RADIOLOGY AND ONCOLOGY 
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CONTENTS 
NUCLEAR MEDICINE 
1s quantitative salivary gland scintigraphy a mandatory examination prior to and after radioiodine therapy? Bohuslavizki KH, Brenner W, Tinnemeyer S, Lassmann S, Kalina S, Mester J, Clausen M, Henze E  5  
Relative DNA concentration in thyrocytes from scintigraphycally hot nodi Budihna NV, Zupanc M, Zorc-Pleskovic R, Porenta M, Vraspir-Porenta O  13  
Diagnostic value of currently available tumor markers in thyroid cancers Brenner W, Bohuslavizki KH, Klutmann S, Henze E  18  
Value of scintigraphic imaging in the detection of pancreatic tumors ­role of FDG-PET Bohuslavizki KH, Mestner J, Brenner W, Buchert R, Klutmann S, Clausen M, Henze E  21  
Nuclear medicine IBM PC PIP-GAMMA-PF computer system Fidler V, Prepadnik M, Fettich J, Hojker S  27  
EXPERIMENTAL ONCOLOGY  

Study of blood perfusion with Patent Blue staining method in LPB fibrosarcoma tumors in immuno-competent and immuno-deficient mice after electrotherapy by direct current 
Jami T, An DJ, Belehradek J Jr, Mir LM, Serša G, Cemažar M, Kotnik T, Pušenjak J, Miklavcic D 
CLINICAL ONCOLOGY REPORTS 
Superficial thermoradiotherapy: Clinical results favor immediate irradiation prior to hyperthermia Lešnicar H, Budi/zna M  39  
Radiotherapy in nephorblastoma. Pre-and postoperative combination treatment. Radiotherapy in localized (stage II, III, IV) and metastatic disease. Acute and long-term side effects.  
Jereb B  48  
Thre-layer template for low-dose-rate remote afterload transperineal interstitial brachytherapy Kuhelj J, Strojan P, Burger J  54  

ESTRO teaching course in Basic Clinical Radiobiology Cemažar M  56  
Study tour in Cambridge: A report Weninger C  60  
SLOVENIAN ABSTRACTS  62  

NOTICES 
Radiology and Oncology is now available on the itemet at: http:/ /www.onko-i.si/radiolog/rno l .htm 
Radio/ Oncol 1997; 31: 5-12 
Is quantitative salivary gland scintigraphy a mandatory examination prior to and after radioiodine therapy? 
Karl Heinz Bohuslavizki,1 Winfried Brenner,1 Stephan Tinnemeyer,1 Stefan Lassmann,1 Sonia Kalina,1 Janos Mester,2 Malte Clausen,2 Eberhard Henze1 
1 Clinic oj Nuclear Medicine, Christian-Albrechts-University, Kiel, Germany, 2 Department oj Nuclear Medicine, University Clinic Eppendorf, Hamburg, Germany 
The aim of this study was to evaluate possible deterioration of saliva,y gland function due to low dose radioiodine therapy using quantitative saliva,y gland scintigraphy (qSGS). In addition, the prevalence of salivary gland impairment (SG[) was estimated in thyroid patients. Prior to routine thyroid scintigraphy, qSGS was pe1formed after i.v. injection of 36-126 MBq Tc-99m-pertechnetate, and the uptake was calculated asa measure of parenchymalfunction. 144 patients unde1went qSGS prior to and 3 months after radioiodine therapy. The prevalence of SGI was estimated from qSGS in another 674 patients submitted to thyroid scintigraphy. Despite salivary gland stimulation with ascorbic acid during radioiodine therapy a significant dose related parenchymal impairment of 15-90 % could be measured after the application of 0.4-24 GBq of l-131. The prevalence of SGJ was 77/674 = 11.4 % and 52/674 = 7.7 % in one/two and threelfour glands, respectively. Thus, qSGS should be applied in all patients prior to and after radioiodine therapy to quantify 
and to document both the preexisting and the treatment induced SGJ even by low dose /-131. With respect to forensic reasons qSGS might even be applied mandat01y. 
Key words: salivary glands -radionuclide imaging -iodine radioisotopes -adverse effects 
Introduction 
Radioiodine therapy using I-131 has been known to be effective for almost 50 years both to reduce hypetthyroidism or to treat differentiated thyroid carcinoma and its iodine trapping metastases. De­spite an almost selective uptake of iodine in thyroid cells it can be mistaken for chlorid due to its similar atomic diameter and its comparable electrical charge. This leads to an undesired accumulation of I-131 via an energy consuming Na•/K+/2c1--co­transport1-4 in acinar cells of salivary glands as well as in gastric parietal cells. Therefore, a parenchy­mal impairment of salivary glands is a well-known 
Con-espondence to: Dr. Karl H. Bohuslavizki, Christian­Albrechts-University of Kiel, Amold-Heller-Str. 9, D-24105 Kiel, Germany, Tel.: +49 431 597-3076, Fax: -3065. 
UDC: 616.3!6-001.29:539.163 
undesired side effect of high dose radioiodine ther­apy as used in thyroid cancer with cumulative ac­tivities up to 40 GBq I-131.5-7 Consequently, radio­iodine therapy is performed under salivary gland stimulation using sialogoga, e.g. chewing gum or vitamin C drops in order to minimize the intraglan­dular transit tirne of I-131 and, thus, to minimize salivary gland impairment.6-11 
However, there are only rare data on parenchy­mal damage in salivary glands after low dose radio­iodine therapy as used for the treatment of benign thyroid diesease. This is mainly due to the Jack of an easy to perform method which yields quantita­tive data on parenchymal function of ali major sali­vary glands. However, recently a normal data base for quantitative salivary gland scintigraphy has been established12· 13 on a large number of healthy sub­jects, and its value for the detection of mild paren­chymal impairment has been demonstrated success­
17 
fully in Sjogren's syndrome.14­
Bohuslavizki KH et al. 
The aim of this study was therefore first to enlarge this normal <lata base in order to reduce the standard deviation of these reference values, second to quanti­fy possible parenchymal damage in salivary glands due to low <lose radioiodine therapy performed under salivary gland stimulation and third to estimate the prevalence of salivary gland impairment in patients submitted to thyroid scintigraphy. 
Materials and methods 
Patients 
In a total of 1.130 patients quantitative salivary gland scintigraphy (qSGS) was performed prior to thyroid scintigraphy. Therefore, an additional radi­ation burden was omitted, and ali patients gave their informed written consent. Details of patient populations investigated are given in Table 1. 
In order to enlarge our nomal <lata base published previously1 2· 13· 16 we included 312 patients without any salivary gland diseases. Inclusion and exclu­sion criteria were described in detail elsewhere. 12 
144 patients underwent quantitative salivary gland scintigraphy prior to and 3 months after radioiodine therapy with different cumulative activities up to 24 GBq I-131. 68 patients received radioiodine ther­apy for hyperthyroidism and 11 for thyroid cancer. Details of these patients are given in Table 2. Radi­oiodine therapy was performed under salivary stim­ulating conditions by peroral application of 200 mg ascorbic acid (Cebion®) three times a day during their stay in hospital. 6-II 
The prevalence of salivary gland impairment was estimated from results of quantitative salivary gland scintigrapy obtained from another 674 patients sub­mitted for thyroid scintigraphy. Prevalence was giv­en both for single parenchymal damage covering one or two salivary glands and for globa) parenchy­mal damage covering three or four salivary glands. 
Table 2. Applied cumulative activity of I-131 in GBq and details of patient characteristics of the radioiodine therapy group: 
-I-131 Age 
[GBq]  range  mean±SD  n  f/m  
0.4-0.6  25-74  44.2 ± 7.4  44  34/10  
0.7-1.1  36-83  56.1 ± 9.3  41  30/11  
1.4-1.5  28-76  46.9±8.7  25  19/6  
3.0  20-81  42.5 ± 11.3  19  14/5  
6.0  19-65  43.7 ± 9.4  9  5/4  
24.0  29-76  58.4 ± 10.2  6  4/2  

Quantitative salivary gland scintigraphy 
Quantitative salivary gland scintigraphy was per­formed in a standardized method as described pre­viously12· 16 after intravenous injection of 36-138 MBq Tc-99m-pertechnetate. For quantification one rectangular ROI over the brain, which served as a common background ROI, and four irregular ROis over both parotid and submandibular glands were used. ROis were copied from the study performed prior to radioiodine treatment to the study obtained after radioiodine treatment. 
As a measure for parenchymal function of major salivary glands the uptake of Tc-99m-pertechnetate was calculated in percentage of the injected activi­ty. 18-26 For compensation of noise and, thus for stabi­lization of data, the uptake was averaged from 12-14 min p.i. (U 12.14). Saliva excretion was stimulated by 3 ml diluted lemon juice 15 min p.i., and excretion fraction (EF) was calcultated from mean uptake at 17-19 min p.i. (U17_19) expressed in percent of the uptake (U12_14) measured according to equation l. 
EF [%] = U 12.14 -U 11-19 • IOO 
(Eq. 1) 
u12.14 
Table l. Patient characteristics of different populations investigated. 
Age 
Group range mean±SD n f/m 
Normal date base  18-82  44.2 ± 7.4  312  216/96  
Radioiodine therapy  19-83  55.1 ± 12.3  144  106/38  
Thyroid scintigraphy  19-83  48.7 ± 9.4  674  453/221  

/s quantitative salivary gland scintigraphy a mandatory examination prior to and after radioiodine therapy? 
In order to test the reproducibility of salivary gland scintigraphy the same scintigram of a patient from the normal <lata base was reevaluated 10 times by 13 differently experienced technicians. Intraob­server reproducibility was expressed as variation coefficient and relative variation coefficient. To es­timate the interobserver reproducibility the mean of both uptake and excretion fraction derived of ali technicians was first calculated. Interobserver re­producibility was then expressed as percent devia­tion of each individual technician from this mean. 
Statistics 
Results are given as mean ± one standard deviation. Two-tailed students t-test for unpaired <lata were used to evaluate statistical differences, with p < 
0.05 considered to be statistical significant.27 Indi­vidual results of patients below the 2-sigma range of the normal <lata base were taken as pathological. 
Results 
Normal data base 
The original scintigramm of a patient from the nor­mal <lata base is shown in Figure l. The mean ± one standard deviation of Tc-99m-pertechnetate uptake of ali patients is given in Figure 2 for the major salivary glands. The corresponding normal values of Tc-99m-pertechnetate uptake and excretion frac­tion are summerized in Table 3. Tc-99m-pertech­netate uptake amounted to 0.45 ± 0.14 % and 0.39 ± 0.12 % for parotid and submandibular glands, respectively. The corresponding values for excre­tion fraction were 49.5 ± 10.6 % and 39.1 ± 9.2 %. 
A 
Excellent values were found for intraobserver re­producibility indicated by variation coefficients of 
0.3 and relative variation coefficients of below 2 %. The deviation of the individual mean from the mean of ali technicians of 1.1-5.2 % indicated an excel­lent interobserver reproducibility as well. 
Parenchymal impairment after radioiodine 
The uptake of Tc-99m-pertechnetate of parotid and submandibular glands prior to and after radioiodine therapy as well as the decrease of Tc-99m-pertech­netate uptake in percent of pretreatment values are given in Table 4 and Figure 3. A significant activity related decrease in parenchymal function could be shown in ali subgroups even after as less as 0.4-0.6 GBq I-131. Parenchymal impairment increased from 
0.15 % after 0.4-0.6 GBq I-131 to about 90 % after 24 GBq I-131. A patient receiving 6 GBq I-131 is shown in Figure 4. 
Prevalence oj parenchymal impairment 
Significant parenchymal impairment was seen in 129/674 patients. Of these, one or two salivary glands were affected in 77/674 = 11.4 %, and three or four salivary glands were affected in 52/674 = 7,7 % of these patients. 
In 69 of these 129 patients the etiology of paren­chymal impairment could be evaluated successfully. In single salivary gland damage chronic sialolithiasis and external radiation therapy could be detected in 32 and 7 patients, respectively. In patients with glo­ba! salivary gland impairment rheumatic diseases and drugs with anticholinergic side effects, i.e. neu­roleptic and antidepressant drugs, were causal in 1 O and 20 patients, respectively. However, in 60/129 = 
C 
Figure l. Sialoscintigramm of a normal patient at 13 min after injection of Tc-99m-pertechnetate prior to (A) and at 18 min 
p.i. after 3 ml of lemon juice p.o. as a sialogogum (B), and parametric image (C) for visualization of saliva excreted from salivary glands. ROis used for quantification are shown in A. 
Bohuslavizki KH et al. 
Left parotid gland 
Right parotid gland 
0.5 
I ~ 
f1f!it!llltlllt,f1Itlt!I i5 ,111tilllllll1,111tltil 
:§' 1 f 
0.00 o.o l...!....------10----:::-26­
10 T" [ . ] 20 
ime mm 0 Time [min] 

Left submandibular gland Right submandibular gland 
0.5 
0.5 
~ 
~ 


f1111t!llillllt,t11titlf ~ tlfi!tltlltfllt1tlftftlf 
~ 
;g. 
f 

f 8­
0.00 0.00 
10 20 10 T" [ . J 20 
Time [min] ime mm 
Figure 2. Time-activity-curves of Tc-99m-pertechnetate uptake in major salivary glands. Mean ± one standard deviation of 312 patients. 
Table 3. Normal values of Tc-99m-pertechnetate uptake in percent of injected activity, and excretion fraction (EF) in percent of uptake. Numbers represent mean ± one standard deviation (n = 312). RPG, LPG: right, left parotid gland. RSG, LSG: right, left submandibular gland. 
RPG LPG RSG LSG 
Uptake [%] 0.46 ± 0.15 0.44 ± 0.14 0.39 ± 0.12 0.39 ± 0.12 EF[%] 48.2 ± 10.5 50.9 ± 10.5 38.2 ± 9.1 39.9 ± 9.2 
Table 4. Mean ± one standard deviation of pertechnetate nptake in percent of injected activity in salivary glands prior to and after radioiodine therapy with different cumulative activities of I-131 in GBq, and decrease of parenchymal function in percent of pretreatment values (ti. Uptake). Note, that left and right parotid and submandibular glands were lumped together, respectively. 
a: decrease of parenchymal function was calculated versus normal <lata base since no pretreatment values were available. 
Cumulative ativity I-131 n Parotid glands Submandibular glands 
[GBq] priorto I-131 after I-131 ti. Uptake prior to I-131 after I-131 ti. Uptake 
0.4-0.6 44 0.42 ± 0.14 0.36 ± 0.13 14.3 0.36 ± 0.13 0.31 ±O.II 13.9 0.7-1.1 41 0.40 ± 0.19 0.33 ± 0.13 17.5 0.35 ±0.16 0.28 ±0.10 20.0 1.4-1.5 25 0.38 ± 0.12 0.30 ± 0.14 21.1 0.32 ± 0.15 0.23 ± 0.14 28.1 
3.0 19 0.44 ± 0.17 0.32 ± 0.16 27.3 0.37 ± 0.11 0.25 ± 0.09 32.4 
6.0 9 0.46 ± 0.10 0.29 ± 0.12 34.8 0.42 ± 0.21 0.29 ± 0.19 30.9 
24.0 6 0.04 ± 0.03 90.9" 0.05 ± 0.02 86.8" 
Normal <lata base 312 0.45 ± 0.14 0.39 ± 0.12 
!s quantitative salivary gland scintigraphy a mandatory examination prior to and after radioiodine therapy? 
0.6 
1 
n = 312 n = 44 n = 41 n = 25 n = 19 n=9 n=6 p < 0.05 p < 0.05 p < 0.02 p < 0.01 p < 0.01 p < 0.001 
o 
....., 
~ 
~ 
Q) 

041 . 

