RADIOLOGY AND ONCOLOGY 
Radiology and Oncology is a journal devoted to publication of original contributions in diagnostic and interventional radiology, computerized tomography, ultrasound, magnetic resonance, nuclear medicine, radiotherapy, clinical and experimental oncology, radiobiology, radiophysics and radiation 
protection.  
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Ljubljana, Slovenia  
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Ljubljana, Slovenia  
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Ljubljana, Slovenia  
Editorial board  Tullio Giraldi  Branko Palcic  
Udine, Italy  Vancouver, Canada  
Marija Auersperg  Andrija Hebrang  Jurica Papa  
Ljubljana, Slovenia  Zagreb, Croatia  Zagreb, Croatia  
Haris Boko Zagreb, Croatia  Durila Horvat Zagreb, Croatia  Dušan Pavcnik Ljubljana, Slovenia  
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INTERVENTlONAL RADIOLOGY A>ID COMPUTERIZED TOMOGRAPHY 
Emloscopic retrngrade pancreatography in t!Jc diagnosis of dironic pancrcatitis Riihinic M 
Adin.: hlcediug <lue to p:rnt:rcaHtis diagnowrl hy contrast enlrnneed CT Pwi,,is J; Rci{ S 
NUCLEAR MEDICU\E 
273 277 
Radiopro!cdio11 of saliv,iry glancls hy amifostinc in high-dose nidioiodinc therapy investigated in a new rabhit animal model Hiihner R-H, Bolwsluvizki KH Brenner \F. Klutmmrn S, Fe_Hrabend B . .!. S, Me.1·/l'i" 1. r/m1sm tv1, !Irn.e F 279 
Diagnostic valuc of plauar myocardial perfusiou scintigraphy in paticnts with coronary a1·lcry disease K!.1111:it M. :'.!il/1n1U .',/. Zon11,.u !) 

EXPERTIMENTAL Ol\COLOGY 
Interstitial fluid pressurc as an ohstacle in treatment ot' solid tumors l'ufrnjnk / Mik/11\'('.'ii' f) 291 
The urnkinase-type plasminogen activator. its inhibitors and its receptor ­the new prognostic factnrs in solid cancers /11,1 i!nnr S. T, Nudo/f'/ 298 
305 


Diagrwsis and tn:atmeni of radiation damage -the acute radiation syndrome 
X/1,I11w1111 .\ JJo!tus/iiv, :/;/ Kil. !Jn:1111r:r \\'. Jfrm:c !: 
RADIOPHYSICS 
Comparison of TDF and LQ models using the bioeffects algorithm of a treatment planning system 
Ho AK, Sibata CH, Thomadsen BR 
BOOKREVIEW 
Atlas of applied internat !iver anatomy. Gadžijev EM, Ravnik D Snoj M 319 
IN MEMORIAM: t prof. dr. Ludvik Tabor 
Jevtic v 320 REPORT 
European Association of Radiology; Junior radiologists exchange programme 1998  
Blery M, Ramalho VM  322  
SLOVENIAN ABSTRACTS  323  

NOTICES 327 
Radio/ Oncol 1997; 31: 273-6. 


Endoscopic retrograde pancreatography in the diagnosis of chronic pancreatitis 
Milivoj Rubinic 
Division of Gastroenterology, Department of Interna! Medicine, University Ho~7Jital Rijeka, Croatia 
The importance of endoscopic cholangiopancreatography (ERCP) in the diagnosis of chronic pancreatitis is the basic topic of the paper. The method is considerably more sensitive than any other radiological, especially noninvasive method used in diagnostics. Especially thanks to this combined endoscopis radiologi­cal method, chronic pancreatitis is at presen/ classified in three groups. Thus, it is possible to make exact plans for the further treatment, which may be either medica[ ( endoscopical), or surgical. An analysis is here made of 370 patients with whom chronic pancreatitis was established by this method. OJ this number 286 (77 %) were men, and 84 (23 %) women. Most of the patients were between40 and 50 years of age, their number being 204 (55 %). Here they appear classified into three groups according to the mentioned classification method. The group of mild chronic pancreatitis includes 154 (42 %) patients, 123 (33 %) patients show moderate changes, mul 93 (25 %) patients /zave markecl changes. It is important to point out that 211 (74 %) oj 286 patients in their case history mentioned the consumption of alcohol and nicotine for more than five years. 
Key words: pancreatitis-diagnosis, cholangiopancreatography, endoscopic retrograde; chronic disease 
Introduction 

Endoscopic retrograde Cholangiopancreatography (ERCP), a combined radiological method, was in­troduced into clinical practice 25 years ago and became a routine procedure in thc diagnostics of biliopancreatic system complaints. 14 It has since taken a special place in the diagnostics of chronic pancreatitis, whcre it is much more sensitive than any other noninvasive radiological method such as ultrasound and computerized tomography.5·8 
Except in thc appraisal of the severity of chronic pancreatitis on the basis of changes in its dueta! system, it also serves to the planning of any further treatment, which may bc either medica! (endoscop-
Correspondence to: Prof. dr. Milivoj Rubinic, Interna! Clinic-Gastroenterology, Krešimirova 42, 51000 Rijeka, Croatia. 
ical), or surgical.9•10 The aim of the paper is to illustrate: thc valuc of ERCP in the diagnostics of chronic pancreatitis and to make an analysis of the rcsults obtained. 

Material and methods 

An analysis of 370 successful ERCPs in which chronic pancrcatitis had been established was made. The indication was made on the basis of the pa­tients' case history, clinical picture, lab reports, and the pancreas ultrasound examination of ali patients was carried out as well. ERCP was made a tech­nique as it was described and adopted by a great number of authors. In this case the special attention was given to the pre-ERCP control to detect pre­filling changcs of parenchima, such as calcification 
UDC: 616.37-002.1-072.l before the central film examination.2•5• 7· 11 
274 RubinicM 
Figure 1. Mild changes chronic pancreatitis. Normal ductus pancrcaticus (P) and > 3 changes laterni duet (arrow). 
l<igure 2. Moderate changcs chronic pancrcatitis. Dilalation of ductus pancrcaticus (P) and 3 changes laterni duet (arrow). 
Ali ERCP findings have been classified by using the international system of 1984 (Table which is ilustrated at Figures 1, 2, 3. 
Results 
Of 370 successfully matic ERCPs, where chronic pancreatitis had been found, 286 were men, and 84 (23 % ) women. The average agc of ali pa­tients analysed was under 40, 93 (25 % ); between 40 and 50 were 204 (55 %) patients, and 73 (20 %) patients were above 50. By using the abovc men­tioned classification the group of mild changes com­prised 154 (42 %) patients, the group of moderate changes 123 (33 %) patients, and the most severely affected group of marked changes 93 (25 % ) pa­tients. In this last group it is of intercst to mention that it comprised 8 I (87 % ) men, and only 12 
% ) women, ali of them alcohol and nicotine con­sumers for five years of more. And of ali lhe 286 
'Figure 3. Marked chungcs chronic pancrcatitis. Thc same 
as Figure 2 with extrcmly dilatation of ductus pancreaticus 
(Pand arrow). 
men analysed, the case history of 211 (74 %) in­cluded a record of the consumption of these harm­ful agents. 
Discussion 
Chronic pancreatitis in its mild form presents a difficult diagnostic problem.x, 11· 14 In its severe form, with or without complications, the diffilculty is increased by a very serious therapeutic But it is exaclly through lhe ERCP that today we have also numerous nonsurgical possibilities in the treatment of this disease at our disposal. 14•rn Anoth­cr important fact to be pointed out is, thanks to this method, that the classification of chronic pancreati­tis has been effected into three forms, which in turn is important for the treatment of this disease. 11 • 12 
To make the cndoscopic trcatment of this disease easier, there exist today also other classifications at our disposal, al!hough they are rarely used. 16 This papcr deals with the analysis of 370 ERCPs in 

Endoscopic retrograde pancreatography in the diagnosis r>["chronic pancreatitis 
Table l. Classification of chronic pancrcatitis. 12 
Terminology  Main pancrcatic  Number  
duet  of dameged  
branches  
of pancreatic  
duet  

Normal finding  unchanged  none  
Border pathological  
finding  unchanged  <3  
Mild changes  unchanged  3 or > 3  
Moderate changes  pathologicaly  
changed  >3  
Marked changes  pathologicaly  
chang_ed*  >3  

* With one, or more than one critcria: big cyst, obslruction, marked dilatation or marked changcs of organ shape. 
wbicb cbronic pancreatitis bas been establisbed. It is evident tbat in 77 % of tbe cases men are pre­dominant, wbicb is tbe result of tbe more frequent use of noxious agents sucb as alcobol and nicotine. It bas been furtber noticed tbat tbe disease occurs at tbe most reproduciblc stage, and tbat is bctwecn 40 and 50 years of age. Similar dala bave been estab­lisbed also by otber autbors. 19 
Tbe internationally acccpted classification bas becn used also in tbis paper, in wbicb 42 % cases of mild, 33 % cases of medium, and 25 % cases of severe cbronic pancreatitis bavc been found. It is not possiblc to compare tbese <lata witb tbe perti­nent literature, as tbe severity of tbe disease is dependent upon tbe duration of tbe period of tirne during wbicb tbe noxious agents bave been con­sumed, tbe type of alcobol and nicotine, and a number of otber external and interna! factors. 20-22 It is sometimes difficult to make or solve tbe differ­ential diagnosis of pancreas carcinoma regardless tbe series of metbods used, noninvasive radiologi­cal or invasive endoscopic ones.23•25 And to con­clude witb, it is exactly tbanks to tbe ERCP com­bined endoscopic radiological metbod tbat cbronic inflamatory pancreas diseases can be establisbed at an early stage, to differentiate tbis metbod from otber radiological non-invasive examinations. In se­vere cascs of tbe disease, besides for making a strictly correct diagnosis, the metbod offers also at present wide tberapeutic possibilities. 

References 

1. Me Cunne WS, Shorb PE, Moscovitz H. Endoscopic canulation of ampula of Vatcr. A preleminary repott. Ann Surg 1968; 167: 752-6. 
2. 
Soehendra N. Technik, Schwerigkeiten und Ergebnisse dcr endoscopischrelrograden Cholangio-Pankreato­graphie (ERCP). Chirurg 1977; 48: 98-104. 

3. 
Rubinic M, Švalba B. Endoskopska retrogradna holan­giopankreatografija (ERHP). Radio/ lugosl 1984; 18: 95-8. 

4. 
Shimizu S, Tada M, Kawai K. Diagnostic ERCP. En­doscopy 1994; 26: 88-92. 

5. 
Malaferheimer P, Buhler M. Corelation of imaging and function in chronic Pancreatitis. Radio! Ciin North Am 1989; 27: 51-7. 

6. 
Hesse! SJ, Sigelman SS, Neil BJ, Sander R. A prospec­tive evaluation of computcd tomography and ultra­sound of the pancreas. Radiology 1986; 143: 129-33. 

7. 
Rosch T, Classen M. Role ofERCP in Chronic Pancrc­atitis. In: Beger HD, ed. Chronic Pancreatitis. Springer Verlag, 1990; 319-29. 


8. 
Rosch W. Vertung bildgebender Ve1:fi1hren bei der chronischen Pankreatitis. Pcrimed Fachbuch mbh Er­langcn, 1989. 

9. 
Mulferheimer P, Buchler M. Indications for Endoscop­ic or Surgical Therapy in Chronic Pancreatitis. Endo­scopy 1991; 23: 185-90. 


10. 
Genen JE, Rolny P. Endoscopic therapy of acute and chronic pancreatitis. Gastrointest EllClosc 1991; 37: 377-82. 

11. 
Nagata A, Honna T, Tomai K. A study of chronic pancreatilis by serial endoscopis pancreatography. Gas­troell/ero!ogy 1981; 81: 884-91. 

12. 
Axon A TR, Classen M, Cotton PB, Cremar M, Freeny PC, Lees WE. Pancreatography in chronic pancreatitis international definitions. Gut 1984; 25: 1007-12. 

13. 
Niedrcan C, Grendcll JH. Diagnosis of chronic pancre­atitis. Gastroenterology 1985; 88: 1073-81. 

14. 
Grabner W, Koch H. ERP bei chronischer Pankrcatitis. In: Grabner W, Mann HPK, eds. Klinik der chronischen Pankreatitis. Perimed Fachbuch mbh Erlangen, 1989. 

15. 
Oelckers M, Wurbs D. Einsatz der ERCP bei Pan­kreaserkrankungen. Z Gastroenterol 1992; 30: 379-84. 

16. 
Cremer M, Deviere M, Delhaye M, Boize N. Stcnting in Severe Chronic Pancreatitis: Rcsults of Medium­Term Follow-up in Seventy-Six Patients. Endoscopy 1991; 23: 171-6. 

17. 
Binmoeller KF, Jue P, Seifert H, Izbicki J, Soehendra 


N. Endoscopic Pancreatic Stent Drainage in Chronic Pancreatitis and a Dominant Structure: Long-Term Re­sults. Endoscopy 1995; 27: 638-44. 

18. 
Sahel J. Endoscopic Retrograde Pancreatography Find­ings and Their Grading in Chronic Pancreatitis. In: Malfertheimer P, Ditschuneit H, eds. Diagnostic proce­dure.1· in pancreatic disease. Springer Verlag, 1988; 96-107. 

19. 
Lowenfels AB, Maisonneuve P, Cavallini G. Prognosis of Chronic Pancreatitis: An International Multicenter Study. Am .1 Gastroellterol 1994; 89: 1467-71. 


276 RubinicM 
20. 
Sarles H. Chronic pancreatitis etiology and pathophys­iology. In: Gole LW, ed. The exocrine pancreas biolo­gy pathobiology and diseases. Raven Press-New York, 1986: 527-46. 

21. 
Miyake H, Hared H, Kinischicka K. Clinical course and prognosis of chronic pancreatitis. Pancreas 1987; 2: 378-85. 

22. 
Folsch UR. Chronische Pankreatitis. Therapiawoche 1990; 40: 634-8. 


23. 
Lowentfels AB, Maisonneuve P, Cavallini G. Pancre­atitis and the pancreatic cancer. N Eng J Med 1993; 328: 1443-7. 

24. 
Bedford RA, Howerton DH, Geenen JE. The Current Role ofERCP in the Management ofBening Pancreat­ic Disease. Endoscopy 1994; 26: 113-9. 

25. 
Lankisch PG, Staritz M, Freise J. Sicherheit bei der Diagnostik der chronischen Pankreatitis. Z Gastroen­terol 1990; 28: 253-8. 



Radio/ Oncol l 997; 3 l: 277-8. 



Active bleeding due to pancreatitis diagnosed by contrast enhanced CT 
Tamas Puskas and Szabolcs Rac 
Department of Radiology Markusovszky Teaching Hospital Szambathely, Hungwy 
The authors presen/ the case of a 55 -year -old male patient in w/10111 an active bl~eding developed in to pancreatitis, which was diagnosed by the contrast enhancement CT. So the verification of the process is rare but, the necessity and the advantage of contrast material administration during CT is emphasized. Finally, they summarize the special CT appearances of active bleeding which is definitive enhancement of contrast developed in the centre of the lesion. 
Key words: pancreatitis-diagnosis; gastrointestinal hemorrhage-diagnosis; tomography, x-ray computed; radiographic image enhancement 
Introduction 

The course of acute pancreatitis can be mild, medium, and severe. The history, physical and laboratory find­ings are prirnary in setting up the diagnosis. Among the imaging systems CT is the most appropriate meth­od in defining severity and cornplications of the acute phase. 1 Follow up examinations of chronic pancreati­tis can be performed by the ultrasound (US). When clinical and laboratory data suggest bleeding, Doppler US ancl angiography are needed. 
Case report 

A 55-year-old male patient was admitted to the surgi­cal department of Markusovszky Hospital because of the abdominal pain and vomitting. In his previous history the medica! treatment for chronic pancreatitis and laparotorny for a pseuclocyst were mentioned. His physical and laboratory findings were ali normal: Hb: 7,7 mmol/1., HCT: 0,36, WBC: 7,4 G/1., serum amyla­se: 233 U/1., senun lipase: 160 U/1., but the elevatecl serum bilirubin: 23 mmol/1. The chest and the abdom-
Correspondence to: Tamas Puskas M.D., Dcpmtment of Radiology Markusovszky Teaching Hospital, Markusov­szky str. 3., H-9701 Szombathely, Hungary. 
UDC: 6!6.37-073.756.8:6!6.37-005. I 
inal racliography were negative. A Levin tube was introcluced to the stomach, and the patient receivecl infusion. His condition improved so much that he was able to walk to the clepartment of radiology where the abclominal US was carried out: a 7 cm diameter low echogenity, well circumsclibecl mass was seen behincl the stomach. For the better visualisation a CT exami­nation was performed: the head and body of the pan­creas were swollen, but the tail coulcl not be well discerned. In the lesser sac, a high, mixed density mass appeared, similar to that found by the US (Fig-

Pusktis T (md Rde S 
ure 1). After the administration of contrast material a definitive enhancement developed in the centre of the lesion (Figure 2). These US and CT findings prompt-
Figure 2. Aftcr conlrasl material administration a definitive enhancement developed clearly showing lhe rupture of the lienal artery pseudoaneurysm. 
ed us to diagnose pancreatitis caused by the active bleeding from the rnptured pseudoaneurysm of the lienal artery. Unfortunately, we were not able to per­form angiography and the needed embolization be­cause our equipment did not actually work, being under repair. Next day the patient's condition wors­ened dramatically. He went into shock, and vomilted blood. Emergency laparotomy rcvealed that the stom­ach was filled with blood, and that a 3 cm long rupture appeared on thc posterior wall. A large, bloody, necrot­ic cavity was found in the regi on of the pancreatic taiL The source of thc bleeding was the artery lienalis airnded in the bottom of this cavity. Splenectomy and ligature of the lienal artery were performed. The pa­tient was treated in the intensi ve care unit, but he died after a few days. 
Discussion 

Enzymes released as a consequence of pancrealitis may cause the formation of peripancreatic vessels. Pseudoaneurysm formation or, in rare cases, activc bleeding can develop. In case of the suspected ac­tive bleeding, a life-threatening complication, a rap­id correct diagnosis, and the verificalion of the source of blceding are imperative. The Doppler US and the selective angiography are the examinations of choice in these cases. When bleeding is provcd, the percutaneous embolization is a possible thera­peutic approach. 2 
The symptom-free active abdominal bleeding is rare. It may be incidentally revealed by CT after the blunt abdominal trauma. In the acute phase of pancreatitis a contrast, enhanced dynamic CT ex­amination can exactly define the boundaries of in­tact and damaged parcnchyma. In addition, the ac­tive bleeding causes characteristic changes observ­able by a contrast enhancement. Jeffrey et al. sum­marized the CT features of active bleeding, not due to pancreatitis but based on their own experience and literature dala. s.9 
Circumscript form: On nalive seans the density of haematoma is higher /70-80HU/ than the sur­rounding organs' density. After the contrast materi­al administration, a definitive enhancement can be seen within the haematoma (130-l S0HU). 
Diffusc form: The high density area in the perito­neal cavity or the extraperitoneal space with mas­sive enhancement after the contrast material. It is important to mention lhat the degree of contrast enhanccment is similar to the enhancement of the neighbouring vcssels in both forms. 
When bleeding invades into a preformed pseudo­cyst, and the patient is free of symptoms, the high density of the pseudocyst content on native seans may call our attention to bleeding, and the degree of contrast enhancement can its presence. 
References 
1. 
Haaga JR, Alfidi RJ. Computed tomography rfthe w!wle body, St. Louis: The C.V. Mosby Co., 1988: 905. 

2. 
Uflacker R, Diehl JC. Successful embolisation of a blccding splenic mtery pseudoaneurysm secondm-y to nccrotizing pancreatitis. Gastmi11testi11a/ Radiology 1982; 7: 379-82. 

3. 
Walter JF. Chuang VP, Booksteiu JJ, Reuter SR, Cho KJ, Puhrnmo CM. Angiography of massive hemorrhage sec­ondary to pancrcatic disease. Radiology 1977; 124: 337-42. 

4. 
Federle MP, Goldberg HI, Kaiser JA, Moss AA, Jeffrey RB, Mali JC. Evaluation of abdominal trauma by Com­puter Tomography. Radiology 1981; 136: 637-44. 

5. 
Goldstein AS, Scalfani SJ, Kupferstein NH, Bass I, Lewis T, Panetta T, Phillips J, Shaftan GW. The diagnostic superiority of computerized tomography. J Trawna 1985; 25: 938-41. 

6. 
Jeffrcy RB, Laing FC, Federle MP, Goldman PC. Com• putcd tomography of splenic trauma. ·Radiology 198 I; 141: 729-32, 

7. 
Sivit CJ, Pcclet MH. Taylor GA. Lifc threatcning intra­peritoneal bleeding: demonstration with CT. Radio/ogy 1989; 171: 430-35. 

8. 
Jeffrey RB, Cardoza JD, Olcolt EW. Detection of aetive intraabdominal arterial hemo1Thage. AJR 1991; 156: 725­29. 

9. 
Triller J, Maddern G, Scilcr Ch. Erosion of lhe splenic artery and colon by a pancreatitis pseudocyst, with mas­sive inlestinal bleeding. Journal of Intervent Radio/ 1991; 6: 25-8. 



Radio/ Onco/ 1997; 31: 279-85. 

Radioprotection of salivary glands by amifostine in high~dose radioiodine therapy investigated in a new rabbit animal model 
Ralf-Harto Hiibner,1 Karl H. Bohuslavizki,1 Winfried Brenner,1 Susanne Klutmann, Feyerabend,3 Jutta Liittges,3 Stephan Tinnemeyer,1 Janos Mester,2 Malte Clausen,2 Eberhard Henze1 
Departments ci 1Nuclear Medicine and 3Pathology, Christian-Albrechts-University of Kiel, Germany 2Department of Nuclear Medicine, University Hospital Eppendmf, Germany 
Sctliva1)' gfand damage following high-dose radioiodine treatment (HD-RIT) is a well known side effect. Since dijferentiated tlzyroid cancer (DTC) has a very good prognosis, the reduction of long•lerm side eftect is 
major imerest. Therefore, the radioprotective of amifosline was investigated in a rabbit animal model. Quantitalive salivary gland scintigraphy was pe1formed 011 5 rabbits prior to and up to 3 monlhs after HD-RIT applying l GBq /./JI. The uptake Tc-99m-perteclmeta/e was calculated as a measure of parenchymal functio11. Three cmimals received 200 mg/kg amifostine prior to HD-RIT, and two served as controls. Salivary glands were examined histopathologically. In two con/rol rabbits HD-RIT significanlly (p<0.001) reduced pertechnetate uptake by 63 % and 46 % in parotid mul submandibular glands, respec· tively, and lipomatosis was found histopalhologically. In con/rast, in three rabbits treated with am(fostine parenchymal ftmction was not decreased signijkantly (p = 0.953), and lipomatosis was negligible. In conclusion, salivwy gland impainnent induced by HD-RIT can be evaluated quantitatively by salivary gland scintigraphy in rabbits, and amifostine signijicantly reduced saliVCII)' gland damage induced by HD-RIT. These encouraging results need further evaluation in patients since it may help to increase the quality of life of patients with dif.fentiated thyroid cancer. 
Key ;vords: SaliVCIIJ' glands radiation e.ffects; radiation·protec1ive agents; amifostine; radiotherapy· adverse eftects; rabbits 
Introduction 

A standard therapy in differentiated thyroid cancer requires a total thyroidectomy and a high-dose rndioiodine therapy in order to cornpletely ablate thyroid rernnants. 1 Apart from thyroid tissue the /3­emitting iodine isotope 1-131 used for radioiodine therapy is accumulated actively by an ATP dcpend-
Correspondencc to: Dr. Karl H. Buhoslavizki, Dcparlmcnt of Nuclear Medicine, Christian-Albrechts-Univcrsity of !Gel, Arnold-Heller·Str. 9, D-24105 Kiel, Germany. Phone: +49 4 31 5 97 -30 76, Fax.: +49 4 31597 30 65. 
UDC: 616.316-001.28·084 
ent Na•/K+/2CJ--cotransport due to its similar atom­ic diameter and its cornparable eleetric eharge.2-<> This causes an undesired aeeumulation of I-131 in parietal cel!s of thc stomach as wcll as in acinar cells of salivary glands.(>-9 Consequently, well rec­ognized side effccts of high-dose radioiodine thera­PY are transient gastritis and long-lasting xerosto­
16 

mia. rn-Thercfore, a radioiodine therapy is per­formed under salivary gland stimulation in order to decrease the impairment of sa!ivary gland func­tion.11-23 However, even under salivary gland stimu­lating conditions, a parenchymal damage could be shown after high-dose radiodiodine therapy using 
24 

quantitative salivary gland scintigraphy. 13· -27 Since 
Hiibner R.Jf et al. 
differentiated thyroid cancer has very good progno­sis, reduction of long-term side effects following high-dose radioiodine therapy is important for the patients' quality of life. 1 
In the last few years various reports dealt with raclioprotective effects of amifostine,2x-33 a phos­phorylated aminothiol chemically described as S-2­[3-aminopropylamino]-ethylphosphorotioic acid (Fi­gure 1). Since amifostine accumulates markedly in salivary glands,34 it has been used successfully in external radiotherapy in patients with head and neck tumors in order to prevent xerostomia.35-4° 
HN-CHz-CH-CH-NH-CH-CH-S-PO(OH)
222222 
t [ 
Alkaline Phosphatase) 
HN-CH-CH-CH-NH-CH-CH-SH 
222222
Figure l. Chemical structure of amifostin (above) and its active metabolite WR-1065 (below). 
Therefore, it looked worthwhile to transfer the 

radioprotection of salivary glands by amifostine to 
high-dose radioiodine therapy in order to prevent 
patients from xerostomia, and, thus, to increase the 
tolerance of high-dose radioiodine therapy. 
As a first step we established a rabbit animal 
model and report on first results. 


