·-_. AND _, O .NCOLOGY , ... ---..-··-· 1 :•J.:-.:.·, ";'.>•·1 o]TI. 1996 Vol. 30 No. 2 Ljubljana ISSN 1318-2099 U DC 616-006 CODEN: RONCEM SLABOST IN BRUHANJE STA NAJHUJŠA STRANSKA UCINKA KEMOTERAPIJE IN RADIOTERAPIJE o 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 Glaxo ExportUmited Podružnica Ljubljana, Cesta v Mestni log 55, 1115 Ljubljana, p.p. 17, Slovenija Telefon: (386 61) 123 10 70, 123 20 97, 123 23 19, Telefax: (386 61) 123 25 97 RADIOLOGY AND ONCOLOGY Radiology a11d 011cology 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 Be11ulic Ljubljana, Slovenia Associate editors Gregor Serša Ljubljana, Slovenia Viljem Kovac Ljubljana, Slovenia Editorial board Tullio Giraldi Bra11ko Palcic Udine, Italy Vancouver, Canada Marija Auersperg Ljubljana, Slovenia A11drija Hebra11g Zagreb, Croatia ]urica Papa Zagreb, Croatia Haris Boko Durtla Horvat Zagreb, Croatia Zagreb, Croatia Duša11 Pavc11ik Nataša V. Budih11a Laszlo Horvath Ljubljana, Slovenia Ljubljana, Slovenia Pecs, Hungary Stoja11 Ples11icar Malte Clause11 Berta Jereb Ljubljana, Slovenia Kiel, Germany Ljubljana, Slovenia Ervi11 B. Podgoršak Christoph Clemm Vladimir Jevtic Montreal, Canada Munchen, Germany Ljubljana, Slovenia Mario Corsi Udine, !taly H. Dieter Kogelllik Salzburg, Austria Ja11 C. Roos Amsterdam, The Netherlands Christia11 Dittric/1 Vienna, Austria lva11 Lovasic Rijeka, Croatia Horst Sack Essen, Germany Iva11 Dri11kovic Zagreb, Croatia Marijall Lovre11cic Zagreb, Croatia Slavko Šim1mic Zagreb, Croatia Gillia11 Duches11e Luka Milas Lojze Šmid London, Great Britain Houston, USA Ljubljana, Slovenia Bela Pomet Maja Osmak Andrea V eronesi Budapest, Hungary Zagreb, Croatia Gorizia, Italy Publishers Slovenian Medica[ Society -Section of Radiology, Section 4 Radiotherapy Croatian Medica[ Association -Croatian Society of Radiology Affiliated with Societas Radiologorum Hungarorwn Friuli-Venezia Giulia regional groups of S.l.R.M. (Italian Society r.f Medica! Radiology) Correspondence address Radiology and Oncology Institute of Oncology Vrawv trg 4 I 000 f_jubUana Slovenia Phone: + 386 61 1320 068 Fax: + 386 61 1314 180 Reader for English Olga Shrestha Design Monika Fink-Serfo Key words and UDC Eva Klemencic Secretaries Milica Harisch Betka Savski Printed by Tiskarna Tone Tomšic, Ljub(jana, Slovenia Published quarterly Bank account number 50101 678 48454 Foreign currency account number 50100-620-l 33-27620-5130/6 LB -Ljubljanska banka d. d. -Ljubf;jana Subscription fee fi1r institutions J 00 USD, individuals 50 USD. Single issue fi1r institutions 30 USD, individuals 20 USD. Accorcling to the opinion r.f the Government of the Republic of Slovenia, Puhlic Relation and Meclia Ojfice, the journal RADIOLOGY AND ONCOLOGY is a publication of informative value, ancl as .meh subject to taxation by 5 % sales tax. Inclexed wul abstractecl hy: BIOMEDICINA SLOVENICA CHEMICAL ABSTRACTS EXCERPTA MEDICA/ELECTRONIC PUBLISHING DIVISION CONTENTS DIAGNOSTIC AND INTERVENTIONAL RADIOLOGY Complcmentarincss of thc radiological finding and transbronchial lung biopsy for definitivc diagnosis of diffusc interstitial lung disease Mažuranic' !, fvanovi-Hen:eg Z 89 Effects of nonionic radiographic contrast media on renal function after cardiac catheterisation Dmbnic-Kovac' D, Cerne A, Krc11\jec !, Globokar-Zajec M 95 Percutancous drainagc of a pancrcatic pscudocyst into the stomach Sever M, .le/ene f,' Šurlan M, Vic/111ar D 100 NUCLEAR MIWICINE lnsulin depcndency of F-18-tluorodeoxyglucosc accumulation in breast carcinoma cells compared, to Tl-201 uptake Wolf H, Brenner W, Stein V, Tinnemeyer S, Bolwslavizki KH, Teichert U, Clausen M, Henze E 104 Positron emission tomography (PET) in ischemic heart discase Bohuslavizki KH, Brenner W, Clausen M, Henze E 108 Papillary thyroid cancer in two sistcrs Garda.fonic" J, Smoje J, Karner !, Vc'ev A, Topuzovic" N 113 EXPERIMENTAL ONCOLOGY Effcct of thc typc of application in Newcastle discase virus on the Erlich ascitcs tumor Milanez T, Ko.fok R, Cemr A CLINICAL ONCOLOGY Cathepsins and thcir cndogenous inhibitors in clinical oncology Stmjan P Langerhans celi histiocytosis. Fivc new cases and revicw of the literature Stiakaki E, lydaki E, Bolonaki !, Kambourakis A, Kanavams /. Giannakopoulou C, Kalmanti M 120 134 RADIOPHYSICS lonization gradient chambcr in absolntc photon and elcctron dosimetry Zankowski C, Podgor.'fok EB BOOK REVIEW Epithelial hyperplastic lesion of the larynx. Vinko Kambic and Nina Gale Jereb M, Jereb B 142 RSNA NEWS 143 NOTICES 144 Radio! Onco! 1996; 30: 89-94. Complementariness of the radiological finding and transbronchial lung biopsy for definitive diagnosis of diffuse interstitial lung diseases Ivica Mažuranic and Zlata Ivanovi-Herceg Clin.ical Institute fc,r Thomcic Radiology, Clinical Hospital for Lung Diseases -Jorclanovac, Zagreb, Croatia In this study 52 filtlients ad111i11ed to hospila! Ji>r transbmnchial biopsy c.( the !ungs (TBB) due 10 ww­11111estically, cli11ically and mdio/ogically suspec1ed di[(use i111ers1i1ial lung disease (DILD) were examined. Using classirnl radiological sy111pto111atology tele radiograms were recorded ( F-F 180 cm) of the che.1·t PA mul pro.file, by high voltage technique ( 125 kV). The pcuients were selected ,viti, regard to contraindications for general anaesthesia, and TBB. TB/3 was carried out Ul1(/er general anaesthesia wilh combined use oj a rigid cmcl Jlexibile bronchoscope, witholll racliological control. The perce11tage of aclequate biopsy finclings was ver)' sati..f'actory (94 %), as was also the case with regarcl to siif!icient pathoanatomic (51 %) and rndiological (42 %) Ji11cli11gs, by which a deJinitive cli11ical diagnosis can be nwde without the need for other test.1·. /11 the same way the percentages c.( aclequately si!fficient patlwanatomic ( 16 %) mul radiological (39 %) Jindings were very stati.1factory, /Jy which, co111bined with other test.1·, deflnitive clinical diagnosis can be concluded. In no single clisease were both findings insufficient, which indicates their complementariness, and in this way they are si(fficient judging by the clinical status, BAL and biochemical.findings, with regard to the fina/ clinica/ diagnosis. Key worcls: Jung diseases, interstitial-pathology; biopsy; thoracic radiography lntroduction lnlerslitial Jung diseases are a heterogeneous group or diseases characterized by damage to the support­ive structure of the Jung units for gas exchange, periaveolar and alveoral tissue. In the acute phase alveolitis occurs, accompanied by prolonged, unre­strainecl inflammation or neighbouring parts of the interstitium ancl blood-vessels, and arter a long pe­riod the inflammatory changes ancl consequent in- Corrcspondcncc to: Ivica Mažuranic, M.O., M.Se., Thc Cli­nical Institute for Thoracic Radiology, Clinical Hospital for Lung Discascs Jonlanovac, Jordan ovac 104, 41000 Zagreb, Croatia. UDC: 6l6.24-002.17-076 terstitial Jung fibrosis damage the Jung parenchyma, leacling to impairment of gas exchange and vemila­tion. This diverse group of approximately 125 dis­eases has many common characteristics, including similar clinical symptomatology, graded radiologi­cal findings, consistent alterations in Jung functions and typical cytological and histological appearance. Bronchoscopy demonstrated its great value by facilitating the use of biopsy forceps to take tissue samples J'or histological and cytological analysis. Probably no other diagnostic or therapeutic tech­nique changed pulmological work so radically in sueh a short tirne. lnterstitial disease have recently become the sub­ject of great interest for radiologists. On the chest X-rays and imaging techniques this special group of diseases is characterized by multiple diffusely Mažurw1i<' I wul !vwwvi-Herceg Z distributed lesions. According to these radiological criteria, complex clinical symptomatology, consist­ent changes in lung function, bronchoalveolar lavage (BAL), approximate pathoanatomic diagnosis can be made. The interstitial sample is an antithesis for the eonsolidatory alveolar process. It is a disorder within the lung architecture caused by an abnormal accummulation of tissue in the parenchymal lung interstitium. In this study we compared thc findings of trans­bronchial Jung biopsy (TBB), which is accepted as suitable in histopathological diagnosis or dilTuse interstitial lung diseases (DILD), with the radio­logical finding. The aim of lhe study was to deter­mine the specific diagnostic value of each method separately and the possible additional benefit when both methods are inlerpreted simultaneously. Patients and methods In this investigation 52 hospitalized patients were examined (27 women and 25 men, range 16-76 years) in the Bronchoscopy unit at The Clinical Hospital for Lung Diseases -Jorclanovac. The patients were admilted for bronchological examination with transbronchial lung biopsy (TBB) because of anamnestically, clinically and racliolo­gically suspected disease of the lung interstitium. Teleradiograms (F-F 180 cm) of the chest PA and profile were rccorded by high voltagc technique ( 125 kV) on a Thoramat Siemens aparatus and, when necessary, tomography was pcrforrned. Such a radiological technique racilitated lhe taking of a biopsy sample in the area of the pathological pro­cess, with maximum accuracy, and without the use of a discope. As patients with DILD are regularly followed up long-term, it is essential to recluce the dose of exposure to ionizing radiation. Namely, dur­ing one minute of diascopy patients receive a dose which is equivalent to one hunclrecl chest X-rays. Although unrclated to ILO classifieation, thc in­terstitial lesions were considered as patognomonic for certain diffuse interstitial lung disease. Prior to bronchoscopy the following tests wcre carried out: gas analysis of arterial bloocl, coagulo­gram, hacmograrn, electrolytes, urca, crcatinine clc­arence and an ECG. The patients were selccted with regard to contra­indications for this cxamination (pulmonary hyper­tcnsion, hcmorrhagic diathcsis, asthrna, hypoxia where pO2 is less than 8,7 kPA inspite of oxygen administration, acute hypcrcapnia where pCO2 is more than 6 kPA, severe arhithmias, status within 3 months after the rnyocardial infarction, bacl general condition, hacrnogram, electrolytes, local finding of thc bronchial mucosa). Following prernedication with 0.8-1 mg Atropin, the anesthesizcd (narcotic, hypnotic ancl dcpolariz­ing muscle relaxants) patient was intubated with a rigid bronchoscope ("Wolf'). During the broncho­scopy the patient was ventilated according to Ven­turi's method, and a liberbronchoscope (Olympus BS I O") was then introduced by which 2-3 biopsy samples were taken (by a standard technique) of TBB from the pathologically changed lung paren­chyma, without using radiological control. The bi­opsy sample was placed in l O% formalin and sent to thc Institute for Pathology, Clinical Hospital Cen­tre Rebro for pathoanatomical analysis. After the procedure the patient rested for 25 hours, with an obligatory control X-ray within 8 hours of the pro­cedure. Table l. Dependcnce or succesl"ul Tl313 on examination techniques. Cornparison or the results or this study with the results or other authors. Authors Attemptcd biops. Adequate biops. Examination techniqe N N % Anderson i Fiberbronchoscopy + dia. Fontana 450 378 84 + local anaesthesia R. Petit 66 47 71 Fibcrbronchoscopy + dia. + local anacsthcsia J. Malcnic 66 59 89 Combined + dia. + general anacsthesia Wal 53 50 94 Fibcrbronchoscopy + dia. + 1 ocal anaesthcsia Own results 52 49 94 Combincd without dia. + general anaesthesia Levin 22 21 Fiberbronchoscopy + dia. + local anaesthcsia Mean (apart l"rom own rcsults) Diilgnosis o(difli,se interstitiilf lung disei/se Table 2. Complirncntarincss of radiological and pathoanatomic lindings in thc diagnostics of DlLD. Pathoanatomic linding Radiological finding N % N %, Sufficicnt 25 51 21 43 Adequatcly surticient 8 16 19 39 lnsufficicnt 16 33 9 18 Total 49 100 49 100 Table 3. Complimentariness of radiological and pathoanatomic lindings in thc linal diagnosis of DILD. Final Surticient Adcquatcly sufficicnl lnsufficicnt dg. DILD N PA RTG PA RTG PA RTG Fibrosis 20 16 5 2 l) 2 6 Sarcoidosis 16 5 11 2 4 9 1 Pneumonia intcrstitial 2 2 2 Vasculitis Total 25 21 8 18 17 l) Results By simultaneous use of priliminary radiological di­agnostic treatment and combincd TBB tcchnique, thc number of satisfactory samplcs was vcry high, up to 94 %. This rcsult is comparablc with thc per­centages of othcr techniqucs (bronchofibcrscopy with radiological control, combinccl techniques with radiological control) in approximately the same numbcr of cases (Table 1 ). The percentagcs of sufficient intcrprctations or pathoanatomic (51 %) and radiological tindings (43 %) wcre very satisl'actory and would enablc a definitive diagnosis, without othcr clinical dala, and also adequatcly sufficient pathoanatomic ( 16 %) and radiological tindings (39 %) with which, together with clinical data, the rinal diagnosis could be made. Thc pcrcentagc of insutlicient pathoanatornic tind­ings was higher (33 %) than radiological tindings ( 18 %) (Table 2). As to the pathoanatomic criteria, the initial dif­ruse interstitial fibrosis is a dominant finding. Pul­monary fibrosis, which is in fact compatible with the definitivc stage of other interstitial diffuse lung diseases, was found in 18 paticnts, while radiologi­cal findings of sarcoiclosis was founcl in 15 patients. In interstitial pneurnonia the radiological finding was su!Ticient while the pathoanatomical finding was not. Both the pathoanatornic and racliologic linclings werc sufficicntly adequate in pulrnonary alveolar microlithiasis. as well as sufficient in as­bestosis. In hypersensitive pneumonitis only the