~ 
...., 
~ 

C. 
::i ~ 
~ \ 

1 
0.2 
1 

o.o ..... --...... ------------.----------..... -----..... ----...... -­
Norma1s 0.4-0.6 0.7-1.1 1.4-1.5 3.0 6.0 24.0 Cumulative Activity 1-131 [GBq] 
Figure 3. Mean uptake of pertechnetate in parotid (circles) and submandibular (squares) glands in normals and patients prior to (open symbols) and after (filled symbols) radioiodine treatment with increasing cumulative activities of 1-131. Note, that left and right parotid and submandibular glands were lumped together, respectively. For standard deviation see table 4. 



Figure 4. Sialoscintigramms 13 min after injection of Tc-99m-pertechnetate of a patient prior to (A) and and 3 months after (B) radioiodine therapy with 6 GBq-1-131 due to fol­licular thyroid carcinoma. Numbers denote mean uptake of Tc-99m-pertechnetate in percent of injected activity in pa­rotid (upper) and submandibular (lower) glands, respec­tively. Observe the srna!! ectopic thyroid remnant within the thyroglossal duet prior to therapy. 
46.5 % of the patients with parenchymal impairment there was no reason detectable for their deminished uptake of Tc-99m-pe1technetate. 
Discussion 

Normal data base 
A valid quantification of salivary gland function is mandatory to detect even mild or beginning paren­chymal impairment.'7 Beside various semiquantita­tive and not routinely practical methods (for an over­view see12) the calculation of Tc-99m-pertechnetate uptake in percent of the activity applied has been suggested18-26 in analogy to well established state-of­the-art quantitative thyroid scintigraphy.28 However, vatiable study protocols, small patient numbers and a Jack of inclusion and exclusion critetia may be the main reasons for clearly different reference values and markedly enhanced standard deviations. 
On the other hand, a reduction of standard devia­tion is desirable in order to ease the differentiation of normal and pathological parenchymal functions. This can be achieved both by enhancing the number of patients and by thoroughly selected inclusion and exclusion criteria. In our study Tc-99m-pe1technetate uptake was 0.45 ± 0.14% and 0.39 ± 0.12% for parotid and submandibular glands, and excretion frac­tion was 49.5 ± 10.6% and 39.1 ± 9.2%, respective­ly. The validity of our reference values is supp01ted first by the similar shape of our time-activity-curves (see Fig. 2) and those reported as N(ormal)-type curves derived from qualitative salivary gland scin­tigraphy29· 30 and second by successful demonstration of mild parenchymal impairment in patients suffer­ing from ongoing Sjogren's syndrome.'7 
Bohuslavizki KH et al. 
The excellent values measured for both intra-and interobserver reproducibility indicate a high repro­ducibility of salivary gland scintigraphy. Therefore, variability of Tc-99m-pertechnetate uptake of the reference values probably reflect physiological var­iability of parenchymal function in salivary glands. 
Parenchymal impairment after radioiodine 
Parenchymal impairment of salivary glands as an undesired side effect of high <lose radioiodine the­rapy as used in thyroid cancer with cumulative ac­tivities up to 40 GBq I-131 could be shown in up to 80 % of the patients.5-7 Consequently, radioiodine therapy is performed under salivary gland stimula­tion using sialogoga, e.g. chewing gum or vitamin C drops in order to minimize the intraglandular transit tirne of I-131 and, thus, to minimize unde­sired parenchymal impairment.6-11 However, there are only Iimited data on parenchymal damage in salivary glands after low dose radioiodine therapy as used for treatment of benign thyroid disease. 
Radioiodine therapy was performed under sali­vary stimulating conditions using ascorbic acid per­orally three times during the patients stay in our therapeutic ward.6-11 However, despite this com­monly accepted procedure a dose related decrease of parenchymal function could be shown even after as less as 0.4-0.6 GBq I-131. This mild impairment of parenchymal function measured after radioiod­ine treatment did not cause any hyposialia which is in agreement to common clinical experience due to severa! reasons. First, a loss of function of some 15 to 33% could be demonstrated after low dose radio­iodine therapy. Second, it is known from various diseases of both endocrine and exocrine glands that a loss of up to 90% of parenchyma is necessary to result in clinical symptoms, e.g. diabetes mellitus, diabetes insipidus, Sji:igren's syndrome, chronic pancreatitis with exocrine insufficiency, hypopitui­tarism.31 Third, patients with high dose radioiodine treatment with 24 GBq complained about hypo­sialia/asialia. The latter is in good agreement both with our observation that parenchymal function was impaired to about 90% and with data reported in the 
16 
literature.5• 
Impairment of parenchymal function was meas­ured 3 months after radioiodine therapy. It is un­clear up to now whether repair mechanisms may lead to a (partial) restoration of parenchymal func­tion. This is suggested by a long-term follow-up in a few of our patients (unpublished data). 
Quantification oj parenchymal impairment with respect to forensic reasons 
As to our knowledge there are no valid data in the literature concerning the prevalence of parenchy­mal impairment in salivary glands. Most probably this might be due to a lack of an easy to perform examination which yields valid quantitative data on salivary gland function. Using quantitative sal­ivary gland scintigraphy we found a pathological­ly ecreased parenchymal function in 19.1% of674 patients investigated. Single and globa! parenchy­mal dysfunction contributed approximately to equal amounts. Beside common reasons of globa! parenchymal impairment, e.g. rheumatic diseases, drugs with anticholinergic effect, i.e. neuroleptic and antidepressant drugs should be kept in mind.32 However, we could not evaluate any reason in as much as 60/129 = 46% of these patients even though the patients history was obtained very care­fully. 
However, both the knowledge and extent of any kind of preexisting parenchymal damage is essen­tial since salivary glands may be damaged even after low dose radioiodine. Consequently, clinical significant functional impairment may occur, and forensic problems may arise. Therefore, it is es­sential not only to inform patients with preexisting parenchymal impairment about possible occurence of hyposialia but to increase salivary gland stimu­lation during radioiodine therapy. Thus, quantita­tive salivary gland scintigraphy should be per­formed in ali patients prior to and after radioiod­ine therapy in order to exclude or to quantify radi­oiodine induced parenchymal impairment in salivary glands. 
Conclusions 
Quantitative salivary gland scintigraphy is an easy to perform method with excellent intra and interob­server reproducibility which can be performed prior to thyroid scintigraphy without any additional radi­ation burden. It should be performed prior to radio­iodine therapy in order to document salivary gland function, and it should be repeated 3 months after radioiodine therapy in order to either exclude or quantify possible radioiodine induced parenchymal impairment of salivary glands. With respect to fo­rensic reasons quantitative salivary gland scintigra­phy might even be applied mandatory. 

!s quantitative salivary gland scintigraphy a mandatory examination prior to and after radioiodine therapy? 
Acknowledgment 

We thank A. Bauer, R. Bradtke, C. Fock, I. Ha­mann, K. Nielsen, S. Ossowski, M. Reymann and 
E. Schmidt for perfect technical assistance. 
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Bohuslavizki KH, Brenner W, Wolf H, Sippel C, Ton­shoff G, Tinnemeyer S, Clausen M, Henze E. Value of quantitative salivary gland scintigraphy in the early stage of Sjogren's yndrome. Nucl Med Commun 1995; 16: 917-22. 

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Harden RM, Hildrich TE, Kennedey I, Mason DK, Pa­padopoulos S, Alexander WD. Uptake and scanning of the salivary glands in man using pertechnetate-99m­Tc. Ciin Sci 1967; 32: 49-55. 

19. 
Havlik E, Scherak O, Bergmanu H, Kolarz G. Techne­tiumspeicherung der Parotis -Wertigkeit von Funk­tionsparametem beim Sjogren-Syndrom. Nuklear­medizin 1976; 15: 142-5. 

20. 
Hugh I, Holtgrave EA. Entztindliche Erkrankungen der Parotis -Korrelation von Speicheldriisengraphie und Funktionsszintigraphie. Lmyng Rhinol 1974; 53: 213-22. 

21. 
Kolarz G, Bergmanu H, Havlik E, Scherak O, Thumb 

N. 99 m-Tc-Uptake der Parotis bei Sjogren-Syndrom. Verh Dtsch Ges Rheumatol 1976, 4: 498-503. 


22. 
Schall GL, Larson SM, Anderson LG, Griffith JM. Quantification of parotid gland uptake of pertechnetate using a gamma scintillation camera and a "regio-of­interest system. Am J Roentgenol Radium Ther Nucl Med 1972; 115: 689-97. 

23. 
Schneider P, Traurig G, Haas JP. Quantitative Funk­tionsszintigraphie der Speicheldrtisen. Fortschr Riint­genstr 1984: 140: 93-6. 

24. 
Spens E, Dietzel C, Klaua M, Grimm D. Computerszin­tigraphische Untersuchungen zur Funktion der GroBen Kopfspeicheldrtisen. Stomatol DDR 1990: 40; 52-4. 

25. 
Stephen KW, Chisholm DM, Harden RM, Robertson JWK, Whaley K, Stuart A. diagnostic value of quanti­tative scintiscanning of the salivary glands in Sjogren' syndrome and rheumatoid arthritis. Ciin Sci 1971: 41: 555-61. 

26. 
Stephen KW, Robertson JWK, Harden RM. Quantita­tive aspects of pertechnetate concentration in human parotid and submandibular salivary glands. Br J Radio! 1976: 49: 1028-32. 

27. 
Sachs L: Applied statistics A handbook of techniques. 2nd edition, New York: Springer 1984. 

28. 
Joseph K: Statische dynamische und quantifizie1te Schil­drtisenszintigraphie. Nuklearmediziner 1979; 2: 83-10 l. 



Bohuslavizki KH et al. 
29. 
Mitas S, Kokono M, Matuoka Y, Irimijiri S. Diagnostic 31. Isselbacher KJ, Braunwald E, Wilson JD, Martin JB, availability of RI-sialography in Sjcigren's syndrome. Fauci AS, Kasper DL (eds.): Harrison's principles of The Ryumachi 1981; 11: 305-16. interna! medicine. 13th edition. New York: McGraw­

Hill 1994. 


30. 
Sugihara T, Yoshimura Y. Scintigraphic evaluation of the salivary glands in patients with Sjogren' s syn­32. Borg S, Brodin K. Antidepressant drugs. In: Dukes drome. lnt J Oral Maxillofac Surg 1988; 1988: 17: MNG (eds). Meyler's side effects of drugs. Amster­71-5. dam: Elsevier 1992; 30-78. 


Radio/ Oncol 1997; 31: 13-7. 
Relative DNA concentration in thyrocytes from scintigraphically 
hotnodi 
Nataša V. Budihna,1 Miran Zupanc,1 Ruda Zorc-Pleskovic,2 Miran Porenta,1 Olga Vraspir-Porenta2 
1 Department oj Nuclear Medicine University Medica! Centre, Ljubljana, Slovenia, 2 Institute oj Histology, Medica! Faculty, University oj Ljubljana, Ljubljana, Slovenia 
The aim of our study was to study the cytological appearance and the relative DNA content of scintigraphically hot thyroid nodi. Methods: Sixty-seven patients with hyperthyroidism due to hot nodi were treated. The relative DNA content of thyrocytes in hot nodi was determined by single celi cytophotometry and compared to results of cytology, and scintigraphy. T4, T3, TSH and thyroglobulin were measured in sera of the patients as well. Results: The modal value of the relative DNA concentration in thyrocytes was in 16 hot nodi diploid (Type 1), in 21 hyperdiploid (Type 2). The 12 nodi with diploid (Type 3) as well as 18 with hyperdiploid (Type 4) moda! value of the relative DNA concentration had signs of increased proliferation. The thyrocytes of 4 normal controls were diploid. Cytomorphological signs of atypia and degenerative changes of thyrocytes were significantly more frequent in Types 3 and 4 than in Types 1 and 2. Conclusion: Dominant scintigraphically hot thyroid nodi are diploid or hyperdiploid. Some of them are in the state of proliferation. DNA cytophotometry can be useful as an additional diagnostic method in cases with thyroid (hot) nodi of uncertain cytology, especially when therapy with low dose of radioiodine is planned. 
Key words: hyperthyroidism -radionuclide imaging; DNA; cytophotometry 
Introduction 

Autonomous nodi are present in about 40% of pa­tients with endemic goiter. 1 Scintigraphy _with tech­netium (99"' Te) or iodine (1 31J) regularly shows an autonomous nodule as a hot spot with a more or less suppressed paranodal thyroid gland. A hot spot on the scan of the thyroid can present a trne adeno­ma, a hyperplastic clone of hyperactive autono­mous thyrocytes or a highly differentiated follicular 
Correspondence to: Nataša V. Budihna, M. D., Ph. D., De­partment of Nuclear Medicine, University Medica:! Centre, Zaloška 7, 1000 Ljubljana, Slovenia. 
UDC: 616.441-008.61-09 l.83 
carcinoma. It is therefore desirable to differentiate among these conditions before the therapy is given, although in general the incidence of thyroid carci­noma is low.2•3 The aim of our study was to deter­mine a pattern of DNA distribution in hyperactive thyroid nodi. 
Materials and methods 