Materials and methods 

In order to investigate the cytoprotective effect of amifostine an animal model was established. Five male New Zealand white rabbits aged three months, weighing 2.5±0.1 kg, were treated with l GBq I-131 intravenously in order to ablate the thyroid and to destruct salivary gland parenchyma. Prior to the ap­plication of radioiodine ali animals received 4 mg Dexamethason (Fortecortin®, Merek, Darm­stadt) and 0.5 mg Tropisetron (Navoban®, Sandoz, Niirnberg) as antiemetic treatment. In addition, three out of five rabbits received 200 mg/kg amifostine (Ethyol®, Essex, Mtinchen), and two rabbits servecl as controls, receiving physiological saline solution. 
To quantify parenchymal function, salivary gland scintigraphy was performed prior to as well as four weeks, eight weeks and twelve weeks after the appli­cation of 1-131. Rabbits were put in prone position directly onto a low energy high resolution collimator of a large field of -view gamma camera (Boclys­can, Siemens, Erlangen). After injection of 100-140 MBq Tc-99m-pertechnetate sequential images of one minute each were acquired up to 25 minutes. Images were stored digitally in a 256 x 256 matrix. For quan­tification one rectangular background ROI was posi­tioned caudally to the left parotid gland, ancl five oval ROis were drawn over both paroticl and subma­nidbular glands and the thyroid gland, respectively. ROis were copicd from the study performcd prior to radioiodine treatment to the studies obtained after ra­dioiodine treatment. As a measure for parenchymal function the uptake of Tc-99m-pertechnetate was cal­culated in percent of the injcctecl activity. For com­pensation of noise and, thus for stabilisation of data, uptake was averaged from 21.-23. minute post injec­tion. Whole body distribution ofTc-99m-pertechnetate in a rabbit is shown in Figure 2A and ROis used for quantification are depicted in Figure 28. 
Twelve weeks after radioiodine therapy ali ani­mals wcre saclificed to remove salivary glands for histopathological examination. Salivary glands were stainecl with Hematoxilin/Eosin in conventional manner. 
Animal studies were approved by the local gov­emment (XI 330a 72241.11-17). 
Data are given as mean ± one standard deviation. Two-tailed U-test according to Wilcoxon, Mann and Whitney was used to evaluate statistical differ­ences between animal subsets.41 For p<0.05 data were considered to be statistically significant. 


Results 
Co111rols 
Details of Tc-99m-pertechnetate uptake in salivary glands of controls and amifostine rabbits are given in Table l. Salivary gland scintigrams of a control rabbit are given in Figure 3 (upper row). In controls thyroid uptake declined to almost zero as early as four weeks after radioiodine treatment, thus doeu­menting a thyroid ablative dose of raclioiodine. In parallel, parenchymal function of salivary glands decreased. Twelve weeks after the injection of I­131 Tc-99111-pertechnetate uptake was reduced by 63 % and 46 % in parotid and submandibular glands, respectively, (Figure 4, open symbols). 
Amifostine group 
Rabbits treated with amifostine exhibited complete ablation of the thyroid four weeks after the applica­tion of I-13 l as well. This is shown in Figure 3 (lower row). In contrast, in these animals parenchy­

Radiopmtection of" saliVW)' gla11ds 
Table l. Uptake of Tc-99m-pertechnelate in pcrcent of injected activity prior to, 4, 8, and 12 weeks after the application of 1 GBq Iod-131 in control rabbits and in rabbits treated with amifostine 200 mg/kg body weight. Numbers represent mean of right and left parotid and submandibular glands, respectively. 
Controls  Amifostine  
Parotid glands  Submandibular glands  Parotid glands  Submandibular glands  
prior to 1-131  0.226 ± 0.042  0.295 ± 0.070  0.241 ± 0.030  0.230 ± 0.074  
4 weeks after  O. 140 ± 0.018  0.199 ± 0.046  0.215 ± 0.038  0.215 ± 0.060  
8 weeks after  0.106±0.019  0.187 ± 0.067  0.209 ± 0.032  0.210 ± 0.065  
12 weeks after  0.080 ± 0.011  0.154 ± 0.057  0.208 ± 0.023  0.212 ± 0.057  


B 


Figure 2. Whole body distribution ofTc-99m-pe11echnctate 
(A) and thc magnification of the hcad (B) visualizing thc ROis used for quantification. Numbers reprcscnt uptakc of Tc-99m-pertechnetate in percent of thc injccted activity in parotid, submandibular glands, and thyroid gland, respecti­vely. 
B 
(D(]!IIJ 

,....)004 

;111 
;111 !III 

~ 
OJ 
? 

:, 
o ? 

] 60 
N 
~ 
? f 

§ 40 
o 

o 
z 
p < o.os p < 0.01 p < 0.001 

20 
O Prior to 1-131 4 wk. 8wk. I2wk. 

Figure 4. Normalized uptake of Tc-99m-pcrtechnetate in parotid (circles) and submandibular (squares) glands of control rabbits (open symbols) and of trabbits treated with amifostine (filled symbols) prior to, 4, 8 and 12 weeks after application of 1 GBq 1-131. 

Figure 3. Salivary gland scintigraphy in the control group (upper row) and in the amifostine group (lower row) prior to (A), 4 (B), 8 (C), and 12 weeks (D) after the application of I GBq 1-131. Numbers represent uptake of Tc-99m-pertechnetate in percent of the injected activity in parotid, submandibular glands, and thyroid gland, respectively. 
Hiibner R-H et a/. 
l<igurc S. Hematoxilin/Eosin-stained sliccs of parotid glands of the control group (left), and of the amifostine group (right) twelve weeks after thc application of I GBq I-131. Note a significantly more pronounced lipomatosis in thc control animal. Magnification: 500 times. 
mal function of salivary gland was decreased not significantly (p=0.953) by only 10 % and 7 % in parotid and submandibular glands, respectively (Figure 4, filled symbols). 
Histopathology 

Results of histopathological examinations are given in Figure 5. Salivary glands of control rabbits ex­hibited a marked lipomatosis as a typical sign of radiogenic damage, but no signs of inflammation (Figure 5, left), whereas lipomatosis was much less pronounced in animals treated with amifostine (Figure 5, right). 
Discussion 
Quantification oj saliva,y gland function 

Salivary gland scintigraphy performed in a stand­ardized method as previously described42· 43 facili­tates the quantitative evaluation of salivary gland parenchymal function. It is characterized both by an excellent intraindividual observer variability and reproducibility which enables the detection of changes in parenchymal function in the range of about as less as 5-10 %.26· 27 This enabled both the early detection of beginning Sjogrens syndrome by salivary gland scintigraphy as compared to other imaging modalities44 and the detection of parenchy­mal impairment of salivary glands following low­dose radioiodine therapy.26• 27 Therefore, quantita­tive salivary gland scintigraphy proved to be a suit­able imaging modality for quantitative evaluation of salivary gland timction. 
Amifostine 
Amifostine was originally developped as a radio­protective agent as a part of the Anti-Radiation Drug Development Program initiated by thc United Statcs Army at the Walter Reed Army Institute of Research (Washington) in the early I 950s.29 Since numerous preclinical studies in celi culturc and ani­mal modcls showed that, following dephosphorila­tion to its activc mctabolite WR-1065, amifostine selectively protected normal tissuc from damaging effects of irradiation, severa] clinical studies were initiatcd confirming its radioprotective potcncy in various publications.35-4o. 45 This resulted in an ap­proval of amifostine in Germany in 1995 for thc supportive therapy of patients with ovarian cancer being treated with cisplatin derivatives in order to minimize myelotoxic side-effects of cisplatin.30 
The selective radioprotection of normal tissue by amifostine as compared to tumor tissuc is mainly caused by two effects. First, amifostine is accumu­lated much more in normal tissue, and, second, the alkaline phosphatasc necessary for dephosphorila­tion of amifostinc and thereby activating amifostinc is more active in the alkaline environment of normal tissue than in the acid tumoral tissuc.29• 46-48 
Since amifostin is known to be accumulated cx­
34• 48 51 
tensively in salivary glands29· -it seemed rea­sonablc to use amifostine as protecting agent in pa­tients with head and neck tumors receiving external radiation therapy. Takahashi and coworkers37 studied Ga-67 uptake as an indicator for irradiation-induced damagc in salivary glands of patients with head and neck cancer and showed that pretreatment with ami­fostine resulted in a significantly increased numbcr of Ga-67 negative salivary glands following itrndia­tion. Some studies have been undertaken so far in 

Radioprotection of' salivwy glands 
head and neck tumors yielding vcry promising re­sults concerning the reduction of radiation induccd salivary gland damage.35-4° 
Sincc radiation effects of external radiation and radioiodine therapy are in general caused by thc same mechanisms,10 i.e. the production of frce radi­cals, it seemed promising to transfer the radiopro­teetive effect on salivary glands by amifostine to high-dose radioiodine therapy. 
Animal studies 
In this study I GBq I-131 was applied for complete ablation of the thyroid and for concomittant paren­chymal impairment of salivary glands. In fact, the activity applied caused a complete thyroid ablation in the animals of the control group as well as in animals treated with amifostine as early as four weeks after application of 1-131. Thus, amifostinc did not protect thyroid tissue from I-13 l. This is in accordance with the observation that amifostine is accumulated to an only marginal amount in the thyroid of severa! specimen.47• 52-50 This observation yields the prerequisite for the application in differ­entiated thyroid cancer since protection of thyroid tissue or metastases of differentiated thyroid cancer bas to be excluted. 
In our animal studies wc could show a clear radio­protective effect of amifostine in salivary glands of rabbits treated with-dose radioiodine. This was dem­onstrated scintigraphically by a significantly reduced parenchymal impairment of salivary glands after pre­treatment with 200 mg/kg amifostine. Moreover, in rabbits treated with amifostine we histologically ob­served a markedly reduced lipomatosis without evi­dence of an inflammation. This is in accordance with severa! papers in which lipomatosis is described as a typical late effcct of radioiodine treatment.57-59 Thus, animal studies showed an encouraging radioprotec­tion of salivary glands by amifostine in high-dose radioiodine therapy. 
Conclusion 

Parenchymal damage in salivary glands induced by high-dose radioiodine therapy can be evaluated quantitatively by salivary gland scintigraphy in a new rabbit animal model introduced. Amifostine significantly reduced salivary gland damage induced by high-dose-radioiodine therapy. These cncourag­ing results need further evaluation in patients since it may help to increase the quality of life in patients with diffentiated thyroid cancer by avoiding xeros­tomia. 
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Radio! Onco/ 1997; 31: 286-90. 




Diagnostic value of planar myocardial perfusion scintigraphy in patients with coronary artery disease 
Marko Klancic, 1 Metka Milcinski, 1 Darko Zorman 2 
1 Nuclear medicine, 2 Cardiology, University Medica[ Centre, Ljubljana, Slovenia 
Patients with suspected or praven coronary arte,y disease are investigated using noninvasive a,ul invasive diagnostic methods. Noninvasive myocardial perfusion scintigraphy provides data on myocardial perfusion during stress and at rest. Coronary angiography is invasive morphologic method, performed before corona,y artery dilatation or surgery. Aim oj our retrograde analysis oj planar thallium myocardial pe1fusion scintigrams and coronary angiograms was to assess sensitivity and specificity oj myocardial pe1fusion planar scanning and to evaluate causes oj possible disagreement. Original readings oj myocardial pe1fusion seans mul corona,y angiograms oj I 56 patients with corona,y arte1y disease were compared. When results oj both investigations were partially concordant or discordant, the original studies were reviewed. Concord­ant results oj both examinations were fowul in 62% oj patients. In only 3% (5 patients) the results were discordant and the reason far disagreement oj results oj both studies could not be detected. Most oj the remaining 55 patients had more pronounced myocardial pe1fusion defects than was the estimated severity oj coronary arte1y stenosis, attributed to the different nature oj both investigations. Anomalous coronary arte1y was found in 3% oj ali patients, tortuous coronmy arteries with slow flow oj contrast media in 9 patients (6% oj all) and arterial hypertension with extreme left ventricular wall hypertrophy in one patient. Sensitiv­ity oj the myocardial pe1fusion scintigraphy was 100% and spec(ficity 50%. Positive predictive value far coro1ia1)' arte1y disease was 96% and negative predictive value was 100 %. We cconclude that myocardial perfusion scintigraphy has a definite role in diagnosis mul follow-up oj patients with suspected or praven coronmy artery disease. New techniques and teclmetium labeled tracers improve reliability oj myocardial perfusion scintigraphy and enable reasonable use oj more aggressive diagnostic methods. 
Key words: coronmy disease-diagnosis; heart-radionuclide imaging 
Introduction 

Various diagnostic possibilities exist for patients with suspected or praven coronary artery disease. Clinical <lata are combined with electrocardiogram (ECG) and stress testing. 1 Myocardial perfusion scintigra­phy is significantly more accurate for diagnosing coronary artery disease than the exercise ECG.2.1,4 
Correspondence to: doc. dr. Metka Milcinski, Nuclear medi­cine, University Medica! Center, Zaloška 7, 1525 Ljubljana; Tei: +386 61 316 855, Fax: +386 61 132 72 72, e-mail: meta.milcinski@mf.uni-lj.si 
UDC: 616.127-005.8:539.163 
Additional invasive approaches are needed for evalu­ation of the diseasc extent, severity and before the therapeutic interventions. Coronary angiography de­tects morphological changes utilizing intracoronary injection of the contrast media.5•6.7 Myocardial per­fusion scintigraphy uses photon or positron emmit­ting substances to assess myocardial perfusion. Among first radiopharmaceuticals and until recently 
•9 

the most widely used was thallium 201.3.4·8Results of the myocardial perfusion imaging and the coro­nary angiography are usualy compared. Their con­cordance depends on the degree of coronary artery disease, previous myocardial infarction and techni­cal factors.3•10•11 As treatment of patients with coro­
Diagnostic value <fplanar myocardial pe1fi1sion scinrigraphy in parients with coro11a1y arte1y disease 287 
nary artery disease depends on the results of diag­nostic tests, they have to be accurate. 
Our retrograde analysis of myocardial perfusion scintigrams and coronary angiograms in paticnts with coronary artery disease was performed to as­sess sensitivity and specificity of myocardial per­fusion planar scanning and to evaluate causes of possible disagreament. 
Patients and methods 

Consecutive patients, referred for suspected or pro­ven coronary artery disease to myocardial perfusion scintigraphy in two and a half years period were included. The tirne between perfusion scintigraphy and the coronary angiography had to be less than six months. No acute coronary event or therapeutic intervention between both examinations was al­lowed. 
In the two and a half years' period more than 1000 patients had myc:icardial perfusion scintigra­phy and 341 of them had coronary angiography. Only 156 of those had both investigations performed in up to 6 months period and both studies available in the archives. Clinical data (gender, age, previous myocardial infarction, possible fibrinolytic thera­py, arterial hypertension and angina) were analysed. Left bundle branch block was searched for in ECG. Data are given in Table 1. 
Table l. Patients' <lata. 
Number % of ali 

Men  133  85  
Women  23  15  
<40 years  2  1  
40-50 years  43  28  
>50-60 years  64  41  
>60-70 years  42  27  
>70 years  5  3  
Time between investigations  
<lmonth  84  54  
l-3months  46  29  
4-6months  26  17  
Hypertension  92  59  
Angina pectoris  
Typical  125  80  
Atypical  26  16  
Myocardial infarction  92  59  
Ventriculography  
antcrior wall hypokincsia  87  56  
inferior wall hypokinesia  47  30  
Collateral at1eries  77  49  
Lcft bundle branch block  5  3  
Thrombolytic therapy of myocardial  
infarction  24  15  

Myocardial pe1fusion scintigraphy was performed using planar scintigraphy (General Electric 300 gamma camera, Macintosh II fx computer, LEAP collimator, 64 x 64 matrix, 7 minutes per view) in best septal (LAO 30 -45 degrees), anterior and Ieft laterni projection. Thallium (TICI 201, 74 MBq) was injected during submaximal, simptome limited or during pharmacologic stress (dipyridamol 0,56 mg/kg body weight). Scintigrams were acquired immediately after stress (stress imaging) and three to four hours latter (rest imaging). Visual analysis of myocardial perfusion scintigrams was performed; perfusion was described as normal, diminished or absent for anteroseptal, posterobasal, apical, laterni 
3 10 12 

and inferior regions in stress and rest.2•-, 
Left ventricular wall motion was observed on contrast ventriculography and described as normal, hypo-, a-or diskynetic for anterior or inferior wall. 
Coronary artery narrowing was evaluated on co­rona,y angiograms for left anterior descending ar­tery (LAD), left circumflex artery (LCX), right coro­nary artery (RCA) and graded as less than 50%, 50-69%, 70-89%, 90-99% or as occluded.5•6 
Data comparison: original readings of myocar­dial perfusion seans and coronary angiograms were compared for LAD, LCX and RCA perfusion terri­tories. Results of comparison were either concor­dant (hypoperfused areas and stenosis in the same regions), partially concordant (not ali areas con­cordant or differing degree of stenosis / traccr accu­mulation) or discordant (perfusion abnormality and coronary artery stenosis on different areas or not detected). When incompletely concordant and dis­cordant results of both studies were found, original studies were reviewed by two experienced nuclear medicine specialists and the cardiologist. 
Statistical methods: patients' data were expressed in percent and average values. Sensitivity, specifi­city, positive and negative predictive value for my­ocardial perfusion scintigraphy were calculated. 13 
Results 

Both examinations gave concordant results in 62% of patients. Only in 3% of ali patients the results were discordant. In the remaining 35% concord­ance was only partial. Distribution of separate coro­nary artery narrowings is shown on Figures 1 a -c. Calculated sensitivity of the myocardial perfusion scintigraphy was 100% and specificity 50%. Posi­tive predictive value for coronary artery disease 
Klancic Metal. 
was 96% and negative predictive value was 100 %. Specificity and sensitivity for separate perfusion areas for men and women are given in Table 2. 
LAD narrowing (%) 
Patients 
(number) 

RCA narrowing (%) 
Pationts 
(number) 

LCX narrowing (%) 


Patients 
(number) 

l<igurc l. Distribution of coronary mtcry narrowings: a) left anterior descending artery -LAD, b) right coronary artery ­RCA, c) left circumflex coronary artery -LCX. 


Discussion 
Myocardial perfusion scintigraphy is a common di­agnostic method in evaluation of patients with sus­pected or proven coronary artery disease. 2• 3• 4 Coro­nary angiography is the golden standard in diagnos­tic evaluation of patients with coronary artery di-
Table 2. Sensitivity and specificity of myocardial perfusion scintigraphy for separate coronary artery perfusion areas in 
a) men, b) women. 
2a:Mcn  Sensilivity  Specificity  
Left antcrior dcscending  
coronary artery  96%  61%  
Right coronary mtery  100%  79%  
Left circumflex artery  89%  94%  

2b: Womcn  Sensitivity  Specificity  
Left anterior desccnding  
coronary artery  93%  38%  
Right coronary artcry  89%  100%  
Left circumflex artery  86%  93%  

sease. It is a morphologic method, performed most­ly in resting conditions; it has to be performed before coronary artery dilatation or surgery.5· 6 My­ocardial perfusion scintigraphy can not give ana­tomic details but provides <lata on myocardail per­fusion during stress and at rest, thus detecting myo­cardial hypoperfusion before symptoms are evident at rest. It can therefore be used as a screening method in patients with intermediate pretest proba­
41415 
bilit y of coronary artery disease. 1•• • Planar meth­od was used until tomographic technique became available also at our institution. The <lata on sensi­tivity and specificity of myocardial perfusion scin­tigraphy vary largely and depend mostly on inclu­sion criteria used for separate study. The sensitivi­ties from 79 to 96% and specificities from 85 to 91 % are common; sensitivities from 20 to 80 % for separate coronary arteries in unselected patients are described.2· 16 Evaluation of the method in separate institutions is therefore needed. Our study is a part of quality control process and helps to assess clini­cal impact of diagnostic procedures. Patients in our study were selected on basis of both investigations performed. Most of them had severe coronary artery disease with angina pectoris, previous myocardial infarction and wall motion abnormalities (Table 1). 
"False positive" myocardial perfusion scinti­grams were detected in 60 patients (38% of all) at the original first reading. The studies were reana­yzed and underlying coronary pathology was de­tected in 55 patients. Most of them had more pro­nounced myocardial perfusion defccts than was the estimated severity of coronary artery stenosis. This is a natura! consequence of the different nature of both investigations. Other causes of "false posi­tive" results were anomalous coronary artery in 5 patients (3% of all), tortuous coronary arteries with slow l1ow of contrast media in 9 patients (6% of 

Diagnostic value ofplanar myocardial pe1ji1sion scintigraphy in patients with com11a1y arte1y disease 289 
ali) and arterial hypertension with extreme left ven­tricular wall hypertrophy in one patient. 
Anterior wall hypoperfusion due to anomalous coronary artery can be present already at rest. Ex­tensive additional patological findings on stress scan are detected.3• 17 An example of coronary angiogram in patient with anomalous coronary artery is shown on Figure 2. Tortuous coronary arteries with slow 
Figure 2. Coronary angiogram, left antcrior oblique projec­tion: anomalous left antcrior dcsccnding coronary artcry. 
flow of contrast media cause inadequate myocar­dial perfusion without coronary artery stenosis.3• 18 An example of coronary angiogram of our patient is shown on Figure 3. In patiens with arterial hyper-
Figure 3. Coronary angiogram, left anterior obliquc cranial projection: tortuous coronary artcry. 
tension, myocardial perfusion abnormalities are at­
• 20 

tributed to diminishecl coronary llow reserve. 19We cletected evident perfusion defect in one patient with normal coronary arteries on angiography. Systolic and diastolic frames from contrast ven­triculography of this patient are presented on Fi­gure 4 (a, b); myoeardial hypertophy with oblitera­tion of myoeardial cavity in systolic frame is evi­dent. 
Figure 4. Contrast vcntriculography, righl anlcrior obliquc projection: lcft ventricular hypcrtrophy. Left ventriclc in n) systolc, b) diastole. 
False positive myocardial perfusion seans are pos­sible in patiens with left bundle branch block.22• 23 In 4 of our 5 patients with this conduction abnormality scintigraphic findings were concordant with angio­graphic findings, reflecting reliability of our nucle­ar medicine specialists. 
The low specificity of myocarclial perfusion seans for LAD perfusion territory in women can be due to the low number of women in our study and to the attenuation of thallium radioactivity in soft tis­
sue_x. lil, 11 
In 5 patients no evident reason for disagreement of results of both studies could be detected. Dis­cordance could be due to the natura! course of coro­nary artery disease23 or episodes of silent ischae­
mia. 25 
In conclusion, myocardial perfusion scintigraphy has a definite role in diagnosis and follow-up of patients with suspected or proven coronary artery disease. New techniques ancl technetium labeled tracers improve reliability of myocardial perfusion scintigraphy and enable reasonablc use of more aggressive diagnostic methods. Scintigraphy can evaluate the functional significance of coronary stenoses, detected by coronary angiography or mag­netic resonance imaging. Development of positron 
Klancic Metal. 
emission tomography and positron emission tracers allows differentiation of viable myocardium and scar tissue in patients after myocardial infarction.4 



References 
l. Detry J-MR, Fox KM. Exercise testing. In: Julian DG, Camm AJ, Fox KM, Hall RJC, Poole Wilson PA eds. Diseases 1~( the heart. Philadelphia: Saunders, 1996: 372-85. 
2. 
Hohnan BL. Cardiac imaging. Nuclear cardiology. In: Brmmwald E. Heait disease. A textbook ofcardiovascu­lar medicine. Philadelphia: Saunders, 1984: 351-99. 

3. 
Beller GA. Myocardial perfusion imaging with tlml­lium-201. In: Marcus ML, Schelbert HR, Skorton DJ, Wolf GL cds. Cardiac imagi11g. A companion to Braun­wald's heart disease. Philadelphia: Saunders, 1991: 1047-73. 

4. 
Huggins GS, Gewirtz H. Clinical prcsentalion and di­agnostic techniques. In: Fuster V, Ross R, Topol EJ eds. Atherosc/erosis and coronary arte1y disease. Phil­adelphia: Lippincott-Raven, 1996: 1401-18. 

5. 
Genssini GG. Coronary arteriography. In: Braunwald 

E. Heart disease. A textbook 1!{ cardiovascular medi­cine. Philadelphia: Saunders, 1984: 279-303. 

6. 
Johnson MR. Clinical aspects of <lata acquisition in coronary angiography. In: Marcus ML, Schelbert HR, Skorton DJ, Wolf GL cds. Cardiac imaging. A com­panion to Braunwald's heart disease. Philadelphia: Saunders, l 991 : 182-210. 

7. 
Zorman D, Milcinski M. Koronarna angiografija pri ishemicni srcni bolezni. Med Raz,r;l 1992; 31: Suppl 2: 32-4. 

8. 
Beller GA. Diagnostic accuracy of thallium-201 myo­cardial perfusion imaging. Circulation 1991; 84: Suppl l: 1-1-1-6. 