ra­diological fincling was sufficicnt. In other cliagnoses bolh pathoanatomic and radiological finclings were adcquately surticient and thereforc in no disease wcrc they both insufficient, which indicates their complcrnentarincss (Table 3). Discussion lntcrstitial lung diseases are currently Lhc object or livcly inlerest because or thcir grcat frcquency, both due to air pollution and othcr harmful ellccts in the environmcnt and becausc of the increasing number of circulating harrnful agcnts. Thcy have become a great health problem becausc of their acute sta­dium, cliffercnt dynamism and responsc to thcrapy and finally their chronic forms, with regard Lo inva­lidity, i.e. rcmaining work ability. H 92 Mažurw1il' I and lvimovi-Herceg Z The protective reaction of the lungs which can include ali types of immunological responses, can occasionally lead to one of many diffuse diseases of the lung interstitium . .i- 5 Diffuse diseases of the lung interstitium are more frequent in their fina! stadium of pulmonary fibrosis with lung function impair­ment of prognosis. They are extremely difficult to classify as there are approximately 125 different diseases, the features of which are often common. Diseases can be classified into known and un­known etiology. Of the diseases of known etiology the largest group comprises occupational diseases due to exposure to atmospheric pollutants. In the case of diseases of unknown etiology the largest group includes idiopathic lung fibrosis, collagen-vas­cular diseases (CYD), and granulornatous sarcoidosis. In many diffuse diseases of the lung interstitium similar conditions are present during their imrnuno­pathological course. They are judged by thc clinical status, characteristic radiological finding, histological sam ples, bronchoal veolar lavage, scintigraphy with Ga-67 and biochemical findings. "-12 By using bronchoscopy it is possible, by a special technique, to obtain a sample of the lung paren­chyma, avoiding open-lung biopsy. IJ Transbronchial lung biopsy was first carried out by Andersen1 .i in 1965 an later in 1975. It was improved by Zavala and became the most modem technique in the diag­nostics of DILD. 15 Current research in this field has shown that thc piece of tissue obtained by TBB is usually small, and there is a possibility that wide­spread changes are not always gripped by the bi­opsy forceps. Consequently the biopsy sample is frequently taken 3 to 6 times, compared to only 2 to 3 limes in our patients. The greater the number of pieces of tissue taken increases the chance of a sucessful diagnosis. "•-17 Pneumothorax is the most frequent complication of the lung biopsy, (1-5 %. Herf. Zavala)."· 1'' In our series. there were two cases of pneumothorax (3,8 %), which required a conservative treatment. Significant hemorrhage (more than 50 ml of blood) is the second most frequent complication ( 1.3 % Herf, 5-9 % Zavala).1 x. 1" We had a moderate hemorr­hage, which ended spontaneously, in two patients. lnterstitial diseases are also currently the object of lively interest of radiologists. According to ra­diological criteria this particular group of diseases differs with regard to the multiple diffusely dis­seminated lesions on the chest X-rays and irnaging techniques, and within the complex of clinical symptornatology, consistent changes in lung rune- tion, bronchoalveolar lavage and celi study approxi­mates pathoanatornic diagnosis. These diseases may, primarily, be Jung diseases or they may be a "re­flection" of sys.temic diseases. They were initially described as milliary diseases, beaause the lesions were the size of a grain of rnillet,20• 21 later as "dif­fuse disseminated",21 or "nodular and reticular".22 They are currently known as interstitial diseases. However, as these diseases encompass occasionally histologically determined both the interstitium and alveolar area some authors consider that "chronic diffuse infiltrative disease" is more appropriate. Ra­diological criteria for these anatomic locations was developed by Felson and later Fraser and Pare as alveolar or acinous lesions, and interstitial lesions.2J·-25 The finest interstitial pattern is "ground-glass", con­sisting of discretely swollen connective structure and inllammatory infiltration without bronc­hiectasis, not covering the outline of the blood ves­sels. Nodular opacities are interstitial, 1-2 mm in size, which cover the outline of the blood vessels (apart from the interstitium they can also be in the alveolars and bronchioles). The reticular pattern re­ lates to swollcn interlobular septa with exudation early stage of librosis chronic stage. The linear pattern -honey combing -typical areas 5-1 O mm in diameter. The reticulonodular pattern corresponds to the size of the nodular opacities and is character­istic for granulomatosisY Theve have been many classifications, particularly for sarcoidosis, since 1940, King. 2'' Wurn, Reinclell ancl Heimeyer, classi­fied sarcoidosis in three radiological stadia, taking into account the course and prognosis of disease, which was the case in our patients. 27 As there is in fact no correlation between differ­ent parameters with regarcl to disease activity (lung function tests, BAL, ACE, scintigraphy with Ga-67) the radiological stage remains the most sensitive in the prognostics or these diseases. 27 Because of the need to systematically evaluate radiological changes caused by inhalation of silicia dusts in various parts of the world the first lnterna­tional Classification for Pneumoconiosis was pro­duced in 1930 by the International Bureau for Work in Geneva and reviewed in 1955, 1958, 1968, 1971 and 1980.28 The ILO classification with standard proposals is clearly written and does not adopt pa­thoanatomic hypotheses. It only describes the round and irregular opacities according to size and profu­sion and does not go into the morphology of lesions which can be misleading.2''· Jo McLoud et al. were the first to apply the modified ILO classification to Dia/.;11osis of'dif.fi1se i11ters1i1ial lu11/i disease other diffuse cliseases of the lung interstitian, aclclecl as a clescription of reticulonodular pattern, charac­teristic for granulomatosis. 31 In our patients reticular ancl reticulonodular pattcrns were dominant in the radiograms, although without ILO classification of lcsion. In our investigation the perccntagc of salisfactory biopsics during which an adequate sample was ob­taincd, was very high (94 %). As such biopsy mate­rial contains al lcast one piccc of lissue wilh cli!Tuse pathological changcs or thc lung. this samplc was consiclcrecl rcpresentali ve This pcrccnlage agrccs with the tests pcrformcd by thc tcchniqucs or olher authors14 · 12-1; with approximalely thc same number of paticnts with an avcrage (apart from inclividual results) of 85 % (Table 1 ). The same pcrcentagc of rcliablc pathoanatomic (51 %) and radiological (43 %) lindings (39 %) com­pm·ecl to aclequatcly sufficient pat110anatomic find­ings (16 % ) ancl greater pcrccntagc or insuflicient pathoanatomical findings (33 %) comparcd to in­sufficienl radiological findings ( 18 %) (Table 2). The most frequenl wcrc derinitive clinical diag­noses of interstitial lung fibroses ancl sarcoiclosis. Both pathoanatomically and radiologically rcliable rindings wcre of the same etiology. Pathoanato­mically reliablc finclings wcre most frequent in in­terstitial lung ribroses ( 18 paticnls) ancl radiolo­gically rcliable lindings in sarcoiclosis ( 15 palients) (Table 3). In no single discasc werc they bolh insuf­ficient, which inclicates their complcmentariness, and thcy are thereforc suflicicnl judging by the clinical status, BAL, and biochemical rinding, with regard to the fina! clinical diagnosis. With respcct to immunopathogcnesis, in many di!Tusc discases of the lung interstitium similar conditions are com­hined in thcir immunopalhological course, which is another complicating ractor in lheir di!Terentiation. Definitive evaluation of lhe evolutiveness or DILD is facilitated by bronchoalveolar lavage (BAL) ancl celi analysis, and in the complex of clinical sympto­matology and consistent changcs of lung functional findings it is possible to make an approximate patho­anatomic cliagnosis, ancl thus TBB, in this casc, is an infcrior test. Rcfcrences 1. Crystal RG. Fulrner JD. Roberts WG, Moss ML, Line BR, Reynolds HY. ldiopathic pulmonary librosis. Clini­cal histologic, radiographic, physiologic. scintigraphic, cytologic and biochemical aspecta. /1111 fntem 1976; 85: 769-78. 2. Scading JG. Talking clearly about diseascs of the pul­monary acinus. 13.f Chart 1978; 72: 1-11. 3. Šorli J. Regionalna funkcija pluca u bolesnika s difuz­nim oboljenjima plucnog intersticijuma. Pluc Bol 1985; 37: 16-21. 4. Mivšek-Mušic E. Imunološka i imunopatološka dijag­nostika difuznih intcrsticijskih plucnih bolesti. Plu( Bol 1985; 37: 5-15. 5. Reynolds HY. Hiperscnsitivily pneumonitis. Ciin Cfwrt Med 1982; 3: 503-19. 6. l-lerceg Z. Car Z. Radiološka slika imunoloških bolesti plucnog intersticija: Radovi i rezi1nci XV III Kongres pneumoftiziologija Jugoslavije Novi Sad 6-9 svibanj 1987. 7. lvanovi-l-lerceg Z. Car Z. Radiološki prikaz imunolo­ških bolesti pluca. Seminar Aktualni problemi iz pneu­moftiziologije. Opatija 23-27 listopad 1978. 8. Herbert Y, Reynolds MD. Classification, delinition and correlation bctwcen clinical and histolo<>ic sta<>in" of interstitia lung diseases. Seminars in Re.1•1';;ra1or; kl.di­ci11e 1984; 6 (1): 1-19. 9. Turner-Warwick M. lnlerstitial Lung Disease. Se111i11ar,1· i11 Re.1pirato1y Medicine 1984; 6(1 ). I O. Rott T. Pregled plucnih granulomatoza. 1'vled Razgl 1985; 24 (Suppl 4): 75-100. 11. La Grasta M. Nova saznanja o intcrslicijskirn bolcstima pluca s osobitim osvrtorn na idiopatsku plucnu librozu. /'111<' Bol 1984; 36: 248-51. 12. Mažuranic l. Vrijednost transbronhalne biopsije pluca u bolesnika s difuznim bolestima plucnog intersticija. Magistarski rad Med. Fakultet Sveucilišta u Zagrebu, 1991. 13. lkcda S. Atlas of flexibile broncholiberscopy. Balti­more and London: University Pat Press, 1974. 14. Andersen HA. Fontana RS. Transbronchoscopic lung biopsy for dilTuse pulmonary diseases. leehniquc and rcsults in 450 casl. Cf1es1 1972; 62 125. 15. Zavala DC. Diagnostic liberoptic bronchoscopy: Tech­niques and results of biopsy in 600 Patients. Chest 1975; 68: 12-19. 16. Sachner MA. Stale of the ari broncho-fibcrscopy. AmRev Resp Dis 111: 62-8. 17. Zavala DC. Transbronchial biopsy in dilTusc lung dis­easc. Chcst 1978; 73 (Suppl 5): 727-33. 18. Herf SIVI, Jurall PIVI, Arora NS. Deaths and complica­tion associated wilh transbronchial lung biopsy. AmRev Respir Dis 1977; 115: 708-11. 19 Zavala DC: Transbronchial biopsy in diffuse lung dis­ease. Chest 1978, 73 (Suppl 5): 727-33. 20. Buechncr I-IA. Thc differenlial diagnosis of miliary dis­ease of the lungs. Med Ciin Norih 1\kl 1959: 43: 89­112. 21. Gould DIV!, Dalrymplc GA. A radiological analysis of disseminate lung disease. A111 .! Med Sci 1959; 238: 621-37. 22. Scading FJ. Chronic lung discasc with diffusc nodular irreticular radiographic shadows. fobercle 1952: 33: 352-8. Mažura11ic I w1d Iva11ovi-Herceg Z 23. Felson B. C/Jest re111ge110/ogy. Philadelphia: W.B. Saun­ders Co., 1973: 314-49. 24. Fraser RG, Pare JAP. Diag11osis l!f'diseases 1!f'the chest. Philadelphia: W.B. Saunders Co., 1970: 85-99. 25. Fraser RG, Pare JAP. Diagnosis of'diseases o(rhe chest. Philadelphia: W. B. Saundcrs Co„ 1977. 26. King DS. Sarcoid diseasc as revealed in Lhe chest rocnt­gcnographic. AJR 1941; 45: 505-12. 27. De Ramee Ra. The rocntgenographic staging of sarcoi­dosis Historic and conterporary pcrspectives. C/Jest 1983; 83 (]): 128-37. 28. ILO 1980 inlernational classificalion of radiographs of thc pneumoconioses. lnternalional Labour Officc Ge­neva 1980. 29. Epslein DM, Miller WT, Bresnilz EA, Levine MS, Gef­ter WB. Application of ILO classificalion to a popula­tion withoul induslrial exposure: Findings to bc differ­enliated from pneumoconiosis. AJR 1984; 142: 53-8. 30. Fitzgerald MX; Carrington CB, Gaensler EA. Enviro­mental lung disease. Med Ciin Norih Am 1973; 53: 593-621. 31. Me Loud TC, Carringlon CB, Gaenslcr EA. Diff usc infillralive lung diseasc: A new sheme for descriplion. 1983; 149: 353-36. 32. Pctil R, Menaul P. Dclagc J. Pcffaut dele Tour M et Molina C 1: la biopsie pulmonaire par la fibroscopie: Etude de cent cas. Le pou11w11 er le Caerur l 978, 34 (6): 393-7. 33. Malenic J, Djukic J. Peribronchialna biopsija pluca kod diseminiranih plucnih lezija. Pluc Bol Tuberk 1979, 31: 148-9. 34. Wall CP, Gaensler EA, Carringlon CB, 1-layes JA: Com­parison of lransbronchial and open biopsies in chronic infillrativc lung diseascs. A111 Rev Respir Dis 1981, 123: 280-5. 35. Levin DC, Wieks AB, Ellis JH. Transbronchial lung biopsy: Use of the fiberoptic broncho-scope: Am Rev Respir Dis 1974, 110: 4-12. Radio/ Onco/ 1996; 30: 95-9. Eff ects of nonionic radiographic contrast media on renal function after cardiac catheterisation Doroteja Drobnic-Kovac1, Andreja Cerne1 , Igor Kranjec 1, Mateja Globokar-Zajec2 'Deportment l;f Cordiovascular Diseoses, Unive1:1·ity Medica[ Centre, Ljubljana, Slovenia 2Department of' Interna[ Medicine, General Hospita/, Novo me.1·10, Slovenia Purpose: The presen/ study was undertaken to elucidate the ejfecls of nonionic radiographic con/rast llledia on systemic and renC1! .fi111ctio11 C1jier mutine cC1rdiac calheterisation. Materials and methods: In /08 consecutive pC1tie11ls, undergoing elec:tive diagnostic or interve11tio11C1I cardiac catheterisation, severni clinical C111d IC1boratorv parameters were deterlllined at baseline wzd 24 lzours qfter the contrasl study. Results: Tlze bC1seli11e serum crealinine leve/ was 94.99 ± 19.44 nzmol/1 and increased lO 96.33 ± 21.08 mmol/1 (P = 0.72). Ac11te re11C1I .fi1i/11re occured in 011/y 1.9 pen:ent r4' patients. The increase in serulll creatinine leve/ depended on the dose r.f' tlze mdiocontrast administered ( P = 0.061 ), bul was not predic teci hv gende1; pre-existing renal insufficiency, hypertension, diC1betes 111ellit11s or congestive heart failure. In C1dditio11, CI nwrked decreC1se in body iveight was observed (fi,!nz 78.8 ± 12.7 kg to 78.4 ± 12. 