SLABOST IN BRUHANJE STA. NAJHUJŠA STRANSKA UCINKA KEMOTERAPIJE IN RADIOTERAPIJE Visokoselektivni antagonist 5-HT 3 receptorjev odgovornih za povzrocitev bruhanja • Preprecuje stranske pojave, ki se jih bolniki najbolj bojijo • Ucinkovitejši je od metoklopramida • Ucinkovitejše preprecevanje bruhanja omogoca aplikacijo agresivnejše kemoterapije • Dobro se prenaša 6/axoWellcome Exp_ort Ltd. Podružnica Ljubljana, Cesta v Mestni log 55, 1101 Ljubljana, p.p. 4296, Slovenija Telefon: (386 61) 331 070, Telefax: (386 61) 333 600 RADIOLOGY AND ONCOLOGY Radio/ogy and Oncology is a journal devoted to publication of original contributions in diagnostic and interventional radiology, computerized tomography, ultrasound, magnetic resonance, nuclear medicine, radiotherapy, clinical and experimental oncology, radiophysics and radiation protection. Editor in chief Tomaž Benulic Ljubljana, Slovenia Associate editors Gregor Serša Ljubljana, Slovenia Viljem Kovac Ljubljana, Slovenia Editorial board Tullio Giraldi Branko Palcic Udine, /taly Vancouver, Canada Marija Auersperg Ljubljana, Slovenia Andrija Hebrang Zagreb, Croatia Jurica Papa Zagreb, Croatia Haris Boko Durda Horvat Zagreb, Croatia Zagreb, Croatia Dušan Pavcnik Nataša V. Budihna Lasr.16 Horvath Ljubljana, Slovenia Ljubljana, Slovenia Pecs, Hungary Stojan Plesnicar Malte Clausen Berta Jereb Ljubljana, Slovenia Kiel, Germany Ljubljana, Slovenia Ervin B. Podgoršak Christoph Clemm Vladimir Jevtic Montreal, Canada Mllnchen, Germany Ljubljana, Slovenia Mario Corsi Udine, ltaly H. Dieter Kogelnik Salzburg, Austria Jan C. Roos Amsterdam, The Netherlands Christian Dittrich Vienna, Austria Ivan Lovasic Rijeka, Croatia Horst Sack Essen, Germany Slavko Šimunic Ivan Drinkovic Zagreb, Croatia Marijan Lovrencic Zagreb, Croatia Zagreb, Croatia Gil/ian Duchesne London, Great Britain· Luka Milas Houston, USA Lojze Šmid Ljubljana, Slovenia Bela Fomet Maja Osmak Andrea V eronesi Budapest, Hungary Zagreb, Croatia Gorizia, ltaly Publishers Slovenian Medica[ Society -Section of Radiology, Section of Radiotherapy Croatian Medica[ Association -Croatian Society of Radiology Affiliated with Societas Radiologorum Hungarorum Friuli-Venezia Giulia regional groups of S.l.R.M. (ltalian Society oj Medica/ Radiology) Correspondence address Radiology and Oncology Institute oj Oncology Vrazav trg 4 1000 Ljubljana Slovenia Phone: + 386 61I320 068 Fax: + 386 61 1314 180 Reader jor English Olga Shrestha Design Monika Fink-Serša Key words and UDC Eva Klemencic Secretaries Milica Harisch Betka Savski Printed by Tiskarna Tone Tomšic, Ljubljana, Slovenia Published quarterly Bank account number 50101 678 48454 Foreign currency account number 50100-620-133-27620-5] 30/6 LB -Ljubljanska banka d. d. -Ljubljana Subscription jee jor institutions 100 USD, individuals 50 USD. Single issue jor institutions 30 USD, individuals 20 USD. According to the opinion of the Government oj the Republic oj Slovenia, Puhlic Relation and Media Office, the journal RAD/OLOGY AND ONCOLOGY is a publication oj injormative value, and as such subject to taxation by 5 % sales tax. lndexed and abstracted by: BIOMEDICINA SLOVENICA CHEMICAL ABSTRACTS EXCERPTA MEDICAIELECTRONIC PUBLISHING DJV1S/ON CONTENTS COMPUTED TOMOGRAPHY Use of computed tomography as an aid to hepatic resections Roic' C, Š111i1 F; Škrgatic' M NUCLEAR MEDICINE Teclmetium labeled autologous polyclonal immunoglobulin G (lgG) f'or scintigraphy of inflammation Budihna NV, K/ad11ik S, Be11ulic" T, Milicinski M 249 Follow:up study of autonomous thyroid adenoma treated with 1-131 Dolgova-Komhin V, Simova N, Bogdanova V, Serqfinwv N, Tadzer IS 255 EXPERIMENTAL ONCOLOGY Current approaches to gene therapy in oncology: construction of tumor vaccines Novakovic' S 260 CLINICAL ONCOLOGY Sarcomatoid carcinoma of the thymus -a case report Hsu NY, Chen CY, Kwang PC, Hsu CR Hsia JY 268 Influence of exogenous hormones on the recurrence and progression of cancer Ur.r-ic'-Vr§caj M, Bebm· S 271 Metastases to the breast from melanoma: a rare manifestation of an unpredictable malignant disease Kovac V, Plesnicar AF 275 Vegetarian diet and cancer Pokorn D 281 Prevention of fertility disturbances in oncological male patients Kovac V 286 RADIOPHYSICS AND RADIOHIOLOGY Monte Carlo simulation of a metal/a-Se Portal Detection Wmzg H, Fallone GB, Falco T Incidence of spontaneous cytogenetic changes in peripheral blood lymphocytes of a human population sample Bilba11 M, Vrhovec S MEDICAL ETHICS Introduction to ethical analysis Zwitter M, Golouh R 305 Ethical principles of autonomy and beneticence in genetic screening for breast cancer Zwitter M, Nilstun T. Golouh R 310 REPORT Seventh international symposium on Neutron Capture Therapy for cancer Ser.fo G, Škrk.! 314 IN MEMORIAM Prof. Krsto Kolaric Roth A 317 NOTICES 319 AUTHOR INDEX and SUB.JECT INDEX, 1996 321 Radio/ 011col 1996; 30: 245-8. Use of computed tomography as an aid to hepatic resections Goran Roic\ Franjo Šmit2, Mladen Škrgatic2 'Children's Hospital u1greb, 2Polyclinicfor Medica! Diagnosis, lllgreb, Croatia The clinical interest in hepatic tumor resection has increased the importance of knowing the segmenwl anatomy of the /iver. C/assical descriptions of the gross anatomic divisions of the !iver were based solely 011 swface structures. These classica/1 divisions of hepatic anatomy are of little help to the surgeon hecause the swface anatomy poorly reflect.1· the organ 's interna! vascular structure. A »surgical vascular subdivision« is a valuable 1eclmique .fbr showing almor111ali1ies of the !iver whether d(lji,se or focal. Cross-sec1io11a/ imaging of 1he /iver with CT provides excellent demonstration of the hepatic vasculature mul ./ Nucl Med 1992; 33: 394-7. 20. Sciuk J. Brandau W. Yollet B et al. Comparison of tcchnetium 99m polyclonal human immunoglobulin and teclrnetium 99m lllonoclonal antibodies for imag­ing chronic osteomyelitis. Eur J Nucl Med 199 I: 18: 401 -7. 21. Goldenberg DM, Larson SM. Radioimrnunodetection and cancer identification. J Nucl Med 1992;33: 803-14. 22. Sykes T R, Woo T K, Baum R P. Qi P Noujaim A A. Direct labeling of monoclonal antibodies with pho­toactivation. J Nuc/ Med 1995; 36: 1913-22. Radio! Oncol 19%; 30: 255-9. Follow-up study of autonomous thyroid adenoma treated with I-131 Vera Dolgova-Korubin, Nina Simova, Vukosava Bogdanova, Nikola Serafimov, Isak S. Tadzer Institute ()l Pathophysiology a11cl Nuclear Meclici11e, Medica! Faculty, Skopje, Maceclonia Twenty seven Jllllients with a11tono111011sly Jiu1ctioning thyroid C1deno111C1 (AFTA), clinically llnd laboratorv euthyroid were treated with 1-131. A acriterion jrH the thera11y was the scintigraphic appearance of AFTA "/101", wul suppressed TRH response rf the patients. The mean weight rij' AFTA was 50.03 ± 28.5 g, administaed radioactivity was 73.3 ± 6.1 MBq per g tissue, and estimated radiation was 262.2 ± 129.9 Gy. Excuninations in the jr1//ow-up period rij' 2-36 1110nths included clinical and laboratory testing, TRH test and thyroid scintigraphy. A.fier thl' therapy. AFTA became unpalpahle in 14 (51.8 %) patients, decreased in 7 (26.0 %) and did not change in 6 (22 %). Ali patients re11wined euthyroid by a/1 criteria, with normal TRH test in 26 (96 %) r!{ them. Two 111011ths qfier the therapy, transitorv suppression or exaggeralio11 r!l TRH test, WC/S found in 3 and 7 patienl resp., but spontaneous rl'slilution occurred later in ali but one, where TRH rl'mained suppressed (3.7 % o{a/1). AFTA appeared cold 011 the sclln r!f'92.6 % r f the treated patil'nts. There WC/S 110 hypothyroidism cifier the therapy. This and 1he achievement r!f' C1b!ation or reduction r.l the nodules in most rf the patients, support the opinion that patients with AFTA and suppressed TRH test, even when euthyroid, should be treated with 1-137. Key ,vords: thyroid neoplasms: adenoma-therapy: iodine radioisotopes: follow-up studies Introduction Plummer's disease is a thyroid disorder in which a part of the tissue is functioning autonomously and the rest of the gland is normally rcsponding to fcedback mechanisms. It is prescnted by a spectrum of structural and runctional abnormalitics which include solitary or multiplc nodulcs, or numerous autonomous centers, and autonomous production of hormoncs in normal or cxccssive quantity.1•2 The last is crucial for the clinical prcsentation of the disorder. When an autonomously functioning thy­roid adenoma (AFfA) produces clinically overt hyperthyroidism, the therapy should be radically- Correspondence to: Prof. Vcra-Dolgova-Korubin, M.D., Ph.D„ Medica! Faculty Skopje. Institute of Pathophysiology and Nuclear Medicine, Bodnjanska 17. 9100 Skopje, Ma­cedonia. surgical or with radio iodine, sometimes after a short-lasting medicamentous treatment.2 The treatment of AFr A in euthyroid patients ris­es many questions: is it nccessary, in which cases and when, and what kind of therapy? Euthyroid clinical picture may be associated with different biological behavior of AFrA: compensated or de­compensated, i.e. scintigraphically presented as iso­fixant or hiperfixant -"warm" or "hot" nodule, comparing to surrounding tissue.) Normal serum levcls of T4, T3 and cven TSH, may be associated with a suppressed response to TRH stimulation as a first sign of disorder.) Kecping in mind the slow evolution of AFrA and the possibility of spontane­ous destruction of adenomatous tissue45 many cli­nicians hesitate to choose a radical therapy. But the follow-up studies of many cascs show steady pro­gression of the disease in some patients, which may cause heart damage,s.r, and Belfiore et al.7 found UDC: 616.44 l-"6.6-08:849.2 that it happened in a higher pcrcent of patients from Do/gova-Korubi11 Vet al. iodine deficient regions than in those from other regions. Here we present results of radioiodine treatment of euthyroid patients with AFf A and our attitude to that problem. Material and methods The study includes 27 patients with AFfA, clini­cally, euthyroid, who were treated with 1-131 and subsequently followed -up. The l Oncology, Department of" Tumor Biology, LJub(jana Slovenia Current conventional treatment c!f" malignancies is hasecl predominantly on the 11se c.f" radio-and chemo­therapy. The mentioned therapies are not directed against cancer tis.rne 011/y and lwve severe dose-/imiting toxic side e.ffecls accompanied with a s11ppressive e.ffect on the patient'.1· imm1111e system. On the other hand, immunotherapy, and especially gene therapy, try to be more selective and less aggressive, having the pw11ose o( triggering a specific i1111111111e response against tumor cel/s. Therefore, differer// approaches to the creation and application 1!{ gene thempy in oncology have been ./(Jrmed in the past.few years, yet the aim o( a/1 c.f" them is the same: to use e.rtended knowledge ahout molecular mechanisms of the disease in order to devise a more specific mode c;f" treat111e11t. The major approach to present-day gene therapy of cancer is the generalion c;f" 1u11wr vaccines as CI pussible .fi1t1tre categmy c;f" cancer treatmenl. The 1nupose of this article is to provide a brief overview on creation and potential applications qf" t11mor vaccines as well as qf" some mode.1· c.j" gene therapy in oncology. Key vvords: neoplasms-therapy; gene therapy; tumor vaccines Introduction Owing to unspecific activities of conventional ther­apies against cancer (radiotherapy, chemotherapy) a treatment of this kind is quite ol'ten accompanied with unrecoverable damage of the normal tissue. The tremendous increase of knowledge in immu­nology as well as the exponential devclopment of recombinant DNA tcchnology conditioned the re­newal of interest for creation 01· different immuno­therapies that were supposed to be more effective, more specific for tumor cells, and cause no or neg­ligible toxic side effects. The goal or each immu­nomodulatory treatment is to stimulatc (enhance) immune response and in this way alter the dynam­ics of host-tumor relationship to therapeutic advan­tage. At the same time. this treatment modality has Correspondence to: Srdjan Novakovic, Dr.Sci., Institute of Oncology. Department ofTumor Biology, Zaloška 2, 1105 Ljubljana. Slovcnia. Fax: + 386 61 131 41 80. UDC: 6 l 6-006.6-097:615.37 I to prevent the development of tumor celi resistance to such treatment, and cause no toxic deposition in the normal tissue. Therefore, for successful crea­tion of immunotherapy, it is important first to un­derstand the relationship between the host and spe­cific tumor cells in orcler to choose the most appro­priate approach. To incluce tumor immunity more specifically and effectively, various methods of im­munotherapy have emerged using different biologi­cal agents such as monoclonal antiboclies, cytokines. tumor antigens, hormones, activated killer cells. immune T cells. DNA and others. 1 -x Vaccination against cancer The idea of vaccination against tumor cells has been a distant goal of immunologist for many years, ever since 1909, when Paul Ehrlich suggested that tumors might cxpress antigens that coulcl be targets of immune system.'' Certainly, at that time there was hardly anything known about tumor-associat­ Current appmaches to gene thernpy in 1111c11/11gy: Construction of' tun111r vaccines ed antigens, B and T lymphocytes, a11tigen-specific receptors on lymphocytes, immunoregulatory cy­tokines elc. However, the observations that there is a· difference in the velocity of tumor growth, and that some tumors stagnale for a longer period of Lime (even some years), indicale lhat organisms possess powerful regulation mechanisms (i.e. im­mune syslem) for tumor growlh conlrol.' And stili, quile oflen tumor cells eseape the conlrol and do not trigger the immune response. Tumor vaccines were thus ereated wilh lhe inlention to rebuild or retrigger the immune system and induce syslemic immunily against tumor cells. Por this purpose, irradiated autologous or allogeneic tumor cells, lysa­tes 01· tumor cells, and occasionally, virnlly infected tumor cells were used as tumor vaccines. To inten­sify additionally lhe immune response, nonspeeific immunoslimulalors (e.g. Cory11ehact<'l'i11111 parvwn or Bacil/11s Ca/111e11e-G11eri11) were added to most of lhe above menlioned preparalions. 11-14 The basic working guide of all lhese experimenls was lo achie­ve an enhanced expression of MHC antigens on tumor cells and to increase lhe cytokine production. Only the exponential developmenl of molecular genetics and monoclonal anlibody reagenls, as well as lhe results of lhe !atest investigalions, provided enough information to allow speculation that di­minished responsiveness or complete unresponsive­ness of lhe immune system could hc predominantly a consequencc of the changes of tumor cells al lhe moleeular leve!. Among thc most imporlanl chang­es which cnabled tumor cells to cscape immune control researchers classi ficd lhe following: "·"' • inadcquale expression of MHC (major histo­compatibility complex) anligens, • prevcntion of tumor specific antigen presenta­tion to T lymphocytes, • absence of adhesion molecules which are im­porlanl for the activalion of immune system, and • production of various t'actors (by tumor cells) which influence (change) thc host immune syslem. Gene therapy and tumor vaccines The "gene lherapy" term has become a new para­digm, associated wilh any kind of disease where lhe origin can be connected wilh the derined genes. Gene lherapy involves a variety of new lechniques for gene transfer, gene replacemenl, gene repair or gene delction. Although the idea of vaccination against tumor cells dates in the beginning of 19th century, the modem tumor vaccines represent just one of the approaches (major) to gene therapy of cancer. In other words, modem tumor vaccines are a form of gene therapy where, by use of different vectors, genes of interes[ are transferred into the tumor cells or into immunocompetent cells. This can be achiev­ed by direct DNA transfer or by using vira! veclors. The most prevalent nonviral techniques used for gene transfer are calcium phosphate transfection, micro1nJection, electroporalion, liposomal gene transfer, injection of naked DNA, and receptor me­diated gene transfer. 