9. 
Kotler TS, Diamond GA. Exercise thallium-201 scin­tigraphy in the diagnosis and prognosis of coronary artery disease. Ann lntern Med 1990; 113: 684-702. 


l O. Gerson MC. Myocardial perfuson imaging kinetics and planar melhods. In: Gerson MC ed. Cardiac nuclear medicine. New York: McGraw-Hill, 1987: 1-24. 
11. HorG, Klcpzig H. Myocardial scintigrnphy with 201Tl: 
II. Clinical applications (Coronary heart disease). Nucl Med 1987; 26: 155-8. 
12. Wilson R, Shea M, de Landsheere I et al. Myocardial blood tlow: elinical application and recent advances. In: Simoons ML, Reiber JHC eds. Nuclear imagi11g in clinical cardiology. Boston: Martinus Nijhoff, 1984: 39-59. 
13. 
Ingelfinger JA, Mostellcr F, Thibodeau LA, Ware JH. Biostatistic in clinical medicine. New York: Macmil­lan, 1986: 1-24. 

14. 
Melin JA, Piret LJ, Vanbutsele RJM et al. Diagnostic value of exercise electrocardiography and thallium my­ocardial scintigraphy in patients without previous my­ocardial infarction: a Bayesian approach. Circulation 1981; 63: 1019-24. 

15. 
Rifkin RD, Hood WB. Bayesian analysis of electrocar­diographic exercise stress testing. N Engl J Med 1977; 297: 681-6. 

16. 
Gerson MC. Test accuracy, test selection and test re­sults interpretation in chronic coronary artery disease. In: Gerson MC ed. Cardiac m1clear medicine. New York: Me Grow Hill, 1987: 309 47. 

17. 
Milcinski M, Budihna N, Klancic M, Zorman D. Anom­alous coronary arteries: cause of "false positive" planar thallium myocardial perfusion seans. J Nucl Cardiol 1995; 2: Suppl 2: Sl5 (abstr). 

18. 
Bortone AS, Hess OM, Eberli FR et al. Abnormal coro­nary vasomotion during exercise in patients with nor­mal coronary arteries and reduced coronary flow re­serve. Circu!atilm 1989; 79: 516-27. 

19. 
Depuey EG, Guertler-Krawczynska E, Perkins JV, Rob­bins WL, Whelchel JD, Clements SD. Alterations in myocardial thallium-201 distribmion in patients with ehronic systcmic hypertension undergoing single-pho­ton emission computed tomography. Am J Cardiol 1988; 62: 234-8. 

20. 
Koga Y, Yamaguchi R, Ogata M, Kihara K, Toshima 


H. Decreased eoronary vasodilatory eapacity in hyper­trophic cardiomyopathy determined by split-dose thal­lium-dipyridamole myocardial scintigraphy. Am J Car­diol 1990; 65: 1134-9. 
21. 
Jazmati B, Sadaniantz A, Emaus SP, Heller GV. Exer­cise thallium-201 imaging in complete left bundle branch block and the prevalence of septal perfusion defects. Am .l Cardiol 1991; 67: 46-9. 

22. 
Knapp WH, Bentrnp A, Schmidt U, Ohlmeier H. Myo­cardial scintigraphy with thallium-201 and (echnetium­99111-hexakis-methoxyisobutiulisonittile in left bundle branch block: a study in patients with and without coro­nary artery disease. Eur J Nucl Med 1993; 20: 219-24. 

23. 
Wajnberg A. The syndrome of angina in patients with normal or nearly normal coronary arteriograms. CVR&R 1992; 48-61. 

24. 
Samman B, Hahn SD, Messinger DE, Heller GV. Spon­taneus silent myocardial ischcmia assessed by techne­tium-99m-sestamibi imaging. J Nuc/ Med 1993; 34: 134-6. 



Radio/ Oncol 1997; 31: 291-7. 



Interstitial fluid pressure as an obstacle i:111 treatment of solid tumors 
Jani Pušenjak and Damijan Miklavcic 
University of Ljubljana, Faculty oj Electrical Engineering, Ljubljana, Slovenia 
Over the past decades a development different anticancer drugs has increased and brought many progressive agents that sho,ved high leve/ oj efficiency in in vitro conditions. U1;fortunately these drugs jailed in solid /Umor treatment in in vivo conditions because of inadequate uptake mul nonoptimal distribu­tion in tumors. Altlwugh tumor.1· have higher permeability and hydraulic conductivity o.f the vessels than normal tissue, the extravasation oj the drug molecules jrom vessels into the tumor interstitium is reduced due to elevated interstitial .fluid pressure (JFP). This property a/so impedes the transport of the molecules through the interstitial space. Furthermore, IFP is uniformly high in the center of the fllmor and declines /O the value o.f the normal tis.me at the rim of the tumor. Thouglt, !FP gradient causes fluid flow whiclt 
'\vashes" drug s out of the tumor 10 its periphe1y where it is reabsorbed the lymphatic system or normal vasculature. Measuremellls of tumor IFP demonstrated that its values can reach 2600 Pa up to 6600 Pa ,vhereas in the normal tissue it is below the atmospheric pres.mre (Jrom -133 Pa to -798 Pa in s.c. wul approxima1ely -346 Pa in muscle). The most Ji·equently used methodsfor instant and direct IFP measurement are: wick-in-needle technique (WIN) and micropuncture technique (MP). Since the reduction of the elevated tumor !FP could jacilitate drug uptake and anti-tumor treatment, many approaches have been testecl. In present paper we represent the results of two physical ( hyperthermia, radiation) and one chemical (vasoactive agents) approach that other authors usedfor IFP reduction. 
Key words: neoplasms-therapy; extracellular space; manomell)' 
Introduction 

A high leve! of drug development techniques, espe­cially genetic engincering, has produced many nov­el drugs for cancer detcction and treatment. 1,2.1 The first step in the development of such a drug is in vitro testing and many agents showcd a very high degree of anti-cancer effectiveness. This stimulated the use of low-molccular-weight conventional drugs, monoclonal antibodies, growth factors, bio­logical response modifiers, immunotoxins, lym-
Correspondence to: Prof. Damijan Miklavcic, D.Sc., Uni­versity of Ljubljana, Faculty of Electrical Engineering, Tržaška 25, SI -1000 Ljubljana, Slovenia. Tei: +386 61 1768 456. Fax: +386 61 ! 264 658, E-mail: dami­jan@svarun.fe.uni-1,i.si 
UDC: 6 l 6-006.6-008.818-08 
phokine activated killer cells, tumor-infiltraling lymphocytes, and others in in vitro conditions.2 Al­though they succeeded in the treatment of leukemi­as and lymphomas they had a minimal effcct on solid tumors (breast, colon, ... ).2•3 The main reason for their limited effectiveness is inadequate and nonuniform distribution of drug molecules or cells in tumors.2·5 Since cellular factors, such as heterogeneity of tumor-associatcd antigcns and in­herent or acquired tumor resistancc can not cxplain this problem, physiological factors have to be con­cerncd. 2 To completc its mission, molccule or the blood-borne anticanccr drug must trave! via blood stream to the tumor. Further it must extravasate across thc microvessel wall into tumor interstitium, whcre it must dispcrsc uniformly in thc tumor in ordcr to reach cach tumor celi. Ali of thcse steps 
Pu.fenjak J and Miklavl'ic D 
are not present in in vitro experiments so eaeb of tbese pbysiological factors could be tbe reason for tbe ineffectiveness of antieancer drug.2·1 
The role of interstitial fluid pressure in trans­port of' molecules through microvessel wall and tumor interstitial space 
As tumor eells proliferate into tbe bost tissue, tu­mor angiogenesis leads to tbe formation of a new, tumor vasculature.2·6 Altbougb tbe tumor mierocir­culation originates from tbe normal bost vascula­ture, its organization may be eompletely different and vary from day to day and from one location to anotber. Vessels in tumor are, compared to vessels in normal tissue, more dilated, sacular and tortuous. Tbey can also contain tumor cells witbin tbe en­dotbelial lining of tbe vessel wall. Furtbermore, tumor microvessels bave wider intercellular junc­tions and discontinuous or absent basement mem­brane. Anotber difference between tbe normal and tbe tumor vasculature is tbat tbe latter bas a large number of fenestrae and blood cbannels wbicb are not lined witb endotbelial cells.2-7 
Figure l. Irregular tumor supplying vasculature of s.c. solid LPB tumor in nude mice (arrows). 
Tbe extravasation of tbe blood-borne molecule tbat bas reacbed tbe tumor vasculature is governed by diffusion and convection. Tbe diffusion is a movement of tbe solute in tbe medium from an area witb bigb concentration to an area witb low concen­tration and is tbe primary way of transport for low­molecular-weigbt bydropbilic and lipopbilic mole­cules. Tbe diffusion is proportional to tbe concen­tration gradient and excbange vessel area. Tbe pro­portionality constant tbat relates transluminal flux to tbe concentration gradient is tbe vascular perme­ability.2-7 Tbe convection on tbe otber band is a way of molecular transport by a stream of fluid. It is proportional to tbe difference between tbe vascular and tbe interstitial bydrostatic pressures minus tbe difference between tbe vascular and tbe interstitial osmotic pressures and also tbe excbange vessel area. Constants tbat relate fluid leakage to tbe pressure gradients are bydraulic conductivity for bydrostatic pressure difference and reflection coefficient for osmotic pressure difference. Tbe equation tbat de­scribes tbe solute flow across tbe vessel wall due to diffusion is:7 
1,= Px A x (cv-c) 
wbere: J, is tbe flow of solute (moles/s or g/s); P is tbe vessel permeability (m/s); A is tbe surface area of tbe vessel (m2); and cv and ci are tbe concen­tration witbin vessels and interstitial concentration of solute, respectively (moles/m3 or g/m3). Tbe flu­id flow across tbe vessel wall is given by:7 
1,=Lrx Ax [ (p,p,)-ax (nv-.n)] 
wbere: J, is tbe volume flow of fluid (m3/s); Lr is tbe bydraulic conductivity (filtration coefficient) of tbe vessel (m/Paxs); A is tbe surfaee area (m2); pv and pi are tbe vascular and interstitial fluid pessures (Pa); nv and ni are tbe colloid-osmotic pressures in vessel and interstitial fluid (Pa); and a is tbe osmot­ic reflection coefficient. In tbe presence of convec­tion and diffusion tbe total solute flow is given by tbe Staverman-Kadem-Katcbalsky equation:7 
1, = P x A x (cv-c,) + J, x (1-aF) x ~c,,,, 
wbere: ar is tbe solvent-drag reflection coeffi­cient; and ~c,m is tbe log-mean concentration witb­in tbe pore. For larger molecules tbe convection is the basic and a faster way of transport, altbougb tbey also trave! by diffusion.2•3•7 Cbaracteristics of tumor vessels described above suggest tbat tbey sbould bave a relatively bigb vascular permeability and bydraulic conductivity. Various studies meas­uring tissue uptake confirmed tbat bypotbesis.2•7 Nevertbelcss, tbe extravasation of anticancer agents in solid tumors is poor. The main reasons are tbat, tumor does not create its own functioning lympbat­ic system, tberefore, tbe excess fluid collects in tbe tumor interstitium and tbat tumor cells prolifcrate in the relatively limited, noncompliant space. Tbese tumor properties cause increase of the interstitial fluid pressure (IFP). The elevated IFP binders the convection across the vessel wall, because tbere is 

lnterstital.fluid pressure as an obstacle in treatment of solid tumor.1· 
no difference between the vascular and the intersti­tial pressure.24·7 First it was assumed that the in­creased IFP causes the vessel occlusion in tumor, since IFP is higher than microvascular pressure (MVP). MVP relates to pressure in vessels with diameter 25 and 250 µm. 8•9 This hypothesis, howev­er, failed to explain why a convection in the oppo­site way did not occur, i.e. fluid flow from intersti­tium into vessel. In addition, tumor vessels are very perfusive and though represent no resistance to the IFP.7-8 Boucher and Jain demonstrated that MVP is increased and equal to IFP, furthermore, they as­sumed that MVP is the principal driving force for the elevated IFP.8 The reasons for the observed increased MVP may bc an increase in viscous and/ or geometric resistance in the venous side of tumor cireulation and that arterioles become less effective in controlling MVP.8 Later they found out that the relationship between these two factors varies from one tumor to another.9 
Another aspect in nonadequate anticaneer agent uptake in tumor is the heterogeneity of the tumor vasculature. In general, solid tumors have three different regions: necrolic zone, semi-necrotie zone and well vaseularized zone. 2 In neerotic and scmi­necrotic zone there is no or very little blood supply and hence no extravasation of anticancer drug takes place. Tumor blood flow in these areas is also low compared to blood flow in normal tissue, whereas in well perfused zone (usually at the tumor periph­ery) tumor blood flow may be higher than that in normal tissue. 2 The increase of intercapillary dis­tance and the decrease of vascular surface area also accompanies tumor vascular hetcrogcneity. In addi­tion, the reduction of tumor blood flow restricts thc extravasation of molecules even more.2 
If the anticancer drug reaches tumor interstitium, it must uniformly distribute through it in order to reach and destroy cach tumor cell. 1·3 The transport of the molecule in the tumor interstitium is also governed by diffusion and convection, only herc the diffusive and the convective flow are propor­tional to gradients instead of differences in concen­tration and pressure, respectively. Proportional con­stants are the diffusion coefficient and the hydrau­lic conductivity. One-dimensional transport by the diffusion in a mcdium is given by Fick's law:4 
JI)= -D x (oC!ax) 

where: J0 is the diffusive flow of the solute per unit area normal to the surface (moles/sxm2 or g/sxm2); D is the diffusion coefficient of the solute in the medium (m2/s), and aC/ax is the concentra­tion gradient of solute (moles/m4 or g/m4) in x dircction. Similary, the convective flow is given by:4 
Je= -C X R„ X K X (op/iix) 

where: Je is the convective flow of solute per unit area normal to the surface (moles/sxm2 or g/sxm2); RF is the retardation factor (solutc convective ve­locity/sol vent convective velocity); C is the con­centration of solute (moles/m3 or g/m3); K is the tissue hydraulic conductivity (m2/Paxs); and ap/ax is the hydraulic pressure gradient (Palm) in x direc­tion. 
Their values in tumor are higher than in normal tissue, but the problem of the heterogeneous distri­bution of anticanccr drug in tumor remains. Theo­retical and practical researches of the IFP profile in solid tumor revealed that it is uniformly high over the center of the tumor and that it drops rapidly at the periphery of the tumor.5,w-12 Unfortunately the convective interstitial fluid flux is created due to pressure gradient at periphery of the tumor. Consid­ering that the tirne a large molecule needs to trave! some distance by diffusion is proportional to the square of the distance and the tirne for a movement by convection is proportional to the distance alone, it is obvious that macromolecule that was washed out of the tumor with the convective flux has a hard tirne diffusing back into the tumor.3.4 
Shortly said, due to heterogeneous tumor vascu­lature, the increased vascular permeability and hy­draulic conductivity, elevatcd IFP, and IFP gradient in tumor very little drug gets in the tumor. Further­more it is washed out rapidly. 
Measurement of interstitial fluid pressure 
Measurement techniques for IFP measuring are nu­merous, but a provocative question appears: which one is referential? Although a method seems to be reliable, accurate and repeatable, it is not necessary that it measures trne IFP value. In 1971 Guyton et al. presented an extended study on IFP. 13 They clas­sified tissue pressure into three categories: solid tissue pressure, IFP, and total tissue pressure, which is the sum of first two. Physiological structures that cause solid tissue pressure are two: I. solid ele­ments in the tissue interstitium such as collagen, elastin, and other types of fibers; and II. interstitial gel composed primary by mucopolysaccharides pos­sibly or probably cross-linked with collagen. IFP 
Pufonjak J and Miklavl'ic D 
on the other hand is the pressure of the free fluid in the tissue interstitium. 13 Nevertheless, other authors called interstitial free fluid phase an abstraction since interstitium may completely consist of a gel. 14 Guyton et al. also critically reviewed a number of measuring techniques which they divided into two groups: needle or capillary pipette techniques and fluid equilibration techniques. 13 They expose one of the fluid equilibration techniques (perforated-cap­sule method) as accurate and reliable technique for IFP measuring. In order to get IFP value with this technique a small hollow plastic sphere with little holes must be implanted into the tissue. It should be implanted for weeks so that interstitial fluid can fill it and creates pressure equilibrium. A needle con­nected to a pressure-measuring device is then in­serted in the sphere through one of the holes.'3 However, this method does not enable instant meas­urements, which is important, when IFP in solid tumor is measured. Therefore, currently only two measuring methods, wick-in-needle and micropunc­ture techniques, are used in tumor IFP measure­ment. In this paper we describe both of them. 
Wick-in-needle (WIN) technique 
The method was first presented by Fadnes et al. in 1977.'5 They took benefits of needle and wick tech­niques and combined it into one. The main problem with the needle technique is the obstruction of nee­dle tip. They solved it by creating a 2-4 mm side­hole cca. 5 mm from the tip of the 0.6mm hypoder­mic needle. The needle is then filled with strand of about 25 mm thick nylon fibers. The hale of the needle tip is not closed, yet densely filling of the wick, there represented a relative larger resistance to fluid comparing to the sidehole. Therefore, the sidehole has the role of the interface area. By in­serting wick into the needle they reduced trauma that a fairly thick cannula, holding the wick in the wick technique, created to the tissue. A wick-filled needle is then connected to a pressure transducer via polyethylene tube and filled with physiologic saline. The whole system is air-proof so that tissue pressure is conducted through water column to the transducer where it is recorded. The calibration is performed by placing the needle in a saline-filled beaker, or in a saline drop, placed at the leve! of needle insertion. The method is simple and conven­ient way of measuring IFP. Pressure measurements are also reproducible and stable. 15 Compared to mi­cropuncture method WIN technique provided com­parable results when s.c. and hindlimb muscle IFP in rats were measured. 14 The major problem with WIN method is that it is stili traumatic (23-260 needles) to the tissue and may change local IFP due to alterations in capillary pressure, permeability and effective surface area. 15 An effect of colloid osmot­ic pressure to IFP measurements with WIN tech­nique should also be considered. The osmotic flow of fluid out of the wick, due to concentration differ­ence of proteins between interstitial fluid and phys­iologic saline in wick, can lower the value of the measured pressure. However, Fadnes et al. pro­posed that small fluid volume contained in the wick prevents this artifact. 15 To minimize osmotic influ­ence furthermore, heparinized (70 units / ml) physi­ologic saline can be used instead of pure physiolog­
16 21 
ic saline.8•· In tumor IFP measurement the accu­rate position or depth (e.g. in steps of 0.1 mm) of the interface spot of the needle can not be deter­mined, however, the evaluation of needle position in tumor can be done. 10 
Micropuncture (MP) technique 
The method was first used by Wiederhielm et al. in 1964.'4 Sharpened glass capillary (micropipette) with tip diameter of 1-4 mm is connected to a servocontrolled counterpressure device. A micropi­pette is filed with 0.5M NaCl solution colored with Evans blue dye. 14 As in WIN technique, the water column is used to measure the pressure exerted by the interstitial fluid to pipette fluid. Servocontrolled counterpressure system responds to the changes in the electrical resistance in the pipette tip. The in­creasing of the fluid pressure surrounding the pi­pette tip causes the tendency of this fluid to enter the pipette. Therefore, the resistance increases and the servosystem applies a counterpressure to obtain the preset resistance (equilibrium of fluids). 14 Since micropipettes are very fragile, a micromanipulator is needed to maneuver it. This also requires the immobilization of the tissue, usually implying gen­eral anesthesia and that insertion of mir::ropipette into the tissue is performed under a guidance of a microscope. 14 The calibration of MP method is the same as in WIN technique but can also be done in a saline test chamber. 5 Guyton et al. in their study characterized MP technique as a method which is only capable of measuring total tissue pressure since it needs larger free-fluid spaces that are those in usual normal tissue. 13 Later Wiig et al. suggested that the requirement for IFP measurement with MP 

lnterstital.fluid pressure as an obstacle in trea/ment rlsolid tumors 
technique is not free fluid but the possibility of moving fractions of nanoliters of fluid into or out of the pipette. 14 They also proposed that the MP tech­nique is the most reliable method for measuring IFP available today. Due to guidance of micropi­pette with micromanipulator very accurate posi­tions (depths) of measurement points could be de­termined. Disadvantages of the method, however, are fragility of the mieropipettes, urgent immobili­zation of the tissue, Iimited insertion range com­pared to WIN technique, and that the stretching or the compressing of the tissue, due to micropipette withdrawal or insertion, causes lower of higher pres­sures, respectively. 14 
Changes in IFP due to different treatment approaches 

In 1950 Young et al. first demonstrated that IFP in solid tumors is increased.22 Since it is known that increased IFP impedes the antitumor treatment many studies were performed to reduce it. 
Hyperthermia 
Hyperthermia is a cancer treatment where tumor is exposed to overheating with temperature up to 42­450C or higher.23 In their research Leunig et al. found out that local hyperthermia at 43°C for 60 min reduces IFP value in amelanotic melanoma A­Mel-3 from 1675.8 Pa to 106.4 Pa.24 They assumed that the main reason for lowering IFP was the re­duction of a local MVP to zero due to impaired tumor microvasculature. Their theory was that at the beginning of hyperthermia blood flow in tumor may increase, thus bringing more drug to the tu­mor. Later, when the reduction of blood flow be­gins, drug remains in tumor. Therefore, decreased IFP may increase the delivery of the drug to the tumor by facilitating the extravasation and by re­dueing the washing out of the drug.24 On the other hand, 1-Iauek et al. treated D-54MG glioma xe­nograft with the exposure to 41.8°C for 4h. They observed no changes in IFP after the tumor treat­ment.25 Inconsistency of bolh studies could be a result of different treatment protocoles as well as different tumor models. Nevertheless, further stud­ies are needed to determine whether hyperthermia has an effect on IFP. 
Radiation 
Radiation is one of the conventional antitumor treat­ments, 1 but the hypoxic nature of the tumor usually impedes the radiation effectiveness."'6 In this field of interest the question appears, how does the radia­tion affect IFP. Znati et al. investigated the effect of radiation on the IFP and determined the mini­mum dose required to affect IFP. 16 They used xe­nografts of LS 174T human colon adenocarcinoma. The radiation dose below I O Gy (2x2.5 Gy) did not significantly change IFP, whereas doses of I O Gy and above (2x5 Gy and 2xl O Gy) decreased IFP value for 332.5 Pa (initial value was 1715.7 Pa). They also found out that the maximum reduction of IFP (35%) after the single-dose irradiation appeared 5 days after the radiation with 30 Gy and then started to increase again. The radiation of 1 O and 20 Gy reduced IFP for 19 and 23% respectively, in both cases 3 days after the irradiation. They as­sumed that the observed decrease in IFP was the result of the reduction of microvascular pressure, due to the decreased venous vascular resistance. Roh et a/. on the other hand measured IFP in carci­noma of the uterine cervix in situ after the irradia­tion.18 They found out very high values of IFP (max­imum value 5453 Pa) which exceeds that in many experimental tumors. They also measured IFP in normal uterine cervix and found it to be between O and 399 Pa. After the fraetionated irradiation from 32 to 60 Gy they observed the decrease in IFP in 4 patients, whereas in 3 patients IFP remained un­changed or increased. The mechanism that eauses the IFP reduction in some tumors and not in others remains unknown. They suggested however, that the correlation between changes in IFP and the tumor response to therapy, which they observed, could be useful in predicting a treatment outcome and in determining future strategies for treatment.18 
Vasoactive agent.1· 
Based on a hypothesis that Iocal MVP governs IFP, we can conclude that changes in MVP should result in IFP changes. To decrease (or increase) MVP two different approaches may be used: decrease (or in­crease) in mean arterial blood pressure (MABP) and increase (or decrease) in tumor venous resist­ance.21 Both physiological factors can be manipu­Iated with drugs that have the effect on vasculature (vasoactive drugs). Lee et el. studied the effects of the pentoxifylline (PTX) on IFP in FSaII murine tumors.21 They found out 55% decrease in IFP which 
Pufonjak 1 and Miklavcic D 
reached its minimum 2 hours and remained up to 4 hours at this leve! after the injection of 100 mg/kg PTX. They suggested that the observed reduction of the IFP was due to decrease in the tumor venous resistance as described in the above hypothesis. In a similar comprehensive study Zlotecki et al. ob­served changes in IFP due to five different vasoac­tive drugs and compared it with mathematical mod­el. 26 Three vasoconstricting agents angiotensin II, epinephrine, and norepinephrine increased IFP as well as MABP. However, the magnitude of increase in IFP (MFP and IFP ratio post/pre) was signifi­cantly different for each agent whereas the increase in MABP was similar. Angiotensin II increased IFP for 838 Pa, epinephrine increased it for 386 Pa and norepinephrine for 186 Pa. Initial values were be­tween 2394 and 2926 Pa. Two vasodilating agents (hydralazine and nitroglycerin) decreased IFP and MABP. Hydralazine which is a long-acting vasodi­lator causes 50% decrease in IFP (2261 Pa) over the first hour and nitroglycerin which is a short-acting vasodilator produced only small, transient 6% (173 Pa) decrease in IFP. Initial values of IFP before the hydralazine injection was 4389 Pa and before the nitroglycerin injection 2886 Pa. These results cor­relate with changes in MABP. In their study they also analysed the experimental results with a math­ematical model. Briefly, they found out that chang­es in IFP are mainly due to the effect of vasoactive agents on tumor or on the surrounding tissue vascu­Iature resistance.26 In a similar study Tveit et al. measured IFP after the administration of norepine­phrine. In contrast to the previous study of Zlotecki et al. they found out that IFP decreased form initial value of 1370 Pa to 931 Pa. This inconsistency of 
their results with results of Zlotecki et al. was not explained.26 
In addition, other studies determining the effects of hemodilution and TNF-a on IFP were also per­formed. 20-27 In both of these studies authors report the decrease of IFP. 
Conclusions 

The elevated IFP together with the heterogeneous blood supply in solid tumors are the reasons for the inadequate uptake and nonuniform distribution of the anticancer drugs (especially macromolecules).18 The main reasons for the increase in IFP are high vascular permeability and hydraulic conductivity, high tumor vascular resistance to blood flow, and Jack of functioning lymphatic system. 16 It was dem­onstrated that IFP is mainly governed by the MVP which is also increased, due to high tumor venous resistance. Therefore, MVP values in tumors are the same as IFP values.8 IFP in tumours is uniform­ly elevated throughout the tumor but drops rapidly in the periphery of the tissue-isolated tumors and at the tumor-normal tissue interface in tumors sur­
35 12 

rounded by normal tissue.2· · · This property caus­
es fluid to ooze out of tumor and thus create radia! convection of macromolecules which are located 
81618 

into the tumor.2•••
Measurement techniques currently used to meas­ure IFP in tumors are two: WIN technique and MP technique. Although MP technique is controlled by the counterpressure system and is though more ac­curate, WIN technique is, in spite of its simplicity, quite adequate to produce reliable and accurate re­sults. Both techniques however, have their benefits and weaknesses. 
Many methods were used to reduce IFP in tumors and thus optimize the anticancer drug uptake but none of them brought satisfactory results. Never­theless, elevated IFP would present very few or no problems for the antitumor treatment with a mole­cule or cell which bas nearly 100% specificity for tumor cells.2 Meanwhile, novel treatment approach­es must be found out that will eliminate these phys­iological barriers and will thus enable antitumor agents to complete their mission.2 Only a complex antitumor treatment which will affect all carcino­genic mechanisms at the same tirne will be a suc­cessful one. Better understanding in IFP represents a step towards the effective antitumor treatment. 
Appendix 

All pressure units in this article are in SI system (Pascal -[Pa]) although pressure units used in refer­ences are in mmHg. Therefore we used transforma­tion equation:28 
101325 Pa= l atm = 760 mmHg 1 mmHg = 133 Pa 
References 

1. 
Haskell CM. Cancer Treatment (third edition). Philadel­phia: W.B. Saunders Co., 1990. 

2. 
Jain RK. Delivery of novel therapeutic agents in tumors: physiological baniers and strategies. 1 Natl Cancer 1 1989; 81(8): 570-6. 


lnterstitalfluid pressure as an obstacle in treatment <ifsolid tumor.1· 
3. 
Jain RK. Baniers to drug delivery in solid lumors. Sci Am 1994; .July: 42-9. 