9 kg, P= 0.00 l ). Conclusion: Thc use of' nonionic c:011/rast media .fi!/· cc11diac ccztheterisation appears to be saje and is associated with a lmv incidence of' arnte renal cumplications. No predicting .fizctors rf nephmtoxicity were observed. Howeve1; the increase in the senull creati11ine and serum creatinine cleamnce 24 hours qfier the procedure depended lw.r;ely 011 the dose <./' radioconlrast agent. We also observed a significant decrease in IJoc/y weight and concluded tlzat prophylactic pre-lzydralion is necessary to preve/11 the neplzrotoxic effect of radioco/llrast agent.1·. Key words: hcart catheterization, contrast media: kidney runction tcsts lntroduction The administration or radiogrnphic contrast media continues to bc a common cause 01· hospital-ac­quired acute renal failure.'-2 During the past dec­ade, nonionic (low-osmolality) contrnst meclia have bcen increasingly cmployed in rndiographic pro­cedures, using intravascular contrast media. as thcy are associated with a decreased incidcnce or sys­temic and organ toxicity comparcd to conventional ionic (high-osmolality) contrast agcnts'·\ A vari­ety or undcrlying conditions (renal insulliciency, diabetes mellitus, congestive hcart failure, hyper- Corrcsponseudocys1 into tile s1011wc/J Figure 1. Schcmalic iluslration of introducing pcrculancous cystogaslric double piglail calhelcr. the pains returncd with palpablc rcsislancc in cpi­gastrium. Control US showed riuicl collcction in bursa omentalis (scc Figure 2). Our radiologisls clecidcd to make percutancously US guided interna! cystogastric drainagc with doublc pigtail catheter and endoscopic assistance. The purpose and the manner or performing the procedure was explained lo lhe palienl in delail, so that the palienl ·s consenl was oblained and the pa­tient was reassured. The procedure was performed in an intervention-radiology room. The palient was lying supine on an X-ray table. Prior to the proce­dure, the patient was re-examined using ultrasound in order to determine the location and direction of access. The patient was then given 5 ml of nora­minophenazone and 5 mg or diazepam i. v .. A tkx­ible gastroscope was introduced into the patient's stomach. The chosen area in tile epigastric region Figure 2. Ullrasonograrn (US) of l1uid collcction in hursa omcnlalis. was washed stcrile and lined witll sterile surgical sllccts. Thc location and direction of puncturing werc finally dctcrmined with a sterile-cncloscd 3.5 Ml-Iz probe with an attachmcnt ror puncturing. Thc skin on lhc antcrior abdominal wall was infiltratcd with I O ml of 2 cyo Xylocaine and a small incision was madc. Puncturing was pcrformed with a 20 cm long 18-gauge necdle wilh mane.Irci. Tile penetra­tion or the needlc inlo the pscudocyst through the anlcrior and posterior stomach walls was observccl on an ultrasound monitor and lhrough a gastroscope. Gastric aecess is a condition ror thc conncction of the pseudocysl with the stomach through a cloublc­pigtail cathetcr in ordcr to allow drainage. The suc­cess or puncturing was chcckcd by aspiration of cystic contents and a shorl nuoroscopic control af­ter lhe administration of the contrasl medi um, while its passage through the stomach was checkcd with a gaslroscopc. A J-typc 0.035" lephlon guide wire was introducecl lhrough thc needle cannula. Thc cannula was rcmovcd and dilation or the channcl was performed with 7F and 8F plastic dilators. A doublc-pigtail cathctcr (8.5 F lhick and 8 cm long) wilh side openings at bolh ends was introduced. It was placed al the tip or a 35 cm long necdlc with 16-gauge thick mandrcl. On thc needlc bchind the pigtail is a pusher wilh which thc tip of thc pigtail catheler was pushcd from the cannula inlo the psc­udocysl, while its base rcrnained in the stomach. The needle cannula, thc wire and the thread which serves for the regulation or the position (depth) of the drainage catheter, and thc werc removed. l02 Sever M era/. Figure 3. (a) US shows smallcr pseudocyst diametcr aftcr percutaneous drainagc and (h) lina! position of the drainage cathcter scen on US, and (c) Xray. The pos1t1on of the pigtail catheter is monitored with an endoscope and adjustcd, and thc thread is cul if its spontancous rcmoval is impossible. Ultra­sonography revealcd rapid drainage of thc pscu­docyst (sce Figure 3a). The position of the drainage catheter could be scen on an X-ray takcn arter the completion or the procedure (see Figure 3 b, c). One month arter the procedure the pseudocyst was not visible on ultrasonography (see Figure 4 a, b), and the patient showed no clinical symptoms. Discussion In the past pancreatic pseudocyst was Lreated only operatively. The introduction of ultrasonography and various catheters enabled other less invasive meth­ods of Lreatmenl. Percutaneous catheter exlernal dra­inage is less comfortable to lhe patient than endo­scopic clrainage (cystogastro -or -cystodudeno -) or interna! cystogastric clrainage with double "J" catheter. Percutaneous double pigtail catheter inter­na! drainage or pancreatic pseudocyst to stomach with ultrasonographic and gastroscopic guiclance cle­scribed rirst by l-lancke 1 is less traumatic to lhe patient, lhan operative procedure by laparotomy.1 There must be proper seleclion or palient: the cyst must be mature (6-8 weeks old to gel thick wall) and in close contacl wilh duoclenum or stomach. Too srna!! residual or stomach following surgcry and bleeding to pseudocyst or infection or its contents does not permil double "J" catheter drainage. The diameler of pseudocyst must be at leasl 5 cm. This selection is possible by US examination. High con­centration or amilase and lipase or pseudocyst con­tent prevents occlusion of catheter lumen. This procedure is reported to be tolerated by pa­tient beller than external drainage.3 The conclition of success is good cooperation between interven­tional racliologist and encloscopist.4 There are re­ports of worth results in infected pseuclocyst ancl Pen:utaneous drainage 1,ta pancreatic pseudocyst inro tile stomac/1 immature pseudoeyst.;.,, Afler the procedure we con­trol the patient every month (bloocl amilase, clinical status, US). The clrain is usually removed by gastro­scope after 1-6 months. The results are goocl if there is a proper selection of patients. There are rcports or reacutisation of inllammation, due to alcohol drinking that demand­ed earlier extraction or catheter, which stimulated inllammation as a "foreign body". Interna! drainage with double pigtail "J" catheter is minimal invasive method which can be made in local anaesthesia, especially in palients with pro­hibitive operalivc risk. Surgical Lreatmenl should be pcrformed whcn cn­doscopical and percutancous procedures are impos­sible or if malignancy is suspected. References 1. Hanckc S, Hcnrikscn FW: Pcrculaneous pancreatic cyslo­gastrostomy guidcd by ultrasound scanning and gastro­scopy. Brit./ Surg 1985; 72: 916-7. 2. Hcyder N, Fliigel H, Domsche W Catheter drainage of pancreatic pseudocysts into the stomach. Endoscopy 1988; 20: 75-7. 3. Das K, Kochhar R, Kaushik SP, Gupta NM, Mchta SK, Suri S, Wig JD: Doublc pigtail cystogastric stcnt in the management of pancrealic pscudocysl. ./ Ciin Utrasou11d 1992; 20: 11-17. 4. Siiubcrli H, Otto R, Hodci K: Perkulane Pankreaspscu­dozyslcn-Drainage: ein sonogrphisch-endoskopisch kombinicrtes Ycrfahrcn. Helv C/Jir Acta 1990; 57: 689-92. 5. Hcyder N, Glintcr E, 1-lahn EG: Endoskopisch-sonogra­pisch Gcfiihrtczystogastrale Kathcterdrainagen pankrca­logcncr Fllissigkcitsansammlungcn. 7: G11stme11tem/ 1992; 30: 553-7. 6. Kolvenbach H, Himer A: lnfectcd pancreatic necrosis possibly duc to combined percutaneous aspiration, cysto­gastric pscudocyst drainage and injection of a sclerosanl. Ec!oscopy 1991; 23: 102-5. Radio/ Oncol 1996; 30: 104-7. Insulin dependency of F-18-fluorodeoxyglucose accumulation in breast carcin01na cells compared to Tl-201 uptake Heike Wolf, Winfried Brenner, Volker Stein, Stephan Tinnemeyer, Karl Heinz Bohuslavizki, Ulrich Teichert, Malte Clausen, Eberhard Henze Clinic of Nuclear Medicine, Christian-Albrechts-University of' Kiel, Kiel, Germany Tiie e.ffect of euglycemic hyperi11suli11is111 on 18F.fluorodeoxyglucose (FDG) uptake in cultures of breast cancer was detennined, in comparison to 2111 TI. Meas11rements of bolh tracers were pe1:f'onned on 168 celi cultllre tubes, with incubation intervals ranging .fi'Om 1 to 240 min. Linear accumu/ation of FDG over time was observed bolh ivith wu/ without insulin. A significant increase .fi'Om 3.52 ± O. 74 % to 5.10 ± 0.32 % over 240 min wa.1· attained qfter adding in.rnli11. In contrast, 201 TI revealed only a slightly sign(ficant increase a.fier insulin. By extrapolating these results to FDG PET tumor imaging, a markedly improved tumor targeti11g might be obtained by providing a stale of euglycemic hyperinsulinism, i.e. replacing the commonly used sing/e FDG injection by a conti111wus FDG/glucose/insulin i11fi1sion. A11 optimum inwging period of I 50 min qfier starting the infi1sio11 can be derivedfinm. 01u· dala, considering the decay of 18F Key words: breast neoplasms; tumor cells, cultured; euglycemic hyperinsulinism; deoxyglucose, 18F-lluo­201 TI rodeoxyglucosc; thallium radiosiotopes, Introduction lncreascd glycolysis is an important characteristic of cancer celi s. 1• 2 Positron emission tomography (PET) with (18FJ-2-t1uoro-2-dcoxy-D-glucosc (FDG) is used as a suitable indicator of the glycolytic activity of tumors. FDG is rapidly transported into the tumor cells and phosphorylated by hexokinase to FDG-6-phosphate, bul is not further metaboli­zed, '· • meanwhile the physiologic substrate glucose enters the glycolytic pathway. lncreased FDG up­take imaged by PET has been reported in many types 01· human tumors, e.g., head and neck cancer,5 lung,'' colon,7·' !iver"· 10 and breast cancer. 1 1. 12· 201 Tl SPECT imaging might work as well as FDG PET in the detection of viable tumor tissue based on the relatively enhanced tumor blood supply. In neoplastic celi cultures the 201 Tl uptake increases in Corrcspondence to: Heike Wolf, Ph. D. Christian-Albrcchts­University of Kiel, Clinic of Nuclear Medicine, Arnold­Heller-Str. 9, D-24105 Kiel, Germany conjunclion with the cell's metabolic activity, the­reby confirming that it might also reflect tumor growth rather than just tumor perfusion.11 In the in-vivo and in-vitro studies so far avail­ 12• 1•-19 able5· controversial effects of plasma insulin and/or glucose levels on FDG tumor targeting have been reported. Agreement consists in most studies that elevated cold glucose levels seem to compete with FDG, thus hampering FDG accumulation. The purpose of this study was to determine the effect of euglycemic hyperinsulinism on lhe cellu­lar uptake of FDG in cultures 01· breast cancer cells, 201 TI and to compare it with lhe uptake of unclcr 201TI identical conditions, since insulin effects on tumor accumulation are also hardly known. Materials and methods Radiophannaceuticals FDG (BTZ Beschleuniger-und Tomographiezen­trum Hamburg, Germany) was obtained with a ra­diochemical purity higher than 98 %. Impurities UDC: 618. l 9-006.6-092.4:616.l53.455.01 like ethanol, acetonitrile and acetone were less than !11suli11 depe11de11cy of' F-!8;/lu11rode11xy1sluc11se (ICClllllllfation 0.06 mg/ml and the glucose concentration was less than 0.6 mg/ml. A commercially available 201 TI thallous chloride was used (Mallinckrodt, Hennet', Germany) as a reference tracer. Cell cultivation The human breast carcinoma celi line (MCF 7, dkfz -Turnorbank, Heidelberg, Gerrnany) chosen for ex­amination was maintained in a medium containing5 mmol/1 glucose, supplemented with I O% fctalcalf serum (Boehringer Mannheim, Mannheirn, Ger­rnany), 0.5 % L-glutamine 20 mmol/1 (Biochrom,Berlin, Germany) and I ml gentamyein 0.1 mg/ml(Merek, Darmstadt, Germany). The celi line grewwell in vitro as a monolayer and had a doublingtirne of approximately 40 h. A Fuchs-Rosenthalcounting chamber was used for celi counting andlhe trypan blue exclusion method for viability de­termination was conducted using an inverted Leitzmicroscope. Tile lota! number of cells ranged t'rom 7.9 to 9.2 million cells per tube with a median of 8.5 million. Celi viability was higher than 90 %. Uptake 111easure111e11ts 30 MBq FDG and 3 MBq 201 TI were added to 250 ml medium, thus maintaining a continuous supply during the whole incubation period. For each tube, 3 ml medium was used, and the exponentially grow­ing cells were incubated with FDG and 101Tl al 37 °C. lnflux was stopped at differenl incubation intervals ranging from I minute to 4 hours, by removing the medium. Subsequently, cells were wa­shed rapidly 3 limes with 4 °C saline solution for a Lota! of 15 seconds and harvested with Lrypsin-EDTA (Sigma Chemie, Deisenhot'en. Germany). Tile radioactivity was measured wilh a gamma well counter in a definite geometry. Tota! activity per culutre tube was attained by measuring the tube before removing the medium. The cellular uptake was determined afler the washing phase. FDG mea­surements were performed first and samples of me­di um and cells were slored for two days Lo deter­mine the 201 TI uptake, after the complele decay of isr. Ali results were corrected for physical decay.Tli assure adequate measurement statistics, six tubes per exposure period were used, totaling 84 culture tubes in ali. The experiment was repeated exactly under the same conditions, bul with an ad­ditional administration ot' insulin, in a quanlily of 0.5 [U to lhe medium, i.e. 2 m[U/ml, providing a complete receptor saturation. Uptake results are presented as the percentage of the activity accumulated within the cells, related to the activity added in each tube normalized to 1 million cells, and expressed as mean ± 1 s.d. For statistical comparison, Student's t-test for unpaired data was used. Results As shown in Figure 1, linear accumulation of FDG over tirne was observcd in nearly ali the exposures, up to a maximum of 240 min. With the longest exposure period of 240 min an uptake of 3.52 ± 0.74 % was measured under baseline conditions. A further significant increase of up to 5. 