11-22 Among lhe biological de­livery systems for gene transfer the cardinal ones are retroviral vectors, adenoviral vectors, adeno­associated virus vectors and other vira! vectors-2' The first studies wilh genetically transformed tu­mor cells (llrnt were used as tumor vaccines) con­firmed that bolh classes of MHC antigens (MHC 1 and MHC II) play an important role in the proccss of triggering of the immune response and thal lhe antitumor activity is predominantly a consequence of activation of cellular immunity.24 Class I MHC anligens are recognized by cytotoxic lymphocytes (CDS+) and their presencc is obligatory for the activation of these cells. On the other hand, class II MHC antigens (they are presenled by antigen-pre­senting cells in lhe form of endosomes or lyso­somes, respectively) take part in the activation of helper T lymphocytcs (CD4+ ), cells which are clas­sified as basic producers of dit'ferenl cytokines. Exaclly, the defect in lhe helper arm (i.e. cylokine producing pari) of lhe immune system is often lhe cause 01· inadequate immunogenicity 01· tumor cells: namely, lhe development of cellular immunity will fail in the case of inadequate cylokine production, regardless of the fact that MHC I antigens are nor­mally expressed and aclive.2' Considering those facls, tumor vaccines were cre­ated predominatcly to achicve: • enhanced production of various cytokines that participate in immune processes (IL-2, GM-CSF, IFN-u, TNF-u), • expression of allogeneic human leukocyte anti­gens (HLA antigens) or • enhanccd concentration of products that are re­sponsible for the expression or the activities, re­spectively, 01· oncogenes (e.g. or the product or p53 suppressor gene). Therefore, depending on lhe manner chosen to fight tumor cells, quite a few di!Terent approaches 262 Novakovi<'S to creation of gene therapy and tumor vaccines have been established. This review will deal with some of them, i.e. those that have becn found most promising and attractive. Prepamtion o{ twnor vaccines with insertion qf" gene.1· coding for allogeneic le11kocyte a11tige11.1· into w1tologo11s lwnor cel/s The purpose of such preparation 01· tumor vaccines is the transfer of gcnes encoding certain antigens (usually present on the surface of antigen-present­ing cells) into tumor cells. B7 antigen is a molecule that normally funclions as an activalion molecule on antigcn-presenting cells (macrophages. B lym­phocytes. dendritic cells). B7 antigen represents a ligand for two types of T lymphocyte receptors i.e. for CD28 (present on CD4+ and CDS+) and CTLA4 (present only on CDS+) receptors. Thc role of CTL4 has not been determincd yet, while on the other hand CD28 is well known to be the cardinal recep­tor for activation of T lymphocytes and for stimula­tion of cytokinc production."' Thcsc data led to formation of a hypothesis about the transfer of a gene coding for B7 antigen into the tumor cells and about thc potenlials of such tumor vaccine to lrig­ger systemic antitumor immunity. So Chen et al.. 1) as well as Townsend and Allison.27 demonstrated that rejection of malignant melanoma cells express­ing B7 ligand rcsulted from the aclivity of CDS+ T lymphocytes. Besides. in these expcrimcnts sys­temic immunity developed (in experimental ani­mals) even against genetically unchanged melano­ma cells (which were thus not expressing B7 lig­and). On the basis of the cited studies we can con­clude that tumor vaccines, created by transferring of B7 gene into autologous tumor cells, activate cytotoxic T lymphocytes and stimulate cytokine production in helper T lymphocytes, thus elTective­ly triggering the development of systemic antitu­mor immunity. On the other hand. thc best results with this kind 01· vaccines can be obtained (owing to the costimulatory mode of action of B7 on CDS+ and CD4+ T lymphocytes) only in tbc presence of MHC class I and class II antigens on tumor cells. Vaccines created wilh insertion ,!( gene.1· coding for difTerenl C\'/okines inlo alllologo11s t11111or ce//.1· lnsertion of genes coding for dilTercnt cytokines might play a role in "ovcrcoming" lhe unrespon­siveness of immune system that derives from ina­bility for normal cytokine production which is actu­ally a consequence of complete absence or inade­ quate expression of MHC II antigens. In contrast to the activities of exogenous cytokines. tbe cytokines produced in genetically changed autologous tumor cells mimic the activities of natura! endogenous cytokines (underlie to some extent the control mech­anisms of tbe organism), whicb on one band im­proves their effectiveness and on the otber band minimizes tbeir toxic side effects. Wben preparing tumor vaccines, dilTerent researchers introduced genes for numerous cytokines or growth factors (IL-1, IL-2, IL-3, IL-4, IL-6, IL-7, IL-1 O. IFN-a, TNF-a, GM-CSF and G-CSFJ, respectively, into tu­mor cells.2x-)2 The effectiveness of vaccines tested on animal tumor models depended upon the type or cytokine produced by tbe cells. upon the abundance of cytokine synthesis and upon the type of tumor used in the study. Fearon et al. demonstrated that transfection of poorly immunogeneic mouse colon carcinoma cells witb IL-2 gene results in reduction of tumorigenic potential of tumor cells and triggers the development of systemic immunityY They con­firmed tbat the phenomenon of systemic immunity results from the inlluence of IL-2 on CD4+ and CDS+ T lymphocytes (activation of T lymphocytes). Similar conclusions were made by Gansbacher et al. arter the transduction 01· IL-2 gene into mouse fibrosarcoma cells (in syngeneic mice) and into human melanoma or renal carcinoma cells (in nude mice). ).u; The facl that IL-2 triggers the develop­ment of systemic immunity through its action upon T lymphocytes was also confirmed by Rusell et al. in experiments with rat tumor model.''' Namely, they lransplanted transfected ral sarcoma cells ei­ther into syngeneic rats or into immunodeficient nude rats. The effect of vaccine in syngeneic rats with normal T lymphocyte production was highly superior to the one in nude rats. On the other hand, partly dilTerent results were obtained by Cavallo et al. )7 In agreement with other authors they demon­strated that vaccines prepared by IL-2 gene trans­duction are capable of challenging the immune re­sponse, which (according to Cavallo et al.) predom­inanlly depends upon neulropbils activated with IL­ 2. Allione et al. created tumor vaccines with transfection of adenocarcinoma cells using genes encoding various interleukins (IL-2. IL-4, IL-7, IL­10), IFN-a, TNF-a or GM-CSF. The best antitumor protection was achieved with inoculation of tumor cells producing interleukins and IFN-, while tile treatment outcome after application of tumor cells producing TNF-a was less favourable.)x Quite inter­esting was also the comparison of the effectiveness Currenl approacl!e.,· /II gene tl!ernpy in oncology: Construction o( 1t111wr vaccines of the therapy with genetically changed cclls, to therapy with tumor cclls admixcd with Corynebac­leriwn parvwn. Namcly, the authors established that the antitumor activity of lhe mixlurc of tumor cells wilh Cory11ebacleri11111 pan1w11 approximated in its degree lhc anlitumor activity of therapy with genet­ically modified cclls. Similar results were observed by Hock cl al., who demonstrntcd that tumor vac­cincs prepared by mixing of tumor cclls with non­speciric immunostimulalors cxerl an antilumor ef­1ect which is comparable to lhc effcct of tumor vaccines crcatcd of genclically transl'ormed cells.1'' In contrnst to lhc aulhors, who achicved rclativcly modest rcsulls with tumor vaccines containing gene for TNF-(,(, Blankenslcin presented encouraging oul­comes (his own and 01· other authors) using lhe vcry same vaccines.40 The anlilumor aclivities of such vaccincs were supposed to be based predominantly on an indirccl elTcct mediated through slimulation of immune system and to a lesser extent on the direet antilumor ellect or TNF-(,(. This kind of slimu­lation or immune system includes the activation or macrophages, as well as CD4+ and CD8+ T lym­phocytes. Vaccines bearing TNF-(,( gene are also suc­cessful in thc case or inhibited T lymphocyle pro­duction, bul anyway, the prescncc of these cells enhances the antitumor effect or such trealment. The best proteclion from challenge wilh wild type tumor cells, as wcll as the most pronounced antilu­mor activity against formed tumors, has been as­cribed to vaccines created of tumor cells bearing gene for GM-CSF. Mulligan and Pardoll studied the elTectiveness or vaccines bearing genes for var­ious individual cylokines or i'or combination or cy­tokines.41 The most promising results were achicved with GM-CSF (in the group or vaccines bearing a gene ror a single cytokine), while the most effec­tive combination 01· genes for preparntion of tumor vaccines comprised genes ror IL-2 and GM-CSF. DranolT et al. quite early discovered thal tumor vaccines wilh GM-CSF gene are superior to vac­cines prepared with genes encoding other cytokines in the case or slimulation of the antitumor immune 10 response.However, the activation of CD4+ and CD8+ T lymphocytes was obligatory ror the devel­opmenl of systemic immunity also with vaccines bearing GM-CSF gene, regardless or the MHC II antigen expression on tumor cells. The ellective­ness or tumor vaccines with GM-CSF gene was finally confirmed by Golumbek et al.. since in their experiments not a single experimental animal im­munized with lhe vaccine developed a tumor afler challenge with highly tumorigenic wild type tumor cells:12 The e!Tect of vaccines with enhancecl ex­prcssion of GM-CSF gene is being ascribecl to the stimulation of diffcrenliation or the precursor blood cells and dendrilic cells (imporlanl antigen-present­ing cells for T lymphocytes). Thus, the basic conclusions of these stuclies coulcl be the following: • even low concentrations or cytokines produced by transformecl cells are capable of stimulating the antitumor immune response (comparable results we­re achieved afler systemic high dosage cytokine therapy which is orten accompanied with numerous loxic side effecls): • imporlanl role of cytokines in the process or activation 01· nonspecific leukocytes e.g. granulo­cytes and macrophages; • cooperation belween granulocytes, macrophag­es, lymphocyles, l'ibroblasls and endolhelial cells represents the basis 01· immune reactions triggered by genelically lransformed cells; • degree or anlitumor activity depends upon the tumor type, the type of cytokine producecl by tumor cells, and upon the abundance or cytokine produc­lion; • T lymphocyte aclivity is supposecl to clepend indireclly upon aclivation or macrophages and olh­er anligen-presenling cells, as well as upon second­arily induced cytokines (which play an importanl role in the aclivalion 01· T cells); • sublethally irradiated genetically changed cells are capable of challenging lhe immune response, yel a less pronounced one in comparison to lhe immune response triggered by proliferating cells, since sublethally irradiatecl cells produce cytokine only during a limited period of tirne ancl because lhe abundance or lumor-associalecl antigens is in­su fficienl; • inserlion of GM-CSF gene inlo lllmor cells does not change their tumorigenic polenlial, yet cells moclifiecl in this way and aflerwards sublethally irradiated, incluce the clevelopment of a long lasting immune memory. App lication ( l /umor spec!f1c a111ige11s as vaccines The idea is to use specific antigens only, instead of intact tumor cells (as carriers 01· usually ill-clefined tumor antigens), for the creation of tumor vaccines. In this case specific immunily can be enhanced (owing to the usage of specific antigens), and also whole work wilh gene lransfcction becomes sur­ 264 Novakovi,' S plus. Thc basic condition for a successful applica­tion of vaccinc is that the choscn antigen has to be expressed exclusively on the specific type of tumor cells and by no means on healthy normal cells. We are witncssing at present the identification of the first gencs coding for human melanoma-associated antigens that are specifically recognizcd by autolo­gous cytotoxic T Iymphocytes. Mage-1 antigen rcp­resents an example of this kind. the antigen that cannot be found on normal cells of adults, but can be detected on approximately 50 % of human rna­lignant melanoma cells.•) /11sertio11 oj" ge11e.1· coding .fi;r .rnhstan,·es tlim make 111111or cel/s .rnsceJJlihle to che111othera1Je11tic dr11g.1· The use of tumor "suicide" gcnes offers an addi­tional approach to the treatment of malignant dis­ease. Thc idea is to modify genetically tumor cells, and to rcnder thcm vulnerable to therapy with sys­temically delivered chemotherapeutic drugs. This kind of application of genetic cngineering in cancer treatment rcpresents gene lherapy in a classical sen­se. Moollen et al. quite early formcd an idea of transferring the classically described "suicide" gene, herpes virus thymidine kinasc (HSVTK) gene, into tumor cclls to make them sensitive to ganciclo­vir.••- .5 Their starting point was lhe fact that normal mammalian cells are inscnsitive to ganciclovir ow­ing to incapability of kinases (prescnt in normal cells) to phosphorylate ganciclovir into toxic me­tabolites. On thc othcr hand. HSVTK phosphor­ylates ganciclovir and its toxic metabolites inhibit DNA polymerase, thus impeding the clongation of DNA moleculc. Therefore, the accumulation of tox­ic metabolites interferes with DNA synthesis, re­sulting in apoplosis and celi death. The mechanism of action in tumor cells may be analogous to the one in virally infected cells, yet lhc cffect of toxic metabolites sprcads out also on gcnetically unchang­ed (not producing HSVTK) tumor cells -i.c. by­stander ellect. The exact mechanism of byslander cffect remains queslionable, bul anyway, there is a hypothesis that toxic metabolites nrny be released from lhe cells (wherc they were produced) in form of lyposomes to entcr genetically unchanged cells and affect them as described above. Besides, the antitumor activity also may be achicved through indirecl mechanisms that include the aclivation 01· immune system. An allirmation derivcs from the observation that the cllect of lherapy with tumor vaccines (prepared with gene coding for HSVTK) followed by ganciclovir treatment is less pronounc­ed in immunosuppressed animals (athymic nude mice)Y Short et al., as well as Culver et al., dem­onstrated the cffectiveness of such system on in­tracranial tumors in experimental animals.•1•- .7 Na­mely, they transfcrred in vivo HSVTK gene directly into tumors using vectors (fibroblasts) and after­wards treated the animals with ganciclovir. Even though they demonstrated that only a small number of tumor cells incorporatcd HSVTK gene, ganci­clovir successfully destroyed both the transfected and the nontransfected cclls. Clinical trials and prospects Preclinical studies have demonstrated that gene ther­apy represents a new and provocative mode of treat­ment with great therapeutic potentials. The insight into the rnechanisms of growth and growth regula­tion of tumor cells has offered multiple potential methods for genetic intervention. Up till now, more than I 00 trials with genetically alterecl tumor vac­cines or gene therapy studies have receivecl approv­al in humans. Most of them are using autologous tumor cells transfected with genes encoding differ­ent cytokines. One of the first tumor vaccines applied in hu­mans was Rosenberg's vaccine using tumor infil­trating lymphocytes stirnulated in vitro with IL-2 and infusing them to the patient with malignant melanoma, along with additional IL-2.