. Dr. Andrej Cör for reading of the manuscript and helpful comments. References 1. Subbaramaiah K, Dannenberg AJ. Cyclooxygenase 2: a molecular target for cancer prevention and treatment. Trends in Pharmacological Sciences 2003; 24(2): 96-102. 2. Rao M, Yang W, Seifalian AM, Winslet MC. Role of cyclooxygenase-2 in the angiogenesis of col-orectal cancer. Int J Colorect Dis 2003. 3. Gately S. The contributions of cyclooxygenase-2 to tumor angiogenesis. Cancer and Metastasis Rev 2000; 19(1-2): 19-27. 4. Subbaramaiah K, Telang N, Ramonetti JT, Araki R, DeVito B, Weksler BB, et al. Transcription of cy­clooxygenase-2 is enhanced in transformed mam­mary epithelial cells. Cancer Res 1996; 56(19): 4424-9. 5. Eberhart CE, Coffey RJ, Radhika A, Gardiello FM, Ferrenbach S, DuBois RN. Up-regulation of cy­clooxygenase-2 gene expression in human colorac­tal adenomas and adenocarcinomas. Gastroen­terology 1994; 107(4): 1183-8. 6. Dannenberg AJ, Altorki NK, Boyle JO, Dang C, Howe LR, Weksler BB, et al. Cyclo-oxygenase 2: a pharmacological target for the prevention of can­cer. Lancet Oncol 2001; 2(9): 544-51. 7. Sung JJ, Leung WK, Go MY, To KF, Cheng AS, Ng EK, et al. Cyclooxygenase-2 expression in Helicobacter pylori-associated premalignant and malignant gastric lessions. Am J Pathol 2000; 157(3): 729-35. 8. Zimmermann KC, Sarbia M, Weber AA, Borchard F, Gabbert HE, Schror K. Cyclooxygenase-2 ex­pression in human esophageal carcinoma. Cancer Res 1999; 59(1): 198-204. 9. Kondo M, Yamamoto H, Nagano H, Okami J, Ito Y, Shimizu J, et al. 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Nor JE, Christensen J, Mooney DJ, Polverini PJ. Vascular endothelial growth factor (VEGF)- medi­ated angiogenesis is associated with enhanced en­dothelial cell survival and induction of Bcl-2 ex­pression. Am J Pathol 1999; 154(2): 375-84. 20. Tomozawa S, Tsuno NH, Sunami E, Hatano K, Kitayama J, Osada T, et al. Cyclooxygenase-2 over- expression correlates with tumour recurrence, es­pecially haematogenous metastasis, of colorectal cancer. Br J Cancer 2000; 83(3): 324-8. 21. Kase S, Osaki M, Honjo S, Adachi H, Tsujitani S, Kaibara N, et al. Expression of cyclo-oxygenase-2 is correlated with high intratumoral microvessel density and low apoptotic index in human esophageal squamous cell carcinomas. Virchows Arch 2003; 442(2): 129-35. 22. Miyata Y, Koga S, Kanda S, Nishikido M, Hayashi T, Kanetake H. Expression of cyclooxygenase-2 in renal cell carcinoma: correlation with tumor cell proliferation, apoptosis, angiogenesis, expression of matrix metalloproteinase-2, and survival. Clin Cancer Res 2003; 9(5): 1741-9. 23. Denkert C, Winzer KJ, Muller BM, Weichert W, Pest S, Kobel M, et al. Elevated expression of cy­clooxygenase-2 is a negative prognostic factor for disease free survival and overall survival in pa­tients with breast carcinoma. Cancer 2003; 97(12): 2978-87. 24. Kambayashi T, Alexander HR, Fong M, Strassmann G. Potential involvement of IL-10 in suppressing tumor-associated macrophages. Colon-26-derived prostaglandin E2 inhibits TNF-alpha release via a mechanism involving IL-10. J Immunol 1995; 154(7): 3383-90. 25. Wattenberg LW. Chemoprevention of cancer. Cancer Res 1985; 45(1): 1-8. 26. Thun MJ, Namboodiri MM, Heath CW Jr. Aspirin use and reduced risk of fatal colon cancer. N Engl J Med 1991; 325(23): 1593-6. 27. Marnett LJ. Aspirin and related nonsteroidal anti-inflammatory drugs as chemopreventive agents against colon cancer. Prev Med 1995; 24(2): 103-6. 28. Giovannucci E, Rimm EB, Stampfer MJ, Colditz GA, Ascherio A, Willett WC. Aspirin use and the risk for colorectal cancer and adenoma in male health professionals. Ann Intern Med 1994; 121(4): 241-6. 29. Giovannucci E, Egan KM, Hunter DJ, Stampfer MJ, Colditz GA, Willett WC, et al. Aspirin and the risk of colorectal cancer in women. N Engl J Med 1995; 333(10): 609-14. 30. Harris RE, Namboodiri KK, Farrar WB. Nonsteroidal antiinflammatory drugs and breast cancer. Epidemiology 1996; 7(2): 203-5. 31. Harris RE, Namboodiri KK, Farrar WB. Epidemiological study of nonsteroidal anti-inflam­matory drugs and breast cancer. Oncology Reports 1995, 2: 591-2. 32. Khuder SA, Mutgi AB. Breast cancer and NSAID use: a meta-analysis. Br J Cancer 2001; 84(9): 1188­92. 33. Panje WR. Regression of head and neck carcino­ma with a prostaglandin-synthesis inhibitor. Arch Otolaryngol 1981; 107(11): 658-63. 34. Reddy BS, Hirose Y, Lubet R, Steele V, Kelloff G, Paulson S, et al. Chemoprevention of colon cancer by specific cyclooxygenase-2 inhibitor, celecoxib, administered during different stages of carcino-genesis. Cancer Res 2000; 60(2): 293-7. 35. Tomozawa S, Nagawa H, Tsuno N, Hatano K, Osada T, Kitayama J, et al. Inhibition of haematogenous metastasis of colon cancer in mice by a selective COX-2 inhibitor, JTE-522. Br J Cancer 1999; 8(8): 1274-9. 36. Oshima M, Dinchuk JE, Kargman SL, Oshima H, Hancock B, Kwong E, et al. Suppression of intes­tinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 1996; 87(5): 803-9. 37. Chen WS, Wei SJ, Liu JM, Hsiao M, Kou-Lin J, Yang WK. Tumor invasiveness and liver metasta­sis of colon cancer cells correlated with cyclooxy­genase-2 (COX-2) expression and inhibited by a COX-2 selective inhibitor, etodolac. Int J Cancer 2001; 91(6): 894-9. 38. Nishimura G, Yanoma S, Mizuno H, Kawakami K, Tsukuda M. A selective cyclooxygenase-2 in­hibitor suppresses tumor growth in nude mouse xenografted with human head and neck squamous carcinoma cells. Japan J Cancer Res 1999; 90(10): 1152-62. 39. Leahy KM, Ornberg RL, Wang Y, Zweifel BS, Koki AT, Masferrer JL. Cyclooxygenase-2 inhibition by celecoxib reduces proliferation and induces apop­tosis in angiogenic endothelial cells in vivo. Cancer Res 2002; 62(3): 625-31. 40. Steinbach G, Lynch PM, Phillips RK, Wallace MH, Hawk E, Gordon GB, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenoma­tous polyposis. N Engl J Med 2000; 342(26): 1946­52. 41. Zhao J. Estrogen biosynthesis proximal to a breast tumor is stimulated by PGE2 via cyclic AMP, lead­ing to activation of promoter II of the CYP19 (aro­matase) gene. Endocrinology 1996; 137: 5739-42. 42. Brueggemeier RW, Quinn AL, Parrett ML, Joarder FS, Harris RE, Robertson FM. Correlation of aro­matase and cyclooxygenase gene expression in hu­man breast cancer specimens. Cancer Letters 1999; 140(1-2): 27-35. 43. Kishi K, Petersen S, Petersen C, Hunter N, Mason K, Masferrer JL, et al. Preferential enhancement of tumor radioresponse by a cyclooxygenase-2 in­hibitor. Cancer Res 2000; 60(5): 1326-31. 44. Patel VA, Dunn MJ, Sorokin A. Regulation of MDR-1 (P-glycoprotein) by cyclooxygenase-2. J Biol Chem 2002; 277(41): 38915-20. 45. Mukherjee D, Nissen SE, Topol EJ. Risk of cardio­vascular events associated with selective COX-2 inhibitors. JAMA 2001; 286(8): 954-9. review Survivin - an inhibitor of apoptosis and a new therapeutic target in cancer Jože Pižem1 and Andrej Cör2 1Institute of Pathology and 2Institute for Histology and Embryology, Medical Faculty, Ljubljana, Slovenia Survivin is a unique member of the inhibitor of apoptosis (IAP) protein family. It inhibits apoptosis by in­terfering with post-mitochondrial events during apoptosis, thus blocking activation of caspases. The expres­sion of survivin is among the most tumour specific of all human genes. It is overexpressed in most human cancers but is not detected in most normal tissues. Some molecular mechanisms of survivin upregulation in cancer have been elucidated, including loss of the wild-type p53. Tumours that overexpress survivin gener­ally bear a worse prognosis and are associated with resistance to therapy. Its differential expression in can­cer versus normal tissues makes survivin detection a useful tool in cancer diagnostics and a promising ther­apeutic target. Survivin targeting has resulted in increased spontaneous and induced apoptosis and inhibi­tion of tumour growth. Some anticancer drugs currently introduced into clinical practice might well act by inactivating survivin. Key words: apoptosis - drug effects; caspases; protein p53; neoplasms Introduction Apoptosis, programmed cell death, maintains the homeostasis in tissues by regulating the balance between cell proliferation and cell death. A diminished ability of cancer cells to undergo apoptosis has been recognised as an important mechanism of tumour growth and progression. Failure