1 O ± 0.32 % was attained after adding insulin, with p :S 0.02 already beginning after an incubation Lime of 20 min. Figure L Cellular uplake of "FDG cxpresscd as 'ľ1 of rnc­dium activily per I million breasl carcinoma cells with and withoul insulin (0.5 mlU/ml medium) at various incubation lime intervals. Rcsulls are givcn as mean of 6 cullure Lubes ± 1 SO. Additional insulin: filled squares; without insulin: open circles. In contrast, rale during the !trst 201 Tl accumulation occured at a high I O to 20 min and then reachecl a plateau. Adding insulin did not induce such marked effecls, as illustrated in Figure 2. By lumping ali the tubes, with and without insu­lin, together, the groups differ with 0.33 ± 0.06 % and 0.25 ± 0.05 %, respectively. Significant differ­ences with p < 0.02 might be obtained in the initial phase, such as at I O, 30, 45 or 90 min, while after a 150 min exposure tirne, both curves converge on each other. 106 Wo(fB etat. Figure 2. Cellular uptake of ""Tl expressed as % of me­dium activily per 1 million breasl carcinoma cells with and without insulin (0,5 m!U/111I medium) at various incubation tirne intervals. Results are given as mean of 6 culture tubes ± 1 SO. Additional insulin: filled squares; without insulin: open circles. Discussion Tumor targeting and quantitative evaluation of tumor tissue viability with FDG and PET have shown en­couraging results, with high tumor/background ra­tios. Attempts have been made to further increase FDG accumulation in tumor tissue for even better scintigraphic tumor delineation, mainly by using additional glucose administration on induce a stale of hyperglycemic hyperinsulinism.1- 1-1 7. 20 In agree­ment with in-vitro studies, examing the same issue, FDG accumulation mainly decreased with elevated plasma or media glucose concentrations12 · i;, 21 ex­ccpt in brain tumor imaging.17 This was interpreted as a competing effect bctwccn cold and labcled glucose leading to the conclusion that FDG tumor imaging ought to be performed under conditions of food abstinence. 14• 15· 18 The purposc and the results of this study havc to be scen in that contexl. Bccause of the obviously hampering FDG accumulation at increascd plasma glucose levels, thc approach was different to ali previously performed studies. The experimental de­sign simulated a stale of euglycemic hyperinsu­linism in conjunction with a relatively constant sup­ply of FDG, maintained for up to 240 min. Provicl­ing this environmcnt to breast canccr cclls a signifi­cant incrcasc of FDG uptakc in tumor tissuc was observccl as seen in Figure 1. This rcsult seems to support the abovc cited hypothesis of competition between cold ancl labcled glucose. The effect of the same study design on 201 TJ celi accumulation was considerably less, and completely concomitant to recent results.19 Particularly during the initial exposure period of up to 150 min, how­ever, insulin increased the 201 Tl uptakc by 50 %. Providecl this also holds true for in vivo scintigraphy, an incrcasc of the tumor/backgrouncl ratio by a fac­tor of 1.5 would stili represent a great progrcss in scintigraphic tumor targeting. Based on this data it secms thus justified to pro­pose a modified application protocol for both 201Tl and FDG tumor imaging, suggesting euglycemic hyperinsulinism and maintaining constant tracer sup­ply for a longer period of tirne. In thc case of 201TI, an approximatcly 60 min infusion might be suggcsted, which causes no adclitional problem, since insulin clamping requires a continuous infusion anyway. In the case of FDG, thc short tracer half lile has to bc considerecl. As scen in Figure 1 constant tracer sup­ply results in linear accumulation, if correctecl for physical dccay. Consiclering 18F decay an accumula­tion typc of curve is obtained, as shown in Figure 3, with maximum tracer concentration and, thus, a pos­tulated optimum for imaging, at approximately 150 min aftcr starting the FDG/insulin infusion. The dose of insulin should be moderate, i.e. 20-30 IU/h, so as not to induce significant hypoglycemia ancl/or clini­cal symptoms, but to raise the plasma insulin leve!. Clinical trials are nceded to validate this poslll­lated approach. The outcome of such trials is diffi­cult to predict, since the effect of euglycemic hyper­ Figure 3. Cellular uplake of "FDG wilh (filled squares) and without (open circles) insulin considering physical decay of "F, as calculated from thc regression curves of Figure l. l11suli11 depe11de11cy of' F-18;/luorodeo,\J'J;iucose acc1111111/a1io11 insulinism on bolh thc tumor and thc surrounding tissuc in vivo is unccrtain bccausc or Lhc various distribution or thc, at least fivc diffcrcnt, glucosc transporting molcculcs, and thc unknown magni­tude as to whcthcr thcsc glucosc transportcrs are involvcd in thc facilitatcd transmcmbrancous gly­colytic flux.12· i-1--is Conclusion Thc accumulation of FDG and, to a lcsscr cxtcnt, that of 2111TL in brcast carcinoma cclls can bc sig­nificantly incrcascd by insulin and euglyccmia. Thc potcntial improvemcnl of PET and SPECT tumor targcting ought to justify furthcr clinical tcsting. Acknowlcdgcmcnts Thc gcncrous supporl in dclivcring or FDG by Dr. B. Ncbcling (Cyclotron, Univcrsity or Hamburg) is highly apprcciatcd. Rcfcrcnccs 1.o Warburg O. On thc origin of canccr cclls. Scirnce 1956;o123: 309-14.o 2.oWeber G. Enzymology of cancer cclls. N lo"11g/ J Med 1977: 296: 486-93. 3. Gallaghcr BM, Fowler JS. Guttcrson NI, MacGregoroRR, Wan CN, Wolf AP. Mctabolic trapping as a princi­pic of radiopharmaccutical dcsign: some factors rc­sponsible for the biodistribution or ['"F] 2-deoxy-2­l1uoro-D-glucosc . .! Nucl Med 1978; 19: 1154-6 l.o 4. Som P. Atkins HL. Bandoypadhyay D, ct al. A l1uori­natcd glucosc analog, 2-['"FJ-rluoro-2-dcoxy-D-gluco­sc: nontoxic traccr for rapid tumor dctcction . ./ N11clo1\iled 1980; 21: 670-5.o 5.o Habcrkorn U, Strauss LG. Rcisser Ch, cl al. Glucoscouptakc. pcrfusion, and celi prolifcration in hcad ando11cck turnors: relation or positron crnissio11 tornographyoto llow cytomctry . ./ N11c/ Med 1991; 32: 1548.55.o 6.o Nolop KB. Rlmdcs CG, Brudi11 LH. ct al. Glucosc utili­ zation in vivo by human pulmonary ncoplasm. Ca11cero987: 60: 2682-9.o 7.o Strauss LG, Clorius JH. Schlag P. ct al. Rccurrcncc of colorectal tumors: PET evaluation. Radiology 1989;o170: 329-32.o 8.o Habcrkorn U, Strauss LG, Dimitrakopoulou A. ct al.oPET studics or nuorodeoxyglucosc 111etabolis1ll in pa- ticnts with recurrcnt colorcctal tumors rcceiving radio­thcrapy . ./ N11cl Med 1991; 32: 1485-90. 9.oYonekura Y, Bcnua RS, Brili AB, ct al Incrcased accu­mulation or 2-dcoxy-2-"F-fluoro-D-glucose in !iveromctastases from col on carcinorna . ./ Nucl Med 1982;o32: 1133-7.o 1 O. Oya N, Nagata Y. lshigaki T, et al. Evalualion of expcri­mcnlal !iver tumors using l1uorinc-l 8-2-fluoro-2-de­oxy-D-glucosc PET../ Nw.l Med 1993: 34: 2124-9. 11.o Kubota K, Malsuzawa T. Amc111iya A. ct al. lmaging ofobreasl canccr with ['"F]lluorodcoxyglucose and posi­tron emission tomography . .l. Comp111 J\ssist 7r111w1;r 1989; 13: 1097-8. 12.o Wahl RL. Cody RL, Hutchins GD, Mudgell EE. Pri­mary and mctastalic breast carcinoma: initial clinicalocvaluation with PET with the radiolabelcd glucose ana­loguc 2-l '"FJ-lluoro-2-dcoxy-D-glucosc. Radio/ogy 1991; 179: 765-70.o 13.o Maublant JC, Zhang Z. Rapp M. Ollicr M. Michelot J. Veyrc A. In vitro uptakc of Tcchnctium-99m-Tchoro­ximc in carcinonia celi lincs and normal cclls: com­parison with Technctium-99111-Scstamibi and Thalliu,ll­20 l. ./ Nuc/ 1\iled 1993; 34: 1949-52.o 14.o Langen K-J, Braun U. Rota Kops E. ct al.The inlluenceoor plasma glucose levcls on lluorinc-l 8-11uorodcoxy­glucose uptake in bronchial carcinomas. J Nuc/ Med 1993; 34: 355-9.o 15.o Lindholm P, Minn H. Lcskinen-Kallio S. Bergman J, Ruotsalaincn U. Jocnsuu 1-1. Influence of th. blood glucosc concenlration on FDG uptakc in canccr a PET study. J Nucl 1\iled 1993: 34: 1-6.o 16.o Minn H. Leskinen-Kallio S. Lindholm P. et al. i'"FJoFluorocleoxyglucosc uptake in tumors: kinctic vs. stc­ady-statc 111cthods with reference to plasma insulin . ./oCo111p111 J\ssisl 1lm1ogr 1993: 17: 115-23.o 17.o lshizu K. Nishizawa S. Yonckura Y, ct al. Effccts ofohyperglyccrnia on FDG-PET in paticnts with brain tu­ mors . ./ Nucl Med 1994; 35: 18.o Wahl RL. Henry Chi\, Ethicr StP. Serum glucosc: cf­fects on tumor and normal tissuc accumulation of 2­l '"FJ-11uoro-2-dcoxy-D-glucose in rodents with rnam­rnary carcinoma. Radiology 1992; 183: 643-7.o 19.o Slosrnan DO. Pugin J. L1ck of corrclation bctwccnotritialcd deoxygJu';;osc, tliallium-201 and tcclrnctium-99m-MIBI celi incorporation undcr various celi strcs­scs. J N11cl Med 1994: 35: 120-6. 20. Okazurni S, lsono K. Enomoto K. ct al. Evaluation ofo!iver turnors using fluorinc-18-Fluorodcoxyglucosc PET:ocharacterization of tumor and asscssment of cffcct or trcatrncnl. ./ Nucl Med 1992: 33: 333-9.o 21.o Amos H. Muslimer TA Asdourian H. Rcgulation ofoglucosc carricrs in chick libroblasts . ./ Supmmolecu/ar Stmc111re 1977: 7: 499-513. Radio/ Oncol 1996: 30: 108-12. Positron en1ission tomography (PET) in ischemic heart disease Karl Heinz Bohuslavizki, Winfried Brenner, Malte Clausen, Eberhard Henze C linic oj' Nuclear Medicine, Clzristian.-Albrechts-University, Kiel, Germany The key .rnbs!mtes o/ any hiuche111ical f!Cllhway mav be labelled by positron e111illi11.g nuclides, without i111erferi11g wilh !heir bio/ogical he/l(fviow: These nuclides desi111egrn1e wilh lwo ga111111a rays in opf!osileedireclions. Differenl kinds o/ PET ca111eras, !heir advantages and disadvanlages are discussed in tenns of geometric resolllfion, nuclides useahle, cos/s, mul logislic proble111.1·. La!esl ca111era lechnology deals with SPECT cc1111em caf!able o/ coincidence de1ec1io11, !hus allowing !o /le1fom1 P/.T i111ages witholll largeeeXf!enses .Jc;r dediccll!'d PL'T sys1rn1s. This could /um FDG inwging towards jusl ano!lter simf!le 11uc/earemedicine f!/'0Ced11re. Titi' lll(fin clinic:a! hrnefil of' 1his 11ie1hod lies in lite f!/'0!4· o/ 1is.1·11e viahilily in aki11e1ic:, hybemctling n1yocardiw11 f!l'ior /o 1hemf!elllic i11l!'rve111io11s. Thus, .fi)J· /}(t/ienl 111wl(fgeme111 PL'T 1vill helf! /oeselec/ the Of!fl/'Of!l'iale !hemf!elllicct! f!/'OCedurl:' and 1ltereby wi/1 increose the he11e.fi1-risk mtio .fi;r theef!Olie111s. Key ,vord1·: myocardial ischemia; lomography, emission-compuled, positron emission lomography, PET; rnyocardial metabolism lntroduction Imaging procedures in nuclear medicine lend lo be non-invasive, simple to perform once the equip­ment is available, and they produce a macroscopic display ot' lhe organ under invesligalion wilh a some­what limited geomelric resolulion. The key mes­sage of nuclear medicine is visualizing bolh (palho-) physiology and melabolism. In order lo i mage pathophysiology and lo cha­ractarize lhe lissue under investigalion small amo­unts o!' radioactive suhstances me incorporated imo lhe palients and their distribulion in the body is delecled and analyzed over time. Single-pholon emit­ters like technelium-99m, thallium-201, iodine-131, iodine-123, and indium-11 l are lhe most ol'ten used radionuclides ror labelling procedures. Once these nuclides are bound to a carrier the physicochemical properlies ot' these carriers are altered. and lhere­ Corn.:spondence lo: Dr. Karl I-1. Bohuslavizki, Clinic of' Nu­clear Medicine. Christian-Albrcch1s-Universi1y o!' Kicl, Ar­nold-Hellcr-Str. 9, D-24105 Kicl. Gcnnany, Tel.: +49 431 597-3061, Fax.: +49431 597-3150. fore their metabolism is somewhal unphysiological. Thus, the challenge for lhe radiochemist with sin­gle-pholon emilling nuelicles is to produce rndio­pharmaceuticals, which despite of their unphysio­logical nature will detect clinically useful signals. This is lhe main limiting raclor in lhe development 01· new tracers for conventional gamma camera tech­niques in nuclear medicine. In contrast, with positron emitling nuclides com­pletely physiological tracers may he developpcd. as shown in this paper. Positron emitters The main advantage of these positrons radiated from the nucleus is their l'ate in tissue. Within a very short distance of aboul I mm lhe posilrons collide wilh an eleclron and bolh corpuscles annihilale, vanishing completely. Their energy is lrnnsforrned to electromagnelic radiation in a characteristic pat­tern. Two photons of exactly 511 keV each radiate J'rom the site of collision in almosl opposite direct­ions. (To be more precise, the angle belween the two photons is about 179 degrees. This facl togelher UDC: 616.12 7-005.4-073.756.8 with lhe average length of radiation of the positrons Positro11 e111issio11 10111ograp/Jy (PET) in isc//e111ic hear/ disease define the lowest possible limit of geomelric reso­lution for physical reasons to aboul 2 mm). This allows for comparalively high resolution metabolic imaging with positron emission tomography (PET). Full wiclth al ha11· maximum is 5 rnm for PET stu­dies. In