•x In this case genetic manipulation was not included in the prepa­ration 01· thc vaccine, but exogcnous biological re­sponse modifiers were applied to augment the im­mune response against tumor cells. Another variant of creation or tumor vaccines was presentcd by Schirrmacher et al., who were employing a two-component human cancer vac­cine. Thc purpose of such a vaccine was simply to challenge the immune system by inserting some vira! antigens into tumor cells, thus rendering the cells much more immunogeneic. The idea was based on the analogy with virally induced tumors which are known to be the most immunogeneic tumors in humans. As the specific cornponent (bearing spe­cific antigens) they used the closest possible match to an individual cancer or a patient, namely autolo­gous canccr cells from rcsccted primary tumor or metastases. The non-lytic virus NOV (Newcastle Disease Virus) was applied as the second, non­specific component for infection of tumor cells. In two clinical studics the vaccines were applied Curre11r a11pmac//es to gene 1//ernpy in 011cologv: Co11s/rnclio11 o( ru11wr vac1·i11es postoperatively in patients with no macroscopic remnant of tumor, but with a high risk of develop­ing rccurrent discase (colorectal carcinoma and breast cancer), while in another thrcc studies the vaccines were applied in combination with biologi­cal response modifiers to patients with remaining metastatic disease: renal carcinoma, mctastatic brcast carcinoma, and rnetastatic ovarian carcinoma.4''e As it was postulated before, prescntly therc are many clinical trials with tumor vaccincs going on and thc studics of Rosenberg and Schirrmacher are the illustrations or only two di!Terent approaches to creation of tumor vaccincs. Also it is worth mcn­tioning thal lately Rosenberg modified his conccpt for generation of tumor vaccines by introducing genes coding for IL-2 or TNF-a into tumor-infil­trating lymphocytes.-"' I-lowever, the transfer 01· preclinical knowledgeeand teclrnology into clinical practice is accompa­nied with certain dilliculties. For now thc major concerns with tumor vaccines are inappropriate ex­pression of the transferred gene, as well as J'rcquenl adverse irnrnunological reactions 01· lhc organism against genetically transf'ormed cells. Certainly, it would bc highly desirablc if gene exprcssion could be regulated in tirne, quantity and place, yet with the currcnt vectors this is impossible. Newer deliv­ery systems should incorporate reatures that permit tissue/cell specific expression and allow tile leve! 01· gene expression to be regulated hy exogenous small molecules administered as a conventional pharrnaccutical agent. In addition, when autologous lllmor vaccines are used, another group of questions, which have to be solved, comes to light. Namely, the hasic term for developmenl 01· human autologous tumor vaccines is to establish primary celi cultures from palient's tumor specimens. Since this is a procedure, which is labour and tirne consuming, there was an idea to use allogeneic cells, slably transfected with cDNA of choice, instead or autologous tumor cells." Al­though the idea is attractive, conventional immu­nology stili dictates that autologous cells are far better for triggering an effective MHC-restricted immune responsc than allogeneic cells. Finally, we also have to bear in mind that I-lock et al. prepared a potcnt tumor vaccine without any kind of gcnetic manipulation to tumor cells.1'' Na­mely. in his experiments sublethally irradiated tu­mor cells admixed with Corynehactl'l'iu111 parvu111 had an immunogeneic activity by ali means compa­rable to thc one of gcnetically transformed cells. Conclusion This article is dealing with a ficki of great impor­tance, extremely fast developing, and extremely wi­de -a fact that makes every general conclusion (become) obsolete in a very short period of tirne. . Anyway. il we try to stress thc major points, we have to admit that new biological approaches to treatmenl of cancer are of central importance not only for the treatment. bul also for understanding or some basic rules governing antigen immune recog­nition, cancer metastasizing, bystander effect etc. Apart from some classical methodological prob­lems that remain to bc sol ved bef'ore fina! assess­ment of gene therapy and tumor vaccines validity will bc given, there are also some social convcn­tions that have to be changed. Namely, quite oftcn are attractive ideas for biotherapy 01· cancer re­ceived with scepticism by established oncologists, and in the majority of cases, such therapy is accepl­able only for a patient who has failed every conven­tional treatmenl. Such patients are by no means the best candidates for establishing an active immune response, and studies 01· this kind can hardly prove the validity of immune therapy. Referenees 1.e Vieweg .J. Boczkowski D. Roberson MK. et a/. Erti­cient gene transl'er with adeno-associated virus-basedeplaslllids complexed to cationic liposo!lles l'or geneetherapy or hu!llan prostate cancer. Cw1cer Res 1995:e55: 2366-72.e 2.e Nakamura Y. Wakillloto H. Abe J. et o/. Adoptive im­lllunothcrapy with murine tumor-specific T lylllpho­cytes enginecrcd to sccrcte intcrleukin 2. Ca11cer Rese1994; 54: 5757-60,e 3.e Tos GA. Cignetti A. Rovera G. Foa R. Retroviral vec­tor-!llediatctl transfer or the tumor necrosis factor geneeinto human cancer cells restores an apoptotic celi deatheprogralll and induces a bystander-killing effect. /3/oode1996; 87: 2486-95,e 4.e Ehrke MJ. Verstovšek S. Krawczyk MC, e/ al. Cyclo­phosphalllide plus tulllor necrosis J'actor-chellloimlllu­nothcrapy curcd 1nice: lifc-long i!llmunity and rejcc­tion or rc-illlplantcd prilllary lymphollla. /111 J Ca11cere1995; 63: 463-71.e 5. Kus B, Scrša G, Novakovic S, Urbancic J, Štalc A.eModil'ication or TNF-phannacokinetics in SA-1 tu­!llor-hearing mice. /111 J Ca11cer 1993; 55: 110-4.e 6.e Novakovic S. Fleischmann RW Jr. Antitumor ellect oreintcrleron-admineistcred by diffcrcnt routes or trcat­!llent. Radio/ 011rnl 1993; 27: 286-':!2.e 7.e Jezeršek B. Novakovic S, Serša G, Auersperg M, Fleis­chmann WR Jr. lnteractions of interl'eron and vinblast­ 266 Novakovi( S ine on experimental tumor model melanoma B-16 i11 vitro. A11ti-Cancer Drug.,· 1994: 5: 53-6. 8. Novakovic' S, Boldogh l. /11 vi1ro TNF-production and in vivo alteration of TNF-RNA in n1ouse peritoneal macrophages after treatmenl wilh different bacterial derivcd agents. Ca11cer Leller.,· 1994: 81: 99-109. 9. Ehrlich P. The collected papers of Paul Ehrlich. In: Hi111n1elweit F, ed. /11mwnology (II/(/ rnncer research. London: Pergamon, 1957 (1909). 10. Stevenson KF. Tumor vaccines. FASEB J 1991; 5: 2250-7, 11. Hui K. Grosveld F. Festenstein H. Re,iection of trans­plantable AKR leukaemia cclls following MHC DNA­mediated celi transfonnation. N(lfure 1984; 3ll: 750­2. 12. Wallich R, Bulbuc N, Hammerling G. Katzav S. SegalS, Feldman M. Abrogation of metastatic properlies of tumor cells by de novo cxpresion of H-2K antigensfollowing H-2 gene transfection. Na111re 1985; 315: 301-5, 13. Chen L. Ashe S. Brady W. et a/. Costimulation ofantitumor immunily by the B7 counlcrreceptor for theT lymphocyte molecules CD28 and CTLA-4. Cel/ 1992: 71: 1093-102, 14. Oettgcn H, Old LI. Thc l1istory of L'anccr immuno­therapy. In De Vita VT. Hellman S, Roscnberg SA eds. Biologic thempy of' cancer. Philadelphia, Lippincott 1991: 53-66. 15. Guo Y, Mengchao W, Chen H, et a/. EITective tumor vaccine gene.·ated by fusion of hepatoma cells with activaled I3 cells. Scie11ce 1994: 263: 518-20. 16. Forni G. Giovarelli M, Cavallo F, e/ 11/. Cylokine-in­duced tumor i111111unogcnicity: f'rom cxogenous cy­lokines to gene therapy. J /,1111111110/her 1993; 14: 253­7. 17. Perucho M, Hanahan D, Wiglcr M. Genetic and physi­cal linkage of exogenous sequences in transfonnedcells. Celi 1980; 22: 309-17. 18. Bo,ms SS. Tar"eled "ene modification for "ene thera­py .f stem celit /111 ./ Celi C/011i11g 1990: st 80-96. 24. Zwiebel AJ, Su N, MacPherson A, Davis T, Ojeifo OJ. The gene therapy of cancer: transgenic immunothera­py. Selili// Helllatol 1993: 30: 119-29. 25. Berd D, Maguire HC, Mastrangelo MJ. lnduction orcell-mediated immunity to autologous melanoma cellsand regression of metastases after treatment with a me­lanoma celi vaccine preceded by cyclophosphamide. Ca11cer Res 1986; 46: 2572-8. 26. Linsley PS, Brady W, Grosmaire L. Aruffo A, DamleNK, Ledbetter JA. Binding of B celi activation antigen !37 to CD28 coslimulates T celi proliferation and inter­leukin 2 mRNA accumulation. J Exp Med 1991: 173: 721-30. 27. Townsend SE, Allison JP. Tumor rejeclion arter directcostimulation of CD8+ T cells by B7-transfected mela­noma cells. Scie11ce 1993; 259: 368-70. 28. Colombo MP, Ferrari G. Stoppacciaro A, e/ al. Granu­locyte colony-stimulating factor gene transfer sup­presses tumorigenicity of a murine adenocarcinoma i11 vivo. J Erp Med 1991; 173: 889-97. 29. Colombo MP, Lombardi L, Stoppacciaro A, et a/. Gran­ulocyte-colony stimulating factor (G-CSF) gene trans­duction in murine adenocarcinoma drives neutrophil­mediated tumor inhibilion i11 vivo. J /111111u110/ 1992; 149: 113-9. 30. Dranoff G. Ja!Tce E. Lazenby A. et a/. Vaccination with irradiated tumor cclls engineered to secrete murine GM-CSF stimulates poleni, specific and long lasting anli-tumor immunity. Pmc Nat/ Arnd Sci USA 1993: 90: 3539-43, 31. Asher AL, Mule JJ, Kasid A, ct al. Murine cells trans­duccd with the gene I'or tumor necrosis factor . Evi­dence for paracrine immune effects of tumor necrosis factor againsl tumors. J /11111w110/ 1991; 146: 3227-34. 32. 1-lock H, Dorsch M, Kunzendorf Uquin Z, Diamanstcin T, Blankenstein T. Mcchanisms of rejection induced by tumor cell-targeted gene transfor of interleukin 2. interleukin 4, interleukin 7, tumor necrosis factor, or interferon . Pmc Nlltl Arnd Sci USA 1993; 90: 2774-8. 33. Fearon ER, Pardoll DM, ltaya T, et lil. lnterleukin-2 production by tumor cells bypasses T helper funclion in the generation of an antitumor response. Celi 1990: 60: 397-403. 19. Kubiniec RT, Liang H, Hui SW. Effects of pulse lengthand pulse strength on translection by electroporation. Gansbacher B, Zier K, Daniels 13, et a/. Intcrleukin-2 gene translerinto tumor cells abrogates tumorigenicity Bio1ec-h11iques 1990: 8: 16-20. 20. Hug P, Sleight RG. Liposomes for the transfonnationof eukaryotic cells. Biochi111 Bioph1·.1· 1\c1a 1991: 1097: 1-17. 21. Vitadcllo M, Schialfo10 MV, Picard A. et a/. Gene transfer in regenerating 111uscle. Hulll Ue11e Ther 1994: 5: 11-8, 22. Wagner E, Curie! D. Col len M. Delivery of drugs, pro­teins and genes into cells using transfcrrin as a ligandfor receptor-mediated endocytosis. Adv Drng Del 1994; 14: 1 13-35. 23. Afione AS, Conrad KC. Flotte RT. Gene lherapy vec­tors as drug delivery systems. C/i11 Plwmwcoki11e1 1995; 28: 181-9. and induces protective immunity. J Exp Med 1990: 172: 1217-24. 35. Gansbachcr B. Zicr K. Cronin K. ct al. Retroviral gene transfer induced constitutive expression of interleLTkin­2 or interferon gamma in irradiated human mela110111a cells. 13/ood 1992; 80: 2817-25. 36. Russcll SJ, Ecclcs SA, Flem1ning CL, et al. Decreased tumorigenicity of a transpantabt'c rat sarcoma I'ollow­ing transfer and cxpression of an IL-2 cDNA. /111 J Ca11cer 1991; 47: 244-51. 37. Cavallo F, Giovarelli M. Guliano A, et lil. Role of neutrophils and CD4+ T lymphocytes in the primary and memory response to noni1nmunogenic murine mammary adenocarcinoma made imunogenic by IL-2 gene. J /111111wwl 1992; 149: 3627-35. C11rre11/ llfJJ)/"1/llches to ge11e thernJJ)' i11 oncology: Co11s//'llclio11 of' 111111or vaccines 38. Allione A, Consalvo M, Nanni P, et a/. lmmunizingand curative potential of replicating and nonreplicatingmurine mammary adenocarcinoma cells engineeredwith interleukin (IL)-2, IL-4, IL-6, IL-7, IL-10, tumor necrosis factor , granulocyte-macrophage colony-stim­ulatin<> factor and -interferon f Surgerv, 2Department of Pathology, Taichung Veteran s General Hospital, Taichu11g, Taiwan, Republic of China A 20-year-old female with a sC1rco111aloid carcinoma ol lhe 1hy111us invading the leji upper lobe c>f' the lung was lrealed with surgical resectiun C111d acUuvant radiutherapv. We repurt CI ca.1·e ur this mre histologic variant ur thymic carcino111a and review the li1erature. Key words: thymus neoplasms; carcinosarcoma; sarcomatoid carcinoma. Introdudion Sarcomatoid carcinoma of the thymus is a rare his­tologic variant 01· thymic carcinoma. which was named by Snover et al in 1982.1 That group also suggested that a thymic carcinorna should fulfill the following criteria: ( 1) anterior mediastinal location and (2) absence of another primary tumor. We have reported 20 consecuti ve cases or thyrnic carcinoma in a 10-year period at our institute.' Among these 20 cases. no histologic variant 01· sarcomatoid car­cinoma has been disclosed. We hereby describe a case od sarcomatoid carcinoma or the thymus that, microscopically, contains both a malignant epithe­lial component and a sarcomatoid component. The expression of cytokeratins and epithelial membrane antigen (EMA) in tumor cells could dillerentiate it fr om true sarcomas which do not stain for these markers.' Case report A 20 year old remale presented with a six 111011th history of increasing dyspnoea and lcft chest pain. Correspondence to: N.Y. Hsu. M.D. Division ol' Thoracic Surgery, Depl. or Surgery, Taichung Veterans General Hos­pital, No. 160, Scction 3. Taichung-K,mg Road. Taichung. Taiwan, Republic of China. UDC: 616.438-006.68 On admission. physical examination revealed de­creased breath sounds in her lert upper chest. No lymphadenopathy was found. The full blood count revealed a haemoglobin of 13.7 g/dl, a white celi count of 7.8 x 10"/1 (neutrophils 7.2, eosinophils 0.2, lymphocyte 1.7), and a platelet count or 371 x 10'1/I. A chest radiograph demonstrated a big mass in the anterior aspect of the lert lung. A computed tomographic (CT) scan or the chest showed a big necrotic tumour, measuring 14 x 12 x 12 cm in size. arising from the anterior mediastinum and invading to the left upper lung field (Figure 1 ). The serum litre of beta-choriogonadotropin (beta-HCG), alfa fcto proteim (AFP) and carcinoembrionic antigen Sarconwtoid carcinonw of' the thymus -a C(tse re1wrt (CEA) were within normal limit. Sono-guided aspi­ration of the tumour was performed, ,llld a cytologi­cal examination showed spindle celi Lumour. 99111 Tc-MDP whole body bone scanning and ]iver sonog­raphy showed no evidence or metastatic foci. An operalion was performed via standard postero­lateral thoracotomy. While the Lumour occupied the whole anterior mediastinum. ils left laterni sile in­vaded the lefl upper lobe of Lhe Jung. Removal of the mediastinal turnour with a left upper lobectomy of Jung was performed. The postoperative course was uneventful, and Lhe inlercostal drain was re­moved on the fifth postoperative day. Histopathological examination of the tumour re­vealed a custers of epithelial cells rnixed with the strap-like spindle cells (Figure 2). An irnmunohis­tochemical study showed a positivc staining for cytokeratin in the epithelial area and in some spin­dle cells (Figure 3). The patient then received radio­therapy with a 6000 Gy tumour dose. There was Figure 2. Clusler ofthymic cpithelial cclls rnixccJ with strap­likc spindle cells (hernatoxylin-eosin. x400). Figure 3. Sarcomaloid carcinorna or Lhe thymus sh,J\\ 111g dark colouration in lhe cpithelial arca and in some spindle celi s (peroxidasc-antiperoxidasc [ PAPJ slaining with cylo­keratin) (original magnification x400). subjective improvement of dyspnoea and chest pain, and the palienl is currently ali ve I O months after surgery with no evidence of Lumour recurrencc or melastasis. Discussion Thymic carcinoma per se is a relatively rare tu­mour. with distinct pathological and clinical char­acteristics. There were eight histological variants of thymic carcinoma, reporled in the literatures with sarcomatoid type among them.,. 