4. 
Jain RK. Transport of molecules in the tumor intersti­tium: a review. Cancer Res 1987; 47: 3039-51. 

5. 
Boucher Y, Baxter LT. lnterstitial pressurc gradients in tissue-isolated and subcutaneous tumors: implications for therapy. Cancer Res 1990; SO: 4478-84. 

6. 
Folkman J. Tumor angiogenesis. Adv Cancer Res 1985; 43: 175-203. 

7. 
Jain RK. Transport of molecules across tumor vascula­ture. Cancer Metast Rev 1987; 6: 559-93. 

8. 
Boucher Y, Jain RK. Microvascular pressure is the principal driving force for interstitial hypertension in solid tumors: implications for vascular collapse. Can­cer Res 1992; 52: 5110-4. 

9. 
Boucher Y, Leunig M, Jain RK. Tumor angiogenesis and interstitial hypertension. Cancer Res 1996; 56: 4264-6. 


1 O. Wiig I-1, Tveit E, I-lultborn R, Reed R, Weiss L. lntersti­lial fluid pressure in DMBA-induced rat mamary tu­mours. Scand J Ciin Lab lnv 1982; 42: 159-64. 
11. 
Jain RK, Baxter L T. Mechanisms of heterogeneous distribution of monoclonal antibodies and other rnac­romolecules in tumors: significance of elevated inter­stitial pressure. Cancer Res 1988; 48: 7022-32. 

12. 
Baxter L T, Jain RK. Transport of fluid and macromole­cules in turnors l. Role of interstitial pressure and con­vection. Microvasc Res 1989; 37: 77-104. 

13. 
Guyton AC, Granger I-IJ, Taylor AE. Interstitial fluid pressure. Physiol Rev 1971; 51: 527-63 

14. 
Wiig I-1, Reed R, Aukland K. Micropuncturc measure­rnent of inlerstitial fluid pressure in rat subcutis and sceletal muscle: comparison to wick-in-needle tcch­nique. Microvasc Res 1981; 21: 308-19. 

15. 
Fadnes I-1O, Rccd RK, Aukland K. lntcrstitial fluid prcs­sure in rats measurcd with a modified wick tcchnique. Microvasc Res 1977; 14: 27-36. 

16. 
Znati CA, Rosenstcin M, Boucher Y, Epperly MW, Bloomer WD, Jain RK. Effect of radiation on intersti­tial fl uid pressure and oxygenation in a human tumor xenograft. Cancer Res 1996; 56: 964-8. 

17. 
Boucher Y, Lee I, Jain RK. Lack of general correlation bctweeen interstitial fluid pressurc and oxygen partial pres­sure in solid tumors. Microvasc Res 1995; SO: 175-82. 


18. 
Roh I-1D, Boucher Y, Kalnicki S, Buchsbaum R, Bloom­er WD, Jain RK. lnterstitial hypertension in carcinoma of utrine cervix in patiens: possible correlation with tumor oxygenation and radiation response. Cancer Res 1991; 51: 6695-8. 

19. 
Boucher Y, Kirkwood JM, Opacic D, Desantis M, Jain RK. lntcrstitial hypertension in superficial metastatic rnelanomas in humans. Cancer Res 1991; 51: 6691-4. 

20. 
Lee I, Demhartner TJ, Boucher Y, Jain RK, lntaglietta 


M. Effect of hemodilution and resuscitation on tumor interstitial fluid pressure, blood flow, and oxygenation. Microvasc Res 1994; 48: 1-12. 

21. 
Lee I, Boucher Y, Demhartner TJ, Jain RK. Changes in tumor blood flow, oxygenation and interstitial fluid pressure induced by pentoxifylline. Brit J Cancer 1994; 69: 492-6. 

22. 
Young JS, Lumsden CE, Stalker AL. The significance of the "tissue pressurc" of normal testicular and of neoplastic (Brown-Pearce carcinoma) tissue in the rab­bit. J Patlwl Bacteriol 1950; 62: 313-33. 

23. 
I-lahn GM. I-lyperthermia for the engineer: a short bio­logical primer. IEEE Transactions on Biomedical En­gineering 1984; BME-31(1): 1-16. 

24. 
Leunig M, Goetz AE, Dellian M, Zetterer G, Gamarra F, Jain RK, Messmer K. Interstitial fluid pressure in solid tumors following hypertherrnia: possible correla­tion with therapeutic rasponse. Cancer Res 1992; 52: 487-90. 

25. 
I-lauck ML, Coffin DO, Dodge RK, Dewhirst MW, Mitchell JB, Zalutsky MR. A local hypertherrnia treat­ment which enhances antibody uptake in a glioma xe­nograft model docs not affect tumour interstitial fluid pressure. lntemational Journal 1!{ Hyperthermia 1997; 13: 307-16. 

26. 
Zlotecki RA, Baxter LT, Bouchcr Y, Jain RK. Pharma­cologic modification of tumor blood flow and intersti­tial fluid pressure in a human xenograft: network anal­ysis and mechanistic interpretation. Microvasc Res 1995; SO: 429-43. 

27. 
Kristensen CA, Nouze M, Boucher Y, Jain RK. Reduc­tion of interstitial fluid pressure after TNF-a treatment of three human melanoma xenografts. Brit J Cancer 1996; 74: 533-6. 

28. 
Illingworth V. The Penguin Dictionwy <!f Physics (sec­ond edition). Middlesex: Penguin Books, 1991, p. 535. 


Radio! Oncol l 997; 31: 298-304. 


The urokinase-type plasminogen activator, its inhibitors and its receptor -the new prognostic factors in solid cancers 


Simona Borštnar, Tanja Cufer and Zvonimir Rudolf 
Institute oj Oncology, Ljubljana, Slovenia 






The urokinase-type plasminogen activator (uPA), its inhibitors (PA!-] and PAI-2) and its receptor (uPAR) play an important role in the degradation oj the intercellular tissue, the process which affects the ability oj cancer cells to invade to surrounding tissue and to metastasize. The results oj clinical studies perf ormed in the past few years point out a significant influence oj uPA, PAI-1, PAI-2 a,ul uPAR on the course oj the disease and survival oj patients with solid tumours, particularly breast cancer. Hopefully the categorization oj patients according to the content oj the serine proteases and its inhibitors in tumour tissues could provide a basis for more rational treatment planning and thus improving patients' survival. 

Key words: neoplasms; prognosis; urokinase; plasminogen inactivators; serine proteinases 




Introduction 




The projection of the progression of the disease and hence the prognosis for each individual patient is of extreme importance in clinical oncology. The treat­ment strategy of solid tumours is nowadays based on the established prognostic factors, such as the patho-histological type, the size of the tumour, and the stage of the disease, but the survival statistics of individual groups of patients with the same values of these prognostic factors is stili diversified. There­fore, the main objective of the research work is to find those tumour characteristics which would ena­ble us to <liscem !ess biologically aggressive tu­mours from the more aggressive ones. In recent years, the methods of molecular biology have helped to identify a number of new factors associated with the differentiation and proliferation of cancer cells, such as: Ki67, cyclin DI, the proportion of cells in S phase of the cell cycle, various growth factors and oncogenes. Although these factors have been proven to influence the differentiation and prolifer-
Correspondence to: Simona Borštnar, Institute of Oncology, Zaloška 2, l l 05 Ljubljana, Slovenia. 



ation of cancer cells, their value as prognostic fac­tors is still questionable. It was found that the abili­ty of cancer cells to invade the surrounding tissue and form distant metastases rather than the differ­entiation and proliferation of cancer cells is of vita! importance for the prognosis of a particular pa­tients. Therefore, an increasing number of investi­gations have been dedicated to the study of factors which define tumor invasiveness. 
The research in vitro showed that the invasion of tumour cells in the neighboring tissue and the for­mation of metastases depend significantly on the content of proteases in the tumor tissue.1•2" There are four recognized classes of proteases: cisteine proteases, (cathepsin B, 1-I and L), aspartyl proteas­es (cathepsin D), metalloproteases (gelatinases, col­lagenases, stromelysins) and serine proteases (plas­minogen activators and the product of their activa­tion -plasmin). Metalloproteases play an important role in the invasion and metastatic growth of tu­mours in animals, but their significance for tumours in humans is stili not totally clear.4 Cysteine pro­teases and the cathepsin C have a proteolytic effect on the intercellular tissue and they are especially important for the 
activation of the urokinase-type 
UDC: 616-006.6'036:612.015.13 plasminogen activator.4·5 .6 
The uroki11ase-type plasmi11ogen octivo/111; its i11hibitor,1· 011d its receptor 
The research work carried out over the last few years revealed a most important prognostic rele­vance of serine proteases.3 There are two types of serine proteases -plasminogen activators: the tis­sue plasminogen activator (tPA) and the urokinase­type plasminogen activator (uPA). The tPA is most­ly present in the blood, where it participates in the intra vascular thrombolysis. 1•3 The uPA is found mostly in the tumour tissue, where it plays, togeth­er with its inhibitors and receptor, a most important part in the activation and regulation of the tumour associated proteolysis in man.3 
Malignant cells, as well as macrophages and fibrob­lasts, present in tumours produce an inactive pro­enzyme (pro-uP A), which is bound to a specific re­ceptor on the cellular membrane -to the uPAR. Through the activation of the cathepsin B and L, the cathepsin D and the plasmin transform the pro-uPA into the active form uPA. The uPA triggers off a cascade-like transformation of plasminogen into the active proteolytic enzyme plasmin, which disintegrates intercellular proteins (fibrin, fibronectin, proteogly­cane and laminin) and which indirectly induces base­ment membranes degradation by the procollagenase IV activation (Figure 1).1.3·5•6 At the same tirne, the proteolytic activity of the uPA produced by malignant cells and macrophages induces the formation of ang­iogenic factors and hence the neo-vascularization both in the primary tumours margins and in metastases. Apart from the presence of proteolytic enzymes, neo­vascularisation is the most important factor for the local growth and metastatie potential of tumours.5 
Proteolysis is also strongly affected by the inhib­itors of the plasminogen activator. The most rele­vant of the four known types are the plasminogen activator inhibitor type 1 (PAI-1) and the plasmino­gen activator inhibitor type 2 (PAI-2). The capacity of the PAI-2 asa pure plasminogen activator inhib­itor is clear and straightforward. Contrary to what is known about the PAI-2, clinical research results display a stronger metastatic potential of tumours with high PAI-1 levels.7·x.9 That may result from the PAI-1 protecting malignant cells against self-de­struction or, another possible explanation, from the PAI-1 functioning as a biochemical marker of ang­iogenesis.9 The activation of the uPA is possible only after its binding to the receptor. The uPAR presence in the membranes of ttunour cells is much more pronounced than in normal tissues.6 In some instances the presence of the uP AR in breast tissue was detected in the tumour itself but not in the normal tissue of the breast. JO The blockade of the uP AR with monoclonal antibodies was found to prevent the invasion of tumour cells through the basement membrane. 
~-· cathcpsin B, L 

pro-uPA -----.. u-PA 1. PAI-1/2 
!~ 
l pro-collagenascs 
y 
plasminogcn -----.. plasmin -----,... 
! 


Figure l. Scheme of the u-PA catalyzed plasminogen­plasmin cascade. Dashed line indicate inhibition. (u-PA -thc urokinasc type plasminogen activator, PAI-1/2 -plasminogen activator inhibitor typc 1/2, u-PAR -specific receptor for u-PA). 
The evaluation of the content of the uPA, PAI-1, PAI-2 and uPAR in tumours can be biochemical and immuno-histochemical. The biochemical meth­od has been applied more frequently in the research performed so far. It involves the extraction of the urokinase system components with special puffers and detergents, and their evaluation with mono­clonal antibodies. The referential values depend on the use and on the type of detergent. The best ex­traction can be obtained with the addition of the triton detergent. 12 The comparison of the values of the uPA content in the tissue of breast carcinoma obtained with biochemical and immuno-histologi­cal methods showed good correlation.13 
The prognostic significance of uPA, PAl-1, PAI­2 and uP AR for different types of cancer 
Breast cancer 
By far the greatest number of studies on the prog­nostic significance of the uPA system components have been made for breast cancer, the most fre­quent type of cancer in women, the incidence of which has been on the increase. 14 The primary treat­ment of breast eancer is devised with respect to the established prognostic factors, such as the size of the tumour, the histological type and the gradus of the tumour, the axillary lymph nodes involvement and the presence of the hormone receptors in the 
Borštnar S et al. 
tumour. 15 Additional prognostic factors are being intensely investigated and the serine proteases be­ing among the most promising ones. 16 
A number of studies proved that the levels of the uPA, PAI-1, PAI-2 and uPAR in the breast carcino­ma tissue are considerably higher than in benign tumours and in normal breast tissues. l.3· 17·1x The con­tent of the uPA can be 11 times, 13 the content of its inhibitor PAI-1 74 times and the content its inhibi­tor PAI-2 29 limes higher in malignant that in be­nign breast tumours. 19 The leve! of the tPA is the same in malignant and in benign breast tumours. 3•20 
The uP A content in the tumour tissue does not correlate with other components of the uPA system and with common prognostic factors, 13·19 The PAI-1 correlates inversely with hormone receptors.8 The PAI-2 correlates inversely with the size of the tu­mour and positive with the age of patients.21 The uPAR correlates inversely with the estrogen recep­tors. 22 
Most of the clinical research has identified bolh the uPA and the PAI-1 as independent prognostic factors for breast cancer. Higher values of both uPA and PAI-1 in primary tumour are not only associated with higher risk of recurrence, but also significantly influence the overall survi val rates. The question of a prognostic value of uP A and its inhibitor in prognostically different sub-groups of 
913172324 25 
patients remains unsolved.7· · ••••While they 
have both proved to be independent prognostic fac­tors in the subgroup of patients with positive lymph nodes,7•8•23 the uPA has not been established as an independent prognostic factor in the group of pa­tients with negative axillary lymph nodes.23 Only one study with small number of patients enrolled reports results supporting the uPA as an independ­ent prognostic factor in this group of patients as well.6 While a study involving over 600 patients revealed only the PAI-1 as an independent prognos­tic factor in patients with negative axillary lymph nodes.7 
The prognostic value improves with the combi­nation of individual system components. In patients with a high leve! of uPA content in primary tu­mours, the high leve! of PAI-2 is an independent prognostic factor while those with low PAI-2 levels have poor prognosis, 21 which is to be expected in the light of the function of the PAI-2 asa pure uPA inhibitor. 
The uPAR has not proved to be such a strong prognostic factor as the uPA and the PAI-1 are. However, patients with a higher leve! of the uPAR in the breast tumour have significantly shorter re­lapse-free and overall survival19 and the uPAR has proved to be an independent prognostic factor in the sub-group of post-menopausal patients with pos­itive axillary lymph nodes.22 
The components of the uPA system are not only prognostic but also predictive factors in breast can­cer patients. In the study of 274 patients Foeckens et al. observed that the response to hormona! thera­py with tamoxifen was better in patients with low levels of uPA, PAI-1 and uPAR and a high leve! of PAI-2 in tumour tissue. 26 
Ovarian cancer 
The established prognostic factors for the ovarian cancer are the performance status, the stage of the disease, the histological type of cancer, the age of the patient, the tumour gradus, the size of the resid­ual tumour after surgery and the presence or ab­sence of ascites.27 
The prognostic significance of the uP A system has been investigated for the ovarian cancer, too, but the studies are few and the number of patients involved is small. 
The levels of the uPA, PAI-1 and uPAR were found to be significantly higher in the malignant tissue than in the benign tumours of ovaries,28•4 which does not apply to the PAI-2.4 The uPA was found to positively correlate with the number of metastatically involved lymph nodes, less differen­tiated tumours and excessive production of ascites.28 
A study of 51 patients with advanced ovarian carcinoma (FIGOIII) revealed that the patients with lower levels of uPA and PAI-1 in the tumour had better prognosis.2x In addition to the size of the residual tumour, the uPA and the PAI-1 levels proved to be the most reliable independent prog­nostic factors for patients with advanced ovarian carcinoma. The uPA and the PAI-1 levels were especially significant in the group of patients with no residual tumour. 2x These are the patients with relatively good prognoses, but their 5-year survival rate is stili around 55%.29 The evaluation of the components of the uPA system offers the possibili­ty to find those with less favorable prognoses among these patients, and to adjust their treatment accord­ingly. 28 
A high content of the PAI-2 in the ascites of the patients with ovarian carcinoma proved to be an independent prognostic factor of the unfavorable outcome of the disease,30 which is a surprising re­

The urokinase-type plasminogen activato1; its inhibitor.,· and its receptor :101 
suit in the light of the capaeity of the PAI-2 as a pure uPA inhibitor. The leve! of the PAI-2 in the tumour was not measured in this study.J0 
Cervical cancer 
The strongest prognostic factors of cervical cancer is the stage of the disease. Other prognostic factors are the size of the tumour, the amount of the cervi­cal stroma involved, the involvement of lymphatic vessels and the presence of metastases in lymph nodes.J' 
There are few data in literature on the prognostic relevance of the Ievels of the uPA system compo­nents for cervical cancer. A elinical study involving 62 patients revealed a correlation between high lev­els of the uPA ancl/or PAI-1 in the tumour and the number of involvecl Iymph nodes. High Ievels of the uPA significantly correlated with relapse free survival, and high Ievels of the PAI-I with early relapses ancl shorter survival.32 
The inclependent prognostic values of the uPA system components for the outcome of cervical can­cer has not been stuclied yet.J2 
Lung cancer 
The prognostic relevance of the uPA system com­ponents has been examinecl in three histological types of pulmonary carcinoma: adenocarcinoma, squamous celi carcinoma ancl Iarge celi carcino­
ma. JJ.34 
A clinical stucly involving !06 patients with pul­
monary aclenocarcinoma showed that the leve! of 
the PAI-1 clicl not correlate with other prognostic 
factors, such as the age and sex of the patient, the 
stage of the clisease, the size of the tumour, the number of the involecl lymph 110des ancl the surgical raclicality. However, the uPA levels were statisti­cally significantly higher in old patients.33 The uPA ancl PAI-1 values clicl not correlate with each oth­er.33 High Ievels of the PAI-1 in the tumour tissue of patients with pulmonary carcinoma significantly correlated with poor survival, whieh was not the case for the uPA.33 The multi-variant analysis showecl that the PAI-1 is an independent prognostic factor for the survival of patients in stages !-III of the clisease. The PAI-1 proved to be an inclepenclent prognostie factor also for patients in a prognostical­ly favorable stage I of the clisease. This fact sug­gests a possible selection of patients qualifying for acljuvant treatment after the surgical removal of pulmonary carcinoma. 33 
A study of the squamous celi canccr of Iungs in 84 patients showed positive correlation belwecn the uPAR ancl the PAI-1.34 None of the uPA systcrn components correlatecl with other prognostic fac­tors. Thc uPA and the PAi-! did not havc any impact on the outcomc of the diseasc, but lhc uP AR correlated significantly with survival.34 Besidcs the size of the turnour, the uPAR was the only addilion­al prognostic factor in squarnous celi pulmonary 
34 

cancer.
In half a smaller group of patients affected by the Iarge celi cancer a correlation was found betwcen the uPAR and PAI-1, and the uPAR and uPA.1· 1 None of the components of the uPA system corrc­lated with other prognostic factors.J4 None of the components of the uPA system had any impact on the outcome of large celi cancer.14 
Gastric cancer 
A number of studies of the prognostic relevancc of the uPA system components in gastric canccr pa­tients have been made. Herc, too, the content of uPA was found significantly higher in the carcino­ma tissue than in the normal mucosa of the stom-­ach.35 The uPA significantly correlated with lhc established prognostic factors of gastric canccr. Higher levels of the uPA were found in more acl­vanced stages of the disease, positivc Iymph nodcs and less clifferentiated tumours.35 
The uPA, the uPAR and the PAI-1 wcrc found to inversely correlate with the length of survival. PAI-2 did not show any impact on the oulcomc the disease.36 Two clinical studies of 203 16 and 97 
3718 
·patients with resectable gastric cancer idcnli­fied only the PAI-1 as an independent nffHmn,1 
18

factor of survival in ali patients, 37·•19 as well as 
subgroups of patients in pathological stagc 
and pNl/2Y' 
Besides the PAi-!, the uPA and the uPAR 
to be indepenclent prognostic factors in thc 
group of patients with diffusc type of gastric carci-­
noma.36 None of the three was confirmed as such 
the subgroup of patients with intestinal type of 
trie carcinoma.36 
Colorectal cancer 
In acldition to the establishcd prognoslic factors colorectal cancer, such as the stagc of thc diseasc and surgical radicallity,39·40 other prognostic factors have been examined, and among them serinc pro­teases are the most promising ones. 
Borftnar Set al. 
Compared with normal mucosa, colon tumours have higher levels of the uPA 41 .42 and its inhibitors PAI-1 and PAl-2, 42.43 and lower levels of the tPA.42 
In the clinical study of 92 patients with colorectal cancer, Ganesh et al. report a positive correlation between the uPA content in the tumour and survival of patients, whereas the P Al-1 did not show any prognostic relevance. 42 
However the PAl-2 content in tumour inversely correlated with survival,42 which is surprising and contrary to the results obtained on breast cancer, where high levels of the PAI-2 in tumours represent a favorable prognostic factor. A high leve! of the uP AR in the tumour was associated with shorter survival of patients.44 
Brain tumours 
The established prognostic factors for brain tumours are the age and the performance status, the radical­lity of tumour resection and the histological type of the tumour.45 Patients with high levels of the uPA in malignant brain tumours or in metastases of Jung cancer, breast cancer, colon cancer or of malignant melanoma, have significantly poorer prognosis.46 
Two clinical studies involving a small number of patients showed that the uPA as well as PA[-! levels are significantly higher in malignant astrocy­toma, especially in glioblastoma, than in the low­gradus glioma and normal brain tissue.46.47 Neither of the two studies examined the correlation be­tween serine proteases and the usual prognostic factors. Independent prognostic valucs of the uPA system components for the outcome of brain tu­mours have not bccn examined in studies made so far. 
Bladder cancer 
Nowadays the depth of invasion and tumour grade are considered to be the most relevant prognostic factors of invasive bladder cancer.48 

According to the data available, the possible role of uP A as a prognostic factor in bladder cancer has been reported only by Hasui et al. They found high­er levels of thc uP A in cancer tissue than in normal urinary bladder tissue and its content increased with the depth of the invasion and the gradus of the tumour.49 A higher leve! of the uPA in the tumour was significantly associated with the local relapse and growth of non-invasive tumours and with the survival of patients with invasive cancer.50•51 
The indepcndent prognostic value of the uPA was not detcrmincd due to the small number of patients involved in this studies. 
Conclusion 
The urokinase type plasminogen activator, its inhibi­tors and receptors have proved to be independent prognostic factors in breast cancer patients. In breast cancer, serine proteases may also predict the re­sponse to hormona! therapy. According to the results of the research performed so far, the uP A and its inhibitors content in tumour tissue also affects the prognosis of patients with many other solid cancers such as ovarian, Jung, gastric, bladder cancer etc . 
Hopefully on the basis the serine proteases, their inhibitors and receptor determination in tumour tis­sue it will be possible to differentiate between bio­logically more and less aggressive tumours in the future. This would enable to select the most suita­ble treatment for individual patients and thus im­prove the patients survival. 
References 
l. Dans>l K, Andreasen PA, Gr0ndahl-Hansen J, Kristensen P, Nielsen LS, Skriver L. Plasminogen activators, tissue degra­dation, and cancer. Adv Cancer Res 1985; 44: 139-266. 
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Markus G. The relevance of plasminogen activators to neoplastic growth. Enzyme 1988; 40: 158-72. 