comparison, realistic dala on rull widlh at half maximum in SPECT studies is some 15 mm. The most widely used posilron emilling nuclides in PET-centers are given in Table 1. Obviously, positron emitling nuclides from nilrogen, oxygen and carbon are ideally suited ror the design or radio­pharmaceuticals with completely physiological be­haviour ('"make as small a change in the molecule to be traced as possible"). This opens tremendous possibililies for 11011-invasive, in-vivo autoradiogra­phic analysis . In a specialized radiochemical labo­ratory any organic substrate of inlerest mighl be labelled. e.g. metabolites including analog substan­ces, receptor ligands and drugs will react chemi­cally ancl biologically in exaclly the same way as their non-radioaclive counterparls, due to lheir iden­tical physico-chemical properlies. Table l. Half-lilc or positron cmilling nuclidcs comrnonly used. Nuclidc half-lik !111in l Rb-82 1.26 min 0-15 2.07 min N-13 9.96 min C-II 20.40 min F-18 109.7() lllin Rh-81 274.80 min A characlerislic fcature or positron ernilling nucli­des is their shorl half-life in lhe range of rninutcs as depicted in Table 1. Therefore, for full ulilisation of the PET technology an onsite cyclolron for lhe gen­eralion or short-lived nuclides and a radiochemical laboralory are required. The radiochemistry needed rnay be characterized by extremely rast synthesis Table 2. Positron crnilling nuclidcs in cardiology. and labclling techniques, cssential for lhese (ultra-) short-lived tracers. Because of these expensive in­stallations, costs have been reduced tentatively by supplying severa] lomographs by one cyclotron only. 1-lowever, the main benel1t of this shipment of shorl­lived nuclides might he for the inital phase of a newly installed PET-center. On the other hand, the short half-lifc of these positron emitters puls a very small radiation burden on the patient, and investigalions may be repeated in a shorl tirne before and following medication or therapeutic interventions. This fact is or special inleresl in diagnostic and therapeulic procedures in cardiology. By applying different lracers myocarclial perfusion and blood pool, rauy acid mctabolism, glucose ulilisation (a marker of ischemia plus rnyo­cardial vitalily) and the receptor status rnay be visu­alized successfully as shown in Table 2. An ideal lracer should clear fasl from the background. shoulcl have a high myocardial uptake of sunicienl dura­lion for imaging, and shoull not influence rneta­bolic pathways. Compcting PET tcchnologies The common axis of the two photons of 511 keV may be scen by scintillation detector blocks with clcctronics. which is able to delect the corrcspond­ing pair of counts by their coincidencc. These emit­ted projection dala is then backprojected in a simi­lar way as is done in X-ray computed tomography. Moreover. bolh machines look quite similar. In modern PET systems a series of delector rings acquire three-dimensional dala wilh high sensiliv­ily. i.c. within a given angle any part of any ring may inleracl with any other part of any other ring for the coincidenl detection of lhe paired gamma rays. This technique will acquire simullaneously ali dala to cover an organ like the hean. Transmission Circulation N-13 NH, (arnmonia) blood 11ow Rb-82 blood 11ow 0-15 H,O blood 11ow 0-15 a11d C-11 CO blood pool Mctabolism Ncuronal rcccptors Varia C-11 pal1nitatc F-18 dcoxyglucosc C-1 1 acetate C-11 amino acids N-13 arnino acids C-1 1 quinucyclidinc F-18 mctaraminol C-1 1 hydroxycphcdrinc F-18 1nisonidazol Rb-81 lipid acid mctabolism glucosc uptakc Krcb's cyclc / oxygcn consumption protein synthcsis protein synthcsis l.1-rcccptor ligand adrcncrgic inncrvation adrcnergic inncrvation detcction or hypoxia potassium pool Bo/ws/avizki KH et al. Table 3. Comparison of lomographic syslems in nuclear cardiology. PET SPECI'+ coincidcncc SPECI' Tract:r Nuclides Nuclide distribution Rcpeated studics Acquisition tirne (hearl) Whole body capability Rcsolution (FWHM) Quanlilation Availability Installation Costs 11er invcstigation physiological short-lived restricted within hours 10 min yes 5 Jlllll prccisc restricted 10 Mili US$ 1200 US$ physiological short-lived rcstrictcd within hours 40 min no 5 Jlllll poor potentially widcspread 1 Mili US$ 600 US$ non-physiological long-livcd widesprcad nexl day 20 min limited 15 mm poor widcspread 1 Mili US$ 300 US$ dara are acquired for physically exacl absorption corrcction. This allows to clisplay the tracer distri­bution in Becquerel per volume and, therefore, ser­ves as a basis for the calculation of quantitative physiological parameters. In contrast, this is quite different in SPECT meas­urements. With single photons the count distribu­tion correlales poorly with the activity distribution, and proves by experience only to be clinically use­ful as given in Table 3. I-lowever, the !atest genera­tion of multi-headecl SPECT systems makes it pos­sible to acquire transmission dala as well. This SPECr transrnission system allows for sufficient absorp­tion correction while scatter remains a major prob­lem. Superb images have been shown, bul the clini­cal value of absorption correction in SPECT stili remains to be evaluated. Positron emission tomography is now around for about 15 years. I-lowever, the limitecl number of PET centers currently installed will not allow rou­tine patient management on a broad basis. The high costs of the systems are due to rather sophisticated harclware required, especially when combining an on-site cyclotron and a radiochemistry with the PET scanner. The initial investment of a complete PET center will require 6-8 Mili US$ and the reimburse­melll for one investigation will approximate 1200 US$. These tinancial considerations will limit the lechnology to clearly derined clinical problems ancl especially to cardiological and brain research. To overcome these limitalions, a new generation of low cost PET scanners are introduced by industry, e.g. AR'T-PET, which may change the benefil-cost rntio towards PET in the near future. The !atest camera technology came up with a machine in a somewhat intermediate position be­tween PET and SPECT.1 A double head gamma camera designecl for excellent SPECT stuclies was equippecl with high countrate capability and coinci­dence detection. Thus, PET and SPECT are achiev­able in a single gamma camera. After a potentially wiclespread installation this may allow tomographic examinations with physiologieal PET-tracers, i.e. tluorcleoxyglucose (FDG), with the intrinsic goocl geometric resolution but without huge expenses ne­cessary for dedicatecl PET centers. Since neither transmission measurements ancl consecutive quan­tification nor whole bocly imaging are feasable so far this system rnay become a worthwhile alter­native in imaging of small organs as the heart and the brain. In these organs, SPECr cameras equipped with high energy 511 keV collimalors have been used. I-lowever, lhcse images lack quality due to the rather limited geometric resolution of this syslem, with a possible role in carcliac studies only. Ischemic heart cliseasc Up to now only in a few PET centers worldwide basic research on myocardial ischemia in animal models has been performed. Subsequenl clinical work bas concentrated on myocarclial ischemia and cardiomyopathies.2· 3 Conclusive results using PET in ischemic heart disease are available only for the last lwo years with about 20-30 original papers based on studies with less than 200-300 patients in total, mostly performed in the US. Normal myocardium utilizes fatty acids for ils energy requirements during rest. At stress lactate acid from the skeleta! rnuscle is taken additionally. During rasting stale there is delinitely no uptake of glucose in the myocardium. In contrasl, the post­prandial endogenous insulin load will result in glu­cose uptake of the myocardium as well. This pat­tem changes quite dramatically during ischemia. Even in the fasting stale myocardial cells will switch towards anerobic energy production using glucose. This glucose uptake signals ischemic, but stili vi­able myocardiurn. On the other hand, in scar tissue l'osi1m11 e111issio11 1011111gmf>lty (PET) in isc/1emic ltear/ disease therc is vcry little uptakc of any traccr bccause of its bradythophic metabolism. In palicnls with ischcmic heart disease PET may irnage non-invasively blood llow and metabolic pa­ramctcrs." During hypoxia fatty acid metabolism is stopped and subsequently switchcd over to aerobic and anaerobic glycolysis, as desribcd above. Using F-18 labelled FDG, increascd glucose utilization may bc detected in regional myocardial ischemia. This metabolic imaging may be combincd with blood llow studics. Rb-825 and N-13-ammonia are com­monly used blood flow tracers. With a doublc traccr technique of FDG and N-13-ammonia it seems pos­siblc to differentiate normal, scarred, and ischemic myocardiurn. In the latter there is decrcascd uptakc or blood flow traccr whilc glucose utilization is enhanccd, thus a "mismatch" bctwccn the two tracer pallcrns occurs. Infarctcd myocardium rnay bc idcn­tified by FDG (and C-11-palmitalc) as a region or abol ished melabolism. MyocardiaI vitality Uncxpccted and partially speclacular rcsults con­cerning demonslralion of remaining vitality in aki­netic myocardial regions, where no Tl-201 uptake could be shown in SPECT studies, have been re­portcd. In one study, up to 58 % of persisting Tl­201 stress and resl perfusion defccls interpreted as scar tissue showcd metabolic residual activily with FDG in PET studics." According to these results PET seems to allow prognostic statemenls concer­ning the prediction or contraction function or akinctic bul stili vita! myocardial tissuc arter revasculariza­lion. This prediclion was truc in one study ror 85 % or thc patiens, whcreas regions idcntilied as scar tissue by N-13-amrnonia and FDC-PET showcd functional improvcmcnl in 8 pcrccnl only.7 Therc­forc. the spccificity ror scar detcction is high for PET. quitc in contrast to SPECT studics pcrformed with Tl-201. Howcvcr, two principal drawbacks underlying FDG-PET should bc mcntioncd. Thcre is no way to diffcrentiate acrobic from anacrobic glycolysis. i.c. poslprandially even normal myocardium shows FDG uptake. This has led to a variety of ditlerent acqui­sition protocols with no commonly accepted pro­cedure so far. Furthermore, following myocardial infarction a solid block or scar tissue may be missing. Histologically, a mixture or scar fibres and stili viable myocardial cells is demonstratcd in these patients. Although these cells will show an inereased FDG uptakc, they remain immobilizecl by surroun­ding scar tissue. Thcrefore, following revasculariza­tion eardiac eontraction will not be enhanced. Be­side this clearly defined value for patients with isehcmic heart disease in cardiological diagnosties, PET has a unique importance for elinical rcsearch due to the ncarly unlimited possibilities of non­invasive in vivo investigations.' Ventricniar tachycardia following myocardiaI infarction One example will be given for currenl PET rcsearch in paticnts with ischemic heart diseasc. Following myocardial infarction some paticnts develop high risk ventricular tachycardias. The site or lhc arrhyth­mogenic substrate may be delineated by PET in two diffcrent ways. First, at the border of a myocardial scar ischemic myocardium is sometimes found. These areas are characterized by a perfusion -me­tabol ism mismatch, i.e. reduced perfusion and cn­hanccd glucosc uptake. In cxactly thcse areas, lo­calized by PET, the electric Cocus during episodes of venticular tachycardia could be confirmed by elektrophysiologic studies." Second, in a more spe­cific approach the reuptakc of adrenergic substances in nerve fibres of the myocardium may be documcn­lated by PET."' Dislurbances or this rcuptake of adrcnergic substanccs may signal membrane insla­bilities and, thus, a tendency towards arhythmia. In carcfully controlled clinical studies it may be possi­ble to link these tindings or scintigraphically proven cardiac neuropathy with ventricular tachycardias ancl with the problem or sudden cardiac death. Conclusions The main clinical benefit of PET in cardiology is to racilitate the prognosis or the success of any re­vascularization. By using a glucose derivate the vi­ability of hybernating myocardium and thereby thc curability may be proven. Otherwise, the impact or PET technology is concentrated mainly on basic research. References 1. Muehlkhner G. Gcagcn M. Countryman P. SPECT scanncr wilh PET coincidcncc capability labstract] . ./ Nuc! Med 1995; 36: P70. Bohuslavizki KH et al. 2. Henze E. The clinical impact of positron emission tomo­graphy (PET) in the cardiological work-up. /111emist 1990; 31: 338-40. 3. 1-lenze E, Milcinski M, Lietzenmayer R, Clausen M. New aspects in nuclear cardiology -PET, NMR and SPECT. Adv Radio/ Oncol 1992; 25: 123-34. 4. Deutsch E. Clinical PET: lts tirne has comc . .! Nucl Med 1993; 34: 1132-3. 5. Reske SN, Henrich MM, Mate E, Weller R, Glalling G, Grimme! S, Weismiiller R, Stollfull J, Hombach V. Non­invasive detcction of resting myocardial blood flow with Rb-82 PET in patients compared to the argon method. Nucl-Med 1993; 32: 276-81. 6. Brunken R, Tillisch J, Schwaiger M. Child JS, Marshall R, Mandclkern M. Phelps ME, Schelbcrt HR. Regional perfusion, glucose metabolism and wall 1110­tion in chronic electrocardiographic Q-wave infarctions. Evidence for persistence of viable tissue in some infarct regions with positron emission tomography. Circu/at/011 1986; 73: 951-63. 7. Tillisch J, Brunken R, Marshall R, Schwaiger M, Mandelkern M, Phelps ME, Schelbert HR. Predic­tion of cardiac wall moti on abnormalities using posi­tron emission tomography. N E11gl .! Med 1986; 314: 884-8. 