4 Various tumours showing the histological features of sarcomatoid carcinoma are seen also in other organs such as: Jung/ pancreas.'' kidney,7 breast.8 and urinary blad­der.9 However. sarcomatoid carcinoma of the thy­mus, as one of the histological variant of thymic carcinoma, has seldom been reported. The clinico­pathologic features of the reported cases are sum­marized in Table 1. Clinically. this tumour mostly occurs in middle or in old age. similarly to the other variants of thymic carcinoma. To our knowledge. this is the youngest case reported in the literature. In our previous study of 20 cases of thymic carci­noma, we found that invasion of the mediastinal stuctures is almost always present, including the inominate vein, mediastinal pleura, perieardium, and lung.2 As compared with thymoma, thymic car­cinorna has a more invasive tendency on computed tomographic scan examinations, and most of the patients have clinical symptoms caused by tumour s compression of the mediastinal vi tal structures.2· In general. thymic carcinoma are immunoreac­tive to EMA and cytokeralin, but not reaetive to AFP, beta-HCG, placenta! alkaline phosphatase. or common leukocyte antigens. 11-13 S no ver et al su­ggest that the presence of keratin within the spindle celi component can justify the use of the term "sar­comatoid carcinoma".2 In one case, initially, germ celi Lumour was high­ly suspected, bul a subsequent study of a series ot· turnour markers disclosed no elcvation serum titre of beta-HCG, AFP and CEA. During operation, we found that the space-occu­pied mediastinal tumour invaded the left upper lobe or the Jung. but fortunately, the hilar struetures such as the left upper !obar bronchus, superior pulmo­nary vein, and pulmonary artery branches to left upper lobe of Jung were pushed laterally by the tumour, and lota! removal of the tumour with a lobectomy could be performed withoul difficulty. 270 Hsu NYet a/. Table l. Reported cases of sarcomatoid carcinoma of the thymus. Year/ Author Age/Sex Symptoms Location/Size/lnvasion Therapy Follow-up 1982/Snover et al '"'· ' 64/M Asymptoms Ant. rnediastinal/ Excision died with 6x5x4.4 cm/­ metastasis at 13 months postop. 1982/Wick et al"''" 53/M Chest pain, dysphagia, SVC Ant. mediastinum/?/SVC RT&CT died with metastasis at 28 1992/Morita et al""'-10 1996/Hsu et al 53/M 20/F syndrome Asymptoms Chest pain, Ant. mediastinum/? lung, pericardium Ant. mediastinum/ Excision Excision + rnonths postop. ? ali ve I O months dyspnoea l4xl2xl2 cm/ RT postop. lung SYC -superior vena cava. RT -radiotherapy, CT -chemotherapy There is stili a limited experience in the manage­ment of thymic carcinoma. Complete resection of these tumours is sometimes difficult because of the presence of invasion of the mediastinal structures. However. surgical resection should be attempled whenever possible to decrease the tumour burden. The role of postoperative irradiation in the treat­ment of sarcomatoid carcinoma of the thymus is unknown because of limited experience in this field. In our previous study of thymic carcinoma, we showed that pathological stage, type of resection, postoperative radiotherapy, and celi type did not indicate a significantly favorable result.2 We presented a 20-year-old patient with a giant tumour, biphasic histology and with evident disease after surgery. She was believed to be at high risk of recurrence. Hopefully, complete resection and ad­juvant radiotherapy in this patients can lead to a more favorable outcome. Reference l. Snover DC, Levine GD. Rosai J. Thymic carcinoma: five distinctive histological variants. A111 .l Surg Pathol 1982: 6(5): 451-70. 2. Hsu CP. Chen CY. Chen CL, Lin CT. Hsu NY, Wang JH, Wang PY. Thymic carcinoma: ten years' experi­ence in twenty patients. .l Thorac Cardiovasc Surg 1994; 107: 615-20. 3. Ogawa K, Kirn YC, Nakashima Y. Yamabe H, Takeda T. Hamashima Y. Expression of epithelial markers in sarcomatoid carcinoma: an immunohistochemical study. Histopatho/ogy 1987: 11: 511-22. 4. Wick MR, Scheithauer BW. Weiland LH, Bernatz PE. Primary thymic carcinomas. Am .l Surg Pathol 1982: 6(7): 613-30. 5. Nappi O, Glasner SD, Swanson PE, Wick MR. Bipha­sic and monophasic sarcomatoid carcinomas of the lung. A reappraisal of 'arcinosarcomas' and 'spindle­cell carsinomas'. Am .l Cli11 Patho/ 1994; 102(3): 331-40. 6. Alguacil-Garcia A, Weiland LH. The histologic spect­rum, prognosis, and histogenesis of the sarcomatoid carcinoma of the pancreas. Cancer 1977; 39(3): 1181-9. 7. Bertoni F, Ferri C, Benati A, Bacchini P. Corrado F. Sarcomatoid carcinoma of the kidney . .l Uro/ 1987; 137(1): 25-8. 8. Meis JM, Ordonez NG, Gallager HS. Sarcomatoid car­cinoma of the breast: an immunohistochemical study of six cases. Virchows Arch 1987; 410(5): 415-21. 9. Torenbeek B, Blomjous CE, de Bruin PC, Newling DW, Meijer CJ. Sarcomatoid carcinoma of the urinary bladder. Clinicopathologic analysis of 18 cases with immunohistochemical and electron microscopic find­ings. A111 .l Surg Pathol 1994; 18(3): 241-9. 10. Morita M. Kakimoto S, !soda K, Sasaki S, Takeuchi A. A case of thymic carcinoma, sarcomatoid type (in japa­nese). Kyobu-Geka 1992; 45(4): 371-4. 11. Battifora H, Sun TT, Bahu RM. Roa S. The use of antikeratin anlisurum as a diagnostic tool: thymoma versus lymphoma. Hu111 Patlwl 1984; 11: 63.5-41. 12. Sloane JP, Ormerod MG. Distribution of epithelial membrane antigen in normal and neoplastic tissues and its value in diagnostic tumor pathology. Ca11cer l 981; 47: 1786-95. 13. Fukai IF, Masaoka A, Hashimoto T, Yamakawa Y. Mizuno T. Tanamura O. Cytokeratins in normal thy­mus and thymic epithelial tumors. Ca11cer 1993; 71: 99-10.5. Radio/ ()II('o/ 1996: 30: 271-4. Influence of exogenous hormones on the recurrence and progres­sion of cancer Marjetka Uršic-Vršcaj and Sonja Bebar Department o{ Gynecology, Institute (){ Oncology, L)ubzjana, Slovenia In the lastfew years, lwmwne replacm1ent therapy (HRT) lws become widely used eve,ywhere in the world. Apart .fimn favourable effects of HRT, .rnch as a significant decrease in the psycho-physical 111e11opause­related dif/iculties, lower 111ortality due to cardiovascular diseases and lower incidence C!( osteoporosis, f some lfll<'Stions related to possihle association between the use o this therapy and the rise, recurrence mul progression of' cancer have not heen rl'solved yet. According to the mqjoritv c!f'studies puh/ished so far, HRT is 1101 associared with an increased risk c!l the onset, recurrence and progression o/ cancer. Moreover, some .findings even indicate the possihility that HRT might exert a protective e_ffect against the rise, recurrence and progression 1 It is bclieved that the more severe menopausal changes seen in patients who have un­dergone surgery for breast cancer could be attribut­able to the loss of this psychologically important ancl typically female external organ. We presume that thesc patients had more frequendy psyhyatrical treatment than others. Considering the fact that elsewhere also HRT was indicated only in patients with severe climac­teric prohlems, mostly owing to the suspected risk for cancer progress. The scientific evidence collect­ecl so far is relatively scarce. None or the retrospec­tive studies published has been able to associate an increased risk of cancer recurrence or progression with the use of HRT.• Moreover, in thc most recent report by Eden et al. published in 19%, it has been suggested that HRT might even exert a protective effect in this respect.5 Some epidemiological data indicate that despite -the risk associated with a greater number of menstrual cycles and the related events, -laboratory evidence on the inlluence of estro­gens on the accelerated growth of mammary cells, and -clinical elTectiveness of tamoxifen (a selective estrogen antagonist) in patients with metastatic breast cancer, The following facts should not be ignored: not ali postmenopausal breast cancer patients have a better prognosis than premenopausal ones, -after completed chemotherapy. the prognosis of premenopausal breast caneer patients with regu­lar menstrual cycles is not worse than that of those without reslored ovarian function; -after two months of tamoxil'en therapy, pre­menopausal patients present with elevated serum estradiol levels; -among premenopausal breast cancer patients OC users do not survive worse than non-users of oral contraceptives. It has been established that some stromal. fatty and carcinoma cells of the breast have the potential of synthesising estrogens locally from androgens, a pre-stage of estrogens. We presume that the leve! of local estrogens in the breast is independent of serum estrogens. The very local values of estrogens seem to be most relevant for the onset and metasta­sizing of breast cancer. It is also believed that tamo­xifen reduces the levels of estrogens in the breast and metastatically changed cells, mainly through the competitive binding to estrogen receptors. Ta­moxifen reduces celi proliferation. Given in low doses, it excrts a cytotostatic elTect (increased G 1 phase of the celi cycle resulting in a prolongation of celi division phase) while in high doses it is cyto­toxic (arrest of G I phase and cessation of celi divi­sion). We presume that the antiproliferative elTect of Tamoxifen is also expressed through growth fac­tors or C protein kinase inhibition.2 Besides being estrogen antagonist, Tamoxifen is also estrogen ag­onist prevailingly active in the !iver, bones and endometrium. While Tamoxifen reduces the risk of the onset 01· thromboembolic conditions and oste­oporosis, it does not alleviate menopausal vasomo­toric disorders. Moreover. it has been found that in 15-20 % of cases Tamoxifen might even worsen these symptoms. The results 01· some studies have shown that a long-term use of Tamoxifen may in­crease by 3-5 times the risk of endometrial earcino­ma.• We stili cannol provide a conclusive answer to the question about the role of hormone receptors in breast cancer patients. Also, the treatment of pa­tients with melastatic breast cancer hides many un­resolved questions. The fact is that an equally long 30 % remission of the disease can also be obtained by adding some estrogens and progesterones in post­menopausal patients with positive estrogen recep­tors.1 The least known. but -according to some reports -perhaps very important is the effect of progester­one on the breast."· 7 We suspect that the effect, which is believed to play a protective role in the rise of breast cancer, is very complex and depencl­ent on severa! factors such as the type, dose and duration of progestagen use. While a short lasling progestagen use should exerl a cell-proliferative ellect, a long-lasting or continuous use should re­sult in antiestrogen, antimitotic and antiprolifera­tive elTect. . Most investigations are centred partic­ularly on this. /J.fh1e11ce rf exogenous hormone.\· on tile recurre11ce and progre,\·sion r.f cancer So, let us conclude our report on hormone re­placement therapy in patients treated for breast can­cer with the statement madc by thc Breast Cancer Committee of the East Oncology Group: There are many facts which speak in favor of the belief that estrogen. therapy in breast cancer patients is safe. Thereforc. the tirne has come for a change! 1 There are but fcw reports on the use of HRT in patients treated for other cancers. and therefore any critical conclusions in this respect would be prema­ture. According to the scarce preliminary reports, HRT is not associated with an increased risk of cancer dissemination; moreover. some of the re­ports even indicate a protective eilcct of HRT, which is rellected in a lower rale of progression and better survival results.' HRT in patients treated for cancer at the Institute of Oncology in Ljubljana. Preliminary results. In our patients treated for cancer, HRT was indicat­ed only when menopausal problems were so severe that they were regarded as life threatening. A revision of the dala on patients treated for cancer at the Institute of Oncology. and receiving HRT was started in February 1996. Up to now. complete data have been collected for 25 patients. The average duration of HRT treatment was 38 months (4-120). In 22 cases both hormones, i.e. estrogens and progesterones. were used in accord­ance with the well known protectivc role of pro­gestagens. In 21 patients, HRT (Cyclomenorrete, Trisequens, Trisequens f tablets) was applied in four week intervals. while the remaining patients received hormones (Gynodian depot injection and Dabroston tablets) in 6-8 week intervals or even less frequently. The uterus was surgically removed in 15 patients. Twenty-four patients were free of recurrence. Progression of the discasc was estab­lished six months after HRT in one patient only: she had a highly malignant leiomyosarcoma of the uterus. With respect to the histologically verified highly malignant tumor, the progression was ex­pected, and was therefore detected relatively early. when thc patient was stili asymptomatic. In this patients HRT was given in 6-8 week intervals. Af­ter the diagnosis of recurrence, the patient was re­operated. and has been wilhoul evidence of the disease 10 months since the primary lherapy. She was further maintained on HRT because of severe menopausal problems. Eight of 25 patients were treated for breast can­cer. Two had metastases in the axillary lymph no­des, 5/7 had negative hormone receptors while in two patients these were positive: one patient had estrogen-and the other one progesterone receptors. Ali those 8 patients received estrogen & progester­one based HRT in the duration of 2 years on aver­age. The mean delay from breast surgery to the start of HRT was 4 years, after a non-hormonal treat­ment had failed and the menopausal problems got progressingly worse. Other patients who received HRT had been pre­viously treated for cancer of the reproductive or­gans. Hodgkin's disease. NH lymphoma or carcino­mas of the thyroid and rectum. So far, none of the patients followed up for 4-120 months has presented with progression. Conclusion and recommendations Recommendations for HRT in women at an increas­ed risk of cancer, and in patients treated for cancer. 1) In women who are believed to be at a higher risk 01· cancer than the rest of normal female popu­lation. HRT is indicated only in the presence 01· menopausal problems, and not as prevention of thromboembolic conditions or osteoporosis. 2) In menopausal patients treated for cancer, HRT is indicated only in the case of severe menopausal problems. 3) In accordance with internationally accepted guidelines, HRT with estrogen alone is indicated in patients who have undergone hysterectomy or had lheir uterine mucosis destroyed by radical irradia­tion. In ali others estrogen & progesterone based HRT should be used. 4) Prior to the administration of HRT, the patient should undergo a gynecological check, clinical breast examination and mammography. Regular fol­low up, including gynecological check and clinical examination of the breast, should be carried out every six months, while control mammographies should follow the routine set by the accepted guide­lines for early detection of breast cancer. 5) In order to get a more comprehensive over­view of the state of the art regarding HRT, further studies are also required in Slovenia, which would hopefully yield results that could prove useful at a national as well as international leve!. Ur.'i/ic-Vr.'i/caj M wul Behar S Acknowledgement The authors sincerely thank the co-workers from the Institute of Oncology in Ljubljana for their pres­entation of advances in the field at the seminar in Budapest. They also thank Mrs. Olga Shrestha for English translation. References 1. Bosze P, Eckhardt S, Marton 1, eds. Hormone replace­111enr rherapy mul cancer. Budapest: European School of Oncology, 1995. 2. DiSaia PJ. Hormone-replacement therapy in patients with breast cancer: a reappraisal. Cancer 1993; 71: 1490-500. 3. Pompe-Kirn V, Primic-Žakelj M, Ferligoj A, Škrk J. Zelllljevidi incide11ce raka v Sloveniji 1978-1987. Ljubljana: Onkološki inštitut, 1992. 4. Sands R, BoshoffC, Jones A, Studd J. Current opinion: hormone replacement therapy after a diagnosis of breast cancer. Menopause 1995; 2: 73-80. 