to undergo apoptosis in Received 11 August 2003 Accepted 2 September 2003 Correspondence to: Jože Pižem, Institute of Pathology, Medical Faculty, Korytkova 2, 1000 Ljubljana, Slovenia. E-mail: jozepizem@hotmail.com the face of unrepaired damage leads to en­hanced mutation, including chromosomal al­terations, and can be a cause of the genomic instability that is a general characteristic of cancer progression.1 Since the first descrip­tion of apoptosis, three decades ago, as a spe­cial type of cell death with unique morpho­logical characteristics, a complex genetic pro-gramme of cell suicide has been elucidated.2,3 In mammalian cells, apoptosis can be trig­gered either by extrinsic or intrinsic path­ways. An extrinsic pathway is initiated by lig­ation of death receptors on the cell surface (CD95/Fas receptor, tumour necrosis factor-. receptor) and acts through the activation of initiator caspase 8. An intrinsic pathway is triggered by multiple death signals, either in­tracellular (unrepaired DNA damage) or envi­ronmental, that all culminate in dysregulation of the mitochondrial function. It results in an increased permeability of the outer mitochon­drial membrane leading to release of mito­chondrial proteins, including cytochrome c and SMAC/DIABLO. These proteins facilitate initiator caspase 9 activation, through a multi-protein complex called apoptosome (Figure 1). Caspases, a family of cysteine proteases, are the key mediator molecules of apoptosis.4 They are present in the cell as inactive pre­cursors (procaspases) and are activated by proteolitic cleavage. Caspases are either ini­tiator caspases (caspase 8 and 9) or effector caspases (caspase 3 and 7). Initiator caspases are activated by self-processing in multimeric protein complexes (such as apoptosome). Activated initiator caspases, in turn, cleave downstream effector caspases in a proteolyt­ic cascade. Both intrinsic and extrinsic path­ways converge to activate effector caspases. Finally, activated effector caspases specifical­ly cleave cellular proteins that are involved in DNA repair, cytoskeletal organisation and nuclear integrity. This is the basis for mor­phological changes of apoptotic cells (nuclear fragmentation, condensation of the cyto­plasm, detachment from the neighbouring cells, apoptotic bodies formation) and their clearance by phagocytosis. Two gene families of apoptosis regulators have been identified - the Bcl2 family, and the inhibitor of apoptosis (IAP) family. Bcl2 pro­teins are thought to regulate mitochondrial Figure 1. Apoptotic pathways and the site of survivin antiapoptotic action. Intrinsic and extrinsic apoptotic path­ways are shown that converge into a common downstream pathway of effector capase activation. Survivin most probably blocks, directly and/or indirectly, caspase 9 activation. permeability by either decreasing or enhanc­ing the release of mitochondrial proteins, par­ticularly cytochrome c, therefore modulating the intrinsic pathway of apoptosis. In con­trast, IAP proteins possess only an inhibitory function and act downstream by preventing activation of caspase 9 in apoptosome and in­hibiting the activity of effector caspases.5 Survivin is a unique member of the IAP family. It is of special interest because it is overexpressed in most human cancers but is not detected in most normal tissues. This fact makes survivin a molecular marker of cancer and a promising cancer therapeutic target. Survivin structure and its subcellular distribution Human survivin is a 16.5 kDa intracellular protein that belongs to the inhibitor of apop­tosis (IAP) gene family. In humans, eight members of the IAP family have been identi­fied, including NAIP, XIAP, c-IAP1, c-IAP2, Ts-XIAP, ML-IAP, Apollon and survivin. IAPs are characterised by carrying 1-3 copies of a 70-amino-acid zinc-finger fold, which is des­ignated the baculovirus IAP repeat (BIR).6 Survivin is the smallest IAP member, having a single BIR repeat and a homodimeric struc­ture.7 It consists of 142 amino acids, its gene spans 14.5kb at the telomeric position of chromosome 17 and has four exons and three introns.8 A single copy of the survivin gene gives rise to three alternatively spliced transcripts. In addition to wild-type survivin, two sur­vivin isoforms are generated by the insertion of an alternative exon 2 (survivin-2B) or re­moval of exon 3 (survivin-.Ex-3).9 Because of the frameshift, the latter has a unique car-boxyl terminus sequence containing a nu­clear localisation signal, which is found ex­clusively in survivin-.Ex-3 and may be impli­cated in subcellular targeting survivin to mi-tochondria and nucleus.9,10 While survivin and survivin-.Ex-3 are both antiapoptotic, survivin-2B has lost its antiapoptotic poten­tial and might be a naturally occurring antag­onist of antiapoptotic survivin variants.10 In mitosis, survivin has been shown to lo-calise to various components of the mitotic apparatus, such as centrosomes and possibly microtubules. In tumour cells, the location of survivin is abnormal, with survivin present diffusely throughout the cytoplasm and often in the nucleus.6,11 Survivin shows a clear cell-cycle depend­ent expression at mitosis. This is largely con­trolled at the transcriptional level and medi­ated by cell-cycle dependent elements and cell-cycle homology regions that are located in the proximal survivin promoter. These re­gions are typically found in genes expressed in the G2/M phase of the cell cycle, such as cyclins A and B. In synchronised HeLa cells, transcription of the survivin gene is increased in G2/M by more than 10-fold, as compared to G1 or S arrested cells.12 Polyubiqutylation and proteasome-dependent degradation at in-terphase and mitotic phosphorylation leading to increased stability at metaphase contribute to survivin accumulation at mitosis. Especi­ally in non-transformed cells (CD34+ bone-marrow-derived stem cells, endothelial cells), survivin is upregulated in response to cy­tokine stimulation in a cell-cycle independent manner.5 Endothelial cells upregulate their survivin expression after stimulation with vascular endothelial growth factor (VEGF).6 Survivin expression in normal and neoplastic tissues Survivin expression has been extensively studied in neoplastic and non-neoplastic tis­sues by Western blotting, in situ hybridisa­tion and immunohistochemistry. Survivin is strongly and diffusely expressed in embryon­ic and foetal organs, but is undetectable in most terminally differentiated normal tis-sues. Adult normal cell types that express survivin include thymocytes, CD34+ bone-marrow-derived stem cells, endothelial cells, basal epithelial cells of colonic mucosa and epithelial cells of normal uterine cervix.5,13 Week signals have been detected in placenta and proliferative and secretory endometri­ um.8,14 Notably, in contrast to normal tissues, sur­vivin expression is dramatically upregulated in cancer, and survivin has been identified as the fourth trancriptome expressed in cancers of colon, lung, breast, brain and melanoma, but low or undetectable in the same normal organs.7 An analysis of a panel of 60 different cancer cell lines revealed ubiquitous expres­sion of survivin in all cell types, but at differ­ent levels.12 The molecular mechanisms of survivin overexpression in cancer seem to be complex and are only partially understood. Given the widespread survivin expression in many types of cancer, it is very likely that multiple pathways are involved in the reactivation of the survivin gene. There is compelling evi­dence that survivin overexpression does not simply reflect the presence of a higher num­ber of proliferating cells, as the percentage of survivin positive cells in a tumour typically exceeds the number of proliferating cells measured by Ki67 labelling.5 Several molecular mechanisms implicated in survivin overexpression in cancer have been elucidated. In neuroblastoma, a fre­quent genetic abnormality is amplification of 17q25, containing the survivin locus.15 Survivin exon 1 sequences are silenced by metilation in normal ovaries, but become un­metilated, and thus transcriptionally active in ovarian cancers.7 Recently, wild-type p53, but not mutant p53, was shown to repress sur­vivin expression in various human cancer cell lines.16,17 A positive correlation between sur­vivin expression and p53 accumulation (indi­cating