3. 
Schmitt M, Janicke F, Graeff H. Tumor-associated pro­teases. Fibrinolysis 1992; 6: 3-26. 

4. 
Schmalfeldt B, Kuhn W, Reuning U et al. Primary tumor and metastasis in ovarian cancer differ in their content of urokinase-lype plasminogen activator, its receptor, and inhibitors types l and 2. Ca11cer Res 1995; 55: 3958-63. 

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Hildenbrand R, Dilger I, Hiirlin A, Stutte HJ. Urokinase and macrophages in tumour angiogenesis. Br J Cancer 1995; 72: 818-23. 

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Conesi M, Blasi F. The urokinase/urokinase-receptor sys­tem and cancer invasion. Bailiere's Clinical Haematolo­gy 1995; 8: 365-8. 

7. 
Foekens JA, Schmitt M, van Putten WLJ et al. Plasmino­gen activator inhibitor-! and prognosis in primary breast cancer. J Ciin Onco/ 1994; 12: 1648-58. 

8. 
Janicke F, Schmitt M, Pache Let al. Urokinase (uPA) and its inhibitor PAI-1 are strong and independent prog­nostic factors in node-negative breast cancer. Breast Can­cer Res Treat 1993; 24: 195-208. 

9. 
Grs>lndahl-Hansen J, Christensen IJ, Rosenquist C et al. High levels of urokinase-type plasminogen activator and its inhibitor PAi-! in cytosolic extracts of breast carcino­mas are associated with poor prognosis. Cancer Res 1993; 53: 2513-21. 



The urokinase-type plasminogen activato1; its inhibitor.1· and its receptor 
1 O. Needham G, Sherbet GV, Farndon JR ct al. Binding of urokinase to specific receptor sitcs on human brcast canccr membranes. Br J Cancer 1987; 55: 13-6. 
11. 
Mohanam S, Sawaya R, McCutchcon R, Ali-Osman F, Boyd D, Rao JS. Modulation of in vitro invasion of human glioblastoma cclls by urokinase-type plasmino­gen-activator-receptor antibody. Cancer Res 1993; 53: 4143. 

12. 
R0nne E, Hy:1yer-Hansen G, Briinncr N et al. Urokinase receptor in brcast cancer tissuc extracts. Enzyme-linked immunosorbent assay with a combination of mono­and polyclonal antibodies. Breast Cancer Res Treat 1995; 33: 199-207. 

13. 
Jiinickc F, Schmitt M, Hafler R et al. Urokinase-type plasminogen activator (u-PA) antigen is a predictor of early relapse in breast cancer. Fibrinolysis 1990; 4: 69­78. 

14. 
Gjorgov AN. Emerging worldwide trends of breast can­cer incidence in 1970s and l 980s: data from 23 cancer registration centers. Eur J Cancer Prev 1993; 2: 423­40. 

15. 
Cufer T. Prognostic factors in breast cancer. Radio/ Oncol 1995; 29: 311-7. 

16. 
Knoop As, LacenkholmA V, Mirza MR, Hansen S, Thorpe SM, Rose C. Prognostic and predictive.fi1ctors in early breast cancer. ESMO Meeting; 1994 Nov. 19; Lisbon. Portugal. Educational Book. European Society for Medica! Oncology, 1994. 

17. 
Duffy MJ, Rcilly D, O'Sullivan C, O'Higgins N, Fen­nelly JJ, Andreasen P. Urokinase-plasminogen activa­tor, a ncw and independent prognostic marker in breast canccr. Cancer Res 1990; 50: 6827-9. 

18. 
Foucre D, Bouchet C, Hacenc K et al. Relationship between cathepsin D, urokinasc, and plasminogen acti­vator inchibitors in malignant vs benign breast tumours. Br J Cancer 1991; 64: 926-32. 

19. 
Duggan C, Maguire T, McDermott E, O'Higgins N, Fennelly JJ, Duffy MJ. Urokinase plasminogen activa­tor and urokinase plasminogcn activator receptor in brcast cancer. lnt J Cancer 1995; 61: 597-600. 

20. 
Jankun J, McITick HW, Goldblatt PJ. Expression and localization of elements of the plasminogen activation system in benign breast disease and breast cancers. J Celi Biol 1993; 53: 135-44. 

21. 
Foekens JA, Buesseckcr F, Peters HA et al. Plasmino­gen activator inhibitor-2: prognostic rclevance in 1012 patients with primary breast cancer. Cancer Res 1995; 55: 1423-7. 

22. 
Gr0ndahl-Hansen J, Peters HA, van Putten WLJ, Look MP, Pappot H et al. Prognostic significance of the re­ceptor for urokinase plasminogen activator in breast cancer. Ciin Cancer Res 1995; 1: 1079-1087. 

23. 
Duffy MJ, Reilly D, McDermolt E, O'Higgins N, Fen­nelly JJ, Andreasen PA. Urokinase plasminogen acti­vator as a prognostic marker in different subgroups of patients with breast cancer. Cancer 1994; 74: 2276-80. 

24. 
Spyratos F, Mmtin PM, Hacene K ct al. Multiparametric prognostic evaluation of biological factors in primary breast cancer. J Natl Cancer Jnst 1992; 84: 1266-72. 


25. 
Bouchet C, Spyratos F, Martin PM, 1-lacene K, Gcntilc A, Oglobine J. Prognostic value of urokinase-type plas­minogen activator (uPA) and plasminogen activator inhibitors PAi-! and PAl-2 in breast carcinomas. Br J Cancer 1994; 69: 398-405. 

26. 
Foeckens JA, Look MOP, Petcrs HA et al. Urokinasc­typc plasminogen activator and its inhibitor PAII: pre­dictors of poor responsc to tamoxifen therapy in recur­rent breast cancer. J.Nat. Cancer lns 1995; 87: 751-6. 

27. 
Ncijt JP. Ovarian cancer: rethinking prognostic fac­tors (lJUf chemotherapy. American Society of Clinical Oncology: Bostrom Corporation for the American So­cicty of Clinical Oncology , 1994: 214-20. 

28. 
Kuhn W, Pache L, Schmalfeldt Bet al. Urokinase (uPA) and PAi-! predict survival in advanced ovarian cancer patients (FIGO III) after radical surgery and platinum­based chemotherapy. Gynecol Oncol 1994; 55: 401-9. 

29. 
Petlersson F (ed.). Annual report of thc results of trcat­ment in gynecological cancer. lnt J Gynecol Obstetr 1991; 21: l-315. 

30. 
Chambers SK, Ge11z RE, lvins CM, Kacinski BM. The significance of urokinase-type plasminogen activator, its inchibitors and its receptor in ascites of patients with epitehelial ovarian canccr. Cancer 1995; 75: 1627-33. 

31. 
Benda JA. Pathology of cervical carcinoma and its prognostic implications. Semin Oncol 1994; 21: 3-11. 

32. 
Kobayashi H, Fujishiro S, Terao T. lmpact of uroki­nase-type plasminogen activator and its inhibitor typc 1 on prognosis in cervical cancer of the utcrus. Cancer Res 1994; 54: 6539-48. 

33. 
Pedersen H, Grl')ndahl-Hansen J, Francis Det al. Urok­inase and plasminogcn activator inhibitor type I in pulmonary adenocarcinoma. Cancer Res 1994; 54: 120-3 

34. 
Pcderscn H, Briinner N , Francis D ct al. Prognostic impact of urokinase, urokinasc receptor, and typc I plas­minogen activator inhibitor in squamous and largc Jung cancer tissue. Cancer Res 1994; 54: 4671-5. 

35. 
Umehara Y, Kimura T, Yoshida M, Oba N, 1--Iarada Y. Relalionship between plasminogen activators and stom­ach carcinoma stage. Acta Oncologica 1991; 30: 815­8. 

36. 
Heiss MM, Babic R, Allgayer H ct al. Tumor-associat­cd proleolysis and prognosis: new functional risk fac­tors in gastric cancer defincd by the urokinase-type plasminogen activator system. J Ciin Oncol 1995; 13: 2084-93. 

37. 
Nekarda H, Schmitt M, Ulm K et al. Prognostic impact of urokinase-type plasminogen activator and its inhibi­tor PAi-! in completely resected gastric cancer. Can­cer Res 1994; 54: 2900-7. 

38. 
Nekarda H, Siewe1t JR, Schmitt M, Ulm K. Tumour­associated protcolytic factors uPA and PAi-! and sur­vival in totally resected gastric cancer. l..ancet 1994; 343: 117. 

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Bcahrs OH, Henson DE, Hutter RVP, Kennedy BJ (eds). AJCC Manual .fi1r staging 1!{ cancer (4th ed.). Philadelphia: Lippincott, l 992. 




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41. 
De Bruin PAF, Griffioen G, Verspaget HW, Verheijen JH, Dooijewaard et al. Plasminogcn activators and tu­mor development in lhc human colon: activity levels in normal mucosa, adenomatous polyps, and adenocarci­nomas. Cancer Res 1987; 48: 4520-4. 

42. 
Ganesh S, Sier CFM, Griffioen G et al. Prognostic rele­vance of plasminogen activators and their inhibitors in colorectal cancer. Cancer Res 1994; 54: 4065-71. 

43. 
Sicr CFM, Verspaget HW, Griffioen G, Verheeijen JH, Quax PHA ct al. Imbalance of plasminogen activalors and their inhibitors in human colorectal ncoplasia. Im­plication of uroki nase in colorectal carcinogcnesis. Gas­troenterology 1991; 101: 1522-8. 

44. 
Gancsh S, Sier CFM, Hcerdling MM et al. Urokinase receptor and colorectal cancer survival. Lancet 1994; 344: 401-2. 

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Levin V A, Gutin PH, Leibel S. Neoplasms of the cen­tral nervous system. In: De Vita JR, Hellman S, Rosen­berg SA, eds. Cancer: Principles and Practice 11{' On­cology. Philadelphia: JB Lippincolt, 1993: 1679-737. 


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Bindal AK, Hammoud M, Shi WM, Wu SZ, Sawaya R, Rao JS. Prognoslic significance of proteolytic enzymes in human brain tumors. J Neuro Oncol 1994; 22: 101­10. 

47. 
Yamamoto M, Sawaya R, Mohanam S ct al. Activities, Localisations, and roles of serine proteases and their inhibitors in human brain tumor progression. J Neuro­Oncol 1994; 22:139-51. 

48. 
Scher H, Shiplcy WU, Herr H. Cancer of the Bladder. In: De Vita VT , Helman S, Rosenberg SA., eds. Can­cer: principles and practice in oncology. 5th ed. Phila­delphia, PA: Lippincott Co,1997: 1300-2. 

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Hasni Y, Suzumiya J, Marutsuka K, Smniyoshi A, Hashida S, Ishikawa E. Comparative study of plasmi­nogan activators in cancers and normal mucosae of human urinary bladder. Cancer Res 1989; 49: 1067­70. 

50. 
Hasni Y, Marutsuka K, Suzumiya J, Kitada S, Osada Y, Sumiyoshi A. The content of urokinase-type plasmino­gen activator antigen as a prognostic factor in urinary bladder canccr. Int J Cancer 1992; 50: 871-3. 

51. 
Hasui Y, Marutsuka K, Nishi S, Kitada S, Osada Y, Sumiyoshi. The content of urokinase-type plasmino­gen activator and tumor recurrence in superficial blad­der cancer. J Urol 1994; 151: 16-20. 



Radio! Oncol 1997; 31: 305-8. 




Interferon alpha (IFN-a) in treatment of malignant diseases 
Berta Jereb 
Institute of Oncology, Ljubljana, Slovenia 
There are severa! natura! varieties of IFN-a in clinical use. Although IFNs were the first cytokines in use as a new treatment modality, we stili know little about their mode of action in malignancies. IFN-a can inhibit cell growth, but it has been shown only recently, 

on malignant cells from patients with multiple myeloma, 
that IFN-a can exert a direct cytotoxic effect on tumor cel/s. The treatment with natura! leucocyte IFN-a in doses used in the early clinical tria/s, are stili most widely used. It has been slwwn that through 
a high /ocal concenlration by local application in malignant melanoma, basalioma, pleural carcinosis, glioblastoma, 
total local tumor con/rol may be achieved. It is thus not known ,vhat the optimal doses of IFN-a are, and they may va,y by the tumor type, as well as from patient to patient. The neccessary duration of treatment 
also remains cm open question. IFNs are a tool far treatment of malignant tumors. Their cytotoxic ejfect, however, is not strong 
enough and does 
not last. At present, there is a vasi jželd of investigative work stil! open -but in the meantime it seems necessal)' to proceed with clinical trials of dif.ferent types of IFN, the natura! IFN-a again beeing the most interesting one. 
Key words: neoplasms-drng therapy; interferon-alpha 

Introduction 

The antiviral and antitumor efficacy of interferon alpha (IFN-a) has been established in the l 960's and l 970's.e1 During the l 970's it was demonstrated that IFN-a has an affects on benign and malignant tumors in man, but the question was whether this was due to the presence of IFN-a or contaminating substances in the preparations.24 By 1979, recombi­nant human IFN-a had been produced in an almost pure form, thus the antitumor effect of IFN-a in man could be established.5•7e
The natura! IFN-a contains severa! species of IFN-a. Individual IFN-a subtypes have been isolat­ed and they have specific activities according to 
Correspondence to: Prof. Berta Jereb, M.D., Ph.D., Institute of Oncology, Zaloška 2, 1105 Ljubljana, Slovenia. Fax: +386611314180. 
UDC: 616-006.6-091.85:615.277.3 


the celi on which they are tested. Much effort has gone into attempts to isolate and purify single sub­types of IFN-a. The natura! mixture of IFN-a, how­ever, seems to be more active than any of its com­ponents: synergistic interactions might exist among IFN-a components. Consequently, new interest was aroused in the natura! IFN-a.e8 
There are severa! natura! varieties of IFN-a in clinical use. IFNs affect thc organism and the tumor in a number of ways. They may act hy altering the immunc response, their antitumor action may be due to the effect on oncogenes, on the growth factor responses, on prolifcration and differentiation, and on their cytostatic effcct. Allthough IFN-s wcre the first cytokines in use as a new treatment modality, we stili know little about their mode of action in malignancies. It is conceivable that their major mode of action varies with the disease and even among individuals. It is likely that the antitumor effccts of IFN-a are due to diffcrent effccts in interaction.2 


306 Jereb B 
Laboratory and clinical studies 
It is a well established fact that IFN-a can inhibit celi growth, but it bas been shown only recently, on malignant cells from patients with multiple myelo­ma, that IFN-a can exert a direct cytotoxic effect on tumor cells.9 
In severa! patients with different tumors such as Kaposi's sarcoma, lymphoma or renal celi carcino­ma there bas been no statistically significant corre­lation between the <lose of IFN-a and the effect of treatment. The treatment with natura! leucocyte IFN-a in doses (3 x 106, 3 times weekly) used in the early clinical trials, are stili most widely used and regarded as the optimal treatment. They were intro­duced mostly for practical reasons such as: they produced a mesurable antiviral effect in monkeys which lasted about 3 days. Due to side effects, no higher doses could be given.2• 10 
On the other band, it bas been shown that high local concentration by local application in malig­nant melanoma, basalioma, pleural carcinosis, gli­oblastoma, may achieve total local tumor con­trol. 11•15 Systemic effect bas been described in breast cancer patients some 20 years ago.7 Some doubts have been expressed that IFN-a can be effective in solid tumors systemically, but in vitro experimental models showed that IFN-a may have effect on tu­mor celi metastasis. Furthermore, subcutaneous in­jections of IFN-a in combination with surgery and radiotherapy were effective in treatment of patients with skeleta! metastases from renal celi carcino­
ma_ 11,.18 Recently it bas been shown that in breast cancer IFN-a is able to reduce celi proliferation, enhance steroid hormone receptors and sensitize breast can­cer cells to tamoxifen treatment. It also increases the activity of medroxyprogesteron and restores hor­mone sensitivity in hormone resistant cells. 19 


Clinical application 
It is thus not known what the optimal doses of IFN-a are, and they may vary by the tumor type, as well as from patient to paticnt. Thc neccessary dura­tion of trcatment also remains an open question. Most tumors recur when IFN-a treatment is discon­tinued. The doses may also vary when IFN-a is combined with chemotherapy or radiotherapy. Side effects should be dealt with to reduce symptoms, but the most efficacious way of deverting compli­cation has been the reduction of the dosage. Moder­ate temperature rises should not be treated since some of the IFN-a effects are known to be cn­hanced by higher temperature. 1 
IFN-a has been effectivc against Kaposi's sarco­ma. In certain groups of patients with HIV infec­tion, IFN-a may enhance the CD 4 + celi count.20• 21 
IFN-a bas some advantages over other treatment modalities in patients with hairy celi leukemia: there is no enhanced risk for infections, as is with chemo­therapy or corticosteroids. Complete remissions ha­ve been achieved in patients with hairy celi leuke­mia following low doses of IFN-a.8 With low doses of IFN-a, the Philadelphia (Ph 1) positive celi clo­nes could be suppressed in patients with chronic myelogenous leukemia. Approximately 70 % of pa­tients with chronic myelogenous leukemia respond to IFN-a treatment and 20 % display complete cy­togenetic remission. In hairy celi leukemia with continuous treatment, additional complete remis­sions were achieved. Therefore it was proposed that treatment of patients with chronic myelogenous leu­kemia should also be prolongued.22 
IFN-a is used for treatment of T as well as B 
lymphomas. There is evidence that IFNs are natura! 
regulators of various B celi functions including the 
induction of blast transformation and plasmacyto 
differentiation in malignant B cells. IFNs also in­
hibit the generation and function of T suppressor 
cells and some of the T-cell lymphomas may re­
spond well to IFN-a treatment. Approximately 50% 
of cutaneous T celi lymphomas respond to high 
dose treatment with IFN-a. It bas been reported 
that some patients with adult T cel! leukemia re­
spond to interferon, impressive responses in combi­
nation with zivudine have been reported in such 
23 25 
patients. 8• ­
IFN-a has antitumor effect in multiple myeloma, 
with a 15% response rate. A particularly beneficial 
effect is noted in IgA myeloma treated with natura! 
IFN-a. Intermittent melphalan (prednisone treat­
ment and IFN-a) is regarded by many clinicians as 
the standard primary therapy for patients with mul­
tiplc myeloma sincc there is evidence of better 
results of chemotherapy when combined with 
IFN-a.2• 26• 27 IFN-a is used in the treatment of renal 
carcinoma and ovarian carcinoma alone and in com­
bination with chemotherapy.27 While with IFN-a in 
breast cancer patients, 22 to 41 % response rates 
were reported, with recombinant IFN-a, this was 
not confirmed. IFN-a has been less effective in the 
treatment of gastrointestinal cancer and of some 
307 

Interferon alpha (IFN-a) in treatment <!f'111alig11ant diseases 


otber solid tumors. 8• 16 In advanced malignant mela­noma tbe response rate of 12-22% witb IFN-a alone bave been reported.2 
Witb IFN-a as adjuvant therapy to surgery, tbe disease free survival of patients with osteogenic 6 
sarcoma bas been 50%.5• 
Experience of the Oncological Institute of Ljubljana 

At tbc Oncological Institute in Ljubljana, IFN-a was introduced in clinical use in 1976 for treatment of patients witb pleural carcinosis from breast can­cer. After intrapleural applications the malignant cells disappeared, however, no systemic effect was noted and tbe advanced metastatic discase progres­sed. IFN-a in patients with plcural carcinosis from breast cancer was continuously studied. There was evidence that IFN-a, as addition to systemic treat­mcnt, is an effective means of paliative trcatment of pleural carcinosis. There were some observa­tions that IFN-a seemed to affect the survival of patients with inflammatory breast cancer and pleu­ral carcinosis.29 
IFN-a bas been shown to be cffective in non­small Jung cancer patients with pleural carcinosis. Following intrapleural applications, the effusion was cleared from cancer cells and haemorrhagic admix­ture in a majority of patients, it did arrest fluid accumulation with minimal side effects ancl proba­bly clicl prolong the survival in these patients.30 In a 11011 randomized clinical tria! of patients with non­small-cell Jung cancer treated with intrapleural ap­plication of IFN-a in combination with radiation therapy it secmecl that thc survival of these patients was prolongued." At present a randomized clinical tria! is underway to study the effect on the survival of patients witb non-small-cell Jung cancer ancl pleu­ral carcinosis, treated with racliation alone or in combination with IFN-a. 
Serum interferone levcls bave bcen studied in patients witb breast cancer and non-small lung can­cer treated witb intrapleural application of IFN-a. A correlation of tbe clinical cffect ancl the levels of serum IFN-a could not be established.'2 
IFN-a bas been given locally in patients witb glioblastoma and malignant astrocytoma. Tbis treat­ment was combinecl with cbemotherapy and radia­tion. The study showed that with this combination therapy the malignant tumor could be eradicated succesfully, as confirmecl by histological examina­tion. Thc trcatmcnt, however, had unacceptable lev­els of neurotoxicity.33 
At the Institute of Oncology in Ljubljana a pro­spcctive randomizecl tria! study was unclertaken in 1988 in patients with malignant melanoma stage IIA and B to establish the role of interferon as an adjunct to surgery. The survival of the 160 patients treated with IFN-a was significantly higher than in the 161 patients of the control group.34 In a random­ized tria! (70 pts) it was further shown that patients with advanced malignant melanoma treated with IFN-a additionally to DTIC havc a significantly bctter survival than those treated with DTIC alone.35 

Conclusions 

There is no cloubt that IFNs are a tool for treatment of malignant tumors. Their cytotoxic effect, how­ever, is not strong enough ancl does not last, cures of svstemic malignant clisease are rather exception­al ;,ith IFN alonc. It seems reasonable to expect that clinical trials with IFN in combination with chemotherapy ancl racliotherapy will improve the results in certain groups of patients. It is possible that with a better understanding of problems, such as antagonism to IFN by some substances, antibod­ies to IFN, the effect of IFN on various oncogenic systems, the clinical use of IFN will yield better results. At present, there is a vast field of investiga­tive work stili open, bul, in the meantime, it seems necessary to proceed with clinical trials of differ­ent types of IFN, the natura! IFN-a again beeing the most interesting one. 
Our experiencc is with IFN-a produced at the Institute of Immunology in Zagreb. In terms of low toxicity, high tolerance and the clinical effect, it concurs with that of others. In our opinion, it con­stitutes a promising tool for further clinical trials. 

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Edsmyr F, Esposti P, Andersson L. Interferon lherapyain <lisseminated renal celi carcinoma. Radiother Oncol 1985; 4(suppl 1): 21.a

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Jereb B, Štabuc B, Us-Krašovec M, Cerar O, Stare J. Intrapleural application of human Ieukocyte interferona(IFN-alpha) in breast canccr patients with pleural carci­nosis. In: Benulic T, Serša G, Kovac V, eds. Advances in Radiology and Oncology. Ljubljana: Radio! lugosl,aI 992; 175-80.a

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Tercelj-Zorman M, Mermolja M, Jereb Metal. HumanaIeukocyte interferon alpha (HLI-alpha) for trcatmenl of pleural effusion caused by 11011 srnall cell Iung cancer: a pilot study. Acta Oncol 1991; 30: 963-5.a

31.a
Jereb B, Petric-Grabnar G, Tercelj-Zorman M et al.aNatura] IFN-alpha for non-srnall-cell Iung cancer withapleural carcinosis. Radio! Oncol 1993; 27: 326-31.a

32. 
Mažuran R, Ikic-Sutlic M, Jereb B et al. Intrapleuralaapplication of natura! IFN al pha in breast cancer pa­tients with pleural carcinornatosis: monitoring of im­rnunotherapy by assaying serum interferon Ievels. .1 Biol Regul /-lo111eost Agenls 1992; 6: 46-52. 

33.a
Jereb B, Petric-Grabnar G, Klun B, Lamovec J, Škrbec M, Šooš E. Addition of IFN-alpha to treatment of rna­lignant brain turnors. Acta On col 1994; 33: 651-4.a

34.a
Rudolf Z. Adjuvant treatment pf malignant melanomaawith human leukocyte interferon after radical surgery:a


l.ageneral analysis. Radio! Oncol 1993; 27: 332-8.a
35.aRudolf Z, Strojan P. DTIC vs. IFN-alpha plus DTIC inathe treatment of patients with metastatic malignant me­lanoma. Neoplasma 1996; 43: 93-7.a

Radio/ Onco/ 1997; 31: 309-14. 