5. Eden JA, Bosh T, Nand S, Wren BG. A case-control study of combined continuous estrogen-progestin re­placement therapy among women with a personal his­tory of breast cancer. Me11opause 1995: 2: 67-72. 6. Gambrell RD. Hormone replacement thernpy in pa­tients with previous breast cancer. Menopause 1995: 2: 55-7. 7. Giacalone PL, Laffargue F. Traitement hormona! sub­stitutif apres cancer du sein. Conlracept Fertil Sex 1994; 22: 741-5. Radio/ 011rn/ 1996; 30: 275-80. Metastases to the breast from melanoma: a rare manif estation of an unpredictable malignant disease Viljem Kovac and Andrej F. Plesnicar Institute r,f' Oncology, Ljub(iana , Slovenia Cancer 111etastases to the breast are not fi·eq11ent. The most common among them are those originating Jiom melanoma. The course of this disease is <./ten 1111predictable, bw the clwnges in the menstrual status may in some patients ind11ce /oca/ changes in the hreast that facilitate the grmvth 1.( melanoma metastases. These changes are prohably caused hy physio/ogical dwnges in serum estrogen leve/s, with the causes behind trci[ftcking <.f melanoma cel/s to the hreast remaining unclear. Patients with melanoma metastases to the breast will be encountered more fi·equently, as the incidence rate of melanoma inc:reases worldwide. These 111l'lastases us11C1l!y 111w1ifes1 themse/ves as palpable 111obile masses. Mammographic findings are of one or more ro1111ded, well-circu111scrihed lesions with slightly irregu/ar margins. The palpahle and the mamnwgraphic di111ensions 1!{ these lesions are usually closely correlated. Fine needle aspiration cytology of described lesions is a quick, sc(/1' wul highly accurate diagnostic procedure. Surgical excision is the appropriate treatment that provides /ocal control ,vith or witho11t adjunctive chemo­wul i11111umotherapy. Although masteclomv has not improved survival, it is so111eti111es required if the tumor is lm/ky, deep-seated, or pailifit!. Key words: breast-neoplasms-secondary; melanoma, melanoma-secondary; carcinoma-diagnosis; carcinoma­treatment Introduction Cancer metastases to the breast are not frequent, with the cxception of those from contralateral breast.1 They represent 2.7 % of ali malignant breast tumors.2 In a serics of wornen treated for breast turnors, less than 1 % had rnetastases to the rnammary gland from other primaries.1- .5 whereas in aulopsy studies the overall frequency of cancer rnetastases to the breasl ranged bctween 1.7 and 6.6 %.1.r, Melanomas are among the most common prirna­ . 5.7-11 ry sites.1­ As the incidcncc or melanoma is increasing ali over thc world,12•1; and as approxi- Correspondence to: Assist. Viljem Kovac, M.O .. M.Se., In­stitute of Oncology. Zaloška 2. I 105 Ljubljana. Fax: +386 61 1314 180. E-mail: vkovac(i'Dmail.onco-i.si UDC: 61 R. l 9-006.6:616-006.8 l mately 20 % of patients will eventually develop metastases,15 an increase in the incidence of melano­ma metastases to the breast can be expected. It is surprising lhat melanoma which originates in the skin and disseminates widely throughout the body, oftcn predominantly in the skin, rarely me­tastasizes to the parenchyma of the breast which is a skin appendage.11 Natura! history of disease Rapid growlh is an irnportanl characteristic of can­ccr metastascs in the breast. 1.1C, Furthermore, cancer mctastases to the breast are generally a harbinger of widc dissemination and fulminant course of the disease. Such patients thus show very short surviv­al, usually lcss than I yearY-'w.ix Kovu( Vand Plesnitar A F The nature of malignant melanoma is orten un­predictable and no other tumor is considered so capricious in its dissemination. 11 No clear predis­posing factors correlating with the dcvelopment of melanoma metastases to the breast have becn iden­tified.'J It is not clear, whether hormonal ractors havc any inllucncc on the natural history or the disease. On the other hand. some rcports suggest that the changes in the menstrual status may induce some local changes in the breast that facilitate the growth of the melanoma melastases siluated the­re. 17·1. These changes are probably caused by physi­ological changes in serum estrogen lcvels. It is interesting to note that estrogen therapy for advanced carcinoma of the prostate n1ay also cause the growth or metastases in the breast and nip­ple.1"·20 Some data suggcst that changcs in hormo­nal factors correlate with the dcvelopmcnt of breast metastascs in males with various cancers4 and in young females with rhalxlomyosarcoma. 21 However, it was reported that the patients with melanoma metastases to thc breast were mostly premenopausal women and some of them were preg­nant.4·11-" Together with the dala that low levels of estrogen receptors have bcen someti mes observed on melanoma cells.22·24 these reports additionally suggesl that there may he some hormonal influence involved in the tra!Ticking of melanoma cells to the breast as well. The role of estrogens and other hormoncs in the natural history of melanoma remains controversial. Extremely poor prognosis was reportcd for patients with melanoma devcloped during pregnancy2' and in postmenopausal period. "'·27 On the other hand, some recent studies show thal pregnancy does not activate cutaneous melanoma or talent melanoma metastascs as well.'"·2', Possible advcrsc or bencfi­cial elTects 01· oral contraccptives, estrogen and pro­gesteronc on the history or melanoma wcre evaluat­ed,22·10·12 hut the results of clinical trials wilh hor­mone thcrapy werc disappointing.21·2411 Additional­ly, it sccms that thc better prognosis or females with melanoma, especially or prcmcnopausal pa­tients,2''·14 cannot simply be cxplained by the pres­ence of stcroids receptors, since they were found in male patients as well.22 A higher proportion or thin melanoma lesions in womcn may contribute to an overall better progno­ sis for them. Nevertheless, survi val rates for wom­en were stili higher than for men, cven when prima­ry lesions were of similar thickness. But, when premenopausal womcn were matched with men by age and location and thickncss of primary lesion, a marketi remale superiority still exists only for those patienls with very thick lesions.27 Despite the fact that patients with melanoma me­tastases to the breast are mostly premenopausal women, their prognosis remains poor. There seems to bc a certain barrier against metastatic dissemina­tion in premenopausal women,'' bul it seems it is no more elTective when melanoma metastases to the breasl are observed in these patients. The occurrence of melanoma in children is un­common. 14·><• In the report on a 14-year-old girl with melanoma metastases to the breasl ancl brain thcre is no record about her menstrual status.1<' It can be presumed lhat her pubertal period was connected with changes in her hormona! status that may have had some influence on the course of the disease. But, the rarily of melanoma before puberly may simply rellect absence or a carcinogenic stimulus and a long latent period. Long median intervals between the initial diag­nosis of primary melanoma and involvement of breast have usually been observed1·1x and the long­est interval of 11 years was registercd in a patient who was pregnant at the tirne of diagnosis. 18 The most common primary sites or melanoma associated with breast involvement are on the arms and lrunk. This is contrary to the most common sites in premenopausal women, namely the lower extremities. Thcre my be a direct lymphatic and vascular drainage from these sites to the breast and this can be regarded as one of thc factors that influ­ence the natura! course of this disease. ,x.n.17 The factors bchind the occurrence of the melano­ma metastases to the breast remain more or less unclear, bul it is possible that patients with this type or metastatic dissemination will be scen more rrequcncy as the incidcnce of melanoma increases worldwide.12·'1 Diagnosis Most patients have a known diagnosis of carcinoma al the tirne or presentation with breast metastas­es.',·"'-17 Occasionally, a breast metaslasis is the first manil'estation of an occult primary lesion.1.1A.s.Jx.J,, Metaslases to the breasl usually manifest them­selves as palpable mobile breast masses that are sometimes adherent to thc skin. 15 Diffuse skin in­volvement or associated subcutaneous nodules can also occur.x The metastases may be multiple and 1vle111s111ses /o lhe hre11s1jimn 111e/11110111ll:" mre 1111111ifesw1ion 0(,111 u11predic111b!e 11111/ig1111111 disellse 277 can bc obscrvcd in both brcasts. J.; Tumor dimcn­sions do not help to distinguish between primary and metastatic canccr. Although it is claimed that metastases are usually smaller than pri111ary tumors, metastases may eventually beco111c huge in size_)') The classic mammographic rinding (Figure 1) consists 01· one or more rounded, well-circu111scribed masses with slightly irregular margins.''·1''··l0.-II Mi­crocalcirications are unusual,'-'' bul it should be stressed that thc presencc or micrncakifications docs not rulc out a metastasis. ''' Sincc a metastatic lesion does not causc a surrounding desmoplastic rcaction in adjaccnt nor111al brcast, thcrc is typical­ly a closc corrclation bctwccn thc palpable size or thc 111ass and its 111a111mographic sizc. 1-''·1'' Howevcr, thc sa111c sizc scen in clinical cxamination or brcast metastases and mammography could lcad to a dilTi­cult di!Tcrential diagnosis with benign breast lc­sions such as cysts or ribroadcno111as. This con­trasts with pri111ary carcino111a or thc hreast, in which thc mammographic abnormality is often s111allcr than thc palpablc mass. Figure l. Patienl with melanoma metasta:-.is to the brcast. Craniocaudale view of lhe lert breast rcveals two well­defined masses. Thcrc is no doubt that mam111ography is thc pri­mary 111cthod to image breast tissuc and cvaluatc specific brcast lcsions. As a pri111ary tcchnique for brcast imaging, computed tomography (CT) com­parcs poorly to mam111ography."2 But. on occasion, brcast lcsions may be bctter visualizcd by CT than by mammography if thc brcasts are dcnsc, or if thc lcsion is located adjaccnt to thc chcst wall.•J Thc supcrb contrast resolution of CT allows a charncter­ization or thc dcnsity or the brcast lesion and may augment the diagnostic possibilitics. However, in most cascs a recognition or a CT abnormality or thc breast suggests the need for mammographic corrc­lation."2 In young women ultrasound cxamination of breast should bc done. We can usually sec mctastases to thc brcast as hypoechogcnic nodules of diffcrent sizes, with rcgular margins and postcrior attcnua­ 00 tion or the posterior ultrasound bcam. Particularly when thc clinical evaluation is sug­gestivc or metastalic disease, diagnostic fine nccdlc aspiration hiopsy may be confirmatory (Figure 2 and 3). Thc celi pattcrn in metastases or melanoma is gcnerally plcomorphic."·1 Special stains (HMB45, S 100, Warthin Starry)1 '··1"-"' and clectron microsco­PY may bc applied to this material as wcll to pro­vide additional diagnostic information. Duc to high diagnostic accuracy, fine necdle aspiration cytolo­gy should bc routincly practiscd as a quick and safc diagnostic procedure. It should bc a very reliable method or distinguishing primary carcinoma rrom metastatic melanoma. Sometimcs ultrasouncl guid­cd and stcreotactic fine needle aspiration hiopsy should bc applicd ir metastatic lcsion is very small and not palpable. Figure 2. Fine needlc aspiralc or 111cla110111a rnelastasis 10 the brcast epythcloid lypc (Gie111sa, objcctive 40). Figure 3. Fine ncedlc aspiralc or melanoma mctastasis 10 the breast -rusoccllular type (Giemsa. objeetivc 40). Kovm" V l/11(/ Plesnihir A F Open biopsy is rarely required for diagnosis if a primary breast tumor is not confirmed by the fine needle aspiration biopsy."·11'·1'1 A1,-;x Unlil some yearseago, the most helpful finding for idenlifying a met­astatic malignancy in the breast was the recognition of the architectural pattern of the tumor, such as the presence of periductal infiltration without the coex­istence of intraductal or intralobular carcinoma. But recently, immunohistochemistry has been suggest­ed to differentiate mctastatic carcinoma from a pri­mary brcast tumor in surgical specimens, and to 111 avoid unnecessary radical surgery. ·1'1 Further re­ports strcss the importance of using a panel of im­munohistochemical markers. For melanoma this should include at least two epithelial markers (i.e. BRST2, Human milk fat globulin 2 -HMFG2, CAM 5.2)eJxA•, and at least two antibodies to melano­ma-associated antigens (i.e. HMB45, S-100, NK I­ C3).Jx.;oe Occasionally, patients with breast metastases from melanoma were initially misdiagnosed.4 The­refore for patients with a previous history of melano­ma, however remote, the diagnosis of breast metas­tases in a premenopausal woman must be consid­ered.1x Treatment Accurate diagnosis of breast metastasis is impor­tant for avoiding unnecessary masteclomy and for implementing appropriate systemic therapy -since the metastatic ]I represents the averaging effecl of the aperture size a. and the multiplicalion with n=+oc comb( i) = L b(.r -11b) 11;;;::-oc represents the sampling with a spacing of h. The measured modulation transfer function is then giv­en by the modulus 01· the Fourier transform of /m (x): MTF,,,(u) l[MTF(u) · .si11c(a11)1: cumh(/m)I which contains truncation error introduced by the multiplication with sinc(au) and aliasing artifact introduced by the convolution with (comb(bu)). Pre­cautions have to be taken in the selection of aper­ture size and sampling rate in order to keep system­atic errors under an acceptable limit. The upper limit of spatial frequency at which the modulation transfer function can be measured is determined by the Nyquist criterion: ll.11,aš 21,· The convolution in Eq. (4) causes overlapping of adjacent cycles. This overlap can be reduced by increasing the aperture size. A larger aperlure re­duces thc ampliludes of the sidelobes of sinc(au) but at the same tirne increases lruncalion error. As a trade-oll of aliasing reduction, the measured modu­lation transfer function will deviate more from the true value. The current convenlion used in modula­tion transfer function measurements is a = 2b, i.e., the aperture should be at least twice the size of the sampling interval. This convention ensures a less than 2 % systematic error in the sampled data.10 Quantum noise in x-ray imaging originates from the fluctuation of the incident photon flux charac­terized by Poisson statistics and the randomness of the amount of energy deposited by each x-ray pho­ton in the receptor. White the former determines the noise leve! of the input, the latter is the reason for the degradation of the signal to noise leve! in­troduced by the receptor. This degradation is usual­ly characterized by the detective quantum efficien­cy defined as DQE = (S:\'R,,,,,)·1 . . '-if\R1 ,J For an amorphous selenium receptor, the energy deposited by an incident photon is used to create electron-hole pairs which are responsible for the formation of the electrostatic image. The number of these charge carriers resulted from E incident pho­tons of energy is given by E,,, .f n(E,E;,,)EdE II M' where 11( E, E;,,) is the average number of photons that deposited the amount of energy E and W is the average energy required to generate one electron­hole pair. The fluctuation of n(E, E;,,) isJn(E,E;,,). Considering the absorbed energy distribution, the total uncertainty is j,\f Therefore, E,,, I 11(F:)F:dE ,C.., JR E,,, { "(E.E,,,) ----y--F:dE DQE = ( i,_ E,,, u(E.E,,,) ,,, .la-dE 11 f where E,,, j n(EE) .Ei ,tf-.,' o Mo111e Car/o Si111lllatio11s ofa 111eta//a-Se Porwl Deteclor 2'!3 is the ilh moment of the normalizecl pulse height spectrum from incident photons of energy E;,,. Eq( 11 lhe DQE at zero spatial frequencybecause spatial information transfer is not consicl­erecl. DQE at a 11011 zero spatial frequency is loweras thc receptor can not fully transfer the informa­tion at lhat detail leve!. DQE as a function of spatialfrequency can be expressecl as DQE(f) = D(JE(O) · MTF2 (f) provicled that quanlum noise is white noise. Thisis justifiable since the input noise is determined bythe Poisson statistics and the output noise is cleter­minecl by the tluctuation in the energy deposited bya photon. Neither of them depends on the spatialfrequency of the input under the assumption that x­rays are photons and the detector is a large continu­um. Monle Car/o Si1111t!ations lmage acquisition in transmission radiology startswith the detection of x-rays transmitted through apatient. The change or some physical observablecaused by the interaction between the x-rays andthe detector is then extracted as the output signal bya certain means. The incident photon generates aphoton-electron "shower" in the detector introduc­ing an uncertainty in the spatial location of theincident point resulting in receptor blur. Due to thestochastic nature or lhe coupled photon-electrontransport. energy deposilion introduces tluctuationin the output signal or quantum noise. 