Subjects 
Sixty-seven hyperthyrotic patients with autonomous goiter, sent to our department for routine investiga­tions before the therapy with radioiodine, were in­
Budihna NV et al. 
cluded in the study. The inclusion criterion was the presence of a single hot node or utmost 3 hot nodi with a discernible dominant hot node. There were 57 females and 10 males, aged 43 to 89 years (mean 
61.5 years). 
The normal control group consisted of 4 females, aged 33 to 37 years, sent to our department for suspected autoimmune thyroiditis. In each of them thyroid disease was excluded by hormona! tests, negative thyroid autoantibodies and by cytological examination of the thyroid. 
Methods 
The fina! clinical diagnosis of thyroid disease was based on the disease history, the physical examina­tion of the patients, the results of thyroid cytology, ultrasonography, scintigraphy, serum T4, T3, TSH and thyroglobulin concentration. The results of cy­tophotometry were compared with cytomorphology (cytology) and fina! diagnosis. 
Scintigraphy and ultrasonography 
The planar scintigraphy of the thyroid was per­formed with Siemens Basicam gamma camera, 20 minutes after intravenous application of 80 MBq of 
131 1 
99"'Tc-pe1technetate. Scintigram with 2 MBq of was accomplished 24 hours after the oral applica­tion of radiotracer. Ultrasonography (US) of the thyroid was performed by using high resolution transducer (10 MHz, Diasonics DRF 300). The di­ameter of dominant hot nodi was measured with US. Scintigraphically hot nodi were identified on the ultrasound scan with the help of scintigrams. Fine needle biopsy of a dominant hot node, guided by US, was done after scintigraphy. Smears for cytology and the single celi cytophotometry were prepared from each sample obtained with fine nee­dle aspiration biopsy. 
Cytomorphology 
Smears were stained by the May-Gruenewald-Giem­sa method. The morphological changes in thyroid cells were grouped into 6 classes: 
normal thyrocytes 2 hyperactive thyrocytes 3 thyrocytes with degenerative changes 4 proliferation or atypical thyrocytes 5 malignancy suspected 6 definite malignancy 
Cytochemical DNA assessment 
The single celi cytophotometry was performed af­ter the Feulgen staining procedure, including acid hydrolysis in 4 N HCI at 28°C for 60 min. DNA measurements were catTied out on microspectro­photometer Opton USPM 30/50 at wave length of 580 nm and diaphragm 0.63. The objective's mag­nification was 25x or 40x. Processing was done by the computer. Hundred and fifty to 200 thyrocytes and 25-100 leucocytes were evaluated in each smear. The moda! relative DNA concentration of leucocytes in the same thyroid biopsy smears served as a reference value for the normal diploid DNA concentration, the so called "L" value.4.5 The thyro­cytes with the moda! relative DNA concentration were considered to be in Gl (gapl) phase of celi division cycle, G2 (gap 2) phase was double moda! value. The cells with the intermediate DNA con­centration were considered to be in S (synthesis) phase. According to their relative DNA content, thyrocytes from hot nodi were classified as diploid (0.75<Gl<l.25 L) and hyperdiploid (1.25 L < Gl). The results were expressed as percentage of thyro­cytes in each class. DNA frequency distribution histograms of thyrocytes in hot nodi were com­pared to the histograms of leucocytes and of normal thyrocytes in control patients. 
Biochemical analyses 
The analysis of serum total triiodothyronine -T3 (normal 1.09-3.12 nmol/1) was done with the RIA method (SPAC T3 -Byk-Sangtec, Dietzenbach), total thyroxine -T4 (normal 53-182 nmol/1) with SPAC T4 -Byk-Sangtec, Dietzenbach, thyrotropin -TSH ( normal 0.17-4.05 mE/1) was measured with the immunoradiometric method, IRMA (Imunote­ch, Marseille) and thyroglobulin -Tg (normal 0-34 µg/1) with the RIA method (Henning, Berlin). 
Statistical analysis 
Mean, standard deviation, median and moda! val­ues and, when appropriate, Chi square test were calculated. 
Results 
Scintigraphy was performed in 67 patients: 37 pts had a solitary hot node, 
18 pts had 2 hot nodi (with 1 dominant node), 
12 pts had 3 hot nodi (with 1 dominant node), 

Relative DNA concentration in thyrocytesfrom scintigraphicaily hot nodi 
The thyroid scmt1grams performed with 99"'Tc­pertechnetate showed the same distribution pattern of radioactivity as the scintigrams with 131J in ali patients. 
Results of cytology, ultrasound investigation, hor­mona[ analyses and Tg of 67 patients with hot nodi are given in Tables 1 and 2. 
Table l. The size and cytological class of 67 scintigraphi­cally hot nodi. 
units mean ± sd median mode 
radius of  cm  2.7 ± 0.7  3  3  
nodi  
cytology  class  2.07 ± 1.1  2  


Table 2. TSH, T4, T3 and Tg in plasma of 67 patients with scintigraphically hot nodi. 
units mean ± sd median 
TSH  mE/1  0.08  0.13  0.04  
T4  nmol/1  151.4  45.5  139  
T3  nmol/1  3.47  0.94  3.39  
Tg  ug/1  58.7  46.9  46  


DNA measurements 
According to the cellular DNA content in hot nodi we noticed four different types of DNA frequency distribution histograms (See also Table 3.): Type 1-moda! class was diploid (mean relative DNA concentration was 1.24 ± 0,05L), Type 2 -moda! class was hyperdiploid (mean rela­tive DNA concentration was 1.57± 0,13 L), Type 3 -moda! class was diploid but some poly­ploid cells were noticed. 
Type 4 -moda! class was hyperdiploid and some polyploid cells were noticed. There was no significant difference in percentage of cells in S phase between different types. 
The results of cytomorphology were compared with individual types of DNA frequency distribu­tion histograms in Table 4. 
The cytomorphology in group of patients with DNA frequency distribution histograms of the types l and 2 differed significantly from the types 3 and 4 (p<0.001). There was no statistically significant dif­ference in the results of cytomorphological exami­nation between types 1 and 2, or 3 and 4. 
Fina[ diagnosis 
By the clinical investigation and the hormone analysis subclinical hyperthyroidism was proved in two patients with antonomous nodi wheres overt moderate hyperthyroidism due to toxic nodular goit­er was proved in 65 patients. One patient had histo­logically verified follicular carcinoma within the solitary hot nodule (cytologic class was 4, DNA frequency distribution histogram was type 4). One patient had oncocytic tumor within 3 hot nodi (cyto­logical class 5, DNA frequency distribution histo­gram was type 3). 
In the control euthyrotic group, ali the results were within the normal limits. 
Discussion 

Two types of hormone producing scintigraphic hot nodi were found considering the moda! value of the relative DNA concentration in thyrocytes: dip­loid and hyperdiploid. The proliferation was appar­ent in some of these nodi. Atypia as noted with the 
Table 3. Types of DNA frequency distribution in 67 scintigraphically hot nodi compared to normal thyroid (controls) and leucocytes. 
Histogram Patients (N) 01(%) s(%) 02(%) >02 (%) 
Type 1  16  94±6  5±6  0.25 ±O.S  1  1.7  
Type 2  21  94±5  4±4  0.7 ± 1.4  0.1  0.4  
Type 3  12  68 ± 19  5±3  23.9 ± 17  2.7  2.8  
Type4  18  78 ± 13  8±8  14± 12  1.7  2.9  
Controls  4  96 ± 3.6  1-8  o  o  
Leucocytes  67  100  o  o  o  
--­ 

Legend: 01, 02, S(%) -percentage of thyrocytes in individual phases of celi division cycle >02 -percentage of thyrocytes with more than tetraploid DNA concentration 
Budihna NV et al. 
Table 4. The comparison of cytomorphologic results in different types of DNA frequency distribution histograms in 67 hot nodi. 
Histogram  Patients  Active  Aniso- Oncocytes  Degenerated  Microfollicles  
(N)  thyrocytes (% pts)  nucleosis (% pts)  (% pts)  thyrocytes (%pts)  (%pts)  

Type 1 16 100 o o o 10 Type 2 21 80 5 o 10 15 Type 3 12 83 42 8 33 25 Type4 18 94 17 6 39 II 
cytomorphology was more frequent in nodi with the signs of proliferation in the DNA frequency distribution histogram. 
In a recent study the somatic mutation of TSH receptor gene was shown in the major part of auton­omous nodi. The proof of this mutation might have an implication on the prognosis of thyroid adeno­ma.6 According to standards somatic mutation is present in 58 % of autonomous nodi in our study. It is apparently more frequent among solitary hot nodi where the average relative DNA concentration was slightly higher than in groups with 2 or 3 hot nodi. 
Severa! authors assume the aneuploidy character­istics of true adenomas.1· 10 Also Lukasz found pre­dominant hyperdiploidy in thyroid adenomas. 11 Ac­cording to these authors it is conceivable that among hot nodi in our patients those with the DNA fre­quency distribution histograms of Types 2 and 4 are true adenomas. In favour of this it is also the cytomorphology, which showed higher grades of atypia in these nodes. 
Among 67 hot nodi in our patients 2 (2.8%) were malignant. Citomorphologically one patient had fol­licular carcinoma (solitary hot node) and the other one (3 hot nodi) oncocytoma. In both cases the single celi cytophotometry showed the DNA distri­bution histograms reflecting proliferation and hy­perdiploidy. Since similar changes were found in some benign follicular nodi as well, such changes can not be considered a proof of malignancy. Con­trary to our experience, Bengtsson et al. 12 considers the DNA cytophotometry convenient for the differ­entiation of malignant from benign lesions in the thyroid. Most other authors believe that DNA cyto­photometry cannot reliably differentiate between 
91314 
thyroid cancer and benign thyroid adenoma,7•• •
The percentage of malignant hot nodi in our pa­tients was small but significant. After our opinion cytomorphology is therefore mandatory in ali dom­inant, especially solitary, hot nodi before the thera­py, especially if the radioiodine therapy is consid­ered. When cytomorphology is inconclusive, the DNA cytophotometry can be of a help in the fina! decision about the therapeutic plan. 
Conclusion 
Two types of DNA frequency distribution histo­grams are found in scintigraphically hot nodi of the thyroid: one with diploid and the other with the hyperdiploid moda! DNA value. Increased prolifer­ation was noted in some hot nodi. Both, benign and malignant hot nodi in the thyroid could be diploid or hyperdiploid. 
The DNA cytophophotometry can be useful as an additional diagnostic tool in the assessment of hot nodi before the therapy, especially when the results of cytology are ambiguous. 
References 
l. Wahl A. Operative Therapie der nichtimmunogenen Hyperthyreose. Krankenhausartzt 1988, 61: 392-4, Suppl. Schielddruese 1987. 
2. 
Ingbar SH. The thyroid gland. In: Wilson JD, Poster DW, eds. Williams Textbook of endocrinology. Phila­delphia: W.B.Saunders Company, 1985: 682-815. 

3. 
Riccabona G. Thyroid Cancer. Berlin, Heidelberg: Springer-Verlag, 1987: 6-17. 

4. 
Auersperg M, Šoba E, Vraspir-Porenta O. Intravenous chemotherapy with synchronisation in advanced can­cer of oral cavity and oropharynx. Krebsforsch 1977, 90: 149-59. 

5. 
Auersperg M, Us-Kra'ovec M, Petrie M, Oblak­Rupareie M, Zorc-Pleskovie R. Osteogenic sarcoma of the temporal bone: case report. Treatment with individ­ualised intraarterial chemotherapy and irradiation. Reg CancerTreat 1989; 2: 9-15. 

6. 
Porcellini A, Ciullo I, Laviola L, Amabile G, Fenzi G and Avvedimento V. Novel mutations of thyrotropin receptor gene in thyroid hyperfuntioning adenomas. Ciin Endocrinol Metah 1994; 79: 657-61. 



Relative DNA concentration in thyrocytesfrom scintigraphically hot nodi 
7. 
Wallin G, Askensten U, Backdahl M, Grimelius L, Lun-deli G, Auer G. Cytochemical assessments of the nucle­ar DNA distribution pattern by means of image and flow cytometry in thyroid neoplasms and in non-neoplastic thyroid lesions. Acta Chir Scand 1989; 155: 251-58. 

8. 
Sprenger E, Lowhagen T, Vogt-Schaden M. Differen­tial diagnosis between follicular adenoma and follicu­lar carcinoma of the thyroid by nuclear DNA determi­nation. Acta Cytol 1977; 21: 528-30. 

9. 
Haemmerli G, Strauli P, Schltiter G. Deoxyribonucleic acid measurements on nodular lesions of the human thyroid. Lab lnvest 1968; 18: 675-80. 


1 O. Joensuu H, Klemi P, Eerola E. DNA aneuploidy in follicu-!ar adenomas of the thyroid gland. AJP 1986; 124: 373-6. 
11. 
Lukasz G L, Balazs Gy, Nagy IZs. Cytofluorimetric measurements on the DNA contents of tumour cells in human thyroid gland. J Cancer Res Ciin Oncol 1979; 95: 265-71. 

12. 
Bengtsson A, Malmaeus J, Grimelius L et al. Measure­ment of nuclear DNA content in thyroid diagnosis. World J Surg 1984; 8: 481-6. 

13. 
Haemmerli G Zytophotometrische und zytogenetische Untersuchungen an knotigen Veranderungen der men-schlichen Schilddriise. Schweiz Med Wschr 1970; 100: 633-41. 

14. 
Johannessen JV, Sobrinho-Simoes M Weil differentiat­ed thyroid tumours. Problems in diagnosis and under­standing. Pathol Ann 1983;18: 255-85. 


Radio/ Oncol 1997; 31: 18-20. 

Diagnostic value of currently available tumor markers in thyroid cancers 
Winfried Brenner, Karl Heinz Bohuslavizki, Susanne Klutmann, Eberhard Henze 
Clinic oj Nuclear Medicine, Christian-Albrechts-University oj Kiel, Germany 
In the jollow-up management oj cancer patients, tumor markers are a power:ful and essential tool jor both early detection oj tumor progress, i.e. relapse ar metastases, and monitoring therapy response. In thyroid cancer well-established tumor markers are available jor the most common tumor types such as papillary and jollicular carcinomas oj the thyroid epithelium and jor medullary thyroid carcinoma, which arises jrom the parajollicular C-cel/s oj the thyroid gland. The tumor markers thyroglobulin, calcitonin, and carcinoembryonic antigen and their employment in routine clinical work-up in patients with thyroid cancer are presented. Furthermore, tissue polypeptide antigen and neuron-specific enolase as potential tumor markers in selected cases oj thyroid cancer are discussed. 
Key words: thyroid neoplasms -diagnosis; tumor markers, biological; thyroglobulin calcitonin -carcinoembryonic antigen -tissue polypeptide antigen neuron-specific enolase 
Introduction 
Carcinomas are the most common tumor type of thyroid malignancies. They may be classified into two varieties depending on whether the tumor aris­es in thyroid follicular epithelium or from the para­follicular C-cells. The general histologic types of the former one are the well-differentiated papillary and follicular carcinoma including the oxyphilic celi subtype, and, least common, the histologically undifferentiated anaplastic carcinoma. The tumor type arising from the C-cells is the so-called med­ullary thyroid carcinoma (MTC), which occurs fa­milial at least in 10%. It usually appears as a com­ponent of multiple endocrine neoplasia (MEN) tpye Ila or Ilb. The thyroid may also be the site of other rare tumors such as squamous celi carcinomas, var­ious kinds of sarcomas and lymphoproliferative dis-
Correspondence to: Dr. Winfried Brenner, Clinic of Nu­clear Medicine, Christian-Albrechts-University, Arnold­Heller-Str. 9, D-24105 Kiel, Germany, Tel.: +49 431 597­3147, Fax: +49 431 597-3150. 
UDC: 6l6.441-006.6-074 
eases, and metastases from primary tumors else­where. 
Tumor markers in thyroid cancer 
The term tumor marker in connection with thyroid cancer implicates a somewhat different and unique quality showing that the most important markers 
i.e. thyroglobulin and calcitonin -are not specific antigens of tumor tissue but common specific com­ponents of normal thyroid tissue. Their use is based on a unique option in thyroid cancer treatment, namely on the possibility of completely removing any thyroid tissue by combined surgical and radio­iodine therapy. Thus, the appearance of any thy­roid-specific substrate in the patients plasma after total thyroid ablation is highly indicative of recur­rence and/or metastases. 
Next to the mostly used tumor markers thyroglo­bulin and calcitonin applied in the sense mentioned above, "classical" tumor markers such as carci­noembryonic antigen, tissue polypeptide antigen, and neuron-specific enolase, which are mainly used 

Diagnostic value oj currently available tumor markers in thyroid cancers 
in others than tumors of the thyroid gland, may be useful for follow-up examinations in selected cas­es. In the following short review, the tumor mar­kers and their indications in thyroid cancers are described. 
Thyroglobulin (TG) 