Diagnosis and treatment of radiation damage -the acute radiation syndrome 
Susanne Klutmann, Karl H. Bohuslavizki, Winfried Brenner, Eberhard Henze 
Department of Nuclear Medicine, Christian-Albrechts-University of Kiel, Germany 
Radiation mainly yields to a damage cif highly reproductive cells, i.e. radiosensitive tissues like bone marrow, gastrointestinal mucosa, and hairfollicles. With increasing doses radiatio11 causes damage of more differentiated, i.e. relatively radioresistant organs like the central ne111ous system as well. The acute radiation syndrome presen/s with an uni/'orm sequence oj 3 phases: the prodromal stage with llll.lpecific symptoms like vomiting and nausea, followed by a phase cif subjective well-being, i.e. the latency phase. The third phase of the acute radiation syndrome has been divided into three major catagories: l. bone marrow syndrome, 2. gas/rointestinal syndrome, mul 3. central nen1ous syndrome. Each syndrome is defi11ed by dose, swvival Lime, and symptoms. Survival of the patients is mainly limited by radioge11ic damage to !he bone marrow, and causal treatment like bone marrow transplantation may be successful after wlwle-body irradiation below 10 Gy. Whereas after applied doses above JO Gy lhe therapeulic approach will predominantly be pa!liative prevenling patients from pain mul sujfering. 
Key words: radiation injuries-diagnosis-lherapy 
Introduction tragedies human data on the effects of a single­
The development of radiation biology began imme­diatly after the discovery of the X-rays by Konrad Wilhelm Riintgcn in 1895. Apart from the useful­ness of radiation in medicine and technology radia­tion-induced damages were observed soon after the first applications of X-rays. Becquercl and Curie suffered from an acute radiation dermatite, the so called radium burn. Curie died of aplastic anemia probably due to chronic radiation exposure. Since the tragedy of Hiroshima and Nagasaki and the accident that occured at the Chernobyl nuclear pow­er station in april 19861 the awareness of the haz­ards of radiation has been increased. Duc to these 
Correspondence to: Dr. Karl H. Bohuslavizki, Department of Nuclcar Medicine, Christian-Albrcchts-Univcrsity of Kicl, Arnold-Hellcr-Str. 9, D-24105 Kiel, Germany Tel.:+49431597 3076,Fax.:+49431597 3065 
UDC: 616-001.26-07-08 
body radiation could have been obtained. 
Even if radiation syndromes are very rare cases in clinical routine patienl management, the knowledge of bolh their clinical symptoms and treatment should be of interesl not only for those professionals dealing with X-rays. However, the clinical symptoms depend on the body region exposed, and the leve! of the radiation dose as well as on the duration of radiation exposure. Therefore, clinical symptoms of radiation syndromes show a great variation. The symptoms oc­curing promptly include simple skin reactions as well as the acute radiation syndrome. On the other hand, the development of neoplasms are well-known as late side effects caused by radiation. Since data on humans being exposed to whole-body irradiation are well­known the sequence and intensity of clinical symp­toms may be used to estimate the radiation dose to which an individual was exposed accidentally. 
In this paper we describe bolh basic mechanisms and effects of radiation in different tissues as well 
Klutmann Set al. 
as clinical symptoms of radiation injury. The latter is examplified by a radiation accident which hap­pened in Israel in 1990. 
Basic mechanisms of radiation damage 
The interaction of radiation with tissue occurs with­in seconds. In the first physical stage high energetic particles deposit their energy within 10-1x to 10·12 seconds predominantly in water moleculs. In the following physico-chemical stage activated parti­cles transfer their energy to biological molecules, thereby producing free radicals via ionization. These radicals internet in the so called chemical stage with surrounding biological molecules, e.g. DNA, RNA or the core membrane. The altered biological molecules lead to delayed biological effects of ra­diation within hours, days or even years. Thus, it is reasonable that biological effects of radiation main­ly depend on the amount of energy (Joule per kilo­gramm = Gy) absorbed in tissues. 
Since different types of radiation yield to same physico-chemical effects, i.e. the ionization with consecutive production of free radicals, their bio­logical effects are mainly comparable. However, different types of radiation differ in their amount of free radicals generated per unit of energy an<l, thus, different types of radiation produce varying <legrees of damage with the same dose. This different rela­tive biological effectiveness is due to the fact that the linear energy transfer (LET) for each type of radiation is different: For the same total dose, the radiation of high LET (alpha particles: LET= 20) produces greater damage than that of low LET radi­ation (X-ray and gamma-ray: LET= 1). 

Moiecular damage 
Molecular damage caused by radiation is based on different mechanisms. From an absorbed dose of 1 mGy single-strand breaks of DNA occur in 50 % of the irradiated cells. However, both single-strand and double-strand breaks of DNA are repairable, thus changes in the genome are effectively avoid­ed. 2-5 From 0.1 to 1 Gy the biosynthesis of DNA, RNA and proteins (in sequence of their decreased sensitivity) is reduced. The production of antibod­ies is altered from an absorbed dose of 2 Gy. 
The radiosensitivity of different cytoplasmic or­ganelles differs. The nucleus and its membrane are more ra<liosensitive than other subcellar structures such as mitochondria, lysosomes, celi membrane und the golgi apparatus. In addition, the radiosensi­tivity of the celi is related to the celi cycle which is divided into four phases. During the mitosis (M) period and the post-DNA synthesis phase (G2) the celi is more radiosensitive than in the late pre-DNA synthesis period (G 1). On the other hand, cells are relativly radioresistant during the non-growth peri­od (GO) and the DNA synthetis phase (S). 
The technique of obtaining synchronized cells has improve<l new tumor therapies: prior to irradia­tion tumor cells are synchronized by celi toxines in or<ler to increase their radiosensitivity. 


Effects of radiation on organs 
In 1906 Bergonie and Tribondeau formulated some references concerning the radiosensitivity of cells: X-rays are more effective on cells that have a great­er reproductive actvity. X-rays are more effective on cells of which the morphology and the function are the least fixed. 
Thus, highly radiosensitive tissues are those with a high reproductive potency, e.g. bone marrow, lym­phatic tissues, reproductive organs, mucosa of the gastrointestinal tract and hair follicles. Conversely, less radiosensitive are skin, eyes, !iver, Jung, and kidneys. A relative radioresistance has been ob­served in severa! tissues, e.g. central nervous sys­tem, heart, muscles, bones and fat tissue. 
Bone marrow syndrome and lymphatic syndrome 
Un<lifferentiated stem cells of the bone marrow are highly radiosensitive cells. Directly after radiation exposure granulocytosis as initial reaction of the bone marrow can be observed. This is followed by a leueopenia within hours due to a depressed celi production of stem cells located in the bone mar­row. 
Radiation-induced bone marrow <lamage is influ­enced by dose rate: the higher the dose rate the greater the damage. An absorbed dose of 2.5 Gy destroys 5 % of the stem cells, whereas after a ra<liation exposure of 6.5 Gy only 5 % of the stem cells maintain their ability to proliferate. Therefore, a little increase of the absorbed radiation <lose cau­ses a marked increase in the number of destroyed stem cells. This illustrates the extreme steepness of the underlying dose-effect-curve. 

Diagnosis and treatment o{ radiation damage -the acute radiation syndmme 
The sequence of celi reduction in thc peripheral blood is uniform. This mainly reflects the diffcr­ence of mean life-time of the different celi types in the pcripheral blood. After a whole-body irradia­tion of 5-10 Gy thc number of lymphocytes de­creases within hours and days followed by a reduc­tion of granulocytcs and thrombocytes. A decline of crythrocytes is seen from the third week aftcr cxposure according to thcir longer mean life-timc. 
Gastrointestinal tract 
The signs and symptoms associated with the gas­trointestinal syndrome may be due to the failure of both intestinal mucosa and the bone marrow.6 Ef­fects of radiation on the gastrointestinal tract are widely varying. An exposure of 4 Gy decreases the motility of the small intestin. After I O Gy a de­creased production of hydrochloric acid can be ob­served followed by fluid and electrolyte imbalance. This imbalance is due to a failure of intestinal ab­sorption which leads to diarrhea and severe dehy­dration. The gastrointestinal damage is also associ­ated with infection. Therefore, postirradiation in­fection may be due to the failure of the intestinal mucosa as well as to the failure of the irradiated bone marrow. The radiation-induced changes of mucosa membranes in association with the de­creased motility may lead to the clinical picture of a radiogenic ileus as a late side effect of irradiation. 
Skin 
Skin changes following radiation of the respective anatomical region differ between individuals. Fur­thermore, different structures of the skin show a different radiosensitivity. Hair follicles are highly radiosensible. An absorbed dose of as less as I Gy leads to an inhibition of growing hair follicles. 4 Gy produce a temporary and 20 Gy a permanent epila­tion. From a radiation dose of I O Gy an initial ery­thema may appear according to capillary dilatation and release of histamine-like substances: the acute radiation dermatite. Months after an irradiation epi­dermis becomes atrophic associated with variations of pigmentation, fibrosis and ulcerations due to rar­ified vascularization. As late side effect of radia­tion skin neoplasms such as spinalioma may occur.7 
Eyes 
Different radiosensitivity occurs in different struc­tures of the eyes as well. The most radiosensitive part of the eye is the Iens, whereas retina! tissue and the optic nerve are relatively radioresistent. After low radiation doses conjunctivitis, blepharitis and an epilation may occur. From a radiation dose of 10 Gy corneal ulcerations may appear as well as radiogcnic cataracts. 
Nervous system 
Nerval tissue consisting of well differentiated cells with an absence of reproductive activity is markedly radioresistant. The spina! cord is the most radiosen­sitive substructure in the central nervous system.8 Radiogenic damage of the spina! cord occurs from 40 Gy with consecutive neurological signs. Post­irradiation effects have been observed such as post radiation myelitis, and hyaline thickening of blood vessels with the development of paralysis.9• 10 In contrast, glial cells like astrocytes, schwann cells or oligodendrocytes have stili reproductive activity and, therefore, they are much more radiosensitive. 
Bone 
The mature adult skeleton is well differentiated and for this reason relatively radioresistant. On the oth­er band, bones of the adolescents may easily be damaged by radiation causing a retardation of growth. In case of unilateral application of irradia­tion an asymmetric growth with inherent orthope­dic problems can be observed. 
Respirato1y system 
Although lung and pleura are relatively radioresist­ant clinical signs of Jung fibrosis and pneumonia may occur after high dose irradiation. Moreover, irradiated lungs have a higher risk of seeondary diseases, e.g. emphysema following chronic bron­chitis, atelectases or neoplastic disorders. 
Acute radiation syndrome 

General considerations 
The acute radiation syndrome has an uniform se­quence of symptoms. The prodromal stage is charac­terized by headache, nausea and vomiting within l to 2 days. These symptoms subside as rapidly as they develop. Thereafter the patient feels more com­fortable which is called the latency phase. From the third day after radiation exposure the main symp­toms of the acute radiation syndrome may occur such as the bone marrow syndrome, the gastrointes­
Klutmann Set al. 
tinal syndrome or the central nervous system syn­drome. The intensity, the tirne course, and the number of symptoms depend on the radiation dose applied. With increasing radiation doses more symp­toms appear earlier, and symptoms are more pro­nounced. 
Prodromal stage 
The prodromal stage is defined by symptoms oc­curing within the first 48 hours after radiation ex­posure. The cardinal symptom of the prodromal stage is vomiting with nausea and Jack of appetite. The tirne of occurence of symptoms can be used as a prognostic factor quoad vitam to estimate the radiation dose applied accidentally. If vomiting oc­curs within two hours after radiation the dose will be potentially lethal. Vomiting within 30 minutes after irradiation is considered being a sign of a certain lethal dose. 
Moreover, there may be some more uncharacter­istic symptoms occuring in the prodromal stagc, i.e. fcver, erythema of the conjunctiva as well as cry­thema of the oropharyngeal mucosa. The latter points on a dose higher than thc LD50• The central nervous system may present with confusion, con­vulsion and unconsciousness in the prodromal stage. 
The therapy of the prodromal stage is limited to palliative treatment, e.g. effective antiemetics. 
Latency phase 
The latency phase is characteiized by subjective well­being for about 1-2 days. This is due to the relatively radioresistant diffcrentiatcd cells which are stili able to function until their physiological degradation. Thus, symptoms of acute radiation syndrome occur when therc is a Jack of supplies caused by the radiation­induced damage of highly reproductive stem cclls. 
Radiation syndromes after latency phase 
The signs and symptoms produced by whole-body exposure are refcrred to as the radiation syndromc. Radiation syndromes have been divided into three major catagories: 1. bone marrow syndrome, 2. gas­trointestinal syndrome, and 3. central nervous syn­drome. Each syndrome is defined by dose, survival tirne, and symptoms. 
Bone marrow syndrome 
Bone marrow syndrome is defined by bone marrow depletion with subsequent pancytopenia yielding to a consecutive decrease of lymphocytes, leukocytes, and platelets within hours to days in the peripheral blood. This is followed by a delayed decrease of red blood cells within days to weeks. The pancytopenia following irradiation is the primary reason for death in bone marrow syndrome. 
For the patient's survival the vitality of a fcw stem cells in thc bone marrow is required. Model calculations revealed that as less as 0.8 % surviving stem cells in the bone marrow are sufficient to maintain the patient's survival. However, the dose­effect-curve is extremly steep. Consequently, only little differences in the dose applied cause marked changes of the survival rate. Thirty days after whole-body exposure with 2,5 Gy 95 % of patients are still alive whereas a dosc of 6,5 Gy kills 95 % of patients. Thus, a 3 fold increased whole-body radiation dosc decreases the patient's survival rate by the factor 20. 
The clinical symptoms are mainly caused by the pancytopenia. Due to low platelet counts hemor­rhagia may occur. A marked neutropenia increases the susceptablility to infection, i.c. infcction with opportunistic gcrms. Concomitant damage of the gastrointestinal tract leads to fluid and electrolyte imbalance. 
The therapy of bone marrow syndrome is adapted to the clinical symptoms. This includes application of antibiotics, antimycotics, infusion of platelets, and the balanced substitution of tluid and electroly­tcs. Moreover, cytokines may be helpful to accelera­te differentiation of stem cells. Bone marrow trans­plantation may be considered in patients with whole­body doses of less than 1 O Gy as the only causal therapeutic approach. 11 -13 
Gastrointestinal syndrome 
The gastrointestinal syndrome is characterized by a damage of mucosa. Complete destruction of proli­fcrating basal cells in the upper gastrointestinal tract, e.g. duodenum and jejunum, can be observed from radiation doses of I O Gy. 
The clinical symptoms are directly derived from the damage described above. Patients may show up with diarrhea, mucosal ulcerations, malabsorption syndrome, tluid and electrolyte imbalance as well as with septic shock caused by an overgrowth of intestinal germs in these immunodeficient patients. 14 
The therapeutic approach is similar to that of treatment of bone marrow syndrome. This includes application of antibiotics, antimycotics, infusion of 

Diagnosis and treatment r!( radiation damage -the acute radiation syndrome 
platelets, and the balanced substitution of fluid and electrolytes as well as parenteral nutrition of the patients. Since gastrointestinal syndrome may oc­cur even below whole-body doses of 10 Gy bone marrow transplantation may be considered useful in these patients. 
Central ne,vous syndrome 
The main pathogenetic mechanism of central nerv­ous syndrome is a damage of small vessels. The resulting vasculitis leads to central edema via an increased permeability of capillaries. The central nervous syndrome is characterized by periods of agitation and apparent marked apathy, followed by signs of disorientation, disturbed equilibrium, atax­ia, diarrhea, vomiting, opisthotonus, convulsions, prostration, coma and death. Death probably results either from a direct neuronal damage or via in­creased intracranial pressure. 15•18 
The therapeutic approach is directed against pain and convulsion, and vomiting in order to relief pa­tients from suffering. Thus, this predominantly pal­liative treatment consists of analgetics, sedative agents, and antiemetic drugs. 
Radiation accident in Soreq (Israel) on 21st of .Tune 1990 
On June 21 st 1990 due to teclmological failure and human error a serious nuclear accident occured at the nutrition radiation factory in Soreq in Israel. A 32­years-old employe was irradiated by a highly active Co-60 source for the duration of about 2 minutes receiving a whole-body dose of some 20 Gy. Within 5 minutes after exposure he started vomiting. Conse­quently, he was submitted to the Tei Aviv hospital 
2.5 hours after the accident. On admission he pre­sented abdominal pain, nausea, persistant vomiting, generalized erythema, blepharoedema, and an in­creased body temperature of 40.7 °C. 8 hours after exposure he was transferred to the bone marrow transplantation unit in Jerusalem . 
Due to suspected immunodeficiency the patient was isolated and his intestine was sterilized by oral antibiotics. To prevent vira! infection the patient was treated with Aciclovir. The application of cy­tokines was performed in order to accelerate differ­entiation of vita! stem cells due to massiv pancyto­penia. Bone marrow transplantation was performed 4 days following irradiation. However, the donor, his brother was not perfectly compatible in his MHC-antigens. At the end of the first week the patient continued vomiting and exhibited both liq­uid and hemorrhagic diarrhca, i.e. gastrointestinal syndrome. Coloscopy revealed marked colitis with edema, hyperemia and multiple ulcerations. This was accompanied by oropharyngeal mucositis and an epilation of head, face, and pubic hair. Due to gastrointestinal syndrome thc patient received parenteral alimentation in order to substitute the imbalance of fluid and electrolytes. 
In the second week multiorgan failure occured with progressive decrease of renal and hepatic func­tion. The patient developped abacterial pneumonia caused by cytomegaly virus, which was treated by virostatics. The paticnt became more and more dis­orientated on day 35 post irradiation, and died on the following day due to respiratory failure. 
Conclusion 

Although acute radiation syndrome is a rarc prob­lem in current clinical practice one should be awarc of the signs and symptoms in order to ensure both immediate diagnosis and adequate subsequent treat­ment in case of radiation accidents. 

Ref'erences 

1. 
Perry AR, Iglar AF. The accident at Chernobyl: radiation doscs and effccts. Radio/ Tecimo/ 1990; 61: 290. 

2. 
Leontjeva GA., Manzighin Y A, Gazicr AL. Thc ultrafast repair of single slrand breaks in DNA of gamma-irradiat­cd chinese hamster cells. /11t 1 Radiat Biol 1976; 30: 577. 

3. 
Cleaver JF. DNA rcpair and radiation scnsitivity in hu­man (xerodcrma pigmentosum) cells. /nt 1 Radiat Biol l 970; 18: 557. 

4. 
Brant TP, Wheatley GA. Repair and replication of X­i1rndiatcd HeLa celi DNA. Int 1 Radiat Biol 1971; 19: 339. 

5. 
Elkind MM, Sutton-Gilbcrt H, Moses WB, Kammper C. Sublcthal and lethal radiation damage. Nature (London) 1967; 214: 1088. 

6. 
Quastlcr H, Lanzlc EF, Keller ME, Osborne JW. Acute intestinal radiation death studies on roelhen death micc. Aml Physiol 1951; 164: 546. 

7. 
Allen, KDA, Frred JH. Skin cancer: corrclation of field sizc and cancerocidal <lose in roentgen treatment. Am J Roentgenol 1956; 75: 581. 

8. 
Boden G. Radiation myelitis of the cevical spina! cord. Br 1 Radiol l 948; 21: 464. 


Klutmann Set al. 
9. 
Wilson SG. Radiation-induced central nervous system death: a study of the pathological findings in monkeys irradiated with massiv doses of cobalt-60 (gamma) ra­diation. J Neuropathol Exp Neurol 1960; 19: 195. 

10. 
Clemente CD, Holst EA. Pathological changes in neu­rons, neuroglia and blood brain barrier induced by X­irradiation of heads of monkeys. Arch Neurol Psychia­l1)1 1954; 71: 66. 

11. 
Malhe PF, Bernard J, Schwartzenberg L, Larrieu MF, LaLanne CM, Dutreix A, Deneux PF, Surmount J, Schwarzmann V, Ceora B. Attempts at treatment of leucemic subjects following remission by total body irradiation followed by transfusion of homologous mar­row. Rev Fr Etud Ciin Biol 1959; 4: 625. 

12. 
Beilby JOW, Cade IS, Jeliffe AM, Packin DM, Stewart JW. Prolonged survival of a bone marrow graft result­ing in a blood-group chimera. Br Med J 1960; 1: 96. 



13. 
Thomas ED, Lochte HL Jr, Ferrebee JW. Irradiation of the entire body and marrow transplantation: some ob­servations and comments. Blood 1959; 14: l. 

14. 
Cronkite EP, Jacobs GC, Breecher G, Dillard GHL. The hemorrhagic phasc of acute radiation injury. Am J Roentgenol 1952; 67: 796. 

15. 
Bond VP, Fliedner TM, Cronkite EP. Evaluation and managment ofthe heavily irradiated individual. J Nucl Med 1960; 1: 221. 

16. 
Kury G, Warrne S, Chute RN. Supralethal lota! body x­irradiation. Arch Neurol 1968; 18: 703. 

17. 
Gangloff H, Hug O. The effects of ionizing radiation on the nervous system. Adv Biol Med Phys 1965; 10: 1. 

18. 
Rider WD. Radiation damage to brain -a new syn­drome. J Can Assoc Radio/ 1963; 14: 67. 


Radio! Oncol l 997; 31: 3 l 5-8. 
Comparison of TDF and LQ models using the bioeffects algorithm 




of a treatment planning system 
Anthony K. Ho,1 Claudi o H. Sibata, 1 Bruce R. Thomadsen2 


1 Roswell Park Cancer Institute, Department oj Radiation Medicine, Elm & Carlton Streets, Bujfalo, N. Y. 14263, USA 2 University of Wisconsin, Medica! Physics & Human Oncology, 1530 Medica! Science Center, Madison, Wl 53706, USA 










In this study, two examples, first with two-field APIPA plans and second with four-field plans are evaluated for Co-60 beams 11sing the bioeffects program of the Radiation Oncology Computer System (ROCS) treatment planning system. The bioe.ffects algorithm enables the summation of two or more treatment plans. Biomodifier tables, which convert the values of dose per fraction delivered over a period of time to Time Dose Fractionation (TDF) are included with the software. The biomodijier table is a standard ROCS two­dimensional table. By using the linear-quadratic (LQ) model, the biological equivalent dose versus the physical absorbed dose was determined and input asea new biomodijier table. The distribution of TDF values and the biological equivalent dose using the LQ model shows that the LQ model may be a better choice for a bioe.lfect algorithm. Furthermore, the LQ model may be implemented in the ROCS system. 

Introduction 


Tbe Time Dose Fractionation (TDF) model I and the linear-quadratic (LQ) modeF are tbeories tbat at­tempt to predict tbe biological effects wbicb occur during a course of radiation tberapy. Tbe TDF model is based on the iso-effoet dose as a function of either tbe overall tirne, or total number of fractions of treatment. TDF bas been used for many years as a time-dose model in radiotherapy since it is simple to use. The LQ model is based on the linear-quadratic sbape of the cell-survival curves. It is postulated that radiation can be divided into two components, the a 
Corrcspondencc to: Anthony K. Ho, Ph.D., Roswcll Park Cancer Institute, Dcpartmcnt of Radiation Medicine, Elm & Carlton Strcets, Buffalo, N.Y. 14263, USA. 
UDC: 616-006.6:615.849.5 


component is more important at low doses, and the f3 component more important at high doses. The pa­rameter a/{3 is tbe dose at which the fractional log celi kili for these two components is equal.2 
In this study, two field AP/PA and four field plans are evaluated using the bioeffects program of the ROCS (Radiation Oncology Computer Systems, Carlsbad, California, U.S.A.) treatment planning system for Co-60 beams. The ROCS treatment plan­ning system bas a bioeffocts algoritbm' whicb sup­posedly enables tbe summation of two or more treatment plans. A treatment is defined as a series of eontours with external beam data, or planes of brachytherapy data. Biomodifier tables, which eon­vert the values of the dose per fraction delivered over a period of tirne to TDF, are ineluded with the software. The table values were derived from work done by Orton.4· 5a
Anthony K. Ho et al. 
Thc biomodificr table is a standard ROCS two­dimcnsional table. By using thc LQ model, thc bio­logical cquivalcnt dosc vcrsus thc physical dosc was dctcrmincd and input as a ncw biomodificr table. Thc distribution is comparcd using thc TDF and thc LQ modcls. 
Materials and methods 
A contour with APIPA scparation of 25 cm and laterni scparation of 38 cm was used for cxtcrnal bcam planning. In thc first cxamplc, a sctup of 80 cm SSD with APIPA 18 x 18 cm2 Cobalt-60 bcams was used to dclivcr 1.8 Gylfraction to thc mid­planc. In thc sccond cxamplc, four ficlds cqually wcightcd, with 18 x 18 cm2 APIPA and 10 x 18 cm2 latcral ficlds, 80 cm SSD Cobalt-60 bcams wcrc used. A total of 45 Gy was dclivcrcd in 25 frac­tions. A typical cxtcrnal bcam biomodificr table providcd by ROCS will convcrt cGylfraction to TDF for thc numbcr of fractions pcr wcck and thc total numbcr of fractions spccificd. In this casc, fivc fractions per wcck wcrc used. 
Thc bcam arrangcment in this simple example was choscn to dcmonstratc the application of thc diffcrent modcls, i.c., TDF and LQ using thc ROCS systcm. Thc contour may bc considcrcd as a thorac­ic region wherc the spina! cord dictatcs the normal tissuc tolerance. 
Withcrs6 and Scalliet7 showcd that calculation of 
isocffcct dosc cquivalcncics whcn altcring thc frac­
tion sizc can be done using thc formula 
wherc D is a reference total cquivalcnt dose dcliv-
D' d + alf] 
D d' + alf] 
crcd at a givcn fraction size d and D' is the un­
known total equivalent dose delivcrcd at a ncw 
fraction sizc d'. 
Using a alf] of 2 Gy for late rcacting tissucs,7 and 
a fraction size of 1.8 Gy, thc equivalcnt total dosc 
may bc computcd, e.g., for thc 1.9 Gy isodosc line 
in thc daily dosc distribution, such that 
Equivalent does using LQ model= (1.9 Gy x 25) 
x (1.9 + 2)1(1.8 + 2) = 48.8 Gy 
The biological cquivalcnt dosc of 48.8 Gy corre­
sponds to an absorbcd dosc of 47.5 Gy. Similar 
calculations wcrc computed for daily doscs from 
0.2 to 2.2 Gy, and thcsc valucs wcrc input asa two­dimcnsional table in thc ROCS bioeffcct program. 
Results 
Figure 1 shows thc total dosc distribution from standard trcatmcnt planning using thc ROCS sys­tcm. A total dose of 45 Gy was dclivercd to thc mid plane, whilc thc maximum dosc was 56 Gy, for a sctup of 80 cm SSD with APIPA Cobalt-60 bcams. 
Figure 2 shows thc TDF isolines using the bioef­fect algorithm of thc ROCS systcm. Thc TDF valuc was about 70 at thc mid plane with a maximum of 97. 
Figure 3 shows thc equivalent dose distribution calculated using the LQ model. Again, 45 Gy was delivered to the mid plane. The maximum biologi­cal equivalent dosc was found to be 61 Gy. 
Figure 4 shows the lota! dose distribution from standard treatment planning using the ROCS sys­tem. A lota! dose of 45 Gy was delivercd to the mid plane, while the maximum dose was 46 Gy, for the four-field setup of 80 cm SSD. 
Figure 5 shows the TDF isolines using the bioe!Tect algorithm of the ROCS system. Thc TDF value was about 70 at the mid plane with a maximum of 73. 
Figure 6 shows the equivalent dose distribution calculated using the LQ model. Again, 45 Gy was delivered to the mid plane. The maximum biologi­cal equivalent dose was found to be 47 Gy. 
Discussion 
The bioeffects program of the ROCS system is lim­ited to a single external plan, which may be used with a brachytherapy plan. The biomodifier tables provided by ROCS, however, are somewhat outdat­ed. Orton8 states that a TDF of 100 is roughly equivalent to normal connective tissue and skin tolerance. In the simple APIPA sctup example where the spina! cord may be the scnsitive normal struc­ture outside the target volume, the dose equivalent may approach the normal tissue tolerance. The TDF in the spina! cord region may only show a value of 70 to 80. 
The LQ model may be implemented herc to dem­onstrate its use in treatment planning. Comparing figures 1 and 3, the biological equivalent lota! dose is higher than the absorbed dose. This is demon­strated by the larger volume of the 50 Gy isodose, and the maximum biological dosc equivalent of 61 Gy. 
In the four-field examplc, the biological equiva­
lent lota! dose (Figure 6) is also higher than the 


Comparison of"TDF and LQ mode/s using the bioeffects algorithlll of"a p!a1111i11g syste111 


Figure l. Tota! dose distribution from the rcgular trcatment l<igure 4. Tota! dosc distribulion from the treatrncnt planning using the ROCS systcm. A tolal dosc of 45 Gy planning using the ROCS syslern. A total or 45 Gy was delivered to thc mid-plane for the AP/PA setup. Num­was deliverecl to lhc mid-plane for thc four-ficld sclup. bers indicate lhc tolal dose (in Gy) to an isodose line. Numbcrs indicate the lolal dose (in Gy) to an isodose line. 