11-" The mag­nitude or receptor blur and quantum noise dependon the energy or the x-rays and the composition andgeometry of the receptor. The coupled photon-electron transport within thedetector was simulated with the Electron Gamma Shower (EGS4) code'. which has been extensivelyused for radiation dose calculation in the energyrange or 1-10 MeV and has been proven to pro­duce reliable results. As a general purpose softwarepackage, EGS4 (National Research Council, Cana­da) consists of two major parts: the system coclethat handles the physics or couplecl photon-electrontransport and the user code that defines lhe geome­lry and type or the medium/rnedia. The user code also specifies which physical observable(s) will bescored. This package also provides two general pur­pose programs, XYZDOS and DOSRZ, to definesimulation geornetry in Cartesian and polar coordi­nate systems which include the Parameter Reduced Electron Step Transport Algorithm (PRESTA) thatreduces the depenclence of chargecl particle trans­port on user-selected parameters. 15 Density effect corrections were also included in the collisional slopping powers. The K fluorescence productionwas not considered since it is not significant in thernegavoltage energy range.'1 The parameters con­trolling the transport were sel as the following: ECUT=AE=0.521 MeV, PCUT=AP=0.01 MeV. where ECUT is the minimum lota! energy of elec­trons that are transported, PCUT is the minimumtotal energy of photons that are transported, AE andAP are the energy thresholcls for creation of sec­ondary electrons and photons, respectively. Mo­noenergetic pholons (0.1-6 MeV) were used in alisimulations. The results of simulation runs are con­sistently well within 1 % of cach other. A layer of amorphous selenium is coated on an8 x 8 in2 metal plate: thc metal-plate is in the beam­entrance side of the detector. As a build up materi­al, the metal plate converts the incident photonsinto electrons. lntuitively, the optimal thickness ofthe metal plate should be the deplh c/,,,," wherc elec­tron equilibrium is reached. Beyond this deplh, en­ergy absorplion decreases because the primary pho­lon beam is attenuated and electrons do not trave! over a certain range. Three of the four receptors(Norancla Advanced Materials !ne., Pointe Claire.QC) have a 2 mm thick aluminum plate wilh dilTer­ent thickness of a-Se: 150 pm, 300 pm and 500 pm.The olher receptor consisls 01· 1 mm copper and 300 pm a-Se. The simulation of the line spread function was run wilh the user code XYZDOS. A 2 pm x 20 cm2 parallel beam of monoenergetic photons is incidentat the center of a 20 x 20 cm2 receptor. The a-Se layer of lhe receptor is dividcd inlo a serics 01· 5 pmwide strips inside which the deposited energies arescored. Evcry two adjacenl poinls are lhen avcr­aged: .[E(.r;J + E(.r;+1l] .r; = (i-l)h. i =, 1.2.:J.· · ·.N. 1,,,(š;) to satisfy the requircment or the adequate aper­lure sizc. According to the Nyquist criterion. lhesampling rate gives a culolT frequency of 100 mm.-1 The selection of the bin width must also ensure that rnultiple scattering can be modelled accurately by the EGS4 Monte Carlo code. The rule of thumb to estimate lhe number 01· multiple scattcring events is 294 \Ľmg H etat. 1.2 1.2 N,,,., dc11.,ily(y/nn'l) · (Z/8)Ľ · .,1,p,izc(1w1). (A) (B) • l McV . 4 MeV . . • • 2McV 5MeV where N,,,, is the number of multiple scattering . s 0.8 0.8 I 1 4 3MeV o hMeV -. events, Z is the atomic number of the material con­u . . 0.6 0.6 • . !, • sidered. For a 5 µm step size in amorphous seleni­ !, • . µ,. 0.4 . N,,,, approximately 35 which is sufficient. . • um, . 0.2 Q !'.'I ••••• 0.2 .. ·-.. --9Qoggcc...;... Oo The MTF is obtained by applying the Fast Fourier CI) .g 2Q........!!.e Transform (FFT) to the discrete LSF. To ensure the o o o 2 4 6 8 10 2 4 6 8 10 () accuracy of the resulls, 30 millions of photons were f-< . 1.2 1.2 used in each simulation resulting in a statistical .s­ (C) 1 LD) 1 uncertainty less than 5 % in each strip. This re­ quires calculation times ranging from 7 to 24 hours on an SGI workstation (IRIS INDIGO, Silicon Gra­phics, Mountainview, CA). In order to calculate the absorption efficiency and the detective quantum efficiency, the energy absorbed in the enlire sensitive volu me and its pulse height spectrum need to be scored. Unfortunately, XYZDOS does not include the option of pulse height spectrum. The simulations had to be run with the more versatile and more user friendly DOSRZ. A pencil beam of monoenergelic photons is incident at the center of the circular detector with a radius of 1 O cm. The effect of the detector shape is negligible since the radius is sulTiciently large for a pencil beam. Equal energy bin widlh was used in the pulse height spectrum: O.O I Me V for incident photons of energy less lhan 3 MeV and 0.03 MeV for 3 MeV and above. Simulation were lerminaled only when the uncertainty in lhe pulse height spectrum be­came less than I O% in each bin. Approximately 72 hours were required for each run. Results Three of the four receptors have a common front metal plate (2 mm Al) bul different a-Se layer ( 150 µm, 300 µm and 500 µm thick) while the other has a I mm thick Cu front plate and 300 µm thick a­Se. The calculated MTFs are shown in Figure 1. Error bars are not plotted because they are smaller than the symbols. For each plate, lhe MTF degradcs as energy in­creases and becomes relatively constant from 2 MeV up to 6 Me V. This indicates that there is a transition of the dominant interaclion from one lype to anoth­er between I and 2 MeY. The MTFs were also calculated for the a-Se/Cu receptor when the Cu plate was used as back plate. Degradation was also observed as the photon energy was increased. 0.8 • 0.8 "O o 0.6 • 0.6 o 0.4 . . . 0.4 1 . • 0.2 0.2 ...-. -gg ••••• •.o•D 'f.!Qr;;iggQ......!8.. -. .ss...ssss o o () 2 4 6 8 10 o 2 4 6 8 10 Spatial Frequency (!/nun) Figure l. The modulation transfer funclions for different energies for various receptors (A) 2 111111 Al/0.15 mm a-Se, (B) 2 111111 Al/0.30 111111 a-Se, (C) 2 111111 Al/0.50 mm a-Se. (D) 1 111111 Cu/0.3 mm The data of ali receptors at each individual energy were plotted in Figure 2. It can be seen that for the Al plate receptors, the MTF decreases as the thick­ness of the a-Se increases at ali energies ( 1-6 Me V). For 300 µm thick a-Se layer, a 2 mm Al plate and a 1 mm Cu plate lead to the same modulation transfer function at I MeV. As the photon energies increases, the Cu plate improves the MTF considerably. When a back Cu plate is used, the MTF is the lowest at 1 Me V but highest for 2 Me V and above. The quantum absorption efficiency is defined as the ratio of the photons that have deposited energy in lhe sensitive volume of lhe detector to ali the incident photons. Figure 3 (A) shows the calculated quantum absorption efficiencies of four receptors. The error bars are too small to be shown in the plots. The quantum absorption efficiency increases as the a-Se layer becomes thicker when the same front plate is used. At I MeV, a front metal plate reduces the probability of absorption due to the attenuation of the primary beam. For energies ;:: 2 Me V, the I mm Cu front plate increases the absorption more than the I mm Cu back plate. A f 1 mm Cu back plate is more efective in absorption than a 2 mm Al front plate. The output signal of a receptor is determined by the average energy deposited by an incident photon. Figure 3 (B) shows the responses of four receptors to 0.6 0.2 Mol/le Car/o Si//lulatio11s of"a //leta/la-Se Portal Detec:tor 295 1.2 monoenergetic photons at different energies. For the 1 II 2 mm Al/0.15 mm a-Sc (A) three Al plates, detcctor response increases with the J CD 2 mm A!/0.3 mm a-Sc thickness of a-Se. For the same thickness of the a-Se C 0.8 1111 o A 2 mm Al/0.5 mm a-Sc layer (300 µm), a I mm Cu front plate results in a .g (.) 1 . 1 mm Cu/0.3 mm a-Se much greater detector response than a 2 111111 Al front C ;:l µ., CI) c<; ... ,........, 0.3 mm a-Sc/1 mm Cu - plate. The co111parative detector response of the Cu . . with respect to Al increases at higher energies. For 1 MeY Clt;i.Q.1,;;QQQQQ..1Ji;;;i 2 Me V and above, it becomes even greater than tl1at of the Al receptor with a thicker a-Se layer (500 µm). o Among ali the receptors, the one with a I mm Cu o 1 2 3 4 'i 6 7 8 9 10 l.2 back plate has the lowest detector response. The statistical factor describes the loss in DQE ·E r ; .,s ;:l "O due to the incomplete absorption of an interacting 0.8 0.6 photon. As shown in Figure 4 (A), the statistical 6 MeY 1. -C factor of a front metal plate receptor decreases as C O O ­ , lhe x-ray energy increases. With the front metal plate as an electron convertor. the pulse height spec­ 0.4 f­ . . .i::iGcr:::oor:i=ioccoo 11, •• 0.2 1­O 1 11118 8 8 i 1 8 II 1 lil III II II ••• o1 2 3 4 5 67 8 910 Spatial Frequency (l/111111) Figure 2. Thc rnodulation transfer l'unelions of four receptor at incident photon energy of (A) 1 Me Vand of (B) 6 Me V. u -. (A) III 2 111111 Al/0.15 nun a•Sc . ! nuu Cu/lU mm a-Sc u E :J 8 2 mm Al/0.J uuu a-Sc O O.Jm111a•Sdl mmCu (.lJ 0.1 A 2 nun AlJU.5 111111 ,1-Sc ::: .Q tra of energy deposition in the a-Se layer have similar shapes at different energies. But the width increases with energy. The drop of the statistical factor is due to this widening. For a back metal­plate receptor, howevcr, the pulse height spectrum becomes narrower when x-ray energy increascs. The smaller variation in thc amount of the energy de­posited per interaction photon is responsible for the slight increase of the statistical factor of the 1 111111 Cu back plate receptor. II 2 111111 Al/0.1 :'i mm a.Sc . 1 mm Cu/O.:, mm a-Sc ... 8 2 mm Al/0.3 nun a-Sc O 0,3 mm a-Se/l mm Cu . o o. . . "' i.i . . u. "" 0.8 .6,, 2 mm Al/0,5 mm a-Sc !III Q O.O! . . li -; • C ' E . . g . o o C . -. . o i ;:l "' f/) 0.6 o • CI 0.001 • o 1 2 3 4 5 6 7 • 0.4 (B) O 1 2 3 4 5 6 __ 7 lx!0° 0.1 g . - ::: ·o o 1 . lxto· " OOI * l t 1 t k ••• o • 2 §C . i 0.001 . 1111 1111 1111 1111 . i; . . t o ., "-III . .. C . &ixW-2 r 8 . • o -. E . i .' 0.0001 O o l 2 3 4 5 6 7 Cl lx10·3 Incident Photon Energy (1 Me V) O 1 2 3 4 5 6 7 Incident Photon Energy (1 MeY) Figure 3. (A) Quantum absorption cflicicncies and (B) De-ler 500 hi1111clear lv1111Jhocytes. These res11/ts represe111 the llll!lagenelic hackgro1111d .fr;r the Sloveniane1•op1t!atio11 a11c! can he 11sed.frJr !he assess111e111 or i11 case o{suspecl ex1Jo.rnre to clastoge11ic age11ts.e Key words: Lymphocytcs: chromosomc aberrations: sister chromatid cxchangc; micronuclci Introduction lntcnsive industrialisation over the past fcw dcc­<1des has rcsulted in thc production and use or nu­merous genotoxic chemicals and sourccs or ionis­ing and 11011-ionising radiation. The need to identify the mutagenic and carcinogcnic c!Tccts of thcse agents on thc human population exposed environ­mentally. profcssionally or accidcntally is thereforc on the incrcase. There are severa! methods with which it is possible to prove changes occurring in DNA molecules. Unfortunately, there are few di­rect methods ror the identification and assessmcnt of the degree or mutations. Among methods for the detection or large chang­l'S in the genome of human somatic cells which are used routinely for mutagenetic monitoring, the ln­ternational Commission ror Protection against En­,·ironmental Mutagens and Carcinogens recom- Correspondence to: Marjan Bilhan. Assist. Dr. Se .. MD. Republic of Slovcnia Institute or Occupational Safcty. Bo­horiceva 22a. Ljubljana. Slovcnia. UDC: 61 r,.155.32-091.85:616.112.9-l 4.24 rnends thc detection or chromosonrnl aberrations, the rnicronucleus test and sister chrornatid exchangc tcchnique.e1 Thc analysis or chrornosomal aberrations in pc­ripheral blood lymphocytes has gained the widest use to date. The methodological and technical con­ditions for this techniquc and the procedure ror the analysis or specimcns are wcll defined, largely ow­ing to the use of specific chromosomal aberrations in biological dosimetry. 2e It is well known, however, that ionising racliation and the 1mtjority of chemical genotoxic agents have di!Terent effects on cellular DNA which is directly included in the Cormation or chrornosomal changes. The frcqucncy or SCE is a sensitive indicator or thc effccts or chemical genotoxic agents and high linear energy transfer (LET) radiation, bul a poor indicator or the cxposurc to low LET ionising radi­ation. u The micronucleus test has almost universal ap­plication in the detection or changes in the cellular genome. Micronuclei may originale frorn acentric fragrnents resulting from two-chain breaks of DNA arter its exposure to radiation, and have shown very 2')8 Bi!bu11 M a11d Vrhovec S g,iod dose-response relalionships. They may also c,rntain severa! chrornosomes which were not dis­tributed equally to daughter celis due to a non­fllnctional cell-division spindle or kinetochores. The b,lter phenomenon is most rrequently caused by cliemical agents.; It therefore seems tliat ali three tests should be used on parallel specimens in order l<< be ahle to assess the lype of exposure: to a p'1ysical or chcrnical agent, or cvcn possibly simul- t. neously Lo bolh calcgories or claslogcns.'' To enable the evalualion and correct perform­ai1ce of cytogenetic population rnoniloring, it is n,xessary to know as much as possible about thc f1equency of normal, spontaneous chromosomal ab­e:-rations. as well as aboul lhe faclors which exert a,i influence on their occurrence.7 Considering the institutions in which the authors 01· this paper work and the legal obligation 01· muta­g::netic monitoring for dcfincd groups 01· pcople who :ire proressionally cxposed to ionising radia­tion, the purpose 01· this study was: -to standardisc laboratory conditions or in vitro c·.1ltivation of lymphocytes in accordancc with thc Protocol or the International Atomic Encrgy Agen­cy, -to dctcrminc the mutagenetic background in a population sample of persons who are not profes­s,onally cxposed to ionising radiation by using thc s:ructural chromosomal abcrration analysis, micro­nuclcus test and SCE rrcquency per celi. Subjects and methods S1c/Jjec/s s The study included 350 subjects, of whom 153 were 1 udents prior to their enrolment at the I-ligh School 01· Radiology, and 197 persons prior to the assump­tion of their duties in radiation zones. It is impor­tant to ernphasise that such a selection 01· thc popu­lation sample enables comparative analyscs rcgard­i11g mutagcnic cllects in conjunction with agc, and even more, lifcstyle factors. The group of students included secondary school s udenls who had just graduated, aged 18 to 20 years. The majority 01· Lhem were non-smokers and persons with an exlremely low previous influence of alcohol, coffce, drugs and ionising radiation used for diagnostic ancl treatment purposes. The second group of test subjects had not been professionally exposed to genotoxie substances be­fore taking 01· blood samples for mutagenetic tests. I-lowever, the age dispersion in this group (20 to 65 years) was significant, and the lifcstyles of its sub­jects had undoubtedly brought along more numer­ous factors with mutagenic characteristics. At the tirne when blood samples for mutagenetic tests were taken, nonc 01· the test subjects showed any subjec­tive troubles nor objective signs or ,icute illness, and none of Lhem hacl been previously subject to major diagnostic or therapeutic irradiation. Tesl sub­jects were both men and women, of whom 34 % were smokers. Me!hods Dala of subjecls was collected by means of fill­ing in Personal I-leallh Questionnaircs. Peripheral blood lymphocytes from subjects were used as cel­lular malerial. Blood samples wcre taken simulta­neously for ali three tests. Structural chromosomal aberrations (CA) Standard in vilro lymphocyte cultures were used for structural chromosomal aberration analysis. 