TG is an iodinated glycoprotein peculiar to the thy­roid, which is essential for synthesis and storage of thyroid hormones. 1 Under physiological conditions usually small amounts of TG can be found in the blood with normal serum levels of less than 50 ng/ ml. Since TG is exclusively produced by thyroid epithelium cells, serum concentrations should be less than 2 ng/ml in athyrotic state. For follow-up examinations the total absence of thyroid tissue is required as achieved by thyroidectomy and subse­quent ablative radioiodine therapy.2 Since TG re­lease is stimulated by TSH, TG measurements should be performed under TSH elevation, i.e. 2-4 weeks after stopping exogenous thyroxin hormone substitution.3 Under TSH supression there may be low TG serum concentrations and, thus, false ne­gative results in 10-20% of the patients with even extended thyroid cancer including metastases or local recurrences. 
Since false negative results may also be caused by plasma antibodies directed against TG, the de­termination of TG antibody concentrations and re­covery measurements after adding a defined amount of TG are essential for reliable TG measurements.4 Taking these prerequisites into account, any post­therapeutic TG elevation indicates either remnant thyroid tissue requiring further ablative treatment or it is indicative of metastases or local recurrenc­es. TG plasma concentrations correlate well with tumor mass thereby indicating successful therapy. Thus, TG is a useful tumor marker for both therapy monitoring and follow-up examinations in patients with differentiated thyroid carcinoma, i.e. follicu­lar, papillary, and oxyphilic celi carcinomas.3 Since TG is usually produced only by differentiated thy­roid carcinomas, TG is neither of use in nearly ali cases of anaplastic carcinomas nor in MTC. 
Tissue Polypeptide Antigen (TP A) 

TP A is a cytokeratin-related non-specific proli­feration marker for nearly ali kinds of carcinomas. 
Its sens1t1V1ty for thyroid cancer including papil­lary, follicular, and medullary thyroid carcinoma, however, is only about 40-60% showing a good correlation to tumor progression or therapeutic res­ponse with a high positive predictive value of 90%.4 In combination with more specific tumor markers such as TG or calcitonin both the sensitivity and the specificity for thyroid cancer can be increased. Ad­ditionally, TPA may be used as a substitute for standard thyroid tumor markers in patients with non-reliable tumor marker values, e.g. in patients with high levels of anti-thyroglobulin antibodies. 
Calcitonin (CT) 

CT, a peptide hormon for regulating calcium me­tabolism, is produced in the C-cells of the thyroid gland, and, to some extent, in the central nervous system. CT release is stimulated by increasing cal­cium levels as well as by pentagastrin and other hormones of the gastrointestinal tract. In thyroid cancer CT is a highly specific and sensitive tumor marker for diagnosis and follow-up of MTC. In patients with clinically manifested MTC the serum levels of CT are elevated in about 90% of the cases so it can be used for differential diagnosis in sus­pected thyroid cancer.4 Furthermore, CT measure­ment in side-specific jugular venous blood samp­ling may be helpful for the localization of occult MTC.3.4 After tumor removement normal serum concentrations indicate successful therapy. How­ever, for follow-up examinations as well as for screening tests in patients with suspected MEN Ila/ IIb or their relatives a pentagastrin stimulation test is mandatory for efficient diagnosis.4 After intrave­nous injection of 0.5 µg pentagastrin per kg body weight only normal serum levels with no signifi­cant increase up to 5 min p.i. as compared to basic CT levels sufficiently exclude MTC or any relapse while a more than 2-fold increase of CT is evident for MTC. 
Carcinoembryonic Antigen (CEA) 

CEA is an unspecific tumor marker with a good sensitivity for colorectal cancer, breast cancer, and MTC. Since up to 10% of extended MTC have no increase of CT serum concentrations even after sti­mulation with pentagastrin a combination of CT and CEA is recommended for the follow-up of pa­
Brenner W et al. 
tients with MTC. The diagnostic sensitivity of CEA ranges from 1 O to 80 % for MTC depending on the stage of disease. However, there is only a weak correlation of CEA serum concentration and tumor relapse with a positive predictive value of 70 %.4 Therefore, CEA provides essential information only in those subjects with no CT release and, thus, false negative CT tests. Furthermore, CEA may serve as a tumor marker in anaplastic thyroid carcinomas in which TG serum levels are in the normal range in most cases. However, increased CEA serum concen­trations are often found in extended disease only. 
Neuron-specific Enolase (NSE) 
Another marker for neuro-endocrine tumors includ­ing MTC is NSE. While this enzyme of the glyco­lysis, the y-enolase of neuro-endocrine cells, is high­ly sensitive for small celi Jung cancer and neuro­blastomas, only a sensitivity of about 15% is re­ported for MTC. Furthermore, the positive predictive value for a relapse in NSE positive pa­tients with MTC averages only 70% and there is no strong 'correlation of NSE serum levels and tumor spread as compared to CT.4 NSE therefore, may be of clinical use only in those patients with non­reliable CT values and it cannot be recommended for routine clinical follow-up examinations. 
Conclusion 
In agreement with the recommendations of the Ger­man Society of Endocrinology the following regi­men of routine tumor marker measurements in pa­tients with cancers of the thyroid gland is suggest­ed:3 
Thyroglobulin: for the follow-up in patients with papillary, follicular, or oxyphilic carcinoma 
Calcitonin: for diagnosis and follow-up in pa­tients with medullary thyroid carcinoma as well as for screening of the relatives of patients with mul­tiple endocrine neoplasia type II 
CEA: for the follow-up in patients with medul­Iary thyroid carcinoma 
In contrast, there is no general recommendation for the use of TP A and NSE. These tumor markers, however, may be useful for the follow-up in select­ed patients with thyroid cancer. 
References 
1. 
Wartofsky L, Ingbar SH. Diseases of the thyroid. In: Wilson JD, Braunwald E, Isselbacher KJ et al. (eds.) Harrison's principles ofinternal medicine. New York: McGraw-Hill. 1991: 1692-712. 

2. 
Mazzaferri EL. Radioiodine and other treatment and outcomes. In: Braveman LE, Utiger RD ( eds.) The Thy­roid. A fundamental and clinical text. Philadelphia: JB Lippincott. 1991: 1138-65. 

3. 
Pickardt CR, Griiters-KieBlich A, GruBendorf Metal. Schilddriise. In: Ziegler R, Pickardt CR, Willing RP (eds.) Rationelle Diagnostik in der Endokrinologie. Stuttgart: Thieme. 1993: 42-78. 

4. 
Liithgens M, Wagener C, Lamerz R, Raue F, Hiifner 


M. Tumormarker. In: Thomas L (ed.) Labor und Diag­nose. Marburg: Medizinische Verlagsgesellschaft. 1992: 1142-240. 

Radio! Oncol 1997; 31: 21-6. 

Value of scintigraphic imaging in the detection of pancreatic tumors -the role of FDG-PET 
Karl Heinz Bohuslavizki,1 Janos Mester,2 Winfried Brenner,1 Ralf Buchert,2 
1 

Susanne Klutmann, Malte Clausen, 2 Eberhard Henze 1 1 2 
Clinic oj Nuclear Medicine, Christian-Albrechts-University, Kiel, Germany, Department of Nuclear Medicine, University Hospital Eppendoif, Hamburg, Germany 
One of the main challenges in diagnostic radiology is the early and the accurate detection of pancreatic carcinoma, which is indeed difficult by morphologically orientated methods, i.e. US, CT, MRI. Therefore, functional imaging using nuclear medicine procedures may be useful. In patients with suspected pancreatic cancer, severa/ imaging procedures have been investigated i.e. immunoscintigraphy, receptor scintigraphy, unspecific pe,fusion scintigraphy. However, none of them convinced in routine patient management. Best diagnostic results with an overal accuracy of about 80% were obtained using F-18-fluorodeoxyglucose positron emmission tomography (F-18-FDG-PET). Due to inherent technical limitations PET probably cannot depict lesions smaller than 10-15 mm in diameter even when using a high resolution PET scanner. Thus, it is probably not suitable far early detection of pancreatic carcinoma. It is not yet clear, whether the performance of FDG-PET is high enough to reduce the current number of diagnostic laparotomies. Prospec­tively pe,formed comparative studies with CT, US, ERCP and MRI using state of the art equipment are stili needed to establish an optimal diagnostic strategy. Beside lesion detection, FDG-PET may offer valid data on both the prognosis of pancreatic masses, and the effectiveness of therapeutic procedures. However, further effort is stili necessary to define the exact position of nuclear medicine in the management of pancreatic cancer. 


Key words: pancreatic -neoplasms -radionuclide imaging; tomography, emission 

computed 


methods, fenorine radioisotopes; FDG-PET -diagnostic value 
The clinical problem 

One of the current challenges in diagnostic radio­logy is the early and the accurate detection of pan­creatic carcinoma and its differentiation from mass­forming pancreatitis using noninvasive imaging methods. 1• 2 The diagnostic accuracy of morpholo­gically oriented imaging techniques is presently sub­optimal. Ultrasonography is hampered by the dor­sal position of the pancreas in the abdomen and the 
Correspondence to: Dr. Karl H. Bohuslavizki, Christian­Albrechts-University of Kiel, Arnold-Heller-Str. 9, D-24105 Kiel, Germany, Tel.: +49 431 597-3076, Fax.: -3065. 
bowel located in front of it. CT and MRI have an excellent geometric resolution, but the differentia­tion between malignant and benign lesions remains difficult even with this leading edge technology. On the other hand, functionally oriented nuclear medicine procedures offer the possibility of imag­ing organ metabolism when using appropriate radio­labelled tracers. At the beginning, the aim of radio­isotope studies was merely the visualization of the pancreatic tissue. For this pmpose Selenium-75­selenmethionine and (1-125)-N,N,N' -trimethyl-N' (2-hydroxy-3-methyl-5-iodobenzyl)-1,3-propanedi­amine (1-123-HIPDM) were tested. Both tracers are accumulated in the normal pancreatic tissue, but 
UDC: 616.44l-006.6-073.756.8 they can not differentiate between malignant tu­
Bohuslavizki KH et al. 
mors and benign lesions. 3· 4 Thus, in the era of high resolution radiological methods they are of a more historical value. Recently, the introduction of sev­era! new types of tracers opened exciting perspec­tives. Therefore, the possibilities of these radio­pharmaceuticals will be discussed. 
Immunoscintigraphy 
Since the mid eighties big expectations have been connected to the introduction of radiolabelled mo­noclonal antibodies against tumor associated anti­genes in oncologic nuclear medicine. The charac­teristic feature of these antibodies is their extreme­ly high specificity. Using chemical procedures, they can be broken either into Fc and F(ab')2 fragments or into Fc and Fab fragments. The F(ab')2 of Fab fragments are responsible for the antigen specifici­ty of the antibodies. These antibodies can be _la­belled with I-123, I-131, In-111 or, recently with Tc-99m. 
Different types of monoclonal antibodies have been tested for the detection of pancreatic cancer. A coctail of I-131 labelled F(ab')2 fragments of anti­bodies directed against the tumor associated anti­genes CA 19-9 and CEA was used by Montz.5 De­spite the detection of some large tumors without elevated leve! of tumor markers in the peripheral blood, this tracer is considered of only limited diagnostic value due to its relatively poor sensitivi­ty. Using In-111 for labelling and SPECT acquisi­tion at least 3 days after the tracer injection some increase in diagnostic accuracy, due to elimination of unspecific early tracer accumulation, was report­ed by Bares in various gastrointestinal carcinomas.6 As a further attempt, preliminary results have been reported with the I-131 labelled murine monoclonal antibody AR-3-IgG 1 directed against the mucin­like antigen CAR-3.7 
Investigations with the In-111 or I-131 Iabelled F(ab')2 fragments of the monoclonal antibody BW 494/32, the corresponding antigene which is often expressed by pancreatic carcinomas, failed as well in presenting a break through in immunoscintigra­phy .8 Nevertheless, in a study with only 3 patients, Abdel Nabi and coworkers presented favourable images of primary tumors as well as of their metas­tases using In-111 labelled monoclonal anti CEA antibody ZCE 025.9 
In conclusion, at present there is no radiolabelled monoclonal antibody available with clearly docu­mented high clinical performance necessary for routine patient management. Despite of this, immunoscintigraphy can be considered as a pos­sible investigation in diagnostically problematic cases. 
Receptor scintigraphy 
New possibilities in tumor imaging have been of­fered recently by the introduction of small receptor analogue molecules. A subgroup of these com­pounds, the radiolabelled somatostatine analogues can be used for imaging of endocrine tumors i.e. of those derived from the so called APUD cells. So­matostatine analogues have been primarily used for imaging of carcinoids and islet cell tumors of the pancreas. Bakker and coworkers reported the suc­cessful Iocalization of pancreatic tumors in rats with I-123-Tyr-3-octreotide. 10 However, the main disad­vantage of this radiopharmaceutical is its predomi­nantly hepatic clearance and therefore its high !iver accumulation, which may mask pancreatic tracer uptake. 
When labelling octreotide with In-111-DTPA, the Ionger halflife of In-111 can be combined with the facilitated renal clearance of the DTPA-containing compound. These features offer the advantage of 24 hours imaging when interferring background activi­ty is already minimized by renal clearance. Bakker and coworkers reported successful investigations of pancreatic tumors in a rat model using (In-111­DTP A-D-Phe 1 )-octreotide. 11 They documented an increasing tracer uptake with tirne within the tumor tissue, which could be clearly visualized by gamma camera scintigraphy in somatostatin receptor posi­tive rat pancreatic carcinoma. 11 As an attempt for supporting surgical interventions, Ohrvall and cow­orkers introduced a non imaging method for the intraoperative detection of tumors and its metastas­es by using a hand-held gamma probe. However, the feasibility of this interesting method is limited by the relatively high background activity. 12 
Unspecific perfusion tracers 
Thallium-201 uptake is considered to reflect the regional perfusion as well as the viability of tumor cells. 13 The theoretical background of this feature of TI-201 is the correlation of the growth of ma­Iignant transformed cells and the activity of the Na/K-ATPase. 14 
In 1993 Suga and coworkers demonstrated the possibility of monitoring the efficacy of antineopla­