Figure 2. TDF isolincs using thc bioeffcct algorilhm of thc Figure 5. TDF isolines thc hiodTcct algoritlun of thc ROCS systcm for thc AP/PA sctup. ROCS syslcm for lhc sclup. 
ll / 1!1 !)\\) _ _!;:.J~ 1 !111111m11 11++ 

l1'igurc 3. The biological cquivalent dosc distribution calcu­
Figure 6. Thc biological cquivalcnl closc distribulion calcu­
latcd using thc LQ model for thc AP/PA sctup. Numbers 
Iated using thc LQ model for lhc f'our-ficld sclup. Nurnlwrs 
indicatc thc lota! biological equivalent dose (in Gy) to an 
indicatc lhc lota! biological cquivalcnt dosc: (in Gy) lo an 
isodose line. 
isodose line. 
Anthony K. Ho et al. 
absorbed dose (Figure 4). This is demonstrated by a larger volume of the 46 Gy isodose, and a maxi­mum biological dose equivalent of 47 Gy. Again, thc TDF isolines in figure 5 do not give any usefnl information. 
The biomodificr tablcs as provided by ROCS for the bioeffect algorithm have very limited use in treatment planning, since they utilize the TDF mod­el. The LQ model is a better algorithm and it may be implemented easily in ROCS. Any model, how­ever, will have to be used with caution since there are always limitations in its practical application. 

References 
l. 011011 CG. Time-dose models. In: Wright A, Boyer A, cds. Advwzces in Radiation Therapy Treatment pla1111in1;. New York: American Institute of Physics, 1983: 27-63. 
2. 011011 CG. Update on time-dose models. In: Purdy J, cd. Advances in Radiation Onco/01;y Physics Dosim­efly, Treatment plw111i111;, and brachytherapy. New York: American Institute of Physics, 1990: 374-89. 
3. 
Ho AK, Podgorsak MB, Sibata CH, Shin KH. Appli­cation of the "Biocffects" algorithm of a trcatmcnt planning system. Medica/ Dosimelly. 1995; 20: 139­41. 

4. 
Orton CG, Ellis F. A simplification in the usc of thc NSD concept in practical radiotherapy. Br J Radio! 1973; 46: 529-37. 

5. 
Orton CG. Time-dose factors (TDFs) in brachythcrapy. Br J Radiol 1974; 47: 603-7. 

6. 
Withers HR, Thames HO, Peters LJ. A new isoeffect curve for change in <lose per fraction. Radiother Oncol 1983; 1: 187-91. 

7. 
Scalliet P, Cosset JM, Wambersie A. Application of the LQ model to the interpretation of absorbed <lose distri­bution in the daily practice of radiotherapy Radiother Oncol 1991; 22: 180-9. 

8. 
Orton CG, Cohen L. A unified approach to dose-effect relationships in radiotherapy I: modified TDF and line­ar quadratic equations. Jnt J Radia/ Oncol Biol Phys 1988; 14: 549-56. 



Radio/ Oncol 1997; 31: 319. 


Book review 




Atlas of applied internal liver anatomy 
Eldar M. Gadžijev and Dean Ravnik 
Springer Verlag Wien New York, 1996. Pages: 204; 1SBN 3-211-82793-5 

Every publieation of a Slovenc medica! book abroad is an important event on its own, and more so if the book appears with such a distinguished publisher as Springer Verlag. This publication out­lines the authors' work in the field of surgical anat­omy of the !iver, which dates back in the recent past, and is emerging as one of the foundation stones of what has been internationally recognized as Ljubljana school of !iver surgery. The book sheds a new light on the relatively complex and insuffi­ciently discussed topic of surgical anatomy of the !iver, the field which is of paramount importanceefor every surgeon and particularly for ali those in­volved in !iver surgery. It is based on the practicaleexperience that the authors have gained during theireactive involvement in the organization of the inter­national school of hepatobiliary surgery held tradi­tionally in Ljubljana.e
The book is written clearly and systematically, starting with the Introduction by Stig Bengmark from Lund, one of the pioneers of European hepatic surgery. This is followed by sections dedicated to the portal vein, hepatic artery, biliary and hepatic vein systems. Ali the chapters are richly illustrated by photographic material based on the human !iver casts produeed according to the authors' original teclmology. Each photograph is accompanied by a schematic presentation of 
the section imaged, as well as by a detailed textual explanation. 1-Iigh­quality photographs present different !iver struc­tures using various colors: thus, the venous system is blue, biliary yellow and arterial red., which renders the presentation of this complex organ very vivid and clear. 
The chapter on the portal venous system is sub­divided into smaller logical units. It is well known that the portal venous system is the one which ­together with the system of hepatic veins -provides the basis for functional surgical anatomy. By means of photographs and text, the chapter clearly presents both main portal branches, sector veins and the veins supplying different segments of the !iver. In the chap­ter on the anatomy of the hepatic artery, the authors describe the course of the left and right hepatic arter­ies, and that of the common hepatic artery. Therc, the presentations of left and right accessory hepatic arteries stand out as parlicularly clear, which is of great importance for the surgeon in planning the procedure. The chapter ends with the presentation of anastomoses between the right and left hepatic arter­ies, and a case of arterial aneurysm. The chapter on the biliary system continues with a detailed descrip­tion of the region up to the leve! of the segmenta! ducts, presenting their standard courses as well as ali possible variations of those. 
The last chapter in the book deals with the sys­tem of hepatic veins, which is of central importance in the functional, i.e. surgical anatomy of the !iver, since it represcnts the basis for segmentation of the !iver according to Couinaud. This chaptcr alsoeshows basic features of the course of hepatic veinseand also some of its variations. The book encls withean alphabetical inclex which renders search of aeparticular entity easier.e


The book represents, on the one band, an impor­tant step forward in understanding the surgical anat­omy of the !iver, and on the other, a relevant contri­bution of the Slovenc medicine towards meclical science in general. This valuable publication is ex­pected to become one of the basic textbooks for surgeons engaged in hepatic surgery, and may also be of interest to other specialists concerned with !iver clisease. It should become part of every Slove­nian medica! library, and should set an example foreother fields of Slovenian medicine. Clearly, thisebook places our medicine abreast with the state ofethe art in the most developed parts of the world.e


Assist.Prof. Marko Snoj, MD, PhD Institute of Oncology, Ljubljana, Slovenia 
Radio/ 011col 31: 320-1. 

Inmemoriam 
Ludvik Tabor 
Rccenlly, we sadly wilnesscd the cnd of the life circle or Prof. Luuvik Tabor, MD, a renown radiol­ogist, !ong-standing university teacher and thc Chairman of the Chair of Radiology. 
He was bom in 1924 in Ljubljana. There he also graduatcd from the Faculty of Medicine. Rela­tively early in his carecr he decidecl to specialize in radiology, which was not vcry popular at the tirne, 

residency with the boarcl exam in acadcmic interests became apparent soon aftcr hc had taken on a position at the Institute of of thc University Hospitals in Ljubljana, whcn his first professional papers started to appear in national as well as intemational medica! jour­nals. 1964 hc was electecl into the title of an 
Assistant Professor of Radiology at the Faculty of Medicine in Ljubljana. His thesis entitled "Genital Tuberculosis in Women and the Problem of Mod­em X-ray Diagnostics" has become a textbook widely used by residents in radiology. In 1970 he successfully defended his Doctoral thesis "Radio­logical Clinical Study of Congenital Anomalies of the Spine and Potential Disability" and thus be­came the first radiologist with doctoral degree in Slovenia. Osteoarticular radiology remained the main field of his interest throughout his profession­al career. From 1960 till his retirement, he func­tioned as a consultant in radiology at the University Department of Orthopedics, organized racliological service and set up a rich archive of radiograms. In 
1974 he was elected Associate Professor and in 1978 Professor of Radiology at the Faculty of Med­icine in Ljubljana. In the academic years 1977-78 ancl 1978/79, he was Deputy Dean of the Faculty of Medicine, and from 1981 all until his retirement in 1993 -i.e. for full thirteen years -Chairman of the Chair of Radiology. As a university teacher and lecturer he contributed to the education of severa! generations of medica! and stomatology stuclents, as well as of those attending the Junior College of Health Professionals, Department for Radiology Technicians, in Ljubljana. Herc, his outstanding role as mentor to residents in radiology, particularly in the field of osteoarticular orthopeclics, cleserves to be pointecl out. 
He upgraded his knowledge in severa! foreign institutions, such as Cochin Hospital in Paris, De­partment of Orthopedics at St.Gallen Canton Hos­pital in Ziirich, and the institutes of racliology in Bonn ancl Tiibingen. 
The main field of his interest was racliological diagnostics of osteoarticular disorders, particularly in the fields of orthopeclics, hematology, injuries and racliology in gynecology and stomatology. His bibliography comprises 131 contributions that have been published in national and intemational jour­nals, as well as 14 scientific research studies. He published three books independently, and two in 

In me111oriw11 321 
collaboration with othcr authors. Hc took activc part as an organizer and speaker at numerous con­gresses ancl meetings of radiologists, orthopeclists and traumatologists in thc country as wcll as in different European ccnters and worldwidc. 
Prof.Dr. Ludvik Tabor playcd an activc role in the establishment of the Institute of Radiology of the University Medica! Center in Ljubljana, as well as through ali the phases of its development, until this institution became the leading radiological center in the country. In 1976, in collaboration with Italian colleagues, he established an Alps-Adria community which resulted in regular annual meetings of radiolo­gists frorn Italy, Austria and Slovenia. Hc was one of the founding rnernbers of the joumal "Radiologia Iugoslavica", and the Editor-in-Chief of the same in years 1976-1981. In thc period 1958-1969, he was the President of the Section of Radiology and Nucle­ar Medicine of the Slovenian Medica! Association. Apart frorn that, he was a long standing Secrctary General of the Society of Radiology and Nuclear Medicine of Yugoslavia. 
He was a mernber of the Intemational Society of Lymphology, European and International Socie­ty of Radiology, member of thc Slovenian Medica! Association (SZD), mcmber of the Section of Radi­ology of SZD, mernber of the Association of Radi­ologists of Yugoslavia, membcr of the Society of Orthopedists and Traumatologists of Yugoslavia, and an honorary rnember of the Society of regis­tered radiology technicians of Yugoslavia. 
He received severa! awards: Golden Plaque of the Association of Medica! Societies of Yugoslavia (1971), Award of the Faculty of Medicine in Ljubljana (1978), Silver Plaque of the Society of Orthopedists and Traurnatologists of Yugoslavia (1978), Meda! ofWork with Golden Wreath (1980), Golden Plaque of the Society of Orthopedists and Traumatologists of Yugoslavia (1981), Plaque of the Association of Radiologists of Yugoslavia (1988), and Award of the University Department of Orthopedics in Ljubljana ( 1993). 
This outline of Professor Tabor's active life would not have been cornplete, had it contained only the description of his rich professional career and ignored yet another very important field of his inter­cst -painting, which was becoming more and more irnportant part of his life as hc grew older. His huge opus of water-paintings was partly exhibited at 23 independent and 30 group exhibitions. Perhaps, through painting he managed to free hirnself of ali the restrictions which a successful medica! career 
imposes on those in pursuit of it. As if in nature and colors of his water paintings he would hope to find a recuperation for the years spent amidst ali shades of gray and black which befit racliologists profession. His attitucle to nature ancl art is best refleetecl in the words that he wrote: "Art is a free recorcling of the vastness of spiritual awareness and sensation of whal nature is offering to us so generously. Can there bc anything more attractive than a record of life's credit to nature, a record that rnakes use of the kalei­closcope of light and shadows of sornething felt and scen through personal experience, a record of the eternally present rhythm of nature! Faced with the modem consurners society which hopes to find hap­piness in piling material goods and momentary en­joyments, incapable of sharing the inner joy of those who can think and act differently, there is nothing left but the possibility of retreat to what nature stili has in store to offer. Some people find it difficult to unclerstand that nowadays more and more people of different profession cledicate their free tirne to paint­ing or some other arls. The answer is quite simple: In view of everything that modem civilization with its hectic daily routine not only offers but directly im­poses on us, the art represents an asylum where we ean again collect and put in order the bits of our shattered souls. To man, arts and nature offer a prom­ise and chancc that in the tirne such as ours he cloes not sink but survives and maintains his human digni­
ty." 
When in 1993 he decicled to retire, he was stili full of plans for future. But unfortunately, the mer­ciless and long-lasting disease which he had leamt to live wilh and successfully fight for years, put an end to his planning and made hirn admit that he !ost the battle. 
It was with great sadness that we partecl with Professor Tabor. We rernernber hirn with due re­spect. We, lhe Slovenc radiologists, are truly obliged to him for everything that he dicl for out profession and Slovenian medicine in generally. He will stay in everyone's memory as a renown and highly respected cxpert, a teacher to rnany genera­tions of radiologists and radiographers, and last but not least, as an artist and great admirer of nature and arts. 
Prof. Vladimir Jevtic, MD, Institute of Radiology University Medica! Center Zaloška 7 1525 Ljubljana 
Radio! Oncol 1997; 31: 322. 

European association of radiology junior radiologists exchange programme 1988 
EUROPEAN ASSOCIATION OF RADIOLOGY 
l. Aims 
To create a direct Jink between Junior Radiologists from Western European countries and their col­leagues from Eastern Europe. The former can share their longer experience with more advanced imag­ing procedures with their Eastern colleagues who have, genera\ly, only recently acquired the same equipment. The fina! goal is to have a common hands-on experience in daily routine clinical prac­tice. Moreover, the Visiting Junior Radiologists will be involved in some theoretical teaching, present­ing a few lectures on the topic chosen for the visit. 
2. Organisation 
Each visit will consist of a one week visit by two Visiting Junior Radiologists. 
3. Finances 
3.1. Travelling and accommodation expenses will be paid by the EAR. 
3.2. Visiting Junior Radiologists will take care of their travelling and claim their expenses to the EAR. 
3.3. Host Institutions will take care of lodging, using low-budget accommodations, preferably with­in the university complex. 
4. Applications 
4.1. The EAR Executive Bureau selects the Institu­tions to be visited, matching them in accordance with the Junior Radiologists Forum, with the junior applicants. 
4.2. The Host Institutions must send their propos­als for the tutorial week to the Secretary General of the EAR (see address below), indicating: 
-details of the equipment available in their Insti­
tution -their topics of interest (consider alternatives) -the preferred period of the year for the visit -the availability of low-budget accommodations 
4.3. The Visiting Junior Radiologists must send to the Chairman of the Junior Radiologists Forum (see address below) their application, with a short CV and written authorisation from their chairman to participate in the Exchange Programme. A copy shall be sent to the Secretary General of the EAR. The application must indicate: 
-the main field of expertise -the equipment worked with -the period of the year most suitable for the 
visit, and the period when not available. 
4.4. Deadline for applications: 1 st November 1997 
The EAR Exchange Programme is sponsored by General Electric Medica! Systems Europe 
Prof. M. Blery EAR Secretary General Dept. of Radiology 
C.H.U. Bicetre 78, rue du General Leclerc F -94270 LE KREMLIN-BICETRE France Fax: ++33 -(0)1-45 21 32 09 E-mail: blery@club-internet.Fr. 
Dr. Vasco M. Ramalho Chairman of EAR Junior Radiologists Forum SPRMN Elias Garcia, 127, 7D P -1050 LISBON Portugal fax: ++351-1-796 98 30 E-mail: sprmn@mail.telepac.pt 

Abstracts 323 
Endoskopska retrogradna pankreatikografija pri ugotavljanju kronicnega pankreatitisa 
RubinicM 
V clanku je poudarjena pomembnost endoskopske retrogradne pankreatikografije (ERCP) pri ugotavljanju kronicnega pankreatitisa. Metoda je znatno bolj senzitivna kot druge radiološke, posebno neinvazivne diagnosticne me/ode. S pomocjo ERCP, ki je kombinirana endoskopska radiološka metoda, razvdcamo kronicni pankreatitis v tri skupine. Tako lahko tudi natancno nacrtujemo nadaljnje zdravljenje, ki je endoskopsko ali klasicno kirurško. V clanku avtor analizira 370 bolnikov, ki jim je bil kronicni pankreatitis ugotovljen z ERCP. 286 (77%) je bilo mo.vkih in 84 (23%) žensk. Vecina bolnikov, to je 204 (55%), je bila starih od 40 do 50 let. Vsi bolniki so bili razvršceni v že omenjene tri skupine. V skupini blagega kronicnega pankreatitisaje bilo 154 (42%) bolnikov, v skupini z zmernimi spremembami je bilo 123 (33%) bolnikov in v skupini znatnih sprememb 93 (25%) bolnikov. Pomembno je poudariti, da je od 286 moških bolnikov 21 I (74%) uživalo alkohol in bilo kadilcev tobaka vec kot pet let. 
Radio! Oncol 1997; 31: 273-6. 
Akutna abdominalna krvavitev zaradi pankreatitisa, diagnosticirana s kontrastno racunalniško tomografijo 
Puskas T, Rac S 
Avto,ja prikažeta primer 55-letnega bolnika, pri katerem se je razvila akutna abdominalna kn,avitev zaradi pankreatitisa. Krvavitev je bila diagnosticirana z racunalniško tomografijo (CT) ob aplikaciji intravenoznega kontrasta. Vendar s CT-jem krvavitev redko pol!jujemo. Avto,ja poudmjata pomembnost in prednost kontrasta pri takšni preiskavi. Razporeditev kontrasta je najizrazitejša v središcu lezije. 
Radio/ Oncol 1997; 31: 277-8. 
Radioprotektivno delovanje amifostina na žleze slinavke zajcev pri visokodoznem radiojodnem zdravljenju 
Hiibner R-H, Bohuslavizki KH, Brenner W, Klutmann S, Feyerabend B, Liittges J, 
Tinnemeyer S, M ester J, Clausen M, Henze E 
Poznan stranski ucinek visokodoznega zdravljenja z radiojodom (HD-RIT) je okvara v delovanju žlez slinavk. Kasni stranski ucinki zdravljenja so pomembni pri zdravljenju dobro diferenciranih .vcitnicnih karcinomov, ki imajo odlicno prognozo. Zato so avto,ji proucevali radioprotektivni ucinek amifostina na zajcjem modelu. Pred in najvec tri mesece po HD-RIT so naredili kvantitativno scintigrafijo žlez slinavk pri petih zajcih in aplicirali 1 GBq J-131. Procent kopicenja Tc-99m-pertehnentata je bil upoštevan kot merilo parenhimske funkcije žlez slinavk. Tri živali so prejele 200 mg/kg amifostina pred HD-RIT in dve živali sta služili le za kontrolo. Žleze slinavke so bile preiskovane histopatološko. Pri dveh kontrolnih živalih se je 12 tednov po HD-RIT procent kopicenja pertehnentata znacilno zmanjšal (p<0,001) -tako pri parotidnih žlezah (zmanjšanje za 63 %) kot pri 
324 Abstracts 
submandibulamih žlezah (zmanjšanje za 46 %). Histopatološko so ugotovili lipomatozo. Nasprotno pa se pri treh živalih, kjer so uporabili am/fostin, procent kopicenja pertehnentata ni znacilno zmanjšal (p=0,953) in se tako tudi parenhimskafunkcija ni bistveno zmanjšala. Prav tako so ugotovili le nepomembno lipomatozo. Zakljucili so, da lahko pri zajcih okvaro žlez slinavk po HD-RIT kvantitativno ocenjujemo s scintigrafijo in da amifostin znacilno zmanjša okvaro žlez slinavk, ki nastane po HD-RIT. Menijo, da so rezultati dovolj ohrabrujoci, da bi amifostin preizkusili tudi na bolnikih z dobro diferenciranim šcitnicnim karcinimom in bi na ta nacin izboljšali njihovo kakovost življenja. 
Radio/ Oncol 1997; 31: 279-85. 

Diagnosticni pomen planarne miokardne perfuzijske scintigrafije pri bolnikih s koronarno boleznijo 
Klancic M, Milicinski M, Zorman D 
Pri bolnikih s koronarno boleznijo uporabljamo neinvazivne in invazivne preiskave za potrditev bolezni ali c1premljanje zdravljenja. Z neinvazivno miokardno pe1fuzijsko scintigrafijo dobimo podatke o prekrvitvi srcne mišice med obremenitvijo in v mirovanju. Koronama angiografija pa je invazivna mo1fološka preiska­va, ki jo je potrebno opraviti pred razširitvijo koronarnih arterij ali pred kirurško revaskularizacijo miokarda. Z retrogradno analizo planarnih scintigramov miokarda, opravljenih ob obremenitvi in v mirova­nju po aplikaciji talija (T/2°1 ), smo želeli ugotoviti obcutljivost in specificnost miokardne perfuzijske scinti­grafije in ugotoviti vzroke razhajanja izsledkov obeh preiskav. Primerjali smo izsledke 156 miokardnih pe1fuzijskih scintigramov in koronarogramov bolnikov s koronarno boleznijo. Kadar se izsledki delno ali povsem niso skladali, smo ponovno proucili obe originalni preiskavi. Pri 62 % preiskovancev so se izsledki obeh preiskav skladali. Pri samo 5 bolnikih (3 %) so bili izsledki neskladni in vzroka nismo ugotovili. Vecina preostalih 55 bolnikov z delno skladnimi izsledki obeh preiskav je imela bolj izražene motnje prekinitve kot je bila ocenjena stopnja zožitve na koronarni arteriji, kar je posledica razlike v naravi obeh preiskav. Anomalije na koronarnih arterijah smo ugotovili pri 3 % preisko­vancev, zvijugane koronarne arterije s pocasnim pretokom kontrastnega sredstva pri 9 preiskovancih (6 % vseh) in pri ene,n bolniku artrijsko hipertenzijo z izrazito hipertrofijo levega prekata. Senzitivnost miokardne pe1fuzijske scintigrafije je bila pri naših preiskovancih 100 % in specificnost 50 %. Pozitivna napovedana vrednost za koronarno bolezen je bila 96 % in negativna 100 %. V zakljucku ugotavljamo, da ima miokardna per:fuzijska scintigrafija nedvomno mesto ,ned preiskavami pri odkrivanju in spremljanju zdravljenja koro­narne bolezni. Miokardna pe1fuzijska scintigrajija je postala le zanesljivejša z novimi tehnikami snemanja in radiofarmacevtiki, ki jih oznacujemo s tehnecijem in tako omogoca racionalnejše nadaljevanje diagno­sti6zih postopkov z bolj invazivnimi preiskavami. 
Radio/ Oncol 1997; 31: 286-90. 