0.3 ml of heparinised whole blood was addecl to 5 ml or the culture medium (GIBCO BRL Chro­mosome med I A wilh Phytohaemaglutinin). The first in vitro celi division cycle was establishecl with an addition of 5 mg/ml of BrclU (Sigma). 0.075 mol/1 potassium chloride was used for the hypotonic procedure. Fixation was performed in a mixture of ice acetic acid and mcthyl alcohol at a ratio of 1 :3. The celi suspension was pipetted onto cold glass slidcs, spccirnens were air-clriecl ancl stained with Giemsa-Sigma. For every test sub­ject, the firsl 200 in vilro metaphases were ana­lysed at I OOOX magnification on a Nikon LABO­PI-IOT2 microscope. Structural damage to chro­mosomes was categorised as chromatid breaks, isochromaticl-chromosomal breaks, acentric frag­menls or clicentric and ring chromosomes. Gaps were nol included in Lhc Lota! numbcr of chromo­somal aberralions. Sisler chromatid exchange (SCE) The same cullure mediurn was used as for the first test. 72-hour lymphocyle cullurcs with the addition of I O mg/ml BrdU were prepared in dark condi­tions. The procedure was performed according to the Kato ( 1974) method.0 /11cide11ce of' spo11/ll11eou.1· C\'/ogenclic c!wnges in pai1,hem! /Jlood !y111phocv/es o( a l,111111111 po1,11lalio11 .1·a111p!e 299 50 cells per subject were analysed, SCE were C<•unted and presented as average numbers per celi. Tile range of SCE frequencies was also recorded for e\'ery subject. Micronucleus test {MN) For this test, 3 mg/ml or cytochalasin B {Sigma) w:1s added to each in vitro lymphocyte culture in the 43rd hour of cultivation. The Fenech-Morley ( 1985) method was used.'' Hypotonic procedure was omitted, and specimens wcre stained according to May-Grlinwald and Giem­s,,. Cells with clearly blocked cylokinesis (CB cells), i.c. binuclear cells, were analysed. 500 cells per pt-rson were inspcctcd and the resulls wcre present­e.perience either ethical bene.fils or ethical costs hy Cl/1 aclion resulting in a greater or diminished respect c! l any c!f" the .fcmr principles. The same action may hring both ethical bene.fits and costs: lying CLh01t1 lhe diagnosis of a serious diseCLse J11CL)' he occasionally hene.ficial bul violates lhe principle of palienl au/onomy. E1hicCLI anCL!ysis may be divided inlo three sleps. In the .first step, elhical hene.fits or costs are ascribed to the involved individual or colleclive su/.jects hej(1re a,1y action is undertaken. In the second step, potential actions of chCLnging the presen/ siluation are discussed; far each c!f" lhese actions, a comparison with the prese/lt situCLtion will reveCLl a ne/ ethical hene.fil or cos/ .fr1r lhe qf/ecled su/.jects. The third step is a recommendation .far lhe most appropriCLte action. This .fina/ slep of elhical analysi.1· is rm interdisciplimt1)' task: a discussion among physicians, psychologists, socio/ogisls, eco110111ists, or polititians will hope.fitlly lead to CL balanced and realistic pro­posal. Key words: medical; ethics, ethical analysis; ethics, institutional; public policy lntroduction The times when moral dilemmas were resolved by aclhering to simple rules do belong to the past. Toclay's worlcl is one of increasing complexity, of breaking the traditional social structure and of indi­vidual responsibility. New information networks and globa! marketing are reaching the most remote sites of the worlcl; at the same time, however, new tech­nologies remain an illusion for majority of man­kind. Medicine is not an exception to these globa! so­cial changes and to the relatecl moral clilemmas. We ali feel the pressure of a wiclening gap between technological clevelopment on one side, and restric- Correspondence to: Matjaž Zwitter, M.O„ Institute ofOnco­logy. 1105 Ljubljana, Slovenia. Fax: +386 61 1314 180. E­mail: mzwitter@mail.onko-i.si UDC: 614.253 tions clue to limitecl resources on the other. Prob­lems of distributive justice are ot'ten linked to un­certainties regarding life-sustaining treatments. The cleclared autonomy of patients in decisions con­cerning their life, treatment and cleath may be in sharp contrast with the principles and rules of be­neficence ancl non-maleficence of the medical com­munity. Even preventive medicine is not free of moral dilemmas: to what extent may we limit indi­viclual autonomy in order to explore patterns or occurrence of human cliseases, and how far shoulcl we go in imposing medically beneficial behaviour in society? The increasing importance of ethical issues in medicine is beyond cloubt. Less clear is the way to greater ethical awareness. Should we teach young physicians detailecl codes ancl rules as seems to be the prevailing practice, or should we rather teach them to define, analyse and solve ethical dilem­mas? Do we neecl consultants in medica! ethics ­ Zwiller M ii}1{/ Golouh R yet another discipline of medicine. or is ethics real­ly evcryhody's busincss'1 First, we will point to a much necded distinction betwecn law, cthical codcs, and cxpert ethical opin­ions. Thc main part of our discussion will be devot­cd to thc prescntation 01· cthical rules, principles and theories and to ethical analysis as a method of approaching an ethical dilemma. Intuition, ethical codes, detailcd guidclines and ethical analysis Any dilemma forccs us to choosc among mutually cxclusivc actions. In cvcryday life. wc rarely fol­low a systematic approach: as Brewin1 noted, lhe most caring doctor may be totally ignorant of aca­demic elhics. Intuition runclions well on an indi­vidual basis and in simple situations. However, in­tuition is of limited uscfulness in complex situa­tions and in argumcnts belween often widely differ­ing vicws. From the timcs of Egyptian papyri, of Hammura­bi and Hippocrates2 to the prescnt day, physicians, their associations and rulcrs or representatives of society have tricd to codify the guidelines of medi­ca! ethics into an obligalory system of rules for members of the medica! profession. No other pro­fession has devoted so much attention to ethical issues: this proves how delicate the field or medica! ethics is and at the same tirne reflects an inability to govern physician's behaviour exclusively by law. Stili, centuries-old ethical codes could not pro­vide an answer to many dilemmas from the increas­ingly complex medica! praclice of today. A re­sponsc to this apparent obsolescence of codes and resolulions has been recenl trend towards their in­clusivity. The rcsult is their progressive complexity and a vanishing dislinction betwecn law. ethical code, and expert ethical opinion. In international documcnts on medica! ethics, vague expressions as a reflection of a compromise among distinct cul­tures are a further limitation to their practical use. Legislation covers the most obvious and easily defined patterns of our behaviour. In addition, we need a simple code or medica! ethics that ali physi­cians will understand and remember and which will not bc subject to revision wilh every new techno­logical dcvelopment: Hippocrates' oath stili remains a beautiful masterpiece or eternal value. Possibly the most unfortunate consequence of recent trends in medica! ethics, with increasingly delailed and hardly undcrstandable guidelines, is the passive role taken by most physicians when approaching an ethical question. In order to allevi­ate this deficiency in medica! education and prac­tice, we bere present the tools for ethical analysis and the lhree-step process 01· formulating and solv­ing an ethical dilemma. Tools for ethical analysis: considered judge­ments, ethical rulcs, principlcs and ethical thcories The practical use of ethical analysis by those who have little insight into philosophy or academic eth­ics demands that we keep the discussion as simple as possible. Nevertheless, we can not avoid a brief and admittedly incompletc prescntation of the main elements of ethical discussion. Considered judgements These are moral convictions in which we have the highest confidence and believe to have the lowest leve! of bias.1 Wrongness of racial discrimination, religious intolerance, torture. or slavery are such widely accepted considered judgements. Ali ethical theories include such considered judgements which are as fundamental to ethics as axioms are to math­ematics. Ethical ntles These appear similar to considered judgements. Such rules are "Speak the truth", "Do not kili", "Help another human being". An important differ­ence from consiclered judgements is that in a proc­ess called balancing, reality of life may force us to abandon one rule in order to comply with another. We may decide to override the rule "Speak the truth" and nol reveal a positive pregnancy test to an overtly aggressive father of a teenager. The rule "Do not kili" may be disregarded in self-defonce or, if ethical analysis permits us to do so, in helping a terminally ill paticnt to die with dignity. The rule "Help another human being" has its limitations: without them everybody would be obliged to give most of the belongings to the poor and physicians would be obliged to work regardless of working hours and payment. !ntmduction to ethica! ana!ysis 307 Ethical principles These are more abslract than rules and are a bridge between rules and ethical theories. An elhical theo­ry, wilh ils philosophical background defines the number and lhe list of principles needed for ils conslruclion. As we will see when discussing the utilitarian and Kantian ethical lheories, a single principle leads to an unrealistic simplification; loo many principles do not conlribute to explanatory power and clarity of a theory. Pollowing the argu­ments presented by Beauchamp and Childress-1 and Gillon.S. it seems that an ethical dilemma may be defined with four basic principles: l. Respect .fcJr w1to11omy: a principle demanding the respecl of lhe decision-making capacities of autonomous persons. An integral part of lhis princi­ple is the right lo be informed: incomplete under­slanding of a siluation frequently leads to depend­ence, inferiority and loss 01· autonomy. 2 No1111wle.ficence: a principle of avoiding the causation of hann. Although similar to the princi­pic of beneficence, the principle or nonmaleficence covers a broader range of people: we are obliged not lo harm unknown people to whom we liave no obligations 01· beneficence. 3. Bene.ficence: a principle of providing benefits and balancing benefits against risks and cosls. Por its prnctical application, the principle or benefi­cence has to be specified: towards whom, in what circumstances and for which personal sacrifices are we obliged to act beneficently? An importanl ele­ment in these specificalions are lraditional rela­tions: our obligations are much greater lowards our own children, parents, or rriends than lowards un­known persons. 4. .!ustice: a principle for dislribuling benefits, risks and cosls fairly. Limited resources invariably lead to a conllicl and a balancing belween the prin­ciples of beneficence and juslice. The principle of justice demands lhat lhe rules for such a process of balancing are clearly derined in advance. Ethica/ lheories Ethical lheories define a system 01· ethical princi­ples, rules and guidelines. A good lheory salisfies eighl condilions: ·1 l. Claritv: without obscurily and vagueness. 2. Coherence: interna! consistency and devoid 01· contradictory statements. 3. Completeness and co111prehe11siveness: focused to cover ali polenlial dilemmas. 4. Simplicity: a few basic norms are preferrable to more norms bul no additional content. S. E.rplanalory power: adequate insight to under­sland moral life. 6 . .lustification power: a good reason for the jus­tification of a decision and also ror the rejeclion of unacceplable oplions. 7. Output power: analysis also for new dilemmas not considered in the construclion of the lheory. 8. Practicahi!ity: not demanding aclions beyond physical or social capabililics of most normal indi­viduals. .A survey of all theories which have been pro­posed as a guide through ethical dilemmas, or or related literature would clearly be beyond the scope of this shorl presentation: lhe work of Beauchamp and Childress -1 is a classical lext offering a compre­hensive and balanced coverage of the lopics. We will only briefly describe lhree groups of ethical theories: consequence-based utilitarian lheories, ob­ligalion-based Kantian or deontological lheories, and common moralily theory based on lhe four aforementioned elhical principles. Utilitarian ethical theories These holll lhal actions are righl or wrong accord­ing to the balance or their good and bad conse­quences. The question of whether we need rules in between lhe elhical lheory and judgement aboul an action, or whether we should simply skip the rules and follow lhe end result divides ulilitarians into "rule ulililarians'' and "acl utililarians". The former strive to idenlify rules which, if always observed, will lead to overall maximal ulility although lhe result in a parlicular case may be suboplimal: the latter simply observe each particular action which should produce maximal balance of posilive value over disvalue, or the least possible disvalue if only undesirable resulls can be achicved. The weakness of ulililarian lheories is apparenl when we realisc lhal lhe aclions lcading to lhe goal -maximum balance of posili ve value over disvalue are ethically unacceptable. Por example, lorluring prisoners may reveal a network or criminals: medi­ca! experimenls on mentally incompelenl persons may lead to importanl discoveries: the limilation or nursing care, or evcn active killing or elderly or incurable palients could save resources for lreat­menl of young patienls with curable diseases. Zwitler M a11d Golouh R Kantian, obligation-based or deontological theory This theory views and judges actions as right or wrong exclusively through moral obligations on which these actions are based. According to the categorical imperative of lmmanuel Kant, "I ought never to act except in such a way that I can also will that my maxim become a universal law." The con­sequences of our actions are irrelevant; our desires or reasoning based on emotions may indeed annihi­late the moral value of an action. In addition, Kant stressed the unique value and rcspect for every hu­man being: "One must act to treat every person as an end and never as a means only." Critics of Kantian deontological ethics maintain that the thcory cannot offer advice in practical life, where we often have to choose among severa! mu­tually exclusive obligations. Beyond responsibility to a single patient, a physician's obligations may include the institution, the rules of a health insur­ance company and to his or her family. The stress on law and obligations on one side, and ignoring motivation originating from emotions, friendship, or family relations on the other, is the weak part of Kantian ethics. Principle-based, common morality theories These are not based on a single ethical principle. While the principle of beneficence is a basis for utilitarian ethics, and the principle of autonomy may be regarded as fundamental to Kantian ethics, the common morality theory seeks a maximal prac­tically achievable balance among the four princi­ples: autonomy, nonmaleficence, beneficence and justice. No priority is attributed to any of these principles; rather, we try to balance between ethical "costs" and "benefits" of each of the prospective possibilities for action. A weakness of the common morality theory is its latitude: by choosing appropriate ethical principles, many opposing actions may be ethically defenda­ble. The common morality theory is somehow in betwecn a true, philosophical ethical theory and a method of ethical analysis. While this theory will be unsatisfactory for those who are seeking the deep philosophical foundations of morality, it may be very helpful in solving practical dilemmas. The three steps of ethical analysis We believe that the common morality theory, with its four principles, offers the best background in ethical analysis, and we will refer to it in this sec­tion. However, the three steps which we now de­scribe are applicable also in conjunction with any other ethical theory. 