8. Schelbert 1-1. Position statement: Clinical use of cardiac positron emission tomography. Position paper of the cardiovascular council of the society of nuclear me­dicine . .! Nucl Med 1993; 34: 1385-8. 9. Reinhardt M, Ganschow U, Vester E, WirrwarA, Strauer B, Vosberg 1-1, Miiller-Giirlner I-IW. Mismatch between glucose metabolism and perfusion in arrythmogenic foci of patients with ventricular tachycardias [abstractJ. Eur .! Nucl Med 1994; 21: 726. 1 O. Schwaiger M, Kalff V, Rosenspire K, Haka MS, Moli na E, Hutchins GD, Deeb M, Wolfe E Jr, Wieland DM. Noninvasive evaluation of the sympathetic nerv­ous system in the human hearl by PET. Circulario11 1990; 82: 457. Radio/ Onco/ 1996; 30: 113-5. Papillary thyroid cancer in two sisters Jasna Gardašanic\ Juraj Smoje1 , Ivan Karner 1 , Aleksandar Vcev2 , Nedeljko Topuzovic1 1 Departments of Nuclear Medicine, 2 Department cl Gastmentemlogy, Osijek Clinical Hospital, Osijek, Cmatia Case reporls 011 lwo sisters wilh his10/ogically co11jim1ed papillary lhyroid rnncer are prese111ed. Gaslro­enterological exami11atio11s were nomwl in bolh palien.ts, Garc/ner's syndrome excluded. It was con.cluded C !hal fcunily history, clinica/ presen/ilion _fi-ee ol u11derlying cancer syndmme, and histopalhologic examina­tion are not adequate .fi)I· reliable d!f!ere11tia1ion hetween occasional and familia/ _/i)lms, unless ge11e1ic markers are availahle. Key words: thyroid neoplasms; Gardner's syndrome, thyroiditis, autoimmune Introduction In contrast to medullary thyroid carcinoma (MTC) which, in part, shows familial occurrence as a part of multiple endocrine neoplasia syndrome type 2 (MEN 2), the nonmedullary forms of thyroid cancer are not generally thought to present familial occur­rence. However, evidence from literature1 -" on thy­roid cancer associated with familial adenomatous gastrointestinal polyposis (Gardner's syndrome) suggests possible inheritance. In a majority 01· fa­milial cases, papillary canccr has bcen described, almost cxclusively in young females, as being twicc more oftcn multicentric in origin, affecting bolh !obes or thc thyroid gland, diagnoscd before the age or 30, and with cxccllent outcome.2·<, In this casc rcport, wc present two sisters with papillary thyroid cancer. The aim or cvaluation was to determine whether thcse cases could be consi­dered a familial discasc. Case report 1 In 1982, P.A., a 42-year-old woman, presented at our Departmcnt for suspcct hypcrthyroidism. The Correspon--group 5 80 --1 v<> o --0-group 6 V} .::: 60 V} 40 20 o -1---1--------, -.---.,--,-----r 20 40 60 80 100 120 140 160 Days after scEAT transplantation Figure 2. Survival or scEAT groups (group 4-control, group 5-ipNDY, group 6-scNDY). Thc animals dicd spontane-. ously. 18,9 x l 01 EAT cclls wcrc transplantcd per animal. The original virus liter was EID 1075; 0,2 ml of NDY di­lutcd 1: 15 with Hanks' solution was applied per animal twicc wcckly. Among scEAT groups the diiTercnccs in survival wcrc smaller than in ipEAT groups (Fig. 2). Thc average timc of survival in control group was 63.3 days, ancl in ipNDY group 75.2 days ancl in scNDY group 65.9 days. Thc diffcrences are not signifi­canl. All the animals diecl spontaneously with tu­mour by l 03"1 day of the experiment. The ejfect of the site of NDV application on the number of metastases In ipEAT the greatest number of tumors was found in mesentery, pancreas and respiratory diaphragm, and smaller number in organs of small pelvic cav­ity, kidneys, suprarenal glands ancl !iver. Metastascs outside abclominal cavity werc found in the lungs, ancl the lymph nodes (inguinal, axillary). Thc lota! number of tumors and mctastases founcl by groups was: control 44, ipNDY 25 ancl scNDY 34. Ascitic fluicl was founcl in 60 % of animals in the control group and in 25 % and 45 % of animals in ipNDY and scNDY group rcspectively. The se tumor in the place of ip EAT injection was founcl in 70 % of animals in control group ancl in 45 % and 60 % of animals in ipNDY and scNDY group respectively. In scEAT groups most of the metastases were in the abdominal organs, while in lungs and lymph nodes they were rare. The Lota! numbcr of metastases per groups are: control 22, ipNDY 16 and scNDY 32. Discussion 1l1e in vivo tumor lherapeutic effect of live NDY has bcen found to depend on many factors of which the virus dosc, the virus strain, the regime of appli­cation, and the tumor mass seem most known. The authors have also found that the tumor inhibitory elTect was besl if the NDY was injected inlo the tumor.-1 The mcchanism of tumor inhibilion by NOV bas been studied quitc extcnsively. One of thc first ideas was that virus incorporates inlo the membranes of tumor cells in the process of buclding and in this way changes antigenicity of tumor cells.7 On the other band, therc is no objective evidence, except in tumor-aclapted NDY strain,8 that NDY multiplies in tumor cel!s. The most argued findings are NDV's elTects on the immune system generally through interferon induction,9 TNF induclion and the sen­sibilization of tumor cells to TNF.10 Some authors have found a selective cytotoxic effect of NDY on tumor cclls in vitro." Usually a few millions of cel!s are used in the cxperiments with ipEAT. We used only a few thou­sands of cells to prolong survival, to allow appear­ance of more metastases and to obtain a more sensi­ EJ/ecr <1( rhe l)'fle o(llf1J1lica1io11 o(Newcasrle disease virus 011 rile Ehrlich ascites 1w11or ble model for therapy testing. The regime or NOV applieation was that proposecl for the biological response moclifiers (BRM),11 because viruses are also lreated as BRMs. 12 Our finding is that ip NOV application has slron­ger tumor inhibitory effecls Lhan se applicalion. Because virus is a dillusible panicle, which is ab­sorbed afler application by mesothelial pores and enclothelial capillary cells inlo blood syslem, ancl the hlood supply area or peritoneum is mueh larger than subcutaneous arca, we can expect thal in ip application there is much higher concentration of virus in lhe blood. This is probably why the influ­ence on the involved mechanisms of tumor inhibi­tion is stronger. The length of survival of experimental groups in ipEAT was longer lhan in scEAT. This is most prob­ably a consequence of bigger tumor masses in lhe begining of the virus therapy in scEAT groups. Other authors have found the same eJTect of tumor rnass, using NOV' or TNF therapy. 1 J It is also the guide­line for the use or BRMs that they should not be used for advanced neoplastic discascs. 11 • According to our rcsults, NOV inhibits tumor metastatic rate which is also rcflcctcd in the re­duccd incidencc of ascitcs appearance. Bolh could be the consequence or Lhe reduccd tumor mass on Lhc peritoneal surfaccs, as a conscqucncc of NOV influence. It was found in vitro thal NOV aclivales periloneal macrophagcs which showed a strong cytostatic elTect againsl tumor cells.7• 15 It was also found lhal thc reduction of ascites appearance is an cffect of increased immunologic potency. 1'' In Lhc scEAT group we found increased melastalic rate afler scNOV. This is probably the resull of repeated peritumoral injcclions wherc we prickecl Lhe tumour cells and introduced lhem inlo the vessels. Aclmowledgement Our thanks are due to Prof. Z. Železnik for virus supply ancl Litration, Mrs M. Prebil and Mrs. T Klemenc for preparation or histologic slides. The work was supponed by The Minislry or Science and Technology or The Republic or Slovenia. References 1. Acha PN, Szyfres B. Zoonoscs and communicable dis­cascs common to man and animals. Washington: World Hcalth Organisation, Scicntific Publication No. 354, 1980. 2. Fenncr 10: Bachmann PA, Gibbs EPJ, Murphy FA, Studdc,t MJ, White IX). \leteri11ary viro!ogy. Academic Pn:ss, 1987 . 3. Csatary LK. Yiruscs in thc trcatmcnt of cancer. /,wt­cet 1971; 2: 825. 4. Casscl WA, Garrett RE. Newcastlc disease virus as an antineoplastic agent. Ca11cer 1965; 18: 863-8. 5. Wheclock EP, Dinglc JH. Obscrvations on the rcpeated administration of' viruscs to a paticnt with acutc leukae­mia. New E11g/ .! Med 1964; 271: 645-51. 6. Reichard KW, Lorenec RM, Cascino CJ, Peeples ME, Walter RJ, Fernand MB, Reves HM, Greager JA. New­castle disease virus selectively kills human tumor cells. .1 Swg Res 1992; 52: 448-53. 7. Schimnacher V, Ahle11 T, Heicappell R, Appclhans B, von Hocgen P. Successf'ul application of non-oncogenic viruses for antimetastatic cancer immunotherapy. Ca11­cer Rev 1986; 5: 19-49. 8. Flanagan AD, Love R, Tesar W. Propagation of New­castlc diseasc virus in Ehrlich ascites cells in vitro and in vivo !'me Soc Exp Bio/ Med 1955; 90: 82-6 . 9. von Hocgen P, Zawatzky R. Schirrmacher V !Vlodilica­tion of tumor cells by a low dose of Ncwcastle disease vin1s. Celi !111111wwl 1990; 126: 80-90. 10. Lorence RM, Rood PA, Kclly KW. Newcastlc diseasc virus as an antineoplastic agent: induction of tumor necrosis factor and augmenlation of its cytotoxicity . .1 Nat/ Cwu:er [11st 1988; 80: 1305-12. 1). Talmedge JE, Hcrbcnnan RB. Thc prcclinical screen­ing laboratory: evaluation of immunomodulatory and therapeutic propcrtics of biological responsc modifiers. Cancer Tre(lf Rep l9&i; 70: 171-82. 12. Oldham RK. Biological rcsponse modificrs. ./ Nat/ Ca11cer 111st 1983; 70: 789-95. 13. Serša G, Novakovic S, ŠtalcA. Tumor mass is a critical factor in pcritumoral treatment wilh tumor necrosis fac­tor. Period Bio/ 1992; 94: 35-40. 14. Tanncbcrger S, Pannuti F. Disillusionments and hopes in thc field of biological rcsponse modiliers. Anticancer Res 1993; 13: 185-92. 15. Heicappell R, Schirrmacher V, von Hocgcn, Ahlcrt T, Appclhans 13. Prevention of mc1astatic spread by post­operative immunotherapy with virally modificd auto­logous tumor celi. l. Paramcters for optimal therapeutic effeets. /111 .1 Ca11cer 1986; 37: 569-77. 16. Culo F, Allcgrctti N. Marušic M. Ascilic vcrsus solid growth of Ehrlich ascitcs tumor influenccd by immu­nological factors. Oncology 1978; 35: 15-2 l. Radio/ 011col 1996; 30: 120-33. Cathepsins and their endogenous inhibitors in clinical oncology Primož Strojan Institute qf' Oncology, Ljubljana, Slovenia The invasion and ,neleislasising 60 ++ vs. +/-n.r NS n.r n.r 1995 (39) Stromal cel!s 0.0001 0.0086 n.r n.r F/U -follow up; DFS -disease free survival; OS -overall survival: EL!SA -enzyme-linked immunossorbent assey; IRMA -immunoradiometric assay; WB Western blotting; EA -enzymatic activity: IHC -immunohistochemistry; MP -menopausal; N -axillary lymph node; ER -estrogene receptor; NS non-significant; n.r. -not repo11ed. *Cut off va!ues for ELISA, IRMA and WB are presented in pmol/mg proteins. Cathepsins all(/ their e11doge11ous i11hibitor,1· in clinica/ onco/ogy nationaL GIF-sur-Yvette, France).40 It quantifies the lota! enzyme concentration (52kDa, 48kDa and 34 kDa forms) present in cytosols of tissue samples. The latter is also used for the determination of steroid receptor concentrations; this altogether pro­vides a more detailed information on biological properties of tumors. Regarding the above men­tioned, cathepsin D already fulfils rnost of the crite­ria that should be considered in introducing a new prognostic rnarker for routine clinical use. How­ever, a number of questions and dilemmas are stil! open, among them also some which have been posed only recently, by studies just completecl: 1) an opti­mal cut-off value should be selected, which would reliably distinguish between patients with favour­able and those with poor prognosis; 2) to find out which forrn of enzyme is the most potent markcr for survival; 3) to establish which type of cells in the tumor is actually overexpressing the cnzyrne; and 4) to determine its prognostic relevance with respect to menopausal status, steroid receptor stallls and axillary lyrnph node involverncnL Sirnilarly, it should be investigated how turnors with high cathep­sin D concentrations respond to adjuvant therapies: the controvcrsial results reported in the literature, rei'erring to the subpopulation of patients with nega­tive axillary lymph nodes, rnay be due to dillerent irnplernentation of adjuvant therapies. Only well­controlled randomised clinical studies using an ac­curately derined and standardised methodology will be able to provide answers to the questions posed. Until then, the routine use of cathepsin D as a prognostic rnarker with decisive influence on the seleetion of type or aggressiveness of treatrnent in individual patients rernains unjustiried and contro­versial, despite the promising results obtained so far. Concentration and/or activity of cathepsin D was also measured in other types of cancer. However, its prognostic signilicance was generally not sllldied. A highcr concentration of cathepsin D (from 1.5 to 3-l'old) was established in laryngeal carcinoma tis­sue·1 1 as well as in other types or head and neck tu111ors·12- ., or their regional melastascs;12 as com­pared to the adjoining normal tissue or the same patients. None or these studies was able to conrirm a correlation between tumor concentrntions of the enzyme and the already established clinical and pathohistological prognostic factors. Mctaye et al. reported a 3-fold higher conccntration or cathepsin D measured in 14 samples or thyroid carcinoma tissue than in 7 samples of normal glandular tissue and in 6 samples of benign thyroid nodules. The leve! of cathepsin D in primary tumors coITelated with their size. A similar increase in the enzyme concentra­tion was observed in the tissue of toxic adenomas (8 samples) and in lhe tissue samples from 7 patients with Grave's disease:w Letlo et al. assessed lhe leve! of cathepsin D activity in 67 surgical samplcs of colorectal carcinoma and in matched paired sets of normal mucosa: the enzyme activity