its mutation) has been reported in gas­tric cancer18, pancreatic adenocarcinoma19, but not in transitional cell carcinoma of the upper urinary tract20 or colorectal carcino­ma.21 Upregulation of survivin in colorectal cancer might result from APC (adenomatous polyposis coli) mutations.5 Survivin overexpression has been shown in preneoplastic lesions of the skin (actinic keratosis), pancreas (intraductal neoplasia), uterine cervix (intaepithelial neoplasia) and colonic adenomas, suggesting that survivin upregulation occurs early during tumourigen­ esis.5,12,13,22,23 In colorectal carcinogenesis, there is a significant increase of survivin pos­itive cases in transition from normal mucosa to adenoma with low dysplasia and from ade­noma with low dysplasia to adenoma with high dysplasia.24,25 Three patterns of immunostaining to sur­vivin are generally observed in tumour cells: 1. staining confined to the cytoplasm, 2. pre­dominantly nuclear staining and 3. intense staining of mitotic figures (Figure 2). While early immunohistochemical studies reported the expression of survivin limited to the cyto­plasm, subsequent studies also showed nu­clear localisation of survivin. Differential sub-cellular localisation of survivin could reflect the presence of different survivin splice vari­ants. Survivin and survivin-2B preferentially localise in the cytoplasm, whereas survivin-.Ex-3 localises in the nucleus.10 Never­theless, results might be at least partially in­fluenced by the use of different antibodies that recognise different epitopes. It is possi­ble that the subcellular pools of survivin are immunohistochemically distinct, potentially reflecting post-translational modifications and/or epitope accessibility.5 Survivin function The molecular mechanisms of survivin action are not fully elucidated and are, at least in some aspects, controversial. Nevertheless, it is a generally accepted view that survivin is an inhibitor of apoptosis and it interferes with cell-cycle progression and microtubule stability. There is a huge body of experimental evi­dence characterising survivin as an inhibitor of apoptosis. In cell culture systems, overex­pression of survivin has been consistently as­sociated with inhibition of apoptosis initiated by both the extrinsic and intrinsic pathways.5 Survivin counteracts apoptosis induced by certain chemotherapeutic drugs.12 Apoptosis, either spontaneous or induced, is suppressed in organs and tissues of transgenic animals that express survivin.5 In general, mammalian IAPs block apopto-sis by direct or indirect inhibition of terminal effector caspase 3 and 7 and initiator caspase 9.6,12 There is no good evidence that survivin operates through direct contact with effector caspases. Recent studies suggest that sur­vivin particularly inhibits the intrinsic path­way of apoptosis by interacting with post-mi­tochondrial events, as indicated by its ability to localize to mitochondria and to associate with caspase 9 and SMAC/DIABLO (Figure 1).5,8,26 In addition to its role in inhibiting apopto-sis, survivin localisation to the mitotic appara­tus indicates its role in cell division. Targeting survivin has resulted in aberrant mitotic pro­gression, leading to failed cytokinesis and multinucleation.5 Survivin is indispensable during embryonic development; its homozy­gous deletion in mice leads to inevitable lethality at day 4-5, due to defects in mitotic spindles formation.6 The apparent require­ment for survivin in normal cell division sug­gests that overexpression of survivin in tu­mours could perturb normal cell cycle control. Survivin as a diagnostic and prognostic marker of cancer Its differential expression in cancer, com­pared to most normal tissues, makes survivin a candidate for a molecular marker of cancer. Generally, survivin is (over)expressed in the majority of cases within a certain tumour type, the percent of positive cases ranging typically from approximately 30% to 100%.12 Moreover, in retrospective trials, high sur­vivin expression in tumours has been associ­ated with shortened overall survival, an in­creased rate of recurrence and resistance to radiation and chemotherapy.8,14,24,27,28 These data, in conjunction with a dual role of sur­vivin in inhibiting apoptosis and promoting cell proliferation, indicate that survivin might confer growth and survival advantages for tu­mour onset and progression.5 Indeed, an as­sociation between survivin expression and di­minished apoptotic rates and/or higher pro­liferation activity has been reported.14,24,27,28 There is good evidence that survivin is a pow­erful negative prognostic marker in most tu­mours studied. This fact might warrant a sim­ple immunohistochemical detection of sur­vivin in tumour specimens, which might pro­vide a quick prognostic indicator for identify­ing patients at risk of recurrent disease and those who would benefit from more aggres­sive follow-up and alternative treatment pro­tocols.7 Survivin can be detected in biological flu­ids of cancer patients, as a result of the shed-ding of tumour cells from the primary sites. Survivin detection in the urine has proved to be a specific and sensitive marker of bladder cancer. Alternatively, circulating antisurvivin antibodies have been detected in cancer pa­tients and detecting them could provide a po­tential diagnostic (screening) tool.7 Survivin as a therapeutic target Survivin is an attractive therapeutic target be­cause it is selectively expressed in cancer and is potentially required for the viability of can­cer cells. A survivin-based anticancer therapy would be expected to carry limited toxicity for normal cells and to be effective in remov­ing the general cell-viability system provided by survivin overexpression.29 Various approaches to targeting survivin have been tested in vitro and in vivo. Survivin synthesis (translation from survivin mRNA) can be blocked by using antisense technology and ribozymes. With the use of these ap­proaches, loss of survivin expression can be sufficient to trigger apoptosis, to enhance chemotherapy-induced and radiotherapy-in­duced apoptosis and to dysregulate cell pro­liferation in tumour but not in normal cells.5,30 Experiments using phosphorilation defec­tive survivin mutant Thr34.Ala revealed that phosphorilation of threonin at position 34 is required for cancer cell viability and might contribute to survivin stability at mito­sis. Wild-type survivin is phosphorilated at Thr34 by mitotic kinase Cdc2-cyclin-B1. Survivin mutant Thr34.Ala functions as a dominant-negative mutant that competes with wild-type survivin, thereby blocking its activity. Adenoviral delivery of survivin Thr34.Ala suppressed tumour growth in cancer xenograft models in vivo.6 Survivin phosphorilation at Thr34 can be inhibited pharmacologically by recently de­veloped antagonists of cyclin-dependent ki­nases, such as flavopiridol, which blocks cy-clin-dependent kinases, including Cdc2.5 Recent observations suggest that T cells can mount a cytolytic response against sur­vivin peptides and HLA class I restricted cy­tolytic T cells exist in patients with different cancers in vivo. A cancer specific immune re­sponse to survivin might therefore be used for potential vaccination strategies.5 Survivin is expressed in endothelial cells during angiogenesis and is associated with re­sistance to apoptosis. Ablation of survivin during angiogenesis caused endothelial cell apoptosis and promoted involution of three-dimensional capillary-like vessels in vitro. Therefore, by survivin targeting, tumour growth suppression could be at least partially mediated by inhibition of tumour angiogene- sis.7,31 Conclusions Survivin is an inhibitor of apoptosis and might be required for maintenance of cancer cell viability and cell-cycle progression. Its differential expression in cancer cells versus normal tissues has two important implica­tions; it makes survivin a molecular marker of cancer and an attractive therapeutic target. Survivin is expressed in the majority of vari­ous cancers studied and, notably, it is gener­ally considered a negative prognostic marker of cancer. Various strategies to targeting sur­vivin in cancer cells are currently under in­vestigation, giving promising results in in vit­ro and in vivo models. Moreover, some cur­rently explored anticancer agents might me­diate their anticancer effects by inhibiting the survivin pathway. References 1. Williams GT, Chritohlow MR, Hedge VL, O’Hare KB. Molecular failure of apoptosis: inappropriate cell survival and mutagenesis. Toxical Lett 1998; 102: 485-9. 2. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basis biological phenomenon with wide-ranging impli­cations in tissue kinetics. Br J Cancer 1972; 26: 239­57. 3. Hengartner MO. The biochemistry of apoptosis. Nature 2000; 407: 770-6. 4. Pižem J, Cör A. Kaspaze. Med Razgl 2001; 40: 283­91. 5. Altieri DC. Validating survivin as a cancer thera­peutic target. Nat Rev Cancer 2003; 3: 46-54. 6. Reed JC. The survivin saga goes in vivo. J Clin Invest 2001; 108: 965-69. 7. Altieri DC. The molecular basis and potential role of survivin in cancer diagnosis and therapy. Trends Mol Med 2001; 7(12): 542-47. 8. Tetsuhisa Y, Nobuhiko T. The role of survivin as a new target of diagnosis and treatment in human cancer. Med Electron Microsc 2001; 34: 20-12. 9. Mahotka C, Wenzel M, Springer E, Gabbert HE, Gerharz CD. Survivin-.Ex3 an survivin-.2B: Two novel splice variants of the apoptosis inhibitor survivin with different antiapoptotic properties. Cancer Res 1999; 59: 6097-02. 10. Mahotka C, Liebmann J, Wenzel M, Suschek CV, Schmitt M, Gabbert HE et al. Differential subcel­lular localisation of functionally divergent survivin splice variants. Cell Death Differ 2002; 9(12): 1334-42. 11. Okada E, Murai Y, Matsui K, Isizawa S, Cheng C, Masuda M et al. Survivin expression in tumour cell nuclei is predictive of favorable prognosis in gastric cancer patients. Cancer Lett 2001; 163: 109­16. 12. Altieri DC, Marchisio C. Survivin apoptosis: an in­terloper between cell death and cell proliferation in cancer. Lab Invest 1999; 79(11): 1327-33. 13. Frost M, Jarboe EA, Orlicky D, Gianani R, Thompson LC, Enomoto T et al. Immunohisto-chemical localisation of survivin in benign cervical mucosa, cervical dysplasia, and invasive squa­mous cell carcinoma. Am J Clin Pathol 2002; 117(5): 738-44. 14. Takai N, Miyazaki T, Nishida M, Nasu K, Miyakawa I. Survivin expression correlates with clinical stage, histological grade, invasive behav­iour and survival rate in endometrial carcinoma. Cancer Lett 2002; 184: 105-16. 15. Adida C, Berrebi D, Peuchmaur M, Reyes-Mugica M, Altieri DC. Antiapoptosis gene, survivin, and prognosis in neuroblastoma. Lancet 1998; 351: 882-3. 16. Mirza A, McGuirk M, Hockenberry TN, Wu Q, Ashar H, Black S et al. Human survivin is nega­tively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway. Oncogene 2002; 2: 2613-22. 17. Hoffman WH, Biade S, Zilfou JT, Chen J, Murphy M. Transcriptional repression of the anti-apoptot­ic survivin gene by wild type p53. J Biol Chem 2002; 277(5): 3247-57. 18. Lu C-D, Altieri DC, Tanigawa N. Expression of a novel antiapoptosis gene, survivin, correlated with tumor cell apoptosis and p53 accumulation in gas­tric carcinomas. Cancer Res 1998; 58: 1808-12. 19. Sarela AI, Verbeke CS, Ramsdale J, Davis Cl, Markham AF, Guillou PJ. Expression of survivin, a novel inhibitor of apoptosis and cell cycle regula­tory protein, in pancreatic adenocarcinoma. Br J Cancer 2002; 86: 886-92. 20. Nakanishi K, Tominaga S, Hiroi S, Kawai T, Aida S, Kasamatsu H et al. Expression of survivin does not predict survival in patients with transitional cell carcinoma of the upper urinary tract. Virchows Arch 2002; 441: 599-63. 21. Sarela AI, Scott N, Ramsdale J, Markham AF, Guillou PJ. Immunohistochemical detection of the anti-apoptosis protein, survivin, predicts survival after curative resection of stage II colorectal carci­noma. Ann Surg Oncol 2001; 8(4): 305-10. 22. Satoh K, Kaneko K, Hirota M, Masamune A, Satoh A, Shimosegawa T. Expression of survivin is cor­related with cancer cell apoptosis and is involved in the development of human pancreatic duct cell tumours. Cancer 2001; 92: 271-8. 23. Kim HS, Shiraki K, Park SH. Expression of sur­vivin in CIN and invasive squamous cell carcino­ma of uterine cervix. Anticancer Res 2002; 22(2A): 805-8. 24. Kawasaki M, Toyoda M, Shinohara H, Okuda J, Watanabe I, Yamamoto T et al. Expression of sur­vivin correlates with apoptosis, proliferation, and angiogenesis during human colorectal tumorigen­esis. Cancer 2001; 91: 2026-32. 25. Lin LJ, Zheng CQ, Jin Y, Ma Y, Yiang WG, Ma T. Expression of survivin in colorectal carcinogene-sis. World J Gastroenterol 2003; 9(5): 974-7. 26. Song Z, Yao X, Wu M. Direct interaction between Smac/DIABLO is essential for the antiapoptotic activity of survivin during taxol-induced apopto-sis. J Biochem Chem 2003; 278(25): 23130-40. 27. Sarela AI, Verbeke CS, Ramsdale J, Davis Cl, Markham AF, Guillou PJ. Expression of survivin, a novel inhibitor of apoptosis and cell cycle regula­tory protein, in pancreatic adenocarcinoma. Br J Cancer 2002; 86: 886-92. 28. Ikeguchi M, Ueda T, Sakatani T, Hirooka Y, Kaibara N. Expression of survivin messenger RNA correlates with poor prognosis in patients with he-patocellular carcinoma. Diag Mol Pathol 2002; 11(1): 33-40. 29. Altieri D. Blocking survivin to kill cancer cells. Methods Mol Biol 2003; 223: 533-42. 30. Pennati M, Binda M, Colella G, Folini M, Citti L, Villa R et al. Radiosensitation of human melanoma cells by rybozyme mediated inhibition of survivin expression. J Invest Dermatol 2003; 120(4): 648-54. 31. Tran J, Master Z, Yu Jl, Rak J, Dumont DJ, Kerbel RS. A role for survivin in chemoresistance of en­dothelial cells mediated by VEGF. PNAS 2002; 99(7): 4349-54. Radio/ Oncol 2003; 37(3): 141-53. Deset let revije Radiology and Oncology nekaj bibliometrijskih izmer Musek M, Oven M, Južnic P Izhodišce. Bibliometrija s svojimi metodami predstavlja zelo koristen nabor orodij za anal­iziranje relativne pomembnosti strokovne revije znotraj njene stroke. S pomocjo kvantitativnih meritev vsebine in primerjavami s podobnimi revijami v stroki si tudi uredniki lahko pomagajo pri odlocitvah glede nadaljnih usmeritev uredniške politike. Cilji in metode. Vzeli smo zadnjih deset letnikov (1992-2001) revije Radiology and Oncology in njeno celotno vsebino spustili skozi dvojno merjenje: s prvim merjenjem smo zasledovali cilj, da se s pomocjo raznih kvantitativnih bibliometricnih metod pridobi bolj objektivna slika o celotni reviji in njenem razvoju v zadnjih desetih letih; nato pa smo s pomocjo primerjave s sorodno mednarodno revijo, Neoplasma, ugotovljali, ce so razlike in/ali podobnosti med obema, obravna­vani reviji v korist ali škodo. Rezultati in zakljucek. Rezultati kažejo, da se je revija dobro razvila, toda potrebni bodo dodat­ni napori ožjega uredništva in aktivna pomoc uredniškega odbora, da privabijo vec kvalitetnih clankov in s tem povecajo njihovo število na zvezek, ter da postopoma povecujejo delež eksper­imentalnih clankov, kar, kot kažejo izkušnje, lahko zviša relativni vpliv revije v stroki. Revija bi si lahko tudi povecala ugled tako, da bi vsi avtorji, ki v njej objavljajo, svoje objave v Radiology and Onocology smiselno vkljucevali med citate v clanke, ki jih objavljajo drugje. Radio/ Oncol 2003; 3 7(3): 203-8. Radio/ Oncol 2003; 2 7(3): 155-9. Nepricakovana diagnoza pred ušesne otekline -prikaz dveh primerov Roic G, Posaric V, Marušic A, Boric I, Vlahovic T, Vrlicek K Izhodišca. Pri otrocih so lahko predušesne otekline povezane z najrazlicnejšimi boleznimi. Anamneza, klinicni znaki in slikovne preiskave so veckrat neznacilni. Pri nacrtovanju preiskav moramo pomisliti tudi, da je vzrok takšne otekline sprememba na kosti. Prikaz primerov. Porocamo o dveh primerih bolnikov, ki so bili napoteni v našo bolnico zaradi predušesne otekline in pri katerih smo nepricakovano ugotovili aneurizmalno kostno cisto in ve­likocelicni granulom. Zakljucki. Pomembna je velika pozornost pri ugotavljanju vzroka takšnih predušesnih spre­memb, da se izognemu napacni diagnozi in s tem tudi napacnemu zdravljenju. Rentgenološka preiskava veckrat ne zadošca. Ultrazvok z visoko locljivostjo omogoca natancno preiskavo mehkih tkiv in pomaga pri diferencialni diagnozi ter omogoca natancno lokalizacijo bolezenske spremembe. Dodatna CT preiskava pa prikaže mesto, strukturo in velikost bolezenske spre­membe. Radio/ Oncol 2003; 37(3): 161-5. Ugotavljanje gnojnega hidradenitisa s transrektalno in transperinealno ultrazvocno preiskavo Kolodziejczak M, Stefariski R, Sudol-Szopiriska I, Jakubowski W Izhodišca. Namen clanka je predstaviti uporabnost