1. Ethical assessment of the situation prior to action This is the first step. Ali individual and collective subjects who are affected by the problem are re­corded. For each subject, an assessment is made of a balance between ethical bene.fits resulting from respect of the principles of autonomy, nonmalefi­cence, beneficence and justice, and the ethical costs as a result of the violation of these principles. The same action may bring both ethical benefits and costs to the same individual: lying about the diag­nosis of a serious disease may be sometimes bene­ficial but violates the principle of patient autono­my. 2. Possible actions with lheir ethical implications It is important that ali actions (here including a choice of no action) which could influence the pre­sent situation are recordecl. In preparing such a list, advice from an expert may be needed. For each action, its influence upon the respect or violation of the four principles for ali subjects involved is as­sessed. Some actions may bring new individuals under consideration. 3. Balancing among ethical costs and benefits and recommendation for action The third step is often interdisciplinary. A discus­sion between physicians and such people as philos­ophers, psychologists, technical experts, econo­mists, ecologists, or politicians will hopefully lead to a consensus regarding the best course of action. Ethical analysis frequently begins with a ques­tion regarding the ethical acceptability of a certain action. Even in such a case, however, ali three steps can not be avoided. One can not judge the ethical consequences of a certain action without an insight into the present state, a state which is often not ideal. A proposal for the strict control of private clubs advertising sexual pleasures may be easily rejected on the grounds of limitation of personal autonomy. Nevertheless, such a proposal can only be properly assessed in vicw of the costs of a liberal policy on the sexual abuse of children or adoles­cents. Likewise, the ethical acceptability of animal experiments in the screening of new drugs depends /11troductio11 to ethica/ 0110/ysis on the weight of the problem to be solved, and on the existence of alternative methods. The serious clinical problem of an incurable disease will find more support than an initiative motivated solely fr om commercial interests, or the more so if the same results could be obtained from celi cultures. Our recent discussion on the ethics of genetic screening for breast cancer illustrates how cthical analysis is applied to a particular problem.'' Conclusion Our aim was to present ethical analysis in a way understandable to a professional without training or a deep interest in philosophy. The narrowing of our professional interests should not lead us to leave medica! ethics to a few specialists in yet another medica! speciality. It is critical that we ali partici­pate in discussions which play a decisivc role in the shaping our futurc as profcssionals and as citizens. References 1. Brewin TB. How much ethics is nccded to make a good doctor? Lwu:et 1993; 341: 161-63. 2. Ad Hoc Committee of Medica! Ethics, American Col­lege of Physicians. American College of Physicians Eth­ics Manual. Part 1: History of medica! ethics. The physi­cian and the paticnt, The physician's relationship to oth­er physicians, The physician and society. A1111 /11tem Med 1984; 101: 129-37. 3. Rawls J. Thc indcpcndence od moral theory. Proceed­i11g.1· wul Addresses 1,fthe 1\mericw1 Phi/osophical Asso­ciatio11 1974-1975; 48: 8. 4. Beauchamp TL, Childress JF. Pri11ciples 1!f' biomedical ethics, 4th ed. New York: Oxford University Press, 1994. 5. Gillon R. Medica! ethics: four principles plus allention to scope. Br Med .l 1994: 309: 184-88. 6. Zwitter M, Nilstun T, Golouh R. Ethical principles of autonomy and bencficcnce in genetic screening for breast cancer. Radio/ Onml 1996: 30: 310-13 Radio/ Onco/ 19%: 30: 310-3. Ethical principles of autonomy and beneficence in genetic screening for breast cancer 1 Matjaž Zwitter 1 , Tore Nilstun2, and Rastko Golouh 1 Institute qf' Oncology, l.)ub(jana, Slovenia; 2 Departmenl ol Mediwl Ethics, Lune/ University, Lune/, Sweden For il patient with breast cancer and for her adufl relative, genelic counselling will u.rnally increase their CJutonom\' and !IICI_\' be hene}!cial. No brne/it Ji1r illlto110111y and markedly negative i1ifluence regarding bene/icence III({_\' be C11tri/Ju1ed to genetic screenini in a young relative wlw is 1101 yel in 1he age group a/ risk .. fi;r developing hreC1st cancer. For Cl wonwn witho1tt fcm1ily hiswry (!/' breast canccr, we !71Cl)' expect cm insignifirnnt be11eJi1 with respect to her a1110110111y and beneJicence, and potentia! cost ,!i-0111 her false peret'/Jlion oj' 11 /ow risk Jr1r bre11sl cuncer. These considerations lead to a conclusion tlwt c// the presen/ staleeoj' knowledge, genelic screening jiJr hreC1sl cancer should be restricted to re!CJtives of' patients with hreast cancer w/10 are already in the age group CJI risk .for developing the diseCJse. Key words: breast neoplasms-genetics: genctic screening, ethics medica! Introduction For many decades. familial predisposition towards breast cancer has been recognised as one or the risk factors. Recent research has linked this predisposition to mutation or particular genes. thus allowing us to understand and much more precisely estimate the risk. We start this paper with a brief summary or cur­rent understanding about genetic predisposition to­wards breast cancer. Then the ethical issues are presented and discussed. We conclude by propos­ing some practically-oricnted cthical guidelines for genetic screcning or breasl cancer. Genetic predisposition towards breast cancer The familial breast canccr syndromes include the sile-specific breast canccr. breast cancer with ex- Correspon:_;;J: gsersa@mail.onko-i.si 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 61000 LJUBLJANA TEL 061 15 91 277 FAKS 06 1 2 1 8 1 1 3 ŽR: 501 00-620-1 33-05-1 0331 15-214779 FONDACIJA DR. J. CI-IOLEWA Activity of "Dr. J. Cholewa Foundation" for cancer research and education -report for the first and second quarter of 1996 "Dr. J. Cholewa Foundalion" l'or eaneer research and educalion conlinues ils activiLy in Lhe third quarler or 1996 as ouLlined al Lhe meetings or Lhe executive ancl scientilic councils or the Founclation at the end or 1995, albeil at a slighlly slower pace, as it can he expected in Lhe summer monlhs. The meeting or Lhe assembly or the Founclation Look place in Lhe ene! or .Tune, 1996. The Foundation is prnud to announce thal severni new members or Lhe executive council were presenl al Lhis meeting. Ali new members or the execu­Live council were unanimously elccted Lo this position, ancl in Lhis way Lhe council is now composed of experls in various l'ielcls or oncology l'rnm alrnosl all acLiviLy in cancer research and educalion. Members or Lhe executive council also conlirmed Lhe reporl on Lhe financial situation in Lhe Foundation, as presented hy Lhe Presidenl of Lhe Foundation. Another imporlanl milestone in the developrnenl or the aclivity or Lhe Founda­tion is represented by Lhe meeling helween its representatives and high leve! onicials frorn European School or Oncology frorn Milan. The meeling Look place slightly al'Ler Lhe assemhly of Lhe Foudation, ancl specific points of the collahoration hetween Lhese Lwo inslilutions were discussed. Severni inleresling initiatives were investigated, one or the more imporlanl being Lhe possible inlen­si lication of some of the publishing activity or the European School of Oncology in Ljubljana. Details of the various initiatives in the collaboralion between these two institutions will he further discussed in Lhe coming monlhs of Lhe fina! quarler of 1996. Frnm the activity or the Foundation in the summer monlhs of 1996 it is clear that despite the summer recess it continues Lo l'ollow its slated goals. Toma1. Benulic, MD Borut Štahuc, MD; PhD Andrej Plesnicar, MD Symposium on ORGAN SPARING TREATMENT IN ONCOLOGY Ljubljana, Slovenia 19-21 June 1997 Organized by: Institute of Oncology, Ljubljana, Slovenia U nder the auspices of: Alps Adriatic Working Community Design and Content The Symposium is designed for medica! doctors and other specialists involved in cancer treatment who wish to exchange experiences with oncologists and to contribute to upgrading the knowledge in organ sparing treatment. It will cover the following topics: • Breast Conserving Therapy • Bladder Sparing Treatment in Muscle lnvasive Bladder Carcinoma • Organ Sparing Treatment in Head and Neck Carcinoma • Organ Sparing Treatment in Soft Tissue Tumors • Quality of Life after Organ Sparing Treat111ent Mailing Address Organizing Committee Institute of Oncology Zaloška 2, 1 105 Ljubljana SLOVENJA Phone: +386 61 131 42 25 Fax: +38661 131418 0 E-mail: mcaks@mail.onko-i.si lt's nice to win design awards, but even more gratifying to know our equipment puts people at ease.Take MR systems. Most have long, narrow tunnels that make a 20 minute exam feel like 20 hours. Ours is short and wide -the most open in the industry. Patients can see out, so they don't get anxious or claustrophobic. Children can be held and comforted, rather than sedated. We're pleased when people get excited about our equipment. But even more pleased when they don't. Ld. JWU'e, . bettPY. e PHIILIPS lopami.[Q® 150 -200 -300 -370 mgl/ml- FOR ALL RADIOLOGICAL EXAMINATIONS MYELOGRAPHY ANGIOGRAPHY UROGRAPHY C.T. D.S.A. THE FIRST WATER SOLUBLE READY TO USE NON-IONIC CONTRAST MEDIUM Manufacturer· Distributer Bracco s.p.a. Agorest s.r.l. Via E. Folli, 50 Via S Michele, 334 20134 -Milan -(1) Fax: (02) 26410678 Telex: 311185 Bracco 1 Phone: (02) 21771 e, 34170 -Gorizia -(1) Fax: (0481) 20719 Telex· 460690 AF-GO 1 Phone (0481) 21711 © Eastman Kodak Company, 1990 1 1 1 1 Kodak systems provide dependable performance for advanced diagnostic imaging. Our quality components are made to work together from exposure to viewbox. Kodak X-Omat processors are the most respected in the field. Kodak X-Omatic cassettes are known the world over far unexcelled screen-film contact and dura­bility. Kodak multiloaders have earned an enviable reputation far reliability. The Kodak Ektascan laser printer is changing the look of digital imaging. The list goes on. There are quality Kodak products throughout the imaging chain. Equally important, they are made to work together to achieve remarkable performance and diagnostic quality. Contact your Kodak representative far more information. NI SIE ENS Vaš partner v ultrazvocni diagnostiki: SIEMENS * SONOLINE SL-1 * Možnost prikljucka sektorskega, linearnega, endo-p in endo-v aplikatorja * Izredno ugodna cena (možnost kredita ali leasing-a) * Servis v Sloveniji z zagotovljenimi rezervnimi deli in garancijo * Izobraževanje za uporabnike SIEMENS D.0.0. Dunajska 47, Ljubljana Tel. 324-670 Fax. 132-4281 Novi antibioticni citostatik 1111 1111 ® 1 1 pirarubicin • ucinkovit pri zdravljenju karcinoma na dojkah • pomembno manjša pogostost alopecije • za kakovostnejše življenje bolnic Sestava: 1 steklenicka vsebuje 10mg ali 20mg pirarubicinovega hidroklorida v obliki liofilizirane snovi. Oprema: 10 steklenick po 1 O mg ali 20 mg pirarubicina. Farmakoterapijska skupina po klasifikaciji ATC: citotoksicni antibiotik/antra­ciklin. Indikacije: zdravilo je indicirano za zdravljenje bolnic z napredovano stopnjo karcinoma dojke v sklopu polikemote­rapijskega protokolnega zdravljenja. Pirarubicin uporabljamo pri adjuvantnem in neoadjuvantnem zdravljenju bolnic s karcinomom na dojkah. Kontraindikacije: uporaba Piracina je kontraindicirana pri bolnicah z mocno okvarjenim delovanjem srca, pri nosecnicah in dojecih materah. Previdnostni ukrepi: previdnost je potrebna pri dajanju zdravila bolnikom z okvarjenim delovanjem ledvic in jeter (tveganje, da se zdravilo kopici in okrepi njegovo toksicno delovanje). Pred zacetkom vsakega novega cikla zdravljenja je treba pregledati celotno krvno sliko in bolnicin kardiovaskularni status. Interakcije: znana je delna navzkrižna rezistenca tumorskih celic pri zdravljenju z drugimi antraciklinskimi citostatiki. Doziranje in nacin uporabe: pri zdravljenju bolnic s karcinomom na dojki priporocamo dajanje Piracina v odmerku 50 mg/m2 vsake 3 tedne v sklopu sheme zdravljenja, ki vkljucuje še ciklofosfamid in 5-fluorouracil (shema FPC). Zdravilo uporabljamo izkljucno intravensko. Stranski ucinki: toksicni ucinek, ki omejuje odmerek, je supresija delovanja kostnega mozga. Pri tretjini bolnic nastane reverzibilna granulocitopenija (do izboljšanja pride v treh do štirih tednih). Pri polovici bolnic se pojavi blažja slabost, ki jo spremlja kratkotrajno bruhanje. Mogoce je kardiotoksicno delovanje Piracina, vendar je redkejše in blažje kot pri doksorubicinu. Popolna reverzibilna alopecija se pojavi le pri približno 25 % bolnic. Piracin zelo redko povzroci nastanek stomatitisa in amenoreje. Pliva Ljubljana d.o.o., Dunajska 51 Lekarne, bolnišnice, zdravstveni domovi in veterinarske ustanove vecino svojih nakupov opravijo pri nas. Uspeh našega poslovanja temelji na kakovostni ponudbi, ki pokriva vsa podrocja humane medicine in veterine, pa tudi na hitrem in natancnem odzivu na zahteve naših kupcev. KEMOFARMACUA -VAŠ ZANESLJIVI DOBAVITELJ! I< KEMOFARMACIJA Veletrgovina za oskrbo zdravstva, d.d. / 1001 Ljubljana, Cesta na Brdo 100 Telefon: 061 12-32-145 / Telex: 39705 KEMFAR SI/ Telefax: 271-588, 271-362 injekcije, kapsule, kapljice, svecke tramadol Povrne mik življenja in hudih bolecin ucinkovit ob sorazmerno malo stranskih ucinkih tramadol je registriran tudi pri ameriški zvezni upravi za hrano in zdravila (FDA) Kontraindikacije: Otroci do 1 leta starosll, akutna zastrupitev 3-do 4-krat na dan. Otrokom od 1 leta do 14 lct dajemo v odmerku z alkoholom, uspavali, analgetiki in drugimi zdravili, ki vplivajo l do 2 mg na kilogram telesne mase 3-do 4-krat na dan. Stranski na CŽS, zdravljenje z inhibitorji MAO. Interakcije: Pri socasni ucinki: Znojenje, vrtoglavica, slabost, bruhanje, suha usta ln utrujenost. uporabi zdravil, ki delujejo na osrednje živcevje, je možno Redko lahko pride do palpitacij, ortostaticne hipotenzije ali sinergisticno delovanje v obliki sedacije pa tudi mocnejšega kardiovaskularnega kolapsa. Izjemoma se lahko pojavijo konvulzije. analgeticnega delovanja. Opozorila: Pri predoziranju lahko Oprema: 5 ampul po 1 ml (50 mg/ml), 5 ampul po 2 ml ( 100 mg/ pride do depresije dihanja. Previdnost je potrebna pri bolnikih, 2 m!), 20 kapsul po 50 mg, l O ml raztopine ( 100 mg/ml), 5 sveck ki so preobcutljivi za opiate, in pri starejših osebah. Pri okvari po 100 mg. jeter in ledvic je potrebno odmerek zmanjšati. Bolniki med zdravljenjem ne smejo upravljati strojev in motornih vozil. Med Podrobncj.š<.: informacije so navoljo pri proizvajalcu. nosecnostjo in dojenjem predpišemo lramadol le pri nujni indikaciji. Bolnike s krci centralnega izvora skrbno nadzorujemo. Doziranje: Odrasli in otroci, starejši ocl 14 let: 50 do 100 mg . .. l