Value oj scintig raphic imaging in the detection oj pancreatic tumors -the role oj FDG-PET 
stic treatment using quantified TI-201 uptake in pancreatic cancer. In three patients, the TI-201 up­take by the tumor correlated well with the serum leve! of the tumor marker CA 19-9.15 In a subse­quent publication of this group results with subtrac­tion scintigraphy were presented. 16 When the bound­ary between abnormal TI-201 uptake and adjacent !iver activity was unclear on the TI-201 SPECT image a SPECT image of the !iver using Tc-99m­phytate was acquired and subtracted from the TI­201 image in order to separate hepatic and pancre­atic TI-201 uptake. Using this technique a favo­rable sensitivity of 91 % could be demonstrated. However, in the same study, four of sixteen pa­tients with benign pancreatic disorders exhibited abnormal increased TI-201 uptake. Based on these <lata, TI-20 l scintigraphy is a nuclear medicine method with relatively low cost and acceptable clin­ical performance for detecting pancreatic cancer and can be recommended, especially when PET facility is not available. 
PET investigations using FDG 
The rational of using radiolabelled glucose ana­logues for tumor imaging is based on the increased metabolic activity of tumor tissue. The accelerated rate of glykolysis in aggressive malignant trans­formed tumors was published first by Warburg in 1956. 17 
Fluorodeoxyglucose (FDG), a glucose analogue, is supposed to enter the cells by the same transport mechanisms as used by native glucose. After phos­phorylation, however, FDG-phosphate is trapped intracellulary due to its extremely slow dephospo­rylation as compared to native glucose. This feature enables imaging of FDG distribution by positron emission tomography (PET). Experimental and hu­man studies have demonstrated an increase in FDG uptake in various malignant tumors. 18-20 Ali of these studies have confirmed that an increased FDG up­take is a reliable indicator of the presence of viable malignant tumor tissue. In contrast, benign process­es or metabolically less active neoplasms generally have lower or even normal levels of glucose up­take.21 The mechanism of FDG accumulation in tu­mors is prabably multifactorial. First, it is induced by activation of glucose transporter proteins and elevated glucose consumption, which both are con­sidered to be early and praminent features of an oncogene-mediated malignant transf01mation in celi 

culture systems.22 Second, tumor associated tissue inflammation praduces an increased FDG uptake as weJJ.23 
The value of Fl8-FDG for the detection of malig­nant pancreatic pracesses was first documented in patients by Zanzi and coworkers in 1990. 24 Based on the results of Fl8-FDG-PET, Klever and cow­orkers reported clear differentiation of pancreatic carcinoma and chronic pancreatitis.25 Bares and co­workers26 found focally increased FDG accumula­tion in 12 out of 13 patients with histologically praven pancreatic adenocarcinoma. Eight of nine known lymph nodes and four of five known !iver metastases were detected in their study. In contrast, in two patients with chranic pancreatitis no FDG uptake was documented. One patient suffering from an adenocarcinoma and lacking of FDG uptake had diabetes, probably because the fasting state could not be established sufficiently prior to the study. In a second study with 40 patients investigated by the same group,27 PET helped to correctly classify 25 of 27 malignant pancreatic tumors and 11 of 13 benign disorders of the pancreas. False negative findings were obtained again in 2 patients with insulin-dependent diabetes. False-positive findings were associated either to retraperitoneal fibrosis or, in one patient, to pancreas divisum with chronic pancreatitits. However, FDG-PET was shown to be superior to both CT and ultrasound in the detection of lymph node metastases. These results have been confirmed by Friess and coworkers.28 Fourty one of fourty two patients with pancreatic cancer and four of six patients with a periampullary carcinoma pre­sented a focally increased FDG uptake. In contrast, in 28 of 32 patients with chronic pancreatitis no FDG accumulation occured. 
In a comparative study of 46 patients suspected of having a pancreatic cancer the diagnostic per­formance of FDG-PET was superior to both CT and transabdominal and endoscopic ultrasound.29 This superiority of FDG-PET over CT was also demon­strated by Stollfuss and coworkers.30 Based on the result of a recent comparative study with FDG-PET and TI-201 SPECT in patients with histologically praven pancreatic cancer it can be concluded that, if PET facility is available, FDG-PET is at present the nuclear medicine method of choice.31 
An exciting and widely discussed possibility to increase the performance of PET studies is the use of quantitative methods to obtain numerical values of the phosphorylation rate of deoxyglucose. For this purpose, severa! methods have been suggested. 

Bohuslavizki KH et al. 
Most of them are based on the three-compartment model introduced by Sokoloff.32 However, there are some practical and theoretical difficulties connect­ed to the application of the three compartment mod­el of FDG metabolism, especially to the determina­tion of the velocity constants of the biochemical reactions and to that of the lumped constant.33-35 Therefore, most investigators are simply using ra­tios of FDG uptake in tumors as compared to that in normal tissue. A further possibility of quantifica­tion is the estimation of the net tumor uptake of FDG in the tumor tissue normalized to the body surface or body weight. 
The most widely used quantitative method of estimation of FDG uptake in tissue is the determi­nation of standardized uptake values (SUV). The main advantage of the SUV method is its methodo­logic simplicity. The main disadvantage is the fact, that the SUV itself is time-dependent and, there­fore, potentially subject to error if images are not obtained at the same tirne interval after tracer injec­
tion.36, 37 The impact of quantification of FDG uptake by SUV could be shown in patients with pancreatic cancer. The tumor region exhibited significantly higher values compared to pancreatic regions in patients with pancreatitis.28 Using ROC analysis it could be demonstrated that an SUV value of about 
1.5 optimally separates malignant and benign pan­creatic processes. 30 
However, very recent investigations in clinical patients report a lower accuracy as found in the early works.38· 39 Dohmen and coworkers found an accuracy of about 80% regarding the differentiation of pancreatic cancer from chronic pancreatitis. Fur­thermore, they could not demonstrate any advant­age of using quantitative parameters as compared to the simple visual analysis.38 The limited per­formance of the SUV was also reported by Vomocil and coworkers.39 


PET tracers for endocrine pancreatic tumors 
Results with C-11-labelled L-dihydroxyphenyl­alanine (L-DOPA) and hydroxytryptophane (HTP) have been recently reported in pancreatic endocrine tumors with promising results particularly regard­ing glucagonomas.40 These findings, based on the investigation of 22 patients, suggest further possi­bilities in metabolic characterization of tumors. 
However, the role of FDG in this type of tumors has not yet been explored. 

Multimodality imaging 
The combination of morphologic and functional in­formation is a very new and exciting trend in diag­nostic imaging. It is especially helpful in the exact anatomic localization of functional disorders. De­tailed morphologic information presented by the ex­cellent geometric resolution of CT or MRI can be combined with the visualization of metabolic param­eters and presented in one single image. However, for the coregistration of tomographic images from different modalities sophisticated extemal or ana­tomical markers are needed. The first successful fu­sion of F-18-FDG-PET and MR images using a sys­tem of surface markers in patients with pancreatic adenocarcinoma was demonstrated by Benyounes and coworkers.41 The combined images were impressive for exact delineation of the tumor on the high quality slices of the MR study. Thus, multimodality imaging might be of increasing interest in future studies. 


References 
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Steiner E, Stark DD, Hahn, Haini S, Simeone JF, Muel­ler PR, Wittenberg J, Ferrucci JT. Imaging of pancreat­ic neoplasms: comparison of MR and CT. AJR 1989; 152: 487-91. 

3. 
Yamamoto K, Shibata T, Saji H, Kubo S, Aoki E, Fujita T, Yonekura Y, Konishi J, Yokoyama A. Human pan­creas scintigraphy using iodine-123-labelled HIPDM and SPECT. J Nucl Med 1990; 31: 1015-9. 

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Antunez AR. Pancreatic scanning with selenium-75­methionine, utilizing morphine to enhance contrast: a preliminary report. Clevenland Ciin Quart 1964; 31: 213-8. 

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Montz R, Klapdor R, Kremer B, Rothe B. Immunoszin­tigraphie und SPECT bei Patienten mit Pankreaskarzi­nom. Nuklearmedizin 1985; 24: 232-7. 

6. 
Bares R, Fass J, Truong S, Etili U, Schumpelick V. Radioimmunszintigraphie mit SPECT: Methodik, Prob­leme und klinische Erfahrungen. Nuklearmedizin 1987; 26: 202-5. 

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Mariani-G, Molen N, Bacciardi D, Boggi U, Bonino C, Costa A, Viacava P, Castagna M, Bodei L, Tarditi L. Biodistribution and pharmacokinetic screening in hu­mans of monoclonal antibody AR-3 as a possible im­



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9. 
Abdel-Nabi HH, Schwartz AN, Wechter DG, Higano CS, Ortman-Nabi JA, Unger MW. Scintigraphic detec­tion of gastric and pancreatic carcinomas with In-111 ZCE 025 monoclonal antibody. World J Surg 1991; 15: 122-7. 

10. 
Bakker WH, Krenning EP, Breeman W A, Koper JW, Kooij PP, Reubi JC, Klijn JG, Visser TJ, Docter R, Lamberts SW. Receptor scintigraphy with a radioiodi­nated somatostatin analogue: radiolabeling, purifica­tion, biologic activity, and in vivo application in ani­mals. J Nucl Med 1990; 31: 1501-9. 

11. 
Bakker WH, Krenning EP, Reubi JC, Breeman W A, Setyono HB, de Jong M, Kooij PP, Bruns C, van Hagen PM, Marbach P. In vivo application of ('"In-DTPA-D­Phe')-octreotride for detection of somatostatin recep­tor-positive tumours in rats. Life Sci 1991; 49: 1593­601. 

12. 
Ohrvall U, Westlin JE, Nilsson S, Wilander E, Juhlin C, Rastad J, Akerstrom G. Human biodistribution of ('' 'In)diethylenetriaminepentaacetic acid-(DTPA)-D­(Phe 1 )-octreotide and perioperative detection of endo­crine tumors. Cancer Res 1995; 55 (23 Suppl): 5794s­800s. 

13. 
Ito Y, Muranka A, Harada T, Matsudo A, Yokobayashi T, Terashima H. Experimental study on tumor affinity of TI-201 chloride. Eur J Nucl Med 1978; 3: 81-6. 

14. 
Elligsen JD, Thomson JE, Frey HE, Kruuv J. Correla­tion of Na-K ATPase activity with growth of normal and transformed cells. Exp Celi Res 1974; 87: 233-40. 

15. 
Suga K, Fujita T, Nakada T, Yoneshiro S, Uchisako H, Nishigauchi K, Nakanishi T, Hamada Y. Prliminary TI-201 SPECT for assessment of treatment efficacy in three patients with pancreatic cancer. Ciin Nucl Med 1993; 18: 771-5. 

16. 
Suga K, Nishigauchi K, Kume N, Fujita T, Nakanishi T, Hamasaki T, Suzuki T. Thallium-201 SPECT and technetium-99m-phytate subtraction ]iver imaging in the evaluation of pancreatic cancer. J Nucl Med 1995; 36: 762-70. 

17. 
Warburg O. On the origin of cancercells. Science 1956; 123: 309-14. 

18. 
Som P, Atkins AD, Bandoypadhyay D, Fowler JS, Mac­Gregor RR, Matsui K, Oster ZH, Sacker DF, Shiue CY, Turner H, Wan CN, Wolf AP, Zabinski SV. A fluori­nated glucose analogne, 2-fluoro-2-deoxy-D-glucose (Fl 8): nontoxic tracer rapid tumor detection. J Nucl Med 1980; 21: 670-5. 

19. 
Strauss LG, Conti PS. The application of PET in clini­cal oncology . .1 Nucl Med 1990; 32: 623-48. 

20. 
Hawkins RA, Hoh C, Dahlbom M, Choi Y, Glaspy J, Tse N, Slamon D, Chen B, Messa C, Maddahi J, Phelps 


M. PET cancer evaluation wirh FDG. J Nucl Med 1991; 32: 1555-8. 

21. Hawkins RA. Pancreatic Tumours: Imaging with PET (editorial). Radiology 1995; 195: 320-2. 
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Flier JS, Mueckler MM, Usher P, Lodish HF. Elevated levels of glucose transport and transporter messenger RNA are induced ras or src oncogenes. Science 1987; 235: 1492-5. 

23. 
Kubota R, Yamada S, Kubota K, Ishiwata K, Tama­hashi N, Ido T. Intratumoural distribution of fluorine-18-fluorodeoxyglucose in vivo: high accumultation in macrophages and granulation tissues studied by micro­autoradiography. J Nucl Med 1992; 33: 1972-80. 

24. 
Zanzi I, Robeson W, Vinciguerra V. Positron tomogra­phy (PET) imaging in patients with carcinoma of the pancreas (abstr.). Proc ASCO 1990; 9: A434. 

25. 
Klever P, Bares R, Fass J, Btill U, Schumpelick V. PET with fluorine-18 deoxy-glucose for pancreatic disease. Lancet 1992; 340: 1158-9. 

26. 
Bares R, Klever P, Hellwig D, Hauptmann S, Fass J, Hambuechen U, Zopp L, Mueller B, Buell U, Schumpelick V. Pancreatic cancer detected by positron emission tomography with 18F-labelled deoxyglucose: method and first result. Nucl Med Commun 1993; 14: 596-601. 

27. 
Bares R, Klever P, Hauptmann S, Hellwig D, Fass J, Cremerius U, Schumpelick V, Mittermayer C, Btill U. F-18 fluorodeoxyglucose PET in vivo evaluation of pancreatic glucose metabolism for detection of pancre­atic cancer. Radiology 1994; 192: 79-86. 

28. 
Friess H, Langhans J, Ebert M, Beger HG, Stollfuss J, Reske SN, Buchler MW. Diagnosis of pancreatic can­cer by 2(18F)-fluoro-2-deoxy-D-glucose positron emis­sion tomography. Gut 1995; 36: 771-7. 

29. 
Inokuma T, Tamaki N, Torizuka T, Magata Y, Fujii M, Yonekura Y, Kajiyama T, Ohshio G, Imamura M, Kon­ishi J. Evaluation of pancreatic tumours with positron emission tomography and F-18 fluorodeoxyglucose: comparison with CT and US. Radio/ogy 1995; 195: 345-52. 

30. 
Stollfuss JC, Glatting G, Friess H, Kocher F, Berger HG, Reske SN. 2-(flourine-18)-fluoro-2-deoxy-D-glu­cose PET in detection of pancreatic cancer: value of quantitative image interpretation. Radiology 1995; 195: 339-44. 

31. 
Inokuma T, Tamaki N, Torizuka T, Fujita T, Magata Y, Yonekura Y, Ohshio G, Imamura M, Konishi J. Value of Fluorine-18-Fluorodeoxyglucose and Thallium-201 in the detection of pancreatic cancer. J Nucl Med 1995; 36: 229-35. 

32. 
Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, Sakurada O, Shinohara M. The (C-14)-deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure and normal values in the conscious and anesthetized albina rat. .1 Neuroclzem 1977; 28: 897-916. 

33. 
Huang SC, Phelps ME, Hoffmann EJ, Side1is K, Selin CJ, Kuhi DE. Noninvasive determination of local cerebral metabolic rate of glucose in nonnal human subjects with 18-F-Fluoro-2' -Deoxyglucose and emission computed to­mography. Amer J Plzysiol 1980; 238: E69-E82. 

34. 
Blomquist G. On the construction of functional maps in positron emission tomography . .1 Cerebr Blood Flow Metah 1984; 4: 629-32. 


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Patlak CS, Blasberg RG, Fenstermacher JD. Graphic evaluation of blood to brain transfer constants from 

. multiple tirne uptake data. J Cerebr Blood Flow Metah 1983; 3: 1-7. 

36. 
Hawkins RA, Choi Y, Huang SC, Messa C, Hoh CK, Phelps ME. Quantitating tumour glucose metabolism with FDG and PET (editorial). J Nucl Med 1992; 33: 339-44. 

37. 
Hamberg LM, Hunter GJ, Alpert NM, Choi NC, Babich JW, Fischman AJ. The dose uptake ratio as an index of glucose metabolism: useful parameter or oversimplifi­cation; J Nucl Med 1994; 35: 1308-12. 

38. 
Dohmen BM, Bares R, Teusch M, Buell U. Classifica­tion of pancreatic tumours by FDG-PET: Comparison of visual and quantitative image interpretation by ROC analysis (abstr.). J Nucl Med 1996; 36: 140P. 


39. 
Vomocil B, Hiibner KF, Adams LJ, Smith GT, Buono­core E. The complimentary role of PET using C-11­aminocyclobutanecarboxylic acid (C-11-ACBC) and F-18-FDG in suspected pancreatic cancer (abstr.). J Nucl Med 1995; 36: 193P. 

40. 
Ahlstrom H, Eriksson B, Bergstriim M, Bjurling P, Langstrom B, Oberg K. Pancreatic · neuroendocrine tumours: diagnosis with PET. Radiology 1995; 195: 333-7. 