transrektalne in transperinealne ultarzvocne preiskave pri ugotavljanju diferencialne diagnoze gnojnega hidradenitisa z analno fistulo. Bolniki in metode. Pri 8 bolnikih, ki smo jim klinicno ugotovili analno fistulo (6 bolnikov) ali gnojni hidradenitis (2 bolnika), smo naredili transrektalno in transperinealno ultrazvocno preiskavo, ker smo želeli natancneje opredeliti vnetne spremembe v analnem kanalu. Rezultati. Pri vseh bolnikih je transrektalna ultrazvocna priskava pokazala ohranjene strukture analnega kanala, transperinealna preiskava pa je potrdila superficialno lokacijo patoloških spre­memb. Zakljucki. Transrektalna in transperinealna ultrazvocna preiskava sta koristni za razlikovanje gnojnega hidradenitisa in analne fistule. Uporaba obeh metod omogoca natancno diagnozo. Radio/ Oncol 2003; 3 7(3): 203-8. Radio/ Oncol 2003; 37(3): 167-74. Pljucnica kot vzrok smrti pri bolnikih s pljucnim rakom Zi.ba M, Baranowska A, Krawczyk M, Noweta K, Grzelewska-Rzymowska I, Kwiatkowska S Izhodišca. Na bolnišnicnih pljucnih oddelkih predstavlja pljucni rak resen klinicni izziv. Pri mnogih bolnikih s pljucnim rakom je pljucnica sekundarni vzrok smrti in ne nastane samo zara­di napredovanja osnovne bolezni, ampak tudi zaradi stranskih ucinkov zdravljenja, ki pred­stavljajo negativen vpliv na imunski odgovor organizma. Klinicne in radiološke znake infekci­jske bolezni si lahko napacno razlagamo kot napredovanje pljucnega raka. Tako je pri vsakem poslabšanju bolnikovega stanja izredno pomembno, da ugotovimo pravi vzrok poslabšanja, saj to bistveno vpliva na nacin zdravljenja. Bolniki in metode. Retrospektivno smo analizirali 70 bolnikov, ki so umrli v letih 1997-1999 na Oddelku za tuberkulozo in pljucne bolezni Medicinske fakultete v :Eudiiu zaradi pljucnega raka. Narejene so bile klinicne in bakteriološke preiskave s posebnim poudarkom na ugotavljanju pljucnice kot vzroka smrti. Rezultati. Pljucnico smo diagnosticirali pri 41 bolnikih s pljucnim rakom (58,5%) in streptokok pneumonije je bil najpogostejši etiološki dejavnik pljucne okužbe. Pri bolnikih z drobnocelicn­im rakom pljuc sta obsežnost vnetnih sprememb na rentgenogramih in število leukocitov nega­tivno korelirala s casom hospitalizacije (R = -0,6 in R = -0,54; p<0,05). Zakljucki. Ceprav predstavlja pljucni rak glavni vzrok smrti na našem Oddelku za tuberkulozo in pljucne bolezni Medicinske fakultete v :Eudiiu, pa je bila pljucnica diagnosticirana v kar 58,5 % kot sekundarni vzrok smrti pri bolnikih s pljucnim rakom. Radio/ Oncol 2003; 27(3): 175-81. Radioterapija pri bolniku z ne-Hodgkinovim limfomom testisa, stadij IAE -prikaz primera Juretic A, Živkovic M, Gamulin M, Herceg T, Bagovic D, Kucan D, Zeljko Ž, Ajdukovic R Izhodišca. Namen clanka je opisati obsevalno tehniko pri bolniku, ki smo ga zdravili zaradi pri­marnega ne-Hodgkinoveha limfama (NHL) testisa, stadij IEA. Histološki izvid je pokazal, da je imel bolnik CD20 pozitiven NHL, oz. difuzno folikularen centrocitni (FCC) limfam, gradus III. Ker so primarni NHL-i redki, do sedaj ni bilo izdelanih splošno sprejetih nacel, kako takšne bol­nike obsevati. Bolezen NHL testisa poteka sorazmerno agresivno, zato so ponovitve bolezni pogoste tudi pri bolnikih, ki imajo zgodnji stadij bolezni (stadij I in II), in so bili po dosedanjih nacelih optimalno zdravljeni (z orhiektomijo, polikemoterapijo in obsevanjem). Prikaz primera. Bolniku smo ugotovili natancno diagnozo junija 2001, ko je bila narejena orhiek­tomija. Nato je prejel 6 krogov polikemoterapije (CHOP) in tudi intratekalno kemoterapijo z metotreksatom. Sledilo je obsevanje z enim direktnim poljem in z energijo 6 megavoltov na lin­earnem pospeševalniku. Obsevalno polje je obsegalo kontralateralni testis (skrotum) in ingvi­nofemoralne limfne bezgavke. Obsevalna doza je bila 30 Gy, ki smo jo aplicirali s 15 frakcijami in je bila dolocena na globini 4 cm. Zdravljenje z obsevanjem smo koncali decembra 2001. Bolnika smo redno kontrolirali, tudi ob zadnjem pregledu maja 2003 je bil brez znakov bolezni. Zakljucki. Ker je ponovitev bolezni pri NHL testisov pogosta ekstranodalno ne pa v predelih limfnih bezgavk, ne moremo dokoncno priporociti, katere predele naj pri bolniku obsevamo. Radio! Oncol 2003; 37(3): 183-6. Dolgotrajno preživetje brez znakov bolezni pri bolnici, ki smo jo obsevali zaradi lokalno napredovalega pljucnega raka. Prikaz primera Haraguchi N, Satoh H, Homma T, Sekizawa K Izhodišca. Namen pricujocega zapisa je prikazati primer bolnice z dolgotrajnim preživetjem brez znakov bolezni po zdravljenju z obsevanjem lokalno napredovalega pljucnega raka. Prikaz primera. 58-letno bolnico z velikocelicnim karcinomom pljuc in metastazami v vratnih bezgavkah smo zdravili z radikalnim obsevanjem. 9 let je bila brez znakov bolezni, nato pa smo ugotovili ponovitev bolezni lokoregionalno in z oddaljenimi zasevki. Zakljucki. Kljub dolgotrajnemu preživetju brez znakov bolezni moramo bolnike z nedrobno­celicnim rakom pljuc kontrolirati vse življenje. Priporocamo skrbno spremljanje bolnikov s povecanim tveganjem ponovitve bolezni. Radio/ Oncol 2003; 37(3): 203-8. Radio/ Oncol 2003; 37(3): 187-94. Vloga ciklooksigenaze-2 v malignem tkivu in možnosti uporabe njenih zaviralcev v zdravljenju raka Mateja Legan Encim ciklooksigenaza-2 je inducibilna prostaglandinska sintaza. Njeno povecano izražanje so opisali v številnih premalignih in malignih tkivih. Preko povecanega sprošcanja prostaglandinov pospešuje karcinogenezo, tako da pospeši tumorsko angiogenezo, zavira apoptozo, aktivira ma­triksne metaloproteinaze. Zavira tudi celicno posredovan antitumorski imunski odgovor in šciti pred poškodbami s citotoksicnimi ucinkovinami. Cikloosigenaza-2 je lokalizirana v neoplas­ticnih epitelijskih celicah, endotelijskih celicah novonastalega tumorskega žilja, v fibroblastih in vnetnih celicah tumorske strome. Dokazi iz študij in vitro, raziskave na živalskih modelih ter prvi klinicni rezultati kažejo, da zaviralci COX-2 lahko upocasnijo karcinogenezo z zaviranjem an­giogeneze, zmanjšanjem invazivnosti tumorja in pospeševanje apoptoze tumorskih celic. Rezultati nakazujejo možno in zelo verjetno vlogo zaviralcev COX-2, predvsem selektivnih zavi­ralcev COX-2, v zdravljenju raka kot dodatna (adjuvantna) terapija, oz. so-kemoterapevtik, tako v primarni preventivi, zdravljenju kot tudi zašciti pred ponovitvijo bolezni. Namen preglednega clanka je predstaviti spoznanja o vlogi ciklooksigenaze-2 v malignem tkivu ter poiskati ter­apevtsko mesto zaviralcev COX-2 v klinicni praksi. Radio/ Oncol 2003; 37(3): 195-202. Zaviralec apoptoze survivin kot tarca ciljanega zdravljenja raka Pižem J, Cor A Survivin sodi v družino beljakovin zaviralcev apoptoze (inhibitor of apoptosis, IAP). Zavira ak­tivacijo kaspaz, tako da vpliva na »po-mitohondrijske« dogodke med apoptozo. Survivin se (prekomerno) izraža v vecini tumorjev, v normalnih tkivih pa ne. Poznani so nekateri moleku­larni mehanizmi, ki so odgovorni za prekomerno izražanje survivina v tumorjih, eden takih je izguba divjega tipa beljakovine p53. Tumorji, ki izražajo survivin, so v splošnem manj obcutljivi na zdravljenje, preživetje bolnikov je slabše. Zaradi razlicnega izražanja survivina v tumorskem in netumorskem tkivu je survivin uporaben v molekularni diagnostiki tumorjev, hkrati pa primerna tarca za razvoj takšnega nacina zdravljenja, ki je usmerjeno proti tumorju in cim manj poškoduje normalna tkiva. Zaviranje delovanja survivina vodi v povecano spontano ali sproženo celicno smrt (apoptozo), kar zavre rast tumorja. Nekatera novejša zdravila proti raku verjetno delujejo v veliki meri preko zaviranja delovanja survivina. Notices Notices submitted for publication should contain a mailing address, phone and/ or fax number and/or e-mail of a Contact person or department. Radiation therapy October 19-23, 2003 ASTRO Annual meeting will be held in Salt Lake City, Utah, USA. Contact American Society for Therapeutic Radiology and Oncology Office, 1891 Preston White Drive, Reston, VA 20191, USA; or see http://www. astro.org Breast cancer November 1-5, 2003 The »24th Congress of the International Association for Breast Cancer Research« will be offered in Sacramento, California, USA. Contact Continuing Medica! Education UCDAVIS School of Medicine, 3560 Business Drive, Suite 130, Sacramento, CA 95820, USA; or call +1 916 734 5390; or fax +1 916 453 9429. Pleural