Pritisk medtkivne tekocine kot ovira pri terapiji cvrstih tumorjev 
Pušenjak J, Miklavcic D 
V zadnjih desetletjih je napredek na podrocju razvoja zdravil proti raku omogocil odkritje terapevtikov, ki so pokazali izjemno protitumorsko ucinkovitost v in vitro pogojih. Na žalost ta zdravila niso bila uspdna v in vivo poskusih na cvrstih tumorjih, saj je bila njihova porazdelitev v tumorju nezadostna in neenakomerna. Ceprav imajo tumorji v prime1javi z normalnim tkivom višjo prepustnost in hidravlicno prevodnost žil, je prehod molekul iz tumorskega ožilja zavrt zaradi visokega pritiska medtkivne tekocine (PMT) v tumorju. Ta fiziološka lastnost prav tako ovira transport molekul po tumorskem medcelicnem prostoru. Vrednost PMT je 
Abstracts 325 
v sredi:Vcu tumo,ja enakomerno visoka, na robu ll111101ja pa pade proti vred11osti, ki jo ima PMT v 11orma/11em tkivu. Ta gradient PMT povzroci odtekanje tekoane iz t1111101ja, ki zaradi konvekcije s seboj poteg11e molekule zdravila v tumOJjevo okolico. Tam se molekule zdravila reabsorbirajo ter tako 11e opravijo svoje 11aloge. Meritve kažejo, da PMT doseže v tu11101ju vred11osti od 2600 Pa do 6600 Pa, medtem ko je vrednost v 11ormalnem tkivu nižja kot atmosferski pritisk v okolici ( od -133 Pa do -798 Pa v s.c. in okoli -346 Pa v mišici). Za takojšnje in neposredno me1jenje PMT trenut110 uporabljamo dve metodi: WIN tehniko in mikroprebojno teh11iko. Z11ižanje PMT v tw1101ju bi ve,jetno omogocilo optima/11ejfo vsebnost in porazdeli­tev zdravila v twno1ju in bi s tem izboljfolo protitwnorsko delova11je zdravila. Zato so bili za znižanje PMT v tumOJju preizkušeni razlicni postopki. V tem clanku smo povzeli in analizirali rezultate dveh fizi61ih (hipertermija, obsevanje) in kemi61ega (vazoaktivne snovi) postopka, ki so jih preizkusili drugi avto,ji. 
Radio/ Oncol 1997; 31: 291-7. 
Urokinazni aktivator plazminogena, njegova inhibitorja in receptor -novi napovedni dejavniki pri solidnih rakih 
Borštnar S, Cufer T, Rudolf Z 
Urokinazni aktivator plazminogena (UPA), njegova inhibit01ja (PA!l in PA/2) ter njegov receptor (UPAR) igrajo pomembno vlogo pri razgradnji medcelicnega tkiva in s tem pri prodoru tumorskih celic v okolico ter metastaziranju. Rezultati klinicnih raziskav kažejo na vpliv UPA, PAII, PAl2 ter UPAR na potek bolez11i in preživetje bolnikov s solidnimi tumo1ji, predvsem rakom dojk. Razvr.fcm(je bolnikov glede na vsebnost UPA, PAII, PA/2 in UPAR v tumorskem tkivu bi omogocilo locevanje bolnikov v bo!j in mw;j rizicne skupine. Z agresiv11ejšim zdravljenjem bolnikov v bolj rizicnih sk11pi11ah pa bi dosegli izboljfrmje prognoze, podalj.fonje c<asa brez po11ovitve bolezni in podaljšanje preživetja. 
Radio! oncol 1997; 31: 298-304. 
Zdravljenje malignih bolezni z interferonom-a 
Jereb .B 
V kliniki uporabljamo vec tipov naravnega i11te1ferona-a (IFN-a). Ceprav so inte,feroni bili prvi citokini, ki so se kot metoda zdrav/je11ja uve(javili, .fo vedno vemo zelo malo o J\jihovem nacinu delovanja na maligne bolezni. IFN-a lahko zavira ce/ic'no rast. Šele pred kratkim pa so ugotovili, da JFN-a lahko deluje tudi direktno citotoksicno 11a tumorske celice pri bolnikih z multiplim mie/01110111. Naravni /evkocitni inte1fero11 še vedno najce.'fr<e uporab(jamo v dozah, kakršne so bile objavljene v zgodnjih klinicnih preizkusih. Opisano je bilo, da so z visokimi ko11centracijami IFN pri lokalni aplikaciji malignega melanoma, bazalioma, plevralne karci11oze, glioblastoma ugotovili popolno unicenje twno,ja. Ne vemo pa, katere so optimalne doze interferona. Te so lahko razlicne za razlicne tumo1je, pa tudi razlic11e pri vsakem posamemem bolniku. Pravtako je trajmije zdravljenja še vedno odprto vprafonje. Inte1.feroni so ucinkovita sredstva zdravljenja, vendar njihov citotoksicni utinek ni zadosten in ni dovolj trajen. Odprto je :<:iroko po(je potrebnih raziskav, potrebno je nada(jevati klinicne preizkuse z razlicnimi tipi inte,feronov, pri tem pa je gotovo !FN-a od vsen za klinika najbolj zanimiv. 
Radio! on col 1997; 31: 305-8. 


326 Abstracts 
Diagnoza in zdravljenje radiacijske poškodbe -akutni radiacijski 





sindrom 
Klutmann S, Bohuslavizki KH, Brenner W, Milller A, Henze E 



Sevanje poškoduje predvsem celice, ki se hitro delijo, to so radiosensitivna tkiva, kot so kostni mozeg, mukoza prebavnega trakta in lasni mešicki. S povecevanjem doze se pojavijo poškodbe tudi na bolj radiorezistentnih tkivih, kot je tudi centralni živcni sistem. Akutni radiacijski sindrom lahko razdelimo na tri stopnje: prodromalno fazo z nespecificnimi simptomi kot so slabost in bruhanje, tej sledi faza relativno dobrega pocu(ia, to je latentna faza. V tretji fazi nastopi akutni radiacijski sindrom, ki ga zopet lahko razdelimo v tri skupine: sindrom kostnega mozga, gastrointestinalni sindrom in sindrom centralnega živcnega sistema. Vsak od sindromov je dolocen z dozo, prežive(iem in simptomi. Prežive(ie bolnikov je odvisno od poškodb kostnega mozga, tako da je transplantacija kostnega mozga uspešna po obsevanjih celega telesa z dozami pod JO Gy. Ce je ekspozicija višja od JO Gy, je možna le paliativna terapija za lajšanje bolecin. 
Radio/ Oncol 1997; 31: 309-14. 


Primerjava TDF in LQ modela pri planiranju obsevanja ob uporabi bioefektnega algoritma 

Ho AK, Sibata CH, Thomadsen BR 



Avto,ji so prime,jali in ovrednotili dva obsevalna plana, prvi z dvema poljema (APIPA) in drugi s štirimi polji, oba pa za gama žarke iz izvora Co-60. Pri tem so uporabljali program za planiranje ROCS (Radiation Oncology Computer System), ki upošteva tudi biološki ucinek ali bioefekt. Bioefektni algoritem omogoca seštevanje dveh ali vec obsevalnih planov. V program ROCS so vkljucene biomodifikacijske tabele, s pomocjo katerih je ob upoštevanju casa obsevanja mogoce spremeniti vrednosti obsevalne doze na frakcijo v casovno odvisno dozo na frakcijo (Time Dose Fractionation -TDF). 



Te biomodijikacijske tabele so standardne dvodimenzionalne tabele programa ROCS. Z uporabo linearnokvadratnega modela (LQ) pa so avtorji dolocili biološko ekvivalentno dozo glede na fizikalno absorbirano dozo ter vstavili v program novo biomodifikacijsko tabelo. Primerjava med razporeditvijo TDF vrednosti in biološko ekvivalentno dozo, dobljeno z uporabo LQ modela, kaže, da bi bil LQ model lahko boljši za bioefektivni algoritem, poleg tega lahko LQ model vstavimo tudi v sistem ROCS. 
Radio/ Oncol 1997; 31: 315-8. 


Radio/ Oncol 1997; 31: 327. 
Notices 
Notices submitted for publication should contain a mailing address, phone and/orfax number andlor e-mail of a contact person or departnzent. 

Oncology 

October 13-20, 1997. 
The ESO training course "Cancer Epidemiology and Can­ccr Registry'' will bc offcred in Metsovo, Ioannina, Greece. 
Contact ESO Balkans and Middle East Oflicc, c/o Egnatia Epirus Foundation, 7 A Tzavella St., 453 33 loannina, Greece; or call +30 651 72315/76992; or fax +30 651 36695. 
Life science 

October 16-19, 1997. 
The international confcrence "Life Science '79" will be offcred in Gozd Martuljek, Slovenia. 
Contact Dr Gregor Serša, Institute of Oncology, Depart­ment of Tumor Biology, Zaloška 2, SI-1105 Ljubljana, Slo­venia; oracall +386 61 133 74 10; or fax +386 61 131a41 80; E-mail: gsersa a mail.onko-i.sia
Lymphoma 

October 18-22, 1997. 
The ESO training course will take place inAthens, Greece. 
Contact ESO Balkans and Middle East Otlice, c/o Egnatia Epirus Foundation, 7 A Tzavella St., 453 33 loannina, Grcecc; or call +30 651 72315/76992; or fax +30 651 36695. 
Radiation Oncology 

October 20-24, 1997. 
The "Annual Meeting of Ameiican Society for Thera­peutic Radiology and Oncology ASTRO" will take place in Los Angeles, CA, USA. 
Contact Vicky Carroll, ASTRO office, 1891 Preston White Drive, Reston, VAa22091, USA; orcall +1a703 716a7588;or fax +l 703 476 8167. 
Chest tumours 

October 20-22, 1997. 
The ESO advanced coursc "Chest Tumours" will be hcld in London, United Kingdom. 
As a se,vice to our readers, notice s 1!( meetings or courses will be insertedfree 1!{ charge. Please selll i1if<1r111atio11 to the Editorial 11!Jice, Radiology and Oncology, Vrazov trg 4, SI-1105 Ljubljana, S/ovenia. 
Contact European School of Oncology, Via Ripamonti, 66, 20141 Milan, Italy; or call +39 2 57 305 416; or fax +39 2 57 307 143. 
Radiation Oncology 

October 20-24, 1997. 
The "Annual Meeting of Ame1ican Society for Thera­peutic Radiology and Oncology ASTRO" will take place in Los Angeles, CA, USA. 
Contact Ame1ican Society Therapeutic Radiology/On­cology, 1101 Market Street, 14th Floor, Philadelphia, Pa 19107-2990, USA;oracall+l 215a574a3180;orfax+l 215 928 0153. 
Oncology 

October 22-24, 1997. 
The ESO training course "New drugs in Oncology" will be offered in Ankara, Turkey. 
Contact ESO Balkans and Middle East Otlice, c/o Egnatia Epirus Foundation, 7 A Tzavella St., 453 33 loannina, Grccce; or call +30 651 72315/76992; or fax +30 651 36695. 
Diagnostic radiolugy 

October 23-25, 1997. 
Thc training workshop of the "Recent Europcan Initia­tivcs on Quality Assurance and Radiation Protection in Di­agnostic Radiology'' will be organised in Luxcmbourg. 
Contact Prof. Dr. F.E. Stieve, Bf5 -Institute ofRadiation Hygiene, Ingolstaedter Landstrasse 1, D-85764 Oberschleis­sheim/Neuherberg, Germany; or call +49 89 31603 260; or fax +4989a31603 111; or E-mail fsticvc@bfs.de 
Skin pathology 

October 23-29, 1997. 
The ESO training course will be held in Ioannina, Greece. 
Contact ESO Balkans and Middle East Ofiicc, c/o Egnatia Epirus Foundation, 7 A Tzavella St., 453 33 loannina, Greece; or call +30 651 72315/76992; or fax +30 651 36695. 


FONDACIJA DR.].CHOLEWA 
FONDACIJA "DOCENT DR. J. CHOLEWA" JE NEPROFITNO, NEINSTITUCIONALNO IN NESTRANKARSKO ZDRUŽENJE POSAMEZNIKOV, USTANOV IN ORGANIZACIJ, KI ŽELIJO MATERIALNO SPODBUJATI IN POGLABLJATI RAZISKOVALNO DEJAVNOST V ONKOLOGIJI. 
MESESNELOVA 9 61000 LJUBLJANA TEL 061 1 5 91 277 FAKS 06 1 2 1 8 1 1 3 
ŽR: 50100-620-133-05-1033115-214779 
Activity of "Dr. J. Cholewa Foundation" for cancer research and education -report for the third quarter of 1997 
"Dr. J. Cholewa Foundation" for cancer research and education continues with its activity as it was determined at the Assembly of the Foundalion annual meeting and Executive council meetings in the end of 1996 and in the first half of 1997. The activity of the Foundation has been intensified during the course of 1997, as compared to the activity in the previous year. The Foundation continues to provide grants for cancer research and cancer education purposes to professionals involved in the field of oncology in Republic of Slove­nia. The emphasis ofFoundation's support has been and is being given on providing research and educational grants especially to the applicants from regional hospitals and health centcrs. In this regard, it is especially important that thc collaboration between the Founda­tion and the European School of Oncology from Milan, Italy, is proceeding ahead successfu­ly. As already noted previously, all the applicants awarded educational grants for attending courses or other various meeting by the European School of Oncology are obliged to sprcad thcir newly acquired knowledgc as widely as possible, while it is hoped ancl expectecl that applicants awarclecl research grants prcscnt the results of their research in respectable international scientific journals. 
The Foundation continues to support regular publication of "Radiology ancl Oncology" international scientific journal, ancl of "ESO Challenge", the newsletter of the Europcan School of Oncology. It is expectccl that the activity concerning the organisation of "Oncolog­ical wcckencl" meetings will intensify in the near future, thus presenting the Founclation with a new challenge. As new challcnges arise, the Foundation is proucl to l.avc among its members respectecl experts ancl authors of important cancer textbooks and monographics published recently. 
As the 1997 is coming to its close it is expcctecl that annual meetings of the Executive council ancl the Assembly of the Founclation will take place in the near future. 
Tomaž Benulic, MD 
Borut Štabuc, MD, PhD 
Andrej Plesnicar, MD 


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Kripto koki meningitis 
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Sistemska kandidijaza 
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OrofarinQealna in sluznicna kandidijaza 
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1-2 tedna** 
··pri okužbah sluznice Je morda potrebno 30 dnevno zdravljenje 
Profilaksa: 
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Hitro zdravljenje glivicnih okužb z dolgotrajnim ucinkom 
• pri glivicnih okužbah kože 
• pri vaginalni kandidijazi 
• pri oportunisticnih glivicnih okužbah 
Povzetek informacij za predpisovanje zdravila Indikacije in odmer1<i: obrni. Uporaba pri starejših: kot zgoraj, razen pri ljudeh z ledvicnimi okvarami -glej popolne informacije za pred­pisovanje. Ne priporocamo uporabe pri otrocih mlajših od 16 let, razen kadar se zdi to lececemu zdravniku nujno potrebno -glej popolne informacije za predpisovanje in priporocljive odmerke za otroke starejše od enega leta. Bolniki z l edv icnimi okvarami: morda so potrebni manjši odmerki -glej popolne informacije za predpiso­vanje. Dajanje zdravila: DIFLUCAN lahko dajemo oralno ali v obliki intravenske infuzije. Odmerki so pri oben nacinih enaki. Kontraindikacije: Znana preobcutljivost na flukonazol ali sorodne 

triazole. Opozorilo: Pri bolnikih, pri katerih pride do pomembnega povecanja jetrnih encimov, moramo pred nadaljevanjem zdravljenja z DIFLUCANOM oceniti razmerje med tveganjem in koristnostjo. Porocajo tudi o anafilakticnih reakcijah. Varnostni ukrepi: Ker so na voljo le omejeni podatki, odsvetuje­mo uporabo pri nosecnicah, razen kadar se zdi to lececemu zdravniku nujno potrebno. Dojenje: ne priporocamo uporabe. Interakcije z drugimi zdravili: Potrebno je skrbno spremljanje bolnikov, ki istocasno jemljejo antikoagulanse, oralno sulfonilurejo ali fenitoin, ciklosporin in teofilin. Pri bolnikih, ki istocasno jemljejo rifampicin, so morda potrebni vecj i odmerki DIFLUCANA. Stranski ucinki: Najpogostejši stranski ucinki so vezani na gastrointestinalni trakt: sla­bost, abdominalno nelagodje, diareja in vetrovi. Porocajo tudi o kožnem izp u šcaju. Pri bolnikih s hudo osnovno boleznijo so med zdravljenjem z DIFLU­CANOM in primernimi ucinkovinami opazili spremembe v testnih rezultatih ledvic nih in hematoloških funkcij ter bolezenske spremembe jeter, vendar pa sta klinicna pomembnost in povezava z zdravljenjem še nepotrjeni. Na željo posredujemo dodatne informacije. Pred predpisovanjem DIFLUCANA se je potrebno seznaniti s celotnimi informacijami za predpisovanje zdravila. 
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tramadol 
injekcije, l?.apsule, kapljice, suecke 

Povrn mik vi lj nja 

centralno delujoci analgetik za lajšanje zmernih in hudih bolecin 
ucinkovit ob sorazmerno mato stranskih ucinkih 
tramadol je registriran tudi pri ameriški zvezni upravi za hrano in zdravila (FDA) 
Kontraindikacije: Otroci do 1 leta starosti, akutna zastrupitev 
z alkoholom, uspavali, analgetiki in drugimi zdravili, ki vplivajo na CŽS, zdravljenje z inhibitorji MAO, Interakcije: Pri socasni uporabi zdravil, ki delujejo na osrednje živcevje, je možno sinerglsticno delovanje v obliki sedacije pa tudi mocnejšega analgeticnega delovanja. Opozorila: Pri predoziranju lahko 
pride do depresije dihanja. Previdnost je potrebna pri bolnikih, ki so preobcutljivi za opiate, in pri starejših osebah. Pri okvari jeter in ledvic je potrebno odmerek zmanjšati. Bolniki med zdravljenjem ne smejo upravljati strojev in motornih vozil. Med nosecnostjo in dojenjem predpišemo tramadol le pri nujni indikaciji. Bolnike s krci centralnega izvora skrbno nadzorujemo. Doziranje: Odrasli in otroci, starejši od 14 let: 50 do l 00 mg 3. do 4-krat na dan. Otrokom od J leta do 14 let dajemo v odmerku 1 do 2 mg na kilogram telesne mase 3-do 4-krat na dan. Stranski ucinki: Znojenje, vrtoglavica, slabost, bruhanje, suha usta ln utrujenost. Redko lahko pride do palpitacij, ortostaticne hipotenzije ali kardiovaskularnega kolapsa. Izjemoma se lahko pojavijo konvulzije. Oprema: 5 ampul po J ml (50 mg/ml), 5 ampul po 2 ml ( 100 mg/ 2 ml), 20 kapsul po 50 mg, ! O ml raztopine ( l 00 mg/ml), 5 sveck po 100 mg. 

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Official distributor: ADRIA MED d.o.o., Luize Pesjakove 8a 1000 Ljubljana, Slovenia tel.: --386 61 1379200, tel./fax: --386 61 1376450 
Radio/ Ollcol 1997; 31: 340. 

Instructions to authors 


Editorial policy or thc journal l?adio/ogy mul O/lcology is to publish original scicnlific papcrs, profcssional papcrs, revicw articlcs, case reports and varia (cditorials, rcvicws, short communications, profcssional information, book re­views, letters, ctc.) pcrtincnt to diagnostic and interven­tional radiology, computcriscd tomography, magnetic reso­nance, ultrasound, nuclear medicine, radiothcrapy, clinical and expcrimcntal oncology, radiobiology, radiophysics and radiation protcction. Thc Editorial Board requircs that thc paper has not been publishcd or submitted for publication elsewhere: thc authors are responsiblc for ali slatcmcnts in their papers. Acccptcd articlcs become the property or the journal and thereforc cannot bc publishcd clscwherc with­out written permission from lhe cditorial board. Papers con­cerning thc work on humans, musl comply with the princi­ples of the declaration of Helsinki ( 1964). Thc approval or the ethical committcc must then bc slalcd on thc manu­script. Thc editors rescrvc thc right to rejcct a papcr with questionable justification. 
Submission ofmanuscript: Manuscripts wrillen in Eng­lish should bc submittcd in lriplicalc (the original and two copies), including the illustrations to the Editorial Office: Radiology a11d Oncology, Institute or Oncology, Vrazov trg 4, S1-1105 Ljubljana, Slovcnia; (Phonc: + 386 61 1320068, Fax: +386 61 13 14 180, c-mail: oshrestha@mail.onko-i.si). Authors are askcd to submit thcir manuscripls also onha 3.5" 
1.44 Mb formatted diskette. Thc typc or compulcr and word­processing packagc should be specified (Word for Win­dows is preferred). 

Ali atticles are subjected to editorial rcvicw and rcvicw by lwo independent rcfcrces selectcd by thc editmial board. Manusc1ipts which do not comply with thc tcchnical rcquire­mcnts stated here will be rclurned to the authors for correc­tion before the review of thc referces. Rejected manuscripts are generally returned to authors, howcver, thc journal can­not be held responsible for thcir loss. Thc editorial boanl reserves thc right to ask authors to make appropriatc changes in the content as well as grammalical and slylislic corrections whcn necessary. Thc expcnses of additional cditorial work and requests for reprinls will be chargcd to the authors. 
General instructions: Radiology and Oncology will con­sider manusc1ipts prepared according to thc Vancouver Agreement (N Engl J Med 1991; 324: 424-8, BMJ 199 l; 

302: 6772.). Type the manuscript double spaccd on one sidc with a 4 cm margin at thc top and lcft hand sidc of thc shcct. Write thc paper in grammatically and stylislically corrcct languagc. Avoid abbrcviations unless previously cxplained. The technical dala should confirm to thc SI systcm. Thc manuscript, including lhe rcfcrences may not cxceed 15 typc­written pages, and the numbcr or tigures and tables is lirnited to 4. lf appropriate, organise thc tcxt so that it includes: Introduction, Matc1ial ancl rnethods, Results and Discussion. Exceptionally, thc rcsults and cliscussion can be combined in a single section. Start each section onha ncw pagc and number these consecutivcly with Arabic numcrals. 
Title page should includc a concise and descriptive titlc for the paper; thc full name(s) of thc author(s); the institu­tional affiliation of cach aulhor; thc name and address of thc corresponding author (including telephonc, fax and c-mail) and abbreviatcd title. This should be followed by thc ab­straet page, sumrnarising in lcss Ihan 200 words thc rcasons for thc study, experimenlal approach, the 1mijor findings (with spccific dala if possiblc), and thc principal conclu­sions, and providing 3-6 kcy words for indexing purposes. The text of the repo1t should then procecd as follows: 
I11tmd11ctio11 should dcscribc thc background of the in­vestigation, citing only thc csscntial rcferences and stating the aim ofthc study. 
Material mul metlwds should provide enough informa­tion to enablc expcrimenls to be repcatcd. New methods should be dcscribed in detail. Research on human and ani­mal subjects should indicale that cthical approval of thc study was obtained. 
Results should bc prescnted clearly and concisely with­out repeating the data in the tablcs and figures. Emphasis should bc on clear and prccise prcsentation of results and their significance in relation lo the aim of the investigation. 
Discussion should cxplain the resulls, and not simply rcpcal thern, interpret their significancc and draw conclu­sions. It should review lhc results of the study in thc light of prcviously published work. 
Illustrations ancl tables: Ali illustrations and tables must bc numbercd and refcrred to in lhe text, with appropriate location indicaled in thc text margin. Illustrations must be labelled on the back wilh the author's name, figure number and orienlation, and should be accompanied by a descrip­tivc legend on a scparatc page. Line drawings should be supplicd in a form suitablc for high-qualily reproduction. Photographs should bc glossy prints of high quality with as much contrast as the subject allows. They should be cropped as closc as possible to thc area of inlerest. In photographs mask the idenlities of the patients. Tables should bc typed wilh doublc spacing wilh descriptivc title and, if appropri­ate, units of numcrical rneasurcmenls inclucled in column hcading. 

Ref'crcnccs: Number thc refcrcnces in the order in which they appear in thc tcxl and quolc their corresponding num­bcrs in the text. Authors are responsible for thc accuracy of thcir refcrcnccs. Referenccs to the Abstracls and Lcttcrs to thc Editor musl bc identified as such. Citation of papcrs in prcparation, or submitted for publication, unpublished ob­servations, and personal communications should not be in­cludcd in the reference list. lf essential, such material may bc incorporated in thc appropriatc placc in the text. The style or references is lhat of Index Medicus. Ali authors should be listcd whcn thcir number does not exceed six; whcn thcrc are scvcn or more authors, the first six listcd are followed by "et al". Thc following are some examples of refcrenccs from articles, books and book chapters: 
Denl RAG, Cole P. In vitro maturation of monocytes in squamous carcinorna of the lung. Br J Cancer 1981, 43: 486-95.h
Chapman S, Nakiclny R. A guide to radio/ogical proce­d11re.1·. London: Baillicrc Tindall, 1986. 
Evans R, Alexander P. Mechanisms of exlracellular kill­ing or nucleatcd mammalian celi s by macrophages. In: Nel­son DS, cd. !11111111110/Jiology of' macmphage. New York: Acaclemic Press, 1976: 45-74. 
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