41. 
Benyounes H, Smith FW, Campbell C, Evans NT, Mikecz P, Heys SD, Bruce D, Eremin O, Sharp PF. Superimposition of PET images using l 8F-fluorodeox­cyglucose with magnetic resonance images in patients with pancreatic carcinoma. Nucl Med Commun 1995; 16: 575-80. 



Radio/ Oncol 1997; 31: 27-32. 
Nuclear medicine, IBM PC PIP-GAMMA-PF computer system 




Valentin Fidler, Milan Prepadnik, Jurij Fettich and Sergej Hojker 
Clinic for Nuclear Medicine, University Clinical Centre, Ljubljana, Slovenia 
Our own development of nuclear medicine computer system was mainly due to very high prices of commer­cial systems and was based on our knowledge and experiences in the development of some other nuclear medicine equipment and processing software. 1• 2 The project was started 5 years ago on the low cost IBM PC and after two prototypes a highly professional acquisition board was built along with the acquisition and data analysis software. The acquisition board is characterised by stable functioning and simple installation. After testing different modes of processor input of scintigraphic signals (DMA, PORT) the latest one was chosen because of its simpler programming code, good stability and the possibility of using it in DOS and WINDOWS. The acquisition software consists of a predefined set of acquisition protocols for standard nuclear medicine examinations, simulation of persistence scope with a possibility of changing the image orientation, zoom size, automatic adjustment of the image size, offse( and pixel size, analysis of clinical image data and archiving the patient population and scintigraphic data by using departments network. To the database management and system processing routines -PIP by A. Todd-Pokropek (London University) we added some clinical processing modules for the most common examinations in nuclear medicine. The system was succes.~fully applied in daily routine work at the clinic for nuclear medicine in Ljubljana and in some other places. 
Key words: nuclear medicine; radionuclide imaging; image processing, computer assisted; software 
Acquisition board 

The Gamma camera is functionally connected to the computer via an analogue-digital converter and control logic circuit (Diagram 1.1.). 
l. Position signals 
The position signals X and Y (Diagram 1.2.) are defined by the following characteristics: -the displacement of scintigraphic image from the middle of matrix defined as X or Y offset their variation range (scan height and width) corresponding to X and Y gain -analogue signals in V (volts) 
Correspondence to: Valentin Fidler, Ph.D., Clinic for Nu­clear Medicine, University Clinical Centre, Zaloška 7, Ljubljana, Slovenia. 
X 
y 
z I CONTROL 1--> PC 
LOGIC AND 
PORT 1 CONTROL 

Penistence 
d;,pl,~ . / ' 

irnl _-----",. 
-·~, 

MaTk.erfor 
T 
E o ) 

UDC: 538.163:621.383.8 Diagram 1.1. Functional diagram of interfacing board. 
Fidler Vet al. 
-generally non-symmetric signals in relation to 
ov 
-signal variation means the X -Y range (Sie­mens BASICAM : ± 2V, GE 300 A : ± 1.5 V, Nuclear Chicago Searle : ± 2 V) 
-commonly constant values of X -Y signals until they are changed by Z sampling signal 
-coaxial cabling from gamma camera console to computer interfacing card with 70 Q impedance of BNC connector 
-amplifier needed for more than 1 O m long X ­Y cables 
-IC designed for O V in the middle of the matrix 
-non-symmetric variation of X -Y signals relat­ed to O V means the image offset 


y 
\______J 
~ 


z_JL 
Diagram 1.2. Gamma camera signals: definition of X and Y offset and gain 
2. Logical energy signal 
The logical signal Z, which represents the correct gamma ray energy, starts the X and Y conversion and sampling (Diagram 2.1.). 
X 
y 
nonsymmetric X -Y 

signals 
offset 
ov 
tirne 
z 
tirne 
Diagram 2.1. Shape of Z signal and offset and gain of X and Y signals 
3. Analogue-digital conversion of X and Y signals 
The digitalisation of X and Y signals is character­ised by the following features: 
-the accuracy improvement of signal conver­sion: the AD converter with more bits is used for more reliable higher bits (pp. 12 bits for 1 byte magnitude conversion; after conversion the 4 less significant bits are rejected), dynamic linearity is improved 
-in high count seans ( > 2 million counts) the correction for dynamic non-linearity of ADC should generally be applied 
-each AD converter has its own characteristic linearity curve 
4. Autoadjustment of inte,facing board's gain and 
offset for input gamma camera signals  
The position signals X and Y from camera to the inte1facing card must fit ter matrix.  the the  gamma compu­ 

This can be done basically by two methods either by manual adjustment of the gamma camera posi­tion signals on the interfacing card or by the feed­back intervention "interfacing card -computer" (Di­agram 4.1.). 
The last method considerably improves the effec­tiveness and simplicity of the whole acquisition system. We developed the logica circuit for a con­tinuous change the gain of input X and Y signals from the gamma camera prior the analogue-to-dig­ital conversion. 
The mean value of the gain setting 128 (range 0-255) corresponds to the range of x,y ± 1.5 V for the whole matrix size. If the input signal's range varies up to ± 3 V, then at this gain setting half of the image will be cut in diameter (dia­gram 4.2.). 
With such a range, which can be manually changed for really extremely non-standard gamma camera signals, all the available gamma cameras can be used. 
When the input signals come from the gamma camera with a range of ± 0.75 V and the chosen gain is 128 then the image in the matrix will have half of the diameter' s value of the gamma camera with signals in the range of ± 1.5 V. To set up the interfacing gain we shall start with the highest possible value of gain parameter (255). In this case we shall normally get a minimized image for most gamma cameras. Our task is now to increase 

Nuclear medicine, IBM PC PIP-GAMMA-PF computer system 
A. Offset adjustment 
A. Offset adjustment 
X,Y input X,Youtput 


00 DI Dl 
D3 
from PC 110 port 
D4 
o, .. 
07 

B. Gain adjustment 
B. Gain adjustment 

X~ Y signal input X-Y signaloutput 
+ >--------------.-­
------0 
/ 
D/A converter 
from PC 1/0 port 


Diagram 4.1. Digital gain and offset control of X and Y. 
A. Fixed IC setting B. Initial gain value for iterative loop 
X,Y range=± 1.5 V X,Y ranges : ± 0.5 V -±3 V GAIN= 128 GAIN·= 255 
/,,,,,---------...... ,, 




./-~ 3V 
' ' 
' ( ,.-r ~ 
.......................... ~\ \. ./j 1 
... _ .. .........__ f 
! 
' ' ' 

0.5 V 
......... _____ ..... ,,.,." 
C. Iterative loop 
GAIN l . 2r j 

Diagram 4.2. Adjusting the interfacing card's gain and offset values 
the image size step by step by decreasing the in­terfacing gain value. The problem of non-central positioning of the image in the matrix can be solved simply by moving the image centre to the matrix centre. To start the image position in the matrix centre we set the offset to 128. If the image is not centred (non-symmetrical X,Y range), then we change the offset to a new value which is equal to the displacement of the image centre from the matrix centre. 
Instrumenta[ needs 
To start the gain and offset set-up, the uniform radioisotope source (Co57 plate on collimator or point source 2 m from gamma camera without col­limator) is used. 
Algorithm far autoadjustment of interfacing board's gain and offset 
Initial values The following starting values are chosen: For iter­ative loop gain = 255, offset in both directions = 128 
Main loop 

The scan of 50000 counts in the matrix 256x256 is acquired. The activity profile in X and Y direc­tion with thickness of 3 lines is formed, the maxi­mum number of counts per profile element is searched for and the coordinates of this maximum are used to find the scan edges by applying thresh­old criteria. Displacement of the scan centre from the matrix centre (Diagram 4.3.) is computed on the basis of the following formulas: 
Xds= (XI + Xr)/2 -Xm Yds = (Yu + Yl)/2-Ym 
where XI, Xr are the x co-ordinates of the left and the right scan edge Yu, Yl are the co-ordinates of the upper and lower scan edge Xm, Ym are co-ordinates of the matrix centre Xds, Y ds are displacements of the scan from the matrix centre 
These values are subtracted from the current off­sets. Similarly, the deviations from the scan and matrix size in both directions are computed using the following formulas: 
Dx = (Md -(Xr-Xl))/2 Dy = (Md -(Yl-Yu))/2 
where Md is one dimensional matrix size 
Dx, Dy are halves of the difference between the 

matrix size and the scan size 
These values should be subtracted from the cur­rent gain values if the edge coordinates are comput­ed with high precision. But the smaller the starting image's diameter the less exact computation for edge coordi-nates is possible. The subtracted gain 
Fidler Vet al. 
Dx T(Xl,YI 
) 
C(Xrn,Ym) T(Xd,Yd) Dy 


Diagram 4.3 Definition of iterative loop vaiiables. 
values can lead to the image size greater than the matrix size and therefore it is difficult to find the optimal gain setting using the software technique described above. Because of this we prefer to sub­tract only half of the Dx and Dy and the image size is slowly approaching the matrix size and the cor­responding gain values the optimal settings. 
Stopping condition If Dx and Dy are smaller than 2, the procedure for gain/offset-up is stopped and the coITesponding val­ues for gain and offset stored in the calibration file and set to the interfacing card .. 
To visually check the algorithm's success, ali intermediate seans are displayed during software adjustment of the gain settings until the scan size equals to the matrix size. 
Problems The following problems arise most frequently durign the autoadjustment of gain and offset: 
-insuflicient radioactivity in flood or point source, 
-nonadequately calibrated gamma camera with "holes" or "hot spots" in the scan (the edge co­ordinates can be miscomputed). 
5. Correction oj dynamic non-linearity 
At high count images (over 2 million counts) this correction is necessary to remove the stripes which appear at some horizontal and vertical matrix lines. The stripes in the image appear at ali horizontal and vertical lines where the bit content of the co-ordi­nate is changing from total "l" to "O" in most bit positions ( e.g. from X(Y) = 11111 to X(Y) = 100000) because of the so called bit flipping.The effect of "bit flipping" is not the same for ali co-ordinates in question. Higher content of the "l" bits leads to 
Udig 

Uanalogue 

Diagram 5. Dynamic non-linearity curve. 
more frequent flipping (diagram 5.). To coITect this ADC "malfunction", the uniform distribution of input signals in X and Y direction is applied and the extent of bit flipping is measured in each posi­tion. 
6. Acquisition software 
It consists of four basic units: 
-entering the patient population, instrumen­ta! and acquisition data (part of the PIP system). For clinical work we built a set of predefined studi­es which can be called up to avoid the tirne con­suming input of instrumenta! and acquisition pa­rameters for each patient. A new study protocol can be easily added to the existing set.. 
-functioning as persistence scope 

for checking the patient positioning, the adjust­ment of the zoom and the image orientation and, if necessary (in the installation phase) the adjustment of the image size, offset and pixel size. 
-starting the predefined acquisition 

During the acquisition we have a possibility of finishing the complete study (static and dynamic studies) of finishing the current scan (in static mode acquisition). Each scan is currently displayed if the acquisition tirne is exceeds I O seconds for static acquisition or 2 seconds for dynamic acquisition, otherwise only the frame and group numbers, the tirne, the countrate and the total tirne are displayed (the reason for this is to prevent the count loss in fast framing and scan displaying). 
-storing the sequence of images from virtual memory to hard disk and returning to the main PIP menu (part of PIP system). This phase can be upgraded if required in such a way that the <lata can be stored on some other unit as well (e.g. on ar­chive disk). 
Nuclear medicine, IBM PC PIP-GAMMA-PF computer system 
-hardware and acquisition software installa­tion 
The interfacing card called GAMMA-PF and rel­evant acquisition software were constructed in such a way that the hardware and software can easily be installed (see installation manual). The interfacing card is installed in an empty computer slot like any other computer card without any additional inter­vention in the computer switches. The same is also true for the acquisition software installation which is done by running the INST ALL command from the installation disk. For the optimal image size and shape the software is included which recursively adjusts them from the uniform radiation flux on the gamma camera ( uniform source on the gamma cam­era detector or point source two meters from the detector). No hardware adjustment of the image gain and offset is needed. The functioning of the interfacing card is very stable and no intervention is needed except in the case of electrical or physical damage to the card. 
-maintenance 

The best way of maintaining the interfacing card would be either sending back the malfunctioning interfacing card or which is also acceptable because of the low card price of the card, to have an additional card at hand, which can immediately be installed and the damaged one sent back to the supplier for repah" (highly recommended to prevent any interruption of clinical investigations). 
7. Networking 
The basic function of the nuclear medicine net­work system should be providing the records of the patient population and a scintigraphic <lata acquisi­tion on large scale storage media, communication between the acquisition, processing and reporting stations, printing the reports on network or local printer and access to external network.3 The solu­tion of this task can be achieved by applying low cost network hardware and software (eg NOVEL, MS WORKS for WINDOWS, etc). When planning the network system for the department we should take into account the department's organisation and economy. The network system can considerably lower the overall department's expence per patient's examination study, by increassing the effectiveness of the department in using the digital storage and displaying system as patient study retrieval system and low cost high resolution printer for reporting. Ali these demands can be fullfiled by using the low cost IBM PC hardware and software technology. 
The following basic functions of PIP-GAMMA­PF network (Diagram 7) are available: 
-storing patient study files (IMG, XAC) on the network server's archive disk (hard disk with a capacity more than 2 GB) 
-storing patient's coded images (the image with sequential seans, curves, ROls, patient's population <lata and quantitative estimates of organ's function) on the server's archive disk 
-archiving patient document files (the physi­cian 's report, the image of results, patient popula­tion <lata) on the archive disk 
-printing the patient's documents on the net­work printer (laser or inkjet printer with resolution at least 600x600 dots/inch) 
-distributing the application software from the server's disk to acquisition and processing IBM PC stations 
-access to hospital, regional and international network 
Diagram 7. Functional schema of PIP-GAMMA-PF net­work. 
where A is PIP-GAMMA-PF acquisition system 
P is PIP-GAMMA-PF processing system 
R is PC reporting system (MS WORD) 
S is network server 
D is server's archive disk 
PR is network printer 

The acquisition system needs the following set­tings in PIP.LGO file: acqndir = C:/PIP/DAT A datadir = C:/PIP/DATA archive = H:/PIP/DATA 
where C is the logical label for the system disk in the acquisition system and H is the logical label for the network server's archive disk 
The processing system should be set at the fol­lowing values in PIP.LGO: datadir = H:/PIP/DATA and the output coded result images (PCX format) should be stored in an appropriate subdirectory on H:/GAMMA/ (e.g. H:/GAMMA/LUNGS/), which is for the tirne being programmed in GAMMA-PF user program. 
Fidler Vet al. 
Results 

The following results were achieved in the project: 
-one full-size AT bus professional interfacing card (ISA bus, four layers, PORT input), installa­tion disk and manual 
-simple installation of the interfacing card in an empty slot of IBM PC 
compatible computer and installation of software with the "install" command from the installation disk 
-a simplified and shorter acquisition program­ming code with PORT input of data -a set of predefined studies for clinical examina­tions -the acquisition can be stopped either to finish the current image or to finish the study -the sequence of images is displayed continu­ously -the continuous displaying the frame and group numbers, tirne and count rate 
-acceptable count loss for clinical examinations4 
-a high functioning stability observed over a period of two years 
-network system with acquisition, processing, reporting, archiving, printing and communicating on Iocal or extended IeveP 
-good results with MAG3 kidney studies.5 
Conclusions 
An upgraded four layer professional interfacing card was built for the ISA bus, together with the installa­tion disk and a manual. The whole installation pro­cedure of inserting the interfacing card in an empty slot of on IBM PC compatible computer and the installation of the acquisition software are sim­ple and can be performed by a nuclear medicine technologist. Entering the scintigraphic data has been simplified by replacing the absolute address­ing (DMA) with PORT input/output access. The image orientation, the zoom size, image size and the shape are controlled by software. The ADC dynamic non-linearity correction is applied to high count images. As cardiac gated acquisition with two low-memory buffers has high count loss (over 20% ), there is a need for 32-bit operational system and 32-bit C programming language. 