mesothelioma November 7-8, 2003 The international conference will be offered in Como, Italy. Contact ASK, International Conference Como 2003, Via Tabacchi, 20, 21056 lnduno Olona (VA), ltaly; or call +39 0332 840650; or fax +39 0332 204028; or e­mail ask@skylink.it Lung cancer November 8, 2003 The international conference »Lung Cancer Screening and Early Diagnosis« will be offered in Como, ltaly. Contact ASK, International Conference Como 2003, Via Tabacchi, 20, 21056 Induno Olona (VA), Italy; or call +39 0332 840650; or fax +39 0332 204028; or e­mail ask@skylink.it Radiation oncology November 9-14, 2003 The ESTRO teaching course »Evidence-Based Radiation Oncology: Methodological Basis and Clinical Application« will take place in Lisbon, Por­tugal. Contact ESTRO office, Avenue E. Mounier, 83/12, B-1200 Brussels, Belgium; or call +32 775 93 40; or fax +32 2 779 54 94; or e-mail info@estro.be; or see http:// www.estro.be Radiation oncology March, 2004 The ISRO international teaching course on »Radiation Oncology in the 21st Century« will take place in Cape Town, South Africa. See http://www.isro.be Surgical oncology March 31 -April 3, 2004 The 12th ESSO Congress will be held in Budapest, Hungary. See http://www.fecs.be/conferences/esso2004 Oncology April 15-17, 2004 The European Oncology Nursing Society EONS Spring Convention will be held in Edinburg, UK. See http :j /www.fecs.be/ conferences/ eons4 Radio/ Oncol 2003; 37(3): 209-11. Brachytherapy May 13-15, 2004 The Annual Brachytherapy Meeting GEC-ESTRO will take place in Barcelona, Spain. Contact ESTRO office, Avenue E. Mounier, 83/12, B-1200 Brussels, Belgium; or call +32 775 93 40; or fax + 32 2 779 54 94; or e-mail info@estro.be; or see http://www.estro.be Radiology June 6-8, 2004 The UK Radiological Congress will be held inManchester, U.K. Contact Ms. Rebecca Gladdish, UKRC 2003 Secretariat, PO Box 2895, London WlA SRS, U.K., or call +44(0) 20 7307 1410/20, or fax +44(0) 20 7307 1414; or e-mail conference@ukrc.org.uk/exhibition@ ukrc.org.uk; or see www.ukrc.org.uk Oncology ]uly 3-6, 2004 The 18th EACR (European Association for Cancer Research) Congress will be held in Innsbruck, Austria. See http://www.fecs.be/conferences/eacr18 Paediatric oncology September, 2004 The International Society of Paediatric Oncology ­SIOP Annual Meeting will be held in Oslo, Norway. See http://www.siop.nl Lung cancer September 23-25, 2004 »9th The Central European Lung Cancer Conference« will be offered in Gdansk, Poland. »9th Contact Conference Secretariat, Central European Lung Cancer Conference«, Via Medica, ul. Swietokrzyska 73, 80 180, Gdansk, Poland; or call/fax +48 58 349 2270; or e-mail celcc@amg.gda.pl; or see www.lungcancer.pl Radiation therapy October 3-7, 2004 ASTRO Annual meeting will be held in Atlanta, USA. Contact American Society for Therapeutic Radiology and Oncology Office, 1891 Preston White Drive, Reston, VA 20191, USA; or see http://www. astro.org Therapeutic radiology and oncology October 24-28, 2004 The 23rd ESTRO Meeting will be held in Amster­dam, the Netherlands. Contact ESTRO office, Av. E. Mounier, 83/4, B-1200 Brussels, Belgium; or call +32 7759340; or fax +32 2 7795494; or e-mail info@estro.be; or see http://www. estro.be Medica! oncology October 29 -November 2, 2004 The 28th ESMO Congress will be held in Vienna, Austria. See http://www.esmo.org Radiation oncology November 25-28, 2004 The ISRO international teaching course on »Practical Radiation and Molecular Biology with Mayor Emphasis on Clinical Application« will take place in Chiangmai Thailand. See http://www.isro.be Radiation oncology March, 2005 The ISRO international teaching course on »Palliative Care in Cancer Treatment« will take place in Dar es Salaam, Tanzania. See http://www.isro.be Radiation oncology September -October, 2005 The ISRO international teaching course on »Rational Developments from developing to devel­oped Countries« will take place in Lombok, lndonesia. See http://www.isro.be Notices 211 Oncology October 30 -November 3, 2005 The ESTRO 24 / ECCO 13 Conference will take place in Paris, France. Contact FECS office, Av. E. Mounier, 83/4, B-1200 Brussels, Belgium; or call +32 7759340; or fax +32 2 7795494; or e-mail info@estro.be; or see http://www. fecs.be As a service to our readers, notices of meetings or courses will be inserted free of charge. Please send information to the Editorial office, Radiology and Oncology, Zaloška 2, SI-1000 Ljubljana, Slovenia. Radio/ Oncol 2003; 37(3): 209-11. FONDACIJA DR.].CHOLEWA FONDACIJA "DOCENT DR. J. CHOLEWA" JE NEPROFITNO, NEINSTITUCIONALNO IN NESTRANKARSKO ZDRUŽENJE POSAMEZNIKOV, USTANOV IN ORGANIZACIJ, KI ŽELIJO MATERIALNO SPODBUJATI IN POGLABLJATI RAZISKOVALNO DEJAVNOST V ONKOLOGIJI. MESESNELOVA 9 1000 LJUBLJANA TEL 0 1 51 9 1 2 77 FAKS 01 251 81 13 ŽR: 50100-620-133-05-10331 1 5-214779 FONDACIJA DR.].CHOLEWA Activity of "Dr. J. Cholewa" Foundation for Cancer Research and Education -A Report for the Third Quarter of 2003 The regular annual meeting of the general assembly of the "Dr. J. Cholewa Foundation for Cancer Research and Education" on June 5th, 2003, started with a sombre note. The assembly participants paid their respects to Mr. Srecko Mihelcic, Professor Vinko Kambic and Mr. Metod Rotar, all of them founding members of the Foundation. Ali three long tirne and important members of the Foundation passed away in the year 2002 and ali left an indelible mark on the Foundation's activity and its char­acter. Srecko Mihelcic was a great promoter of the Foundation's activities and an important donor of the Foundation in general. His kindness, his wit and his propensity for ali new ideas coming out on the Foundation's meetings and elsewhere will be greatly missed. Professor Vinko Kambic was a member of the Slovenian Academy of Sciences and Arts and one of the most important figures in medicine and public life in general in Slovenia. His important role in the development and func­tioning of the Foundation cannot be overstressed. Metod Rotar was a senior figure and a doyen of the Slovenian banking in the last decades. His broad-mindedness and simultaneous sirnplicity, both characteristics of great men, made him indispensable for the Foundation. The Foundation rernains grateful for all their contributions to its activity and obliged to their memory. Reports of the Administrative and Supervising Boards of the Foundation and the report by the Health experts Cornrnission of the Foundation were also presented at the annual meeting of the gen­eral assembly. The reports included the detailed business and financial reports. The Foundation will continue to support the regular publication of "Radiology and Oncology" international scientific jour­nal, which is edited, published and printed in Ljubljana, Slovenia. The Foundation will also contin­ue in its activity to prornote cancer biology research, research in cancer epidemiology and clinical cancer research in their many different pathways. Severa! new members were also admitted to the Foundation on that occasion, including Professor Blaž Mlacak, Professor Janez Fischinger, Dr. David Dovšak, Ms. Branka Cimerman, and Dr. Ana Hinterlechner-Ravnik and Dr. Daniel Ravnik, both as life members of the Supervisory Board of the Foundation. At the same tirne the Foundation expressed its deep gratitude to dr. Ana Hinterlechner-Ravnik for her irnportant contribution to the Foundation, dedicated to the memo1y of her late sister, ms. Teja Lavric, Univ. Dipl. Ing .. A memorial "Dr. J. Cholewa" plaque and a charter on the behalf of the Foundation were presented to dr. Ana Hinterlechner-Ravnik by Mr. Slavko Fatur, the President of the "Dr. J. Cholewa Foundation for Cancer Research and Education" for her rnagnanirnous and grace­ful deed. An interesting developrnent may also take place in the near future with the Foundation possibly coming to agreement with KRKA pharmaceutical cornpany from Novo Mesto in southern Slovenia. These initial steps in the possible future collaboration include the consideration of ideas about can­cer research activity to be performed by some of the young researchers from this well-known and re­puted pharmaceutical company. Tomaž Benulic, MD Borut Štabuc, MD, PhD Andrej Plesnicar, MD (t)sanolabor kapsule raztopina za intravensko infundiranje Kontraindikacije: Preobcutljivost za flukonazol, pomožne sestavine zdravila in za druge azole. Socasno jemanje flukonazola s terfenadinom ali cisapridom. Stranski ucinki: Lahko se pojavijo slabost, napenjanje, bruhanje, boletine v trebuhu, driska. Možni so glavobol, kr6 in alopecija. Zelo redke so preobcutljivostne reakcije. Pri bolnikih s hudimi glivicnimi obolenji lahko pride do levkopenije, trombocitopenije, povecane aktivnosti jetrnih encimov ter hujše motnje v delovanju jeter. Oprema in nacin izdajanja: 7 kapsul po 50 mg, 28 kapsul po 100 mg, 1 kapsula po 150 mg -samo na zdravniški recept. 