measured in tumor tissue were 1.3-fold higher that in normal mucosa of the same patients.45 The enzyme activity values found by Tumminello et al. in tumor tissue samples from 21 patients with eolorectal carcinoma were 1.6-times higher than the respective values meas­urecl in normal mucosa or the same patients. A higher activity was observecl in the tissue of Dukes' stage A turnors compared to Dukes' B and C, as well as in lllmors smaller than 5 cm. There were no clilforences in cathepsin D concentration between tumor tissue and paired normal 1m1eosa.4" Cytoplasmic expression of eathepsin D in the cells of gastric adenocarcinoma was studied immunohistoehemically in 62 patients by Theodoropoulos el al.. Increased expression corre­lated with early tumor stages (1 and II), well-and rnoderately di!Terentiated carcinomas, positivc status of estrogene reeeptors ancl a better survival of patients at 36 month:17 Increascd plasma concentrations of cathepsin D assayed in 20 patients with prirnary hepatocellular carcinoma as well as in 7 patiems with !iver rnetastases were reported by Brouillet et al„ The values were signilicantly higher than those established in a group of 56 healthy controls or in 48 breast cancer patients:18 In a group of 72 patients with primary ovarian carcinoma, Scambia and co-workers reported a worse 3-year progression-free survival for patients with high tumor concentrations of cathepsin D. In 12 patients with metastases in the omentum, the enzyme concentrations measured in the metastatic deposits were 2-fokl higher than those found in the primary tumors. Cathepsin D status retained an inclependent prognostic value ror progression when assessed in the mullivariate analysis.49 A correlation between cathepsin D concentration, the grade or tumor differentiation, and the depth or myometrial invasion was also ob­served in 26 patients with endometrial carcinoma: a signilicantly higher increase in enzyme leve! was as­sociated with a higher pathohistological grade and deeper invasion.50 Ca!l1epsi11 B Cathepsin B belongs to the class of cysteine or thiol proteinases. It has cysteine as essential cata­lytic group bound to its active site.50 Human gene 126 Strojan P for cathepsin B is localised on the chromosome 8. 52 As ali known proteinases, it is tirst synthesizcd as a high-molecular-weight inactive precursor wilh a molecular mass of 37 kDa, which changes inlo its enzymatically active mature form in the course of postlranslation processing. The molecular mass of the latter ranges between 23-28 kDa; it is found in the celi -depending on species and tissue of origin as a single-(28 kDa), double-(23 kDa and 5 kDa) or as both singlc and double chain forms.51 It is optimally active at a pH of about 6.0 and is poorly active or inactive within the range of neutral and alkaline pI-1 values, depending on the nature of the substrate51 and the stage of enzyme malurity.°' As cndopcptidase, it exerts an cffccl on numerous proteinic substrates also on the componenls of the extracellular matrix,5" and has the potential or acti­vating the precursors of some collagenases55 and urokinase-type plasminogen activator.5'' Thiol rea­gents and chelators are requircd for its activation, bul it can be activated also by pepsin.'' cathepsin D2) ·2" and metallo-protei11ases.2•s1 It bas been dem­onstrated that enzyme activation can also occur as a result of its autocathalytic activity.°' Cathepsin B is irreversibly inhibited by thiol blocking reagents, and reversibly by leupeptin and other peptide alde­hydes, o:2-macroglobulin and members of cystatin superfamily (i.e. stdins, cystatins and kininogcns). Thc homology of amino acid scqucnccs suggcsls its common cvolutionary origin wilh othcr cystcinc proteinasc class membcrs.51 Unlike in normal cclls, where cathepsin B mol­ecules are found prevailingly in lysosomes, in tumor cclls a great proportion of the cnzymc is found on lhc cytoplasmic membranes.59-(,2 As pro-cnzyme, it can also be released into the slightly alkalinc sur­roundings or the extraccllular spacc, and once acti­vated extracellularly, it may be stable in its activc rorm due to the presence or largc protein substrates such as cxtracellular matrix proteins.5) Corrclation between the enhanced aclivily, mRNA leve!. the rale or mernbranc-bound cathcpsin B and/or thc quantity 01· high-molccular-wcight cnzyme forms relcased into lhc surroundings on one side, and rnalignancy of different tumor lypes of epithelial as well as mescnchymal origin on thc other, has bcen proved in di!Terent i11 vitro and in vivo cxperimcntal models. It seems, howcver, that this correlation is of qualitative rather lhan quanlilalive nalllrc.'') Fur­thermore, the reduced inhibitory capacity of human sarcoma derived sterin A, an importanl intracellular inhibitor of cathepsin B from cyslalin supcrfamily, has bcen demonslratcd too, as a probable result of changes in its structure.''" This indicates that the activity of cathepsin B in malignant tumors is regu­lated at many diffcrent levels. Its altcrations could be attributcd to the modulation of synthesis, activa­tion, processing ancl intraeellular transport of en­zyme molecules ancl/or ehanges in the inhibition by endogcnous inhibitors.51 An increased concentration and/or activity of cat­hepsin B molecules was measurcd in various types of human malignant tumors: carcinomas of the breast,''5-''7 colon and/or rectum;5·'''-''9 stomach,70·71 livcr,72 lung,7!-75 uterinc cervix,7'' head and neck car­cinomas,-n gliomas, 77 and lllmors of the hypophy­sis.7' Therc has been a corrclation establishecl be­l ween the measurecl ll!mor concentration and/or activity of cathepsin B, ancl indiviclual clinical and pathohistological tumor properties; in some tumors, a correlation with treatmenl outcome ancl/or sur­vival was round as well. It should be pointed out that the results or these studies are much less estab­lished and conclusive than those refcrring to cathep­sin D and the survival of breast cancer patients. Lah et al. have reported 18.5-times higher cathep­sin B activity measured in the breast cancer tissue of 50 palients as compared to thc relcvant values measurcd in normal breast tissue or the same pa­tients. Thcre has been no correlation established with pathohistological grade, axillary lymph node involvement, hormone receptor status, and relapse free survival."7 Similar results of cathepsin B activ­ity measurements in 90 matched pairs of breast carcinoma and normal breast tissue samples were reported by Gabrijelcic et al .. Besides the enzyme activity, authors also measured lota! enzyme con­centration in the serum and tissue cytosol: the laller was founcl to be approximately 3.3-fold the concen­tration measured in the serum of healthy controls, while the relcvant cytosol concentrations wcre 8.8­fokl higher, respcctively. Higher enzyme concentra­tions were found in the tumor tissue cytosols from patients withoul axillary lymph node involvemenl and a higher pathohistological grade. In this study, patienls' survival was not considered among the parameters observed.''5 A similar negative correla­lion between cathepsin B concentration in tumor cytosols or 62 breast carcinoma patients and their lymph node status, as well as lhe status of hormone receplors, was reporled by Budihna et al .. Bcsicles, patients with cathepsin B tumor concentrations up to 23 mg/g protcins were found to have worse re­ Ca!iJq,sins and !iJeir e/1//ogenous inl,ihi!ors in clinica/ onco/ogy currence-free survival at 54 months than those with higher tumor concentrations. In the multivariate analysis, besides axillary lymph node status, only cathepsin B proved to be an independent prognostic factor.79 On the contrary, Thomssen el al. reported a better 5-year recurrence-free survival in patients with lower cathepsin B concentrations ( < 1092 ng/mg proteins). In this study of 167 breast cancer patients tumor concentrations or cathepsin B were 11.3-l"old higher than those measured in benign breast tissue, and no correlation to established prognostic l"actors were l"ound. The relevance or cathepsin B as inde­pendent prognostic factor !"or recurrence-free or ovc­rali survival or those patients was not conlirmed by the multivariate analysis.'0 Analysing cathepsin B activity in paired tissue samples from 27 patients with colorectal carcinoma, Sheahan et al. registered 1.4-l"old higher activity in tumor tissue as compared to the adjoining normal mucosa. The highest enzyme activity was estab­lished in a group with Dukes A stage of the dis­ease.''' Similar rindings were reported by Leto el a/.: cathepsin B activity mcasured in carcinomatous tissue rrom 67 patients was 1.4-fold higher than that !"ound in normal mucosa, the increase being evident in patients with Dukes A stage of disease only. There was no correlation with either clinical or pathohistological prognostic ractors established:15 Contrary to that, Campo cl al. round that the el­evated cathepsin B expression correlatcd with ad­vanced stages or diseasc. The expression or enzyme was l"ound to be negative in ali 15 samplcs or nor­n1al mucosa and 17 samples of benign adcnomas. However, in a group or 28 patients with carly, non­metastatic tumors (stages 1-11), the cxpression was negative in 6, low in 17 and high in 5 patients. In 41 patients with advanced, metastatic carcinomas (sta­ges III-IV), the expression was negative in 3, low in 17 and high in 21 patients. Lower overall survival at 84 months or follow up correlated with high cathep­sin B expression in ali cancer patients, whereas arter s trati !kation by stages. the correlation was established only ror those with advanced disease.'''1 Arter having compared 33 match pairs of gastric carcinoma and the adjoining normal mucosa, Wata­ nabe el al. measured 3-fold higher cathepsin B ac­ tivity in tumor tissue samples. The enzyme activity was signilicantly, i.e. 1.9-fold higher in poorly dit'­ l"crcntiated adenocarcinomas than in well ur moder­ mely dilTerentiated tubular adenocarcinornas.70 Pie­ bani cl al. reported the results or their cathepsin B 111easurements in paired tissue samples or 25 pa­tients with gastric cancer. The concentrations found in tumor tissue were twice as high as thosc meas­ured in normal mucosa. Higher enzyme concentra­tions were also founcl in the tissue of patients with regional or hepatic metastases vs. those without mctastases, in poorly or moderately diffcrentiated vs. well difTerentiated tumors, and in cliffuse vs. intestinal tumor types. At 27 months, the survival of patients with cathepsin B lllmor concentrations be­low the cut-off value of 265 ng/mg proteins was bcller than of those with higher enzyme concentra­tions.71 Ebcn el al. have established a 4.5-fold higher cathepsin 13 activity in 65 lung tumor tissue sam­ples as cornpared to the normal Jung parenchyma. The activity was found to be insignilicantly higher in adenocarcinomas than in other histological tumor types. The highest cathepsin B activity levels were measurecl in Jung metastases. There was no correla­tion with stage or disease or pathohistological grade established. Elevatecl activity above the eut-off value or 1674 JlU/mg proteins was related to lower sur­vival rates or the patients at 8 months. 7; Higher cathepsin B activity found in the tissue or lung adenoearcinomas as compared to squamous celi car­cinomas was reported by Krepela el al.71 and by Uithgens et al. who compared adenocarcinoma ca­thepsin B activity to thc activity measured in squa­mous celi and small celi carcinomas.7In the group -1 or 142 patients with primary lung adenocarcinoma, lnoue el al. registered imrnunohistochemically in­creascd cathepsin B expression in thc tumor tissue or cases with stage III and IV or disease as com­pared to that in cases with stage l, which also corre­lated with worse overall 5-year survival ratcs. In a multivariate analysis, cathepsin B exprcssion proved to be an independent prognostic factor associated with death due to disease.81 After having compared 53 matched pairs or head and neck carcinoma and adjacent normal tissue, Kos el al. t'ound 5.4-f"old higher cathepsin 13 con­ centration in tumor tissue samples. There was no corrclation with clinical and pathohistological prog­ nostic factors established, whereas patients' sur­ vival was not included among thc parameters ob­ served:13 In a study by Hi rano cl al., serum cathepsin B levels and its urinary cxcretion were reported to be significantly higher in a group ur 7 patients with distant metastases from a variety or canccrs than in the control non-cancer patients ( 11 samples) or in cancer patients without distant metastases (7 sam­ 128 Strojan P ples). Six weeks after completec.l rac.lica! curative operation the enzyme concentration in the group without distanl metastases c.lecreasec.l to lhe control values. However, in the group of cancer patients with distant metastases after resection of primary tumor, bolh serum and urine enzyme concentrations were stili high as before surgery. In the group without distant metastases, for ali or the resected specimens of cancer tissue. cathepsin B concenlra­tions were significantly, 1.8-times higher than those in normal tissue. x 2 Endogenous cathepsin inhibitors Endogenous, i.e. physiological inhibitors of pro­teinases naturally presenl in tissues, appear always to be proteins. They are involved in the control mechanisms responsible for intra-and extracellular protein breakc.lown, thus protecting the celi against adverse endo-and exogenous proteolysis. The com­pilation of new knowledge and information on these substances contribules to better understanding of their role and importance in lhe process of tumor rise and its consecutive spreac.l. By preserving the delicale balance that exisl between tumor