To improve the speed of the acquisition (first pass studies), upgrading the interfacing card by us­ing the new PCI bus is necessary in the next project activities. 
Acknowledgement 

The research work was granted by the Interna­tional Atomic Energy Agency in Vienna, Austria and the Ministry for Science and Technology of Slovenia. 
References 
l. Fidler V, Prepadnik M. Razvoj PC graficne postaje za medicinsko slikanje. Zbornik prispevkov s kongresa slov­enskega društva za medicinsko informatiko z mednarod­no udeležbo, Bled, 20-23, September 1992: 55-60. 
2. 
Fidler V, Prepadnik M, Hojker S. Development of Non­Symmetric Two-Dimensional Filtering in Fourier Trans­form Space. Information Processing in Medica! Imag­ing. Progress in C/inical and Biological Research, 363, New York: Wiley-Liss, 1991: 95-106. 

3. 
Fidler V, Prepadnik M, Fettich J. Development of Nu­clear Medicine Computer System for Acquisiti.n and Analysis of Scintigraphic Image Data. CADAM-95 (Computer Aided Dala Analysis in Medicine). Institut "Jozef Stefan", IJS Publishing, 125-35. 

4. 
Kopp P. IAEA Gamma Camera Interface Cards. Test Programme and Results for the Slovenian Interface. IAEA report, 1-3,Vienna: 9-th August, 1995. 

5. 
Bergmann. Software control of normal kidney studies. COST B2 project. EANM'95 congress. Brussels: Au­gust, 1995 (in press). 



Radio! Oncol 1997; 31: 33-8. 
Study of blood perfusion with Patent Bine staining method in LPB fibrosarcoma tumors in immuno-competent and immuno-deficient 
mice after electrotherapy by direct current 
Tomaž Jarm1, Dong Jian An2, Jean Belehradek3, Jr., Lluis M. Mir3, Gregor Serša4, Maja Cemažar4, Tadej Kotnik1, Jani Pušenjaki and Damijan Miklavcici 
1University oj Ljubljana, Faculty oj Electrical Engineering, Tržaška 25, SI-1000 Ljubljana, Slovenia, 2Department oj Thoracic Surgery, Xiang Dong Hospital, Liling 412200, Hunan, People's Republic oj China, 3LPPMBI Biochemie-Enymologie, URA 147 CNRS, Institute Gustave-Roussy, 39 rue Camille Desmoulins, F-94805 Villejuif, France, 4/nstitute oj Oncology, Department oj Tumor Biology, Zaloška 2, Sl-1105 LJubljana, Slovenia 
Electrotherapy oj tumors by low-level direct current can be used effectively to reduce tumor mass in experimental and clinical tumor mode/s. The effects oj such treatment on blood perfusion oj tumors were studied on solid subcutaneous LPB fibrosarcoma model in immuno-competent C57Bl/6 mice and in immuno­deficient Swiss nude mice. Tumors were treated for one hour with electric current oj amplitudes 0.6 mA and 
1.0 mA delivered by Pt/lr needle electrodes inserted subcutaneously on two opposite sides oj the tumor. Study oj tumor growth response to single-shot electrotherapy yielded highly significant growth retardation in C57Bl/6 mice but only insignificant effect on tumor growth in nude mice. Effect oj electrotherapy on blood perfusion oj tumors as one oj the proposed mechanisms oj antitumor action was evaluated by tissue staining method using Patent Blue Violet dye. Perfusion was estimated immediately cifter electrotherapy and 24 hours after the treatment. Pe1:fusion oj tumors in C57Bl/6 mice was only moderately decreased due to electro­tlzerapy, whereas in nude mice there was practically no effect observed. The difference in growth response oj the two models indicates that vascular occlusion which occurs due to the products oj electrolysis at the site oj insertion oj the electrodes may not be the major cause far the observed tumor retardation in immuno­competent mice. 
Key words: fibrosarcoma electric stimulation therapy; regional blood flow; direct current electrotherapy, tumor growth retardation, blood perfusion 
Introduction 

It has been demonstrated in severa! studies that electrotherapy by low-level direct current can be applied successfully as a local treatment for solid 
Correspondence to: Damijan Miklavcic, University of Ljubljana, Faculty of Electrical Engineering, Tržaška 25, SI-1000 Ljubljana, Slovenia. Tel.: +386 61 1768-456, Fax: +386 61 1264-658, E-mail: damijan@svarun.fe.uni-lj.si 
malignancies with m1mmum side effects for the host. The antitumor effectiveness has been achieved in various experimental animal tumor models 1·6 and in clinical trials. 7·8 In addition, electrotherapy can be used as an adjuvant treatment to other conven­tional therapies for it has been shown that it poten­tiates the effectiveness of certain biological response modifiers and anticancer drugs, e.g. tumor necrosis factor, interleukin-2 and bleomycin.9· 11 Regardless of the way of its application, either as a single 
UDC: 616-006.327.04-018.5:615.84 treatment or in combination with other therapies, it 
Jarm Teta!. 
is of great importance to understand the mecha­nisms of its antitumor action in order to be able to optimise existing and develop new treatment strate­gies. 
Many attempts have been made to explain antitu­mor effectiveness of electrotherapy. It can hardly be expected that one single mechanism could be responsible for it since the parameters of treatment vary considerably from one author to the other. The differences appear in the type of tumor model, in electrical parameters (e.g. amplitude and shape of the signal), in electrode number and in material and the way of application. 12 
Severa! possible mechanisms that could be re­sponsible for antitumor effectiveness of direct cur­rent electrotherapy have been proposed. When one or more of the electrodes are inserted into the tumor then the extreme pH changes measured in vicinity of the electrodes are believed to be re­sponsible for celi killing. It has also been shown that with an appropriate configuration of multiple electrodes in the tumor it is possible to effectively eliminate most of the tumor mass 13• Surprisingly enough it was found that when electrodes are in­serted subcutaneously on two opposite sides out­side the tumor so that the tumor is brought into so­called "field" configuration, then similar growth retardation is produced as in the case with one of the electrodes in the tumor. For the "field" configu­ration antitumor effectiveness of electrotherapy cannot be ascribed to pH changes and also not to temperature rise which were both not found in the tumor. 12 There was also no correlation found be­tween tumor growth retardation and deposition of the electrode material 14• 
One of the possible mechanisms of antitumor action of sub-thermal low-level direct current elec­trotherapy for electrode configurations where tu­mor is not penetrated by stimulation electrodes is vascular occlusion at the site of insertion of the electrodes. 15 It was suggested that altering the blood supply to tumor tissue might lead to eradication of tumor mass. In one of our previous studies we have found that significant growth retardation of one particular tumor model was indeed accompanied by and correlated to large decrease of tumor blood perfusion as assessed by a tissue staining method. 16 In the present study an attempt was made to investi­gate this effect in LPB murine fibrosarcoma tumor in both immuno-competent and immuno-deficient animals. 
Materials and methods 
Animals and tumors 
Female and male animals of C57Bl/6 strain were purchased from two sources, namely Rudjer Boškovic Institute, Zagreb, Croatia and C.E.R.J an­imal facilities Lava!, France. Nu/nu Swiss nude mice were bred at the animal facilities of the Insti­tute Gustave-Roussy, Villejuif, France. Animals were housed in plastic cages in convenient colonies' and kept at constant temperature of 24 °C. They were watered and fed ad libitum. Additional stand­ard measures were taken in order to prevent infec­tion in nude mice. Animals in good condition and free of any infection, aged 8-12 weeks, were used in experiments. LPB fibrosarcoma cells syngeneic to C57B1/6 mice were cultured in vitro. Solid sub­cutaneous tumors were initiated dorsolaterally in the right flank of mice by injection of 0.8 • 106 and 
1.6 • 106 viable LPB cells in C57Bl/6 and nude mice respectively. Tumors of approximately 7 mm in diameter were obtained about 1 O days latter, when animals were randomly assigned to different experimental groups with 7-9 animals per group in each single experiment. 
Electrotherapy 
Single-shot electrotherapy consisted of constant di­rect current which was applied for 60 minutes. Cur­rent amplitudes used were 0.6 mA and 1.0 mA. Selection of cmTent leve! and duration was based on our previous studies. 12 Current was generated by a multichannel current source thus enabling simul­taneous treatment of up to eight animals. Needle electrodes 1 mm in diameter and 20 mm in length made of Pt/Ir alloy (90/10%) with rounded tips were used to deliver the current. Electrodes were inserted subcutaneously through small punctures in the skin made by a sharp needle. Electrodes were inserted in parallel on two opposite sides of the tumor with the cathode on caudal side of the tumor. Distance between the electrodes was 20-22 mm and each electrode was placed 5-8 mm away from the tumor edge. During electrotherapy mice were anes­thetised by intraperitoneal injection of 100 mg/kg of ketamine (Ketanast, Parke-Davis, Germany), 10 mg/kg of xylazine (Rompun, Bayer, Germany), and 
0.1 mg/kg of atropine. Animals in control groups were treated in the same way except that no current was applied. 

Blood pe,fusion oj tumors after electrotherapy 
Assessment of tumor growth 
Tumor sizes were estimated before electrotherapy (day O) and on the days following electrotherapy. Two largest perpendicular diameters were meas­ured with vernier calliper and tumor volume was calculated using formula V=.ffab 2/6 (a and b being measured diameters). For each individual tumor its doubling tirne (DT) was calculated as a tirne needed for the tumor to double its initial size. Mean aver­age tumor volumes and their standard e1Tors were calculated and presented as growth curves. Mean average doubling times were also calculated for ali experimental groups. Experiments were repeated three times in case of nude mice and twice for C57Bl/6 mice. Statistical significance of differenc­es between experimental groups were evaluated us­ing Student t-test and values of p less than 0.05 were considered as an indication of statistical sig­nificance. 
Assessment of tumor perfusion 
Perfusion study was performed on separate animals from those used in tumor growth study. Saline solu­tion (0.1 ml, 1.25%) of biological dye Patent Blue Violet (Byk Gulden, Switzerland) was injected in retroorbital sinus of animals. After the dye has been left to distribute evenly through tissues for approxi­mately 3 minutes, animals were euthanised and tu­mors were carefully removed. Tumors were cut along their largest diameter and the percentage of stained versus non-stained cross-section area was visually estimated independently by two persons. The mean of both estimations was used as a relative measure of tumor perfusion. Solidly stained parts of the tissue were considered to be well perfused, absence of the dye was an indication of poor per­fusion. Perfusion was assessed immediately after electrotherapy and 24 hours following the treat­ment. For each experimental group the mean value and standard error of the mean were calculated and presented. Student t-test was used to evaluate sta­tistical significance of differences between experi­mental groups. 
In our study Patent Blue Violet dye was used 

instead of a more widely used Evans Blue dye. The 
former yielded a mucq better color contrast be­
tween stained and non:stained parts of tissue than 
the latter. Furthermore, a study performed on fibro­
sarcoma SA-1 tumors in A/J mice has shown that 
both dyes produce essentially the same results. 19 
This was confirmed in control tumors as well as in tumors treated with electrotherapy. Therefore in our opinion the use of Patent blue instead of Evans Blue is entirely justifiable in perfusion studies such 
178 

as ours. ·' 
Results 

Tumor growth 
Application of the single-shot electrotherapy in­duced statistically significant tumor growth delay in immuno-competent C57Bl/6 mice. Typical growth of tumors in one of the experiments is given in Figure 1, where growth delay of treated tumors with respect to control tumors is clearly shown. It was also evident that larger <lose (higher current leve!) yielded better antitumor effects. In Table 1 tumor doubling times (DT/days) are given for ali experimental groups in two separate experiments. Tumors were arrested in their growth and their size was temporarily reduced. When regrowth occurred after severa] days, the growth rate was similar to that observed in control tumors. Apart from the observed fact that control LPB tumors in immuno­deficient mice grew faster than in C57Bl/6 mice it was also demonstrated that electrotherapy was much less effective in the case of nude mice, as shown in Figure 1 and presented in Table 1. Doubling tirne of tumours treated with 0.6 mA electrotherapy was not significantly different from doubling tirne of control tumors. Application of 1.0 mA however yielded significant growth delay but it was stili niuch smaller than in immuno-competent mice. 
Tumor perfusion changes 
In Table 2 perfusion of tumors as assessed by means of Patent Blue staining method is presented. Data of severa] experiments were pooled together. Ali control tumors in both strains of mice were practi­cally completely stained, which indicates that tu­mors at that stage of development were well per­fused. No reduction in staining of tumor tissue was observed in nude mice immediately after electro­therapy regardless of the current leve! applied. In C57Bl/6 mice reduced staining was observed im­mediately after treatment and this effect was main­tained for at least 24 hours. As in the tumor growth study the effect was more pronounced for higher <lose. There was also a large variability in staining among individual tumors treated with electrothera­py. On the other hand staining of control tumors was very uniform in both strains of mice. 