1 viala s 100 ml raztopine za intravensko infundiranje (200 mg/100 ml) -uporaba samo v bolnišnicah. Datum priprave besedila: marec 2003 • sistemske kandidoze • mukozne kandidoze • vaginalna kandidoza • kriptokokoze • dermatomikoze • preprecevanje kandidoze Ucinkovit antimikotik, ki ga bolniki dobro prenašajo. zastopa naslednja podjetja Kottermann (Nemcija): laboratorijsko pohištvo, varnostne omare za kisline, luge, topila, pline in strupe, ventilacijska tehnika in digestorji DAKO (Danska): testi za aplikacijo v imunohistokemiji, patologiji, mikrobiologiji, virologiji, mono-in poliklonalna protitelesa SVANOVA Biotech (Švedska): Elisa testi za diagnostiko v veterini 1 ­ INTEGRA BIOSCIENCES (Svica): laboratorijska oprema za !mikrobiologijo, biologijo celic, molekllJlarno biologijo in: biotehnologijo CORNING (ZDA): specialna laboratbrijska plastika za aplikacijo v imupologiji, mikro­biologiji-virologiji, ipd., rr7ehanske eno­in veckanalne pi9ete in nastavki EVL (Nizozemska): 1 diagnosticni tes.i za uporabo v veterinarski medicini NOVODIRECT BIOBLOCK (F.ancija): kompletna oprema in pripomoc ki za delo v laboratoriju HURNER (Nemcija): ventilacijska tehnika j GFL (Nemcija): laboratorijski aparati, omare in skrinje za globoko zamrzovanje CSL i Biosciences: diagnosticni testi za uporabo v veterirarski medicini ANGELANTONI SCIENTIFICA (Italija): hladilna tehnika in aparati za laboratorije, transfuzijo, patologijo in sodno medicino BIOMERICA (ZDA): hitri testi b diagnostiko, I EIA /R;A testi EHRET (Nemcija): CHARLES I.CHI (Svica): laminar flow tehnika, inkubatorji, specialna oprema za tesriranje izdelkov sušilniki, suhi sterilizatorji in oprema v farmacevtski industriji;aparati za za laboratorijsko vzrejo živali -kletke procesno kontrolo in ko1 trolo kvalitete ROSYS -ANTHOS (Avstrija): fotometri, avtomatski pralni sistem za mikrotitrine plošce LABORMED d.o.o. LABORMED, razstavni salon Zg. Pirnice 96/c Bežigrajski dvor SI -1215 Medvode Periceva 29, Ljubljana Tel.: (O) 1 362 14 14 Tel.: (0)1 436 49 01 Fax: (0)1 362 14 15 in f o@ 1 a bor med. si Fax: (0)1 436 49 05 w w w abormed . s AstraZeneca 4 Vaš partner pri zdravljenju raka dojke in prostate Casodex Zoladex®LA 10.8mg goserelin AstraZeneca . O LI .].1@@J.ldJJ.\ PE: Stritarjeva 5, 4000 Kranj. Slovenija tel.: (0)4/ 2015 050, fax: (0)4/ 2015 055 e-mail: kemomed@siol.net, KEMOMED www.kemomed.si PLASTIKA ZA CELICNE KULTURE f!t I nvitrogen- life technologies CELICNE KULTURE, GELI IN MOLEKULARNA BIOLOGIJA minerva-1'® L,f,,&118,, Biosciences l:Jl•):jiJ biolab,6,& ELEKTRONSKE IN MEHANSKE AVTOMATSKE PIPETE DIAGNOSTIKA SEKVENATORJI MIKOPLAZEM IN LEGIONEL Bayerjev antibiotik za zdravljenje okuib dihal Hitro zdravljenje ABEKB, pljucnice pridobljene v domacem okolju in akutnega vnetja obnosnih votlin ¦ HITRO ZDRAVLJENJE -FK/FD lastnosti zdravila ¦ PREPROSTO ODMERJANJE ENKRAT NA DAN -preprosta uporaba za zdravnika in bolnika ¦ VARNO ZDRAVLJENJE -stranski ucinki so redki -vec kot 16 milijonov bolnikov po vsem svetu ¦ UGODNA CENA KRATKEGA ZDRAVLJENJA http://www.bayer-pharma.si/zdravila Vaše uporabniško ime je ZDRAVNIK, geslo je ZDRAVNIK. Highligths Geneml lJS (gostroentero/Dg't nephro-urology, br811Sf, head and neck, pedioflics),Gynaecology and Obstetrics, Musculoskeleto/ lJS, Vasculor lJS, Surgico/ and lnterventional lJS ( endoluminal intro-operative lJS, /aporoscopic lJS and tissue ablation) New Techno/ogy and Physics (controst agents, harmonics, 30, 8-flow, bioeffects and sofety, and others), Sonography, Veterinary lJS, Miscellaneous Pre-congress events Thomas Jefferson llniversify · Recent advances in ultrasound, Controst agents in ultrosound, IBUS course, Doppler of Arterial and venous circulation, Ultrosonogrophy and endoscopy in cholostosis, Gynaeco/ogico/ Ultrasound and human repraduction, New deve/opments in ultrasound assessment of pelvic mass, Ultrasound in perinotolgy, Ultrosound in veterinory medicine, Endoscopic ultrasound, US course Program Plenary sessions: Breost ultrosound, General Abdomen, Neck ond Thyroid glond, Pediatric US, Doppler Periphery, Ultrasound in perinatology, lnterventional and intro-operotive ultrosound, Ultrosound in cordiology, Musculoskeletol ultrosound, Orthopedics and sport injuries, Carotid arteries and TCD, TCD ond con/rast doppler in neurology, Ultrasound in gynaecology and human reproduction, Physics of ultrasaund, Ultroosound in veterinary medicine, Ultrasound of thorax, Urogenital ultrasound, Ultrasound in Ophtalmo/ogy, Ultrasound in emergency, Safety of Ultrasound, Young investigators session Teatlting sessions: Con/rast agents and breast color dopp/er, G/ u/trasound, Ultrasound of childrens hips, Parathyroid g/ond and ultrasound, Rena/ doppler, RF ablation, 4D echocardiogrophy, Ultrasound in Veterinary medicine Worksltops: locomotive system, Needle biopsys, Carotid arteries, Mammotome biopsy, Termoablation RF, Vein Doppler, TCD Doppler, 4D Doppler Luntlt symposiums, Poster sessions, Meeling witlt lite Prolessor session lnvited speakers J.R. T. C Roelandt · V.Milkov· N.Drinkovic -l. Cikeš -S. Ernst -8. Goldberg -l. Greiner -C Dietrich -N. Juul · 8. Limberg · D. Nilrnberg · H.P. Weskott -A. Bunk -Meck/er · Benhof -l. Sporea · Wlakubowski -l. Lukac· E. lerem · M. Duvnjak · T. Helemberger · D. Giatini ­ l.o Bo/ondi· D. Amy · M. Teboul -W Svenson -8.Salvadori -l. Drinkovic · D. Fmncescatti -l. Derchi -C Martinoli · S. Coste/lani ­ 8. Brk/jacic -V. Demarin -S. Podobnik -E. Halpern · l. Needleman · K. Joger· D.H. Evans · l. Boromo · l. Nazorin · l. Vrdoljak ­ G.oHarmat · A. Vargha · l. Harkany · E. Mertz · 1.8. Hackeloer · D. Jurkovic · V. Vlaisavljevic · M. Podobnik · l. Sretenovic · A. Kurjak ·o S.oKupešic -P. Wells -8. Phillips · 8. Breyer · l. Chitty · D. Pilling · l. Bonoma · M. Teboul · R. Otto · M. Claudon · M. 8. Nielsen ­ C Weismann · G.M. Reutern · N.M. Bornstein · A. Alexandrov· K. Niederkorno Far more informations on registration, abstract submission and hotel information please visit our web site 3rd Conference on Experimental and Translational Oncology Kranjska gora, Slovenia, March, 18-21 , 2004 Organised by: Tamara Lah, Gregor Serša and Janko Kos Topics: • Mechanisms of tumour progression • Tumour markers • Delivery systems in cancer therapy • New drugs and therapeutic targets Location: Hotel Lek 4280 Kranjska Gora, Sloveniahttp://www.hotel-lek.si Correspondence: Conference Secretary: Phone: +386 14231867.0 nf erenca Fax: +386 1 423 503.8. O 0 / ... Email: milena.kis-ce i.retJa koJ"J.'f!c.t r . . '\.e \f0-enta1 cl.lJ.d e.r0 0 .e..,. , :--..$' c,,O .>+"l -c,, \,\ Onco1, 1.;; .o./';f v . •"tr o .v 1.·l O.o F2n -_ O? .,,.-. ­ " " ' .r:::,p . '..J r fj r'r;.-.-w., --,.\\ '-,, 0-;-.. (o ,:;. _. •• t""\h C]) ,;::: ,.... C.., t::: ,.._, ::;_;:-. ::: -. ';':J"'1.::;-.-:::,', , .,....""CJ;:; ;-(. (i)('):, • -:.. .,..,rr >-1,.:....i -c _, '-A · §·.J -• -.J. ;...., --2 • (O-t--J . r-,,.--;....._ i-..J .. 1),ll'r\~'' .. .'( 'l<.,;i_.. s _j_ ,,.. 7y) ,/ ,,,-"-.?'-· , i..... ,..._,_ ....i V / "'J0.I/ l, Uc -..-'--' -:r::; ..:J -. i... -._, -. " '"' v r,... ­ r"-: ,.. ..,( - ­ - -;: ,....J­ = o r:.r:, .J f, -l '2 -:=:li ::'-;. --· ,.,-' -;:. .... ,,.., r,:,...., ,,,,_, ,.,, >' 0'_: _ 1J1r,.u•' .'':-. . .... ''.s. V) $'Q -. V ;;, .Q. ­ . , () _./', ' . . " "....;,'..;;..,.;.. \'->\"-' S::,' '\<) . . . -."'°.N. an Association of Nuctear Me PET LEARNING COURSES 1 Clinical PET Courses: Technologist Courses: Dates: Dates: 06-07.09.2003 27-28.09.2003 04.-05.10.2003 -+ Course will be held in German language ! 08.-09.11.2003 29.