cells, extracellular-matrix-bound growlh factors anc.1 cyto­kines, and constituents or the matrix, these inhibi­tors may exerl a marked cytotoxic elTect on the primary tumor as well as on the existing metastatic lesions. This ability assigns them the role of poten­tial therapeuticals and/or prognostic indicators in ali conditions where proteolytic degrac.lation repre­sents the pathophysiological basis for clinical mani­fcstation of disease, thus also in cancer.x, It seems, however, that it will take long before these sub­stances become a parl or lhe routine therapeulic tools for cancer treatment, considering that ali the studies are stili carried out at a preclinical, i.e. laboratory leve!. The same applies to their prognos­tic value, since unlil now no reports on this issue could be found in the available literature. Probably, in view 01· l'uture clinical use. the most promising of endogenous inhibitors are those which suppress the activity of calhepsins B and D. Con­sidering thal an endogenous inhibitor of cathepsin D in man is not known yel. these are for the tirne being -restricted only to lhe inhibitors of cysteine proteinases. Based upon the evolutionary and struc­lllral similarities. they constilute a single protein superfamily of cyslatins. This is subdivided into three families: steltns (family 1), cystatins (family II) and kininogens (family III). There is yet a group of non-inhibitory proteins (family IV) including hi­stidine-rich glycoproteins and a2H-glycoproteins (Table 4). The members of the first three families, Table 4. Cysteine proteinase inhibitors of cystatin super­family in human. Farnily Examples Oistribution M Name No. Stelins 1 stclinA intracdlular 11.000 stcfin B Cystatins II cystatin C cxtraccllular 13.000 Kininogcns lll HMW-kininogen extracellular 120.000 LMkini68.000 _______ _ _W_-__ _ _nog_en HMW -high molecular weight; LMW -low molccular weight. capable of inhibitory activity, diffcr from one an­other with regard to their binding affinity and bind­ing ratio for different cathcpsin molccules; in ali of them binc.ling is strong though competitive and reversible. Contrary to kininogcns and cystatins, which occur at relatively high concentrations in various biological fluids, stefins can be found prc­vailingly inside the cells. The presence of the mol­ccules of cystatin superfamily inside as well as outside the cells renders them to scrve as a "rcscr­voir" for cysteine endopeptidascs: thcy bind the enzymes when released from lysosomes in order to transport and dcposit thcm at other sites in the celi or organisn1_x.-x,::··· r- irradialion /ime/ . 150 -S 100 3 50 +----­ . o ai -50 Jg -100 -150 -200 -1 o 2 5 Electrode separation (mm) Figure 2. Thc rcsponsc or thc ionization gradient cha1nbcr as a runction or elcctrodc scparation. Thc chambillg-pmver values 011 the W value rec11111111ellded by ICRU.fi>r e/ectmlls ill drv ai,: Bureau lnternational dcs Poids cl !Vlcsurcs. Rcporl. CCEMRl(l)/85-8, 1985. 9.oKlevcnhagcn SC. Detcrmination of absorbcd dose in high cncrgy electron and plmton radiation by means of an uncalibratcd ionization chambcr. Phys Med Bio/ 1991;o36: 239-53.o 1 O. Allix FH. Dctcnnination of A;,,,, and P;.,., in the ncw AAPM radiothcrapy dosimetry protocol. Med Phy.1· 1984; 11: 714-6. 11. Weinhous MS, Meli JA. Dctennining P,.,.., the correc­tion foclor for recombination losses in an ionizalionochamber. Med Phys 1984; 11: 846-9.o Radio! Oncol 1996; 30: 142. Book review Epithelial hyperplastic lesions of the larynx Vinko Kambic and Nina Gale Elsevier Science B.V., Amsterdam, 1995. Pages: 265; Illustrations, Tables, Hard cover. ISBN 0-444-82273-9. Price: 300 DEM Tbis book is tbe result of at least 3 decades' con­tinuous clinical work and researcb at one institution and can be said to present tbe lile experience of an cminent otolaryngologist. lts stated aim -to ad­vance our understanding of laryngeal byperplastic lesions -bas been admirably served in severa[ ways. Tbe autbor's own classification of tbese lesions, introduced in 1971, is similar to the current one of the WHO bul clearer in some points with more logical terminology. The introduction of newer tech­niqucs, sucb as histochcmistry, imunohislochcmi­slry, morpbomelry, clectron microscopy, flow cylo­metry, molecular patbology, etc. bas madc possible a far more exact classification of tbese lesions. This way, precancerosis can be and is clearly delined as atypical bypcrplasia, and is also clearly separated from cancer in situ, wbile, on the olher band, sirn­ple byperplasia and abnormal hyperplasia are clearly defined as benign lesions. Own studies of "normal" distribution of ciliary and stratified squamous epithelium of thc larynx is presented, sbowing no common pattern and marked variation. Own studics on dislribulion of cytokera­lins within laryngeal cpithelium and on smoking­and alcohol-connectecl hyperplasia are presented, as is tbe author's original finding of laryngeal as­bestosis. Strict lerminology is advocated througboul, ren­clcring obsolete such favored terms as "hypcrkera­losis" and "epidermization" and casling doubt on the term "dysplasia". Based on tbis clear classification, the whole ga­mut of laryngeal epitbelial byperplastic lesion is prcsented as clinical entities, corroborated with at leasl 15 years' own expcriencc in each case and this is what, makes this book such a gcm: inlcrlwining thc deepened underslanding of patbology witb clini­cal work in a continuous process tbrougb decades and tben presenting tbe results in a comprebensive, orderly, elegant fasbion. Tbis clearly would not be possible without closely involving an accomplisbed patbologist from tbe very beginning. Tbis book may be taken as an cxample of bow rewarding can be the results of such co-opcration. Thc illustrations are numerous ancl high qualily lhroughoul, lhe bibliography comprehensive. One is really bard put to find an inadequacy in this work, which ought to become a classic in its fielcl. Perbaps, a diagnostic and treatment algorithm, to be used in difficult cases, woulcl be helpful? Maijan Jereb, M.O., Ph.D., Institute for Respiratory Ois­eases, Golnik, Slovenia Prof. Berta Jereb, M.O., Ph.O., lnstitute of Oncology, Ljubljana, Slovenia Radio/ Oncol 1996; 30: 143. RSNA news Radiology grant recipients continue careers in research, academic medicine Chicago -The Research and Education (R&E) Fund of the Radiological Society of North Ameriea is proceeding well loward its goal of attraeting young researchers to careers in radiological research and academic medicine and helping to fill the gap left by cutbacks in government and other unre­stricted funding, according to a survey of grant recipients. A survey of the 147 researchers awarded grants o ver the past l O years through the R&E Fund re­ports that more than 80 percent of respondents holcl a faculty appointment in a meclical school and more than 70 percent have continued in research, apply­ing for additional runding. The R&E Fund was established by the RSNA Board of Directors in November l 984. The first grants were given in 1986. The R&E recipients survey was 11elded by the Society in the summer of l 995 to evaluate whether the R&E Fund was meet­ing its goals and to determine the extent to which past R&E Fund recipients have applied for and received funding to conduct additional research in radiology. The findings are based on a response rale of 89 percent, or 131 of 147 past RSNA grant recipients. Highlights include: • More than 80 percent of survey respondents ( 108 of 131) currently holcl a faculty appointment in a medica! school. • 71 percent (93 of 131 respondents) of past RSNA grant recipients have continued their careers as re­searchers and applied for additional funding. The number of applications submitted per applicant ranged rrom 5.1 to 2.6. • Of past RSNA grant recipients applying for funding for additional research, 773 percent (68 of [Editor's Note: lndividuals interested in donating to or ob­taining information about thc R&E Fund can contact Jennilcr Boylan at the RSNA. 708/571-7868.] 93) were successful in obtaining funding. The per­centage was higher among individuals who had re­ceived RSNA grants before l 994; 78 percent suc­cessfully obtained additional funds. • The 68 reeipients who obtained funding for additional research since their RSNA grant gener­ated 190 research projects and were the principal investigalor in nearly 3 out of every 4 (74 percent) funded projects. • RSNA grant recipients requested a total of $ 151.4 million for additional research over thc 10­year period. More than 34 percent, or $ 52 million, of the requested amount was awardcd. • Between 48 and 84 percent of each category of RSNA grant recipients applied for funding for addi­tional research: nearly 84 percent of scholars; 77 percent of seed grant recipients: 62 percent of fel­lows; and 48 percent of residents. The RSNA Research and Education Fund was established with an initial gift of $ 1 million from the RSNA The RSNA makcs a donation equal to the administrative expenses of the fund each year so that every dollar donated supports programs. To­day, there are ninc grant programs: Scholars Pro­gram; Fellows Program, Rescarch Residcnl Program; Seed Grants; Medica! Student/Scholar Assistant Award; Medica! Student Award; Roentgen Centen­nial Fellow; Roentgen Resident/Fellow Research Award; and Outstanding Researcher Award. The RSNA is an association of 30.000 racliolo­gists and physicists in medicine dedicated to cduca­tion in the sciencc of radiology. Thc Socicty's head­quarters are located at 2021 Spring Rd., Suite 600, Oak Brook, Illinois 60521. Radio/ Oncol 1996; 30: 144-7. Notices Notices submittedfor publication should contain a mailing address, phone andlorfax number of a contact person or department. Radiotherapy SefJlember 1-5, 1996. The ESTRO teaching coursc "Ra'ueto(lnt: zdrcwstvene w:.anizaclje za h(i,fouje bolec"in pri bolnikih z rnk,wim obolenjem 1m11wcfol odJ>rt1t1{iC1 srednje hudo bolec'ino ali bole<'ino drniw stopnje. Kontraindikacije: Zdravila ne smemo dajati otrokom, mlajšim od l leta. Tramadola ne smerno uporabljati pri akutni zastrupitvi z alkoholom, uspavali, analgetiki in drugimi zdravili, ki delujejo na osrednje živcevje. Med nosecnostjo predpišemo tramadol le pri nujni indikaciji. Pri zdravljenju med dojenjem moramo upoštevati, da O, l % zdravila prehaja v materino mleko. Pri bolnikih z zvecano obcutljivostjo za opiate moramo tramadol uporabljati zelo previdno. Bolnike s krci centralnega izvora moramo med zdravljenjem skrbno nadzorovati. Interakcije: Tramadola ne smemo uporabljati skupaj z inhibitorji MAO. Pri socasni uporabi zdravil, ki delujejo na osrednje živcevje, je možno sinergisticno delovanje v obliki povec':ane sedacije, pa tudi ugodnejšega analgcticncga delovanja. Opozorila: Pri predoziranju lahko pride do depresije dihanja. Previdnost je potrebna pri bolnikih, ki so preobcutljivi za opiate, pri starejših osebah, pri miksedemu in hipotiroidizmu. Pri okvari jeter in ledvic je potrebno odmerek zmanjšati. Bolniki med zdravljenjem ne smejo upravljati strojev in motornih vozil. Doziranje in nacin uporabe: Odrasli i11 otroci, starejli od 14 let: Injekcije: 50 do 100 mg i.v.,i.m.,s.c.; intravensko injiciramo pocasi ali infundiramo razredceno v infuzijski raztopini. Kapsule: 1 kapsula z malo tekocine. Kapljice: 20 kapljic z malo tekocine ali na kocki sladkorja; ce ni zadovoljivega ucink.1, dozo ponovimo cez 30 do 60 minut. Svecke: l svecka; ce ni ucinka, dozo ponovimo po 3 do 5 urah. Otroci od 1 do 14 let: l do 2 mg na kg telesne mase. Dnevna doza pri vseh oblikah ne bi smela biti vi.šja od /iOO mg. Stranski ucinki: Znojenje, vnoglavica, slabost, bruhanje, suha usta in u1rujenost. Redko lahko pride do palpitacij, ortostatske hipotenzije ali kardiovaskularnega kolapsa. Izjemoma se lahko pojavijo kcmvulzijc. Oprema: 5 ampul po l ml ( 50 mg/mil, 5 ampul po 2 ml (100 mg/2 ml), 1 O ml raztopine (100 mg/ml), 20 kapsul po 50 mg, 5 sveck po 100 mg. Podrobnej.fo iJ1formacue so l!CI uo(jo pri jJroiZlJC?jalc11. ... KRK. SLOVENIJA KE F R IJ Lekarne1 bolnišnice1 zdravstveni domovi in veterinarske ustanove vecino svojih nakupov opravijo pri nas. Uspeh našega poslovanja temelji na kakovostni ponudbiki pokriva vsa 1 podrocja humane medicine in veterinepa 1 tudi na hitrem in natancnem odzivu na zahteve naših kupcev. KEMOFARMACIJA -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 SIEMENS 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 O.O.O. Dunajska 47, Ljubljana Novi antibioticni citostatik III III ® 1ra 1 pirarubicin • ucinkovit pri zdravljenju karcinoma na dojkah • pomembno manjša pogostost alopecije • za kakovostnejše življenje bolnic Sestava: 1 steklenicka vsebuje 10 mg ali 20 mg pirarubicinovega hidroklorida v obliki liolilizirane snovi. Oprema: 1 O steklenick po 10 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 Radio/ Oncol 1996: 30: 160. 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In vitro maturation of monocytes in squamous carcinoma of the lung. Br .1 Cancer 1981, 43: 486-95. 2. Chapman S. Nakielny R. A guide w radiologirnl pmcedurc.1·. London: Baillierc Tindall, 1986. 3. Evans R. Alexander P. Mechanisms of cxtracellu­lar killing of nuclcated mammalian cells by macro­phages. In: Nelson DS ed. Im111u11obiology of 111acro­phage New York: Acadcrnic Prcss. 1976: 45-74. For repri111 infimnatio11 in North America Contac/: Intematirmal reprint Corporcttion 968 Admiral Ca/lag­lwn Lane, # 268 /> O. Box 12004, Va/lejo; CA 94590, Tei: (707) 553 9230, Fax: (7()7) 552 9524. Navoban® Ttie· 5-HT3 antagonist deve.loped with the patient in mind. Navoban.tropiset,on) Always once a day. Always 5 mg. . SANDO.Z Sandoz Pharma Ltd, Pharma Basle Operations, Marketing & Sales, CH 4002 Basle/Switzerland