-30.11.2003 06. -07 .12.2003 Registration fee: Registration fee: EANM members: € 700 EANM members: € 210 Non members: € 950 Non members: € 350 How to register Each course will aliow a maximum of 20 participants. Registrations wili be accepted on a first come first serve basis, however, EANM members will be given relative priority. Please download and print out the registration form from our homepage www.eanm.org and fax it back to the EANM-secretariat. Goals and curriculum EANM has established the PET learning facility in order to provide the highest standard of education on PET and its relation to other imaging modalities in Europe. A reknowned faculty was asked to prepare powerpoint presentations and case studies to cover ali pertinent areas of PET. At each course instructors wili cover the presentations and case studies in "classroom style" in the lecture room. There wili also be ample tirne tor participants to view case studies in 4 viewing rooms, equipped with state of the art multipurpose viewing stations. One "industry viewing room" features workstations by ali three major manufacturers of PET equipment. For ali further information on the EANM learning courses on clinical PET please contact: Ms. Katharina Riedl-Riedenstein EANM Executive Secretariat Holiandstrasse 14 / Mezzanine A -1020 Vienna, Austria Tei: +43-1-2128030 Instructions f or authors Editorial policy of the journal Radiology and Oncology is to publish original scientific pa­pers, professional papers, review articles, case reports and varia (editorials, reviews, short communications, professional information, book reviews, letters, etc.) pertinent to diag­nostic and interventional radiology, computer­ized tomography, magnetic resonance, ultra­sound, nuclear medicine, radiotherapy, clini­cal and experimental oncology, radiobiology, radiophysics and radiation protection. The Editorial Board requires that the paper has not been published or submitted for publication elsewhere: the authors are responsible for all statements in their papers. Accepted articles become the property of the journal and there­fore cannot be published elsewhere without written permission from the editorial board. Papers concerning the work on humans, must comply with the principles of the declaration of Helsinki (1964). The approval of the ethical committee must then be stated on the manu­script. Papers with questionable justification will be rejected. Manuscript written in English should be submitted to the Editorial Office in triplicate (the original and two copies), including the il­lustrations: Radiologij and Oncology, Institute of Oncology, Zaloška 2, SI-1000 Ljubljana, Slovenia; (Phone: +386 1 5879 369, Tel/Fax: +386 1 5879 434, E-mail: gsersa@onko-i.si). Authors are also asked to submit their manu­scripts on a 3.5" 1.44 Mb formatted diskette. The type of computer and word-processing package should be specified (W ord for Windows is preferred). All articles are subjected to editorial review and review by independent referee selected by the editorial board. Manuscripts which do not comply with the technical requirements stated herein will be returned to the authors for cor­rection before peer-review. Rejected manu­scripts are generally returned to authors, how­ever, the journal cannot be held responsible for their loss. The editorial board reserves the right to ask authors to make appropriate changes in the contents as well as grammatical and stylistic corrections when necessary. The expenses of additional editorial work and re­quests for reprints will be charged to the au­thors. General instructions• Radiology and Onco­logy will consider manuscripts prepared accor­ding to the Vancouver Agreement (N Engl J Med 1991; 324: 424-8, BM] 1991; 302: 6772; JA­MA 1997; 277: 927-34.). Type the manuscript double spaced on one side with a 4 cm margin at the top and left hand side of the sheet. Write the paper in grammatically and stylisti­cally correct language. Avoid abbreviations unless previously explained. The technical da­ta should conform to the SI system. The man­uscript, including the references may not ex­ceed 15 typewritten pages, and the number of figures and tables is limited to 4. If appropri­ate, organize the text so that it includes: Introduction, Material and methods, Results and Discussion. Exceptionally, the results and discussion can be combined in a single sec­tion. Start each section on a new page, and number each page consecutively with Arabic numerals. Title page should include a concise and in­formative title, followed by the full name(s) of the author(s); the institutional affiliation of each author; the name and address of the cor­responding author (including telephone, fax and e-mail), and an abbreviated title. This should be followed by the abstract page, sum­marising in less than 200 words the reasons far the study, experimental approach, the major findings (with specific data if possible), and the principal conclusions, and providing 3-6 key words far indexing purposes. Structured ab­stracts are preferred. If possible, the authors are requested to submit also slovenian version of the title and abstract. The text of the report should then proceed as follows: Introduction should state the purpose of the article and summarize the rationale far the study or observation, citing only the essential references and stating the aim of the study. Material and methods should provide enough information to enable experiments to be re­peated. New methods should be described in detail. Reports on human and animal subjects should include a statement that ethical ap­proval of the study was obtained. Results should be presented clearly and concisely without repeating the data in the ta­bles and figures. Emphasis should be on clear and precise presentation of results and their significance in relation to the aim of the inves­tigation. Discussion should explain the results rather than simply repeating them and interpret their significance and draw conclusions. It should review the results of the study in the light of previously published work. Illustrations and tables must be numbered and referred to in the text, with appropriate location indicated in the text margin. Illu­strations must be labelled on the back with the author's name, figure number and orien­tation, and should be accompanied by a de­scriptive legend on a separate page. Line drawings should be supplied in a form suit­able far high-quality reproduction. Photo­graphs should be glossy prints of high quality with as much contrast as the subject allows. They should be cropped as close as possible to the area of interest. In photographs mask the identities of the patients. Tables should be typed double spaced, with descriptive title and, if appropriate, units of numerical meas­urements included in column heading. References must be nurnbered in the order in which they appear in the text and their cor­responding numbers quoted in the text. Authors are responsible for the accuracy of their references. References to the Abstracts and Letters to the Editor must be identified as such. Citation of papers in preparation, or sub­mitted far publication, unpublished observa­tions, and personal comrnunications should not be included in the reference list. If essen­tial, such material may be incorporated in the appropriate place in the text. References fol­low the style of Index Medicus. Ali authors should be listed when their number does not exceed six; when there are seven or more au­thors, the first six listed are followed by "et al.". The following are some examples of refer­ences from articles, books and book chapters: Dent RAG, Cole P. In vitro maturation of monocytes in squamous carcinoma of the lung. Br J Cancer 1981; 43: 486-95. Chapman S, Nakielny R. A guide to radiolog­ical procedures. London: Bailliere Tindall; 1986. Evans R, Alexander P. Mechanisms of ex­tracellular killing of nucleated mammalian cells by macrophages. In: Nelson DS, editor. Immunobiology oj macrophage. New York: Academic Press; 1976. p. 45-74. Page proofs will be faxed to the correspon­ding author whenever possible. It is their re­sponsibility to check the proofs carefully and fax a list of essential corrections to the editori­al office within 48 hours of receipt. If correc­tions are not received by the stated deadline, proof-reading will be carried out by the edi­tors. Reprints: Fifty reprints are free of charge, far more contact editorial board. Far reprint information contact: International Reprint Corporation, 287 East "H" Street, Benicia, CA 94510, USA. Tei: (707) 746-8740; Fax: (707) 7 46-1643; E-mail: reprints@intlreprints.com