Jarm Teta!. 
Figure l. Growth ofLPB tumors in immuno-competent C57Bl/6 mice and in immuno-deficient Swiss nude mice following a single-shot one-hour electrotherapy with 0.6 mA and 1.0 mA. Data points represent the mean values for 7-8 animals with standard error bars. 
Table l. Effect of one hour electrotherapy (ET) with 0.6 mA or 1.0 mA on growth of LPB fibrosarcoma tumors in C57Bl/6 and Swiss nude mice. Tumor doubling times (DT) are given separately for each experiment and statistical significance of difference of DT in treatment groups with respect to corresponding control group is indicated by value of p as assessed by Student t-test. 
C57B1/6  Swiss nude  
Exp.  Treatment  n  DT(days) mean±SD  p  n  DT(days) mean±SD  p  
control  8  4.0±2.2  8  2.8±1.5  
1  0.6mA/lh  8  6.3±2.9  0.096  8  3.4±1.0  0.362  
1.0mA/lh  8  11.7±5.4  0.002  8  4.5±1.2  0.025  
control  8  2.8±0.7  7  1.8±0.8  
2  0.6mA/lh  8  7.5±2.0  <0.001  7  2.5±1.0  0.174  
1.0mA/lh  8  10.4±3.1  <0.001  7  2.7±0.4  0.021  
control  7  1.9±0.8  
3  0.6mA/lh  6  2.3±0.8  0.388  
I.OmA/lh  7  3.2±1.2  0.034  

Table 2. Percentage of stained tumor cross-section area as an indicator of quality of tumor perfusion for LPB fibrosarcoma in immuno-competent C57Bl/6 and immuno-deficient Swiss nude mice. Perfusion was estimated immediately after one hour electro­therapy (ET) for two current intensities (0.6 mA and 1.0 mA) and 24 hours after 0.6 mA ET. Value of p indicates statistical significance of difference between each particular treatment group and corresponding control group, as assessed by Student t-test. 
C57Bl/6  Swiss nude  
Experimental group  n  % stained (mean±SD)  p  n  % stained (mean±SD)  p  
control  19  98±5  11  100±0  
0.6mA/lh (Oh after ET)  27  80±30  0.013  7  100±0  1.000  
0.6mA/lh (24h after ET)  8  81±35  0.044  
I .OmA/lh (Oh after ET)  30  70±35  0.001  14  98±5  0.200  

1000 700 500 
"'E 
.s 
Q) 300 
E 
:, 
o 
> 
200 
o 
E 
~ 
100 70 50 

o 
"'E 
.s 
Q) 
E 
:, 
~ 
o 
E 
~ 
III ET0.6mN1h A ET 1.0mN1h 
2 4 6 8 10 12 14 16 Time after treatment (days) 
1000 
700 
500 
300 200 
100 70 50 
LPB in Swiss nudes 
• Control III ET0.6mN1h A ET 1.0mN1h 
o 2 4 6 8 10 12 14 16 Time after treatment (days) 

Blood perfusion of tumors after electrotherapy 
Discussion Acknowledgement 
In this study it was demonstrated that low-level direct current electrotherapy induces significant re­tardation of LPB fibrosarcoma tumors growing in immuno-competent C57Bl/6 mice and that this ef­fect is also dose dependent. This is in agreement with our previous work on this and other tumor 
14•20 

models. 12•When LPB tumors were treated in immuno-deficient animals, electrotherapy appeared to be much less effective. In another tumor model of SA-1 fibrosarcoma growing in immuno-compe­tent A/J mice the electrotherapy of the same type as in this study produced similar growth retardation as observed in C57Bl/6 mice. An extensive study on A/J mice by means of Patent Blue staining showed rapid decrease in perfusion during electrotherapy (data not shown). 16•19 Staining was decreased to the mean value of approximately 20% in treated tu­mors and even three days after treatment tumors were only partially reperfused (approximately 50% of stained tumor cross-section), which is very dif­ferent from perfusion of 80% found in LPB tumors for the same treatment (0.6 mA for 60 minutes). That means that vascular occlusion due to electro­therapy in SA-1 tumors was much more expressed than in LPB tumors. Since the dynamics of deper­fusion and reperfusion of SA-1 tumors was in good correlation with dynamics of growth retardation of that particular tumor model it was suggested that vascular occlusion occurring at the site of insertion of the electrodes might be the main factor of antitu­mor effectiveness. The presented study has raised some doubt to this hypothesis because the same extent of LPB tumor growth retardation was ac­companied by a much less expressed occlusive ef­fect. Furthermore, LPB tumors in immuno-deficient animals were significantly less affected by electro­therapy than the same type of tumors in immuno­competent animals, which indicates that host's im­mune response might play an important role in ef­fectiveness of electrotherapy.20 In our opinion, oc­clusion of supplying blood vessels outside the tumor inevitably occurs at the site of electrode insertion due to extreme pH changes that were measured in immediate vicinity of electrodes.12 The extent of this occlusion is probably significantly tumor mod­el-dependent, as indicated by the difference in Pat­ent Blue staining between the two fibrosarcoma models. Some other factors beside interrupted blood 
supply are probably responsible for the observed tumor retardation and immune system of the host organism is one of them. 
The presented research was supported by Ministry of Science and Technology of the Republic of Slov­enia, by CNRS, Institute Gustave-Roussy, Villejuif, France, and by the Ministry of Foreign Affairs of the Republic of France. Two authors wish to ac­knowledge their individual grants; D.J.A. from the Government of the People's Republic of China and 
D.M. from European Commission's Tempus-Phare Programme. 
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2. 
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4. 
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5. 
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Griffin DT, Dodd NJF, Moore JV, Pullan BR, Taylor TV. The effects of low-level direct current therapy on a preclinical mammary carcinoma: tumour regression and systemic biochemical sequelae. Br J Cancer 1994; 69: 875-8. 

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Xin Y-L. Advances in the treatment of malignant tu­mours by electrochemical therapy. Eur J Surg 1994; Suppl 574: 31-6. 

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Plesnicar A, Serša G, Vodovnik L, Jancar J, Zaletel­Kragelj L, Plesnicar S. Electric treatment of human melanoma skin lesions with low leve! direct electric current: an assesment of clinical experience following a preliminary study in five patients. Eur J Surg 1994; Suppl 574: 45-9. 

9. 
Serša G, Miklavcic D, Batista U, Novakovic S, Boba­novic F, Vodovnik L. Anti-tumor effect of electrother­apy alone or in combination with interleukin-2 in mice with sarcoma and melanoma lumors. Anti-Cancer Drugs 1992; 3: 253-60. 

10. 
Serša G, Novakovic S, Miklavcic D. Potentiation of bleomycin antitumor effecti veness by electrotherapy. Cancer Letters 1993; 69: 81-4. 

11. 
Serša G, Golouh R, Miklavcic D. Anti-tumor effect of tumor necrosis factor combined with electrotherapy on mouse sarcoma. Anti-Cancer Drugs 1994; 5: 69-74. 

12. 
Miklavcic D, Serša G, Kryžanowski M, Novakovic S, Bobanovic F, Golouh R, Vodovnik L. Tumor treatment by direct electric cmTent -tumor temperature and pH, 


farm Teta/. 
electrode material and configuration. Bioelectrochem Bioenerg 1993; 30: 209-20. 
13. 
Serša G, Miklavcic D. The feasibility of low leve! di­rect current electrotherapy for regional cancer treat­ment. Regional Cancer Treatment 1993; 1: 31-5. 

14. 
Miklavcic D, Fajgelj A, Serša G. Tumor treatment by direct electric current: electrode material deposition. Bioelectrochem Bioenerg 1994; 35: 93-7. 

15. 
Griffin DT, Dodd NJF, Zhao S, Pullan BR, Moore JV. Low-level direc electrical current therapy for hepatic metastases. I. Preclinical studies on normal !iver. Br J Cancer 1995; 72: 31-4. 

16. 
Jarm T, Wickramasinghe YABD, Deakin M, Cemažar M, Miklavcic D, Serša G et al. Blood perfusion and oxygenation of tumors following electrotherapy -a study by means of near infrared spectroscopy and Pat­


ent Blue staining. Proc. 9th Int. Conf Mechanics in 
Medicine and Biology, Ljubljana, Slovenia, June 30 ­
July 4, 1996, pp. 339-42. 
17. 
Sagar KB, Pelc LR, Rhyne TL, Howard J, Warltier DC. Estimation of myocardial infarct size with ultrasonic tissue characterization. Circulation 1991; 83: 1419-28. 

18. 
Szabo G. New steps in the intra-arterial chemotherapy of head and neck tumors. Oncology 1985; 42: 217-23. 

19. 
Miklavcic D, Jarm T, Cemažar M, Serša G, An DJ, Belehradek J, Jr, Mir LM. Tumor treatment by direct electric current -tumor perfusion changes. Bioelectro­chem Bioenerg 1997 (in press). 

20. 
Miklavcic D, An DJ, Belehradek J, Jr, Mir LM. Host's immune response in electrotherapy of murine tumors by direct current. C.R. Acad. Sci. Paris (submitted for publication). 



Radio/ Oncol 1997; 31: 39-47. 
Superficial thermoradiotherapy: Clinical result favor immediate irradiation prior to hyperthermia 


Lešnicar H, Budihna M 
Institute oj Oncology, Ljubljana, Slovenia 
Purpose. The aim of the present paper is to report the analysis of some relevant tumor andlor therapeutic parameters and to compare different treatment strategies used in our patients treated by local thermoradiotherapy (TRT). Methods and materials. In the period 1989-1995, fifty-two patients with locally advanced tumors accessible to local TRT were treated at the Institute of Oncology in Ljubljana, Slovenia. A majority of 39 (75%) patients failed to respond to previous radiotherapy, while in 13 patients TRT was used as primary treatment. Interstitial TRT (JTRT) as primary treatment was used in I 3 (25%) patients, interstitial hyperthermia combined with simultaneous external irradiation (STRT) in 7 (14%), and external TRT (ETRT) was applied in 32 (61%) patients. Results. In ali 52 patients a complete response ( CR) rate of 60% was achieved, while 2-year recurrence-free and disease-specific survivals were 51% and 45%, respectively. Among tumoral and therapeutic parameters tested, CR rate was found to be significantly influenced by histology other than squamous celi carcinoma (p=0.045), tumor volume < 55 ccm (p=0.02), minimum intratumoral temperature (T,,,;,,);;: 42.5C ( p=0.015), total tumor dose (TTD) of radiotherapy ;;: 45 Gy (p=0.048), fraction size of irradiation used concurrently to hyperthermia > 3 Gy (p=0.03), and by those TRT treatments where irradiation preceded hyperthermia (p=0.026). Repeating of hyperthermia (HT) treatments did not improve the CR rate. The use of RT immediately prior to HT resulted in a 2-year recurrence-free survival (RFS) of 66% compared to 38% for patients in whom HT treatment was followed by irradiation (p=0.07). For the subgroup of 20 patients in whom fraction size of >3 Gy was delivered immediately before HT treatment, an even better RFS of 85% was achieved (p=0.03) . The enhancement ratio of 1.7 was found between the dose response curves for 29 patients receiving RT prior to HT and 23 patients in whom HT was used before RT. Acute and late toxicity of grade 3 and/or 4 were recorded in 28% and 23% of treated patients, respectively. TRT-related acute toxicity was more pronounced in patients with maximum temperature measurements inside the heated volume (T,,,a) 45C (p=0.006), while a higher grade of late toxicity correlated with a tumor volume ;;: 55 ccm (p=0.02) and TD of RT> 45 Gy (p=0.04). There was no significant correlationfound between a higher toxicity grade and CR rate. Conclusions. Our clinical results are in javor of an application of somewhat higher fraction size of RT than conventional, employed immediately before heating, when combined with HT. 
Key words: neoplasms-radiotherapy; hyperthermice, induced; local thermoradiotherapy; advanced tumors; clinical results; prognostic parameters 
Correspondence to: Hotimir Lešnicar, M.D.,The Institute of Introduction Oncology, Zaloška c. 2, 1000 Ljubljana, Slovenia, Phone: +386 61 13 14 225, Fax: +386 61 13 14 180, E-mail ad­
When introduced to clinical practice, local thermo­
dress: hlesnicar@mail.onko-i.si 
radiotherapy (TRT) proved useful first of ali in the UDC: 616-006.6:615.849:615.832.8 treatment of advanced and recurrent/residual tu­
Ldnicar H and Budihna M 
mors, either applied with invasive technique, 1•7 non­invasive technique,8· 12 or in combination of both.U· 14 The advantage ofTRT over radiotherapy (RT) alone was proved in some non-randomized,8• 9• 14· 16 as well as in a few randomized clinical trials. 11-20 Believing in biological reasons for combining RT and hyper­thermia (HT) treatment,21 ·25 at the Institute of On­cology in Ljubljana, efforts were made to devel­op technical equipment and our own treatment strat­egies for the application of TRT prevalently in or­der to overcome radioresistance of locally advanced tumors26 and tumor lesions which failed to respond to previous RT. The aim of the present paper is to report the analysis of some relevant tumor and/or therapeutic parameters in our patients treated by local TRT. 
Materials and methods 
The patients 
Altogether 52 patients (42 male and 10 female) were treated by TRT between 1989-1995 at the Institute of Oncology in Ljubljana, Slovenia; 39 of these were with recurrent and/or residual tumors after previous standard RT and 13 with primary advanced malignancy. Tumor sites were as follows: head and neck region in 46 patients, breast and/or thoracic wall in 5, and inguinal lymphnodes in 1 patient. Histologically, 38 (73%) tumors were sq­uamous celi carcinoma, 8 (15%) adenocarcinoma, 5 (10%) malignant melanoma, and 1 (2%) Mb Hodgkin. By the tirne of combined HT and RT treatment, patients were free of distant metastases and were not receiving any other concurrent cancer therapy. Only patients with Karnofsky performance score ;::a: 70% were eligible for TRT. Tumor volume ranged from 10 -180 ccm (median 54 ccm). 
Hyperthermia devices 
Interstitial heating was performed by means of in­terstitial water hyperthemia system. Prior to clini­cal utilization our device had been tested on experi­mental animals. The results of animal experiments were published elsewhere.27• 28 First clinical experi­ence using interstitial water hyperthermia system showed acceptable homogeneity of temperature dis­tribution inside the heated vol ume. 29• 30 Intratumoral insertion of plastic or metal tubes for application of interstitial water hyperthermia technique was done under a general anesthesia in 20 patients. Percuta­neous heating was pe1formed in 32 patients by non­invasive 432 MHz microwave unit using two dif­ferent antennae to cover adequately the total tumor surface within safety margins. In the majority of cases no water bolus was used. Extensive local anesthesia using 2% Xylocain was utilized with percutaneous application of thermotherapy. 
Radiotherapy 
In 13 patients brachytherapy was applied in combi­nation with interstitial HT. Ir-192 wires were in­serted through the same plastic tube implant as used for HT. In all implants, X-ray and/or ultra­sound verification was used to assure that the im­plant encompassed the whole tumor volume. A dose-rate of O.S -0.7 Gy/h was delivered to the tumor periphery. Tota! tumor dose (TTD) in pa­tients treated by interstitial TRT (ITRT) ranged from 20 -70 Gy (median 60 Gy). In 39 patients percuta­neous RT was applied using a fraction size of 1.8 ­3 Gy. The fraction size of brachyradiotherapy was estimated from dose-rates at the tumor periphery given within 4 hours after HT treatment. 
In 7 patients interstitial heating using metal tubes was performed combined with simultaneous irradi­ation (STRT) by teleradiotherapy using electron beam. In one patients STRT using single fraction of 5 Gy was the only therapy, while in 6 patients TTD of RT ranged from 25 -60 Gy (median 55 Gy). Por the rest of 32 patients percutaneous HT combined with external RT using either electron beam or Co­60 was employed with TTD of 20 -70 Gy (median 40 Gy). 
TTD of RT depended on the tirne interval from previous RT and TTD of previous RT. Tota! cumu­lative dose of radiotherapy did not exceed 100 Gy. Thirteen patients without previous ilrndiation re­ceived 45 -70 Gy (median 60 Gy), while TTD for 39 previously irradiated patients ranged from 5 -66 Gy (median 40 Gy). Fraction size of RT used con­cmTently with HT differed from 1.8 -8 Gy (median 
3.5 Gy). 
Thermoradiotherapy and thermometry 
Thirteen patients receiving interstitial hyperthermia were treated under general anesthesia once only. Hyperthermia session started after steady state tem­perature distribution inside the tumor volume had been reached and lasted 60 minutes. Placement of Ir-192 wires followed immediately after the heating session in 9 cases, while in 4 patients brachythera­

Supe1ficial thermoradiotherapy 
py had to be postponed for more than one hour due to a substantial swelling of the heated region. 
Seven patients were treated with simultaneous interstitial hyperthermia and external irradiation. This specific therapeutic approach has been pre­sented previously.31 On the day before HT treat­ment, metallic tubes were implanted through the tumor volume under a general anesthesia. The next day, the patient was placed in a room close to the linear accelerator, and the implant was connected to a water HT unit. Approximately 30 minutes after the beginning of HT session, the patient and the HT device were moved together to the linear accelera­tor unit and irradiation using electron beam was performed while uninterrupted heating continued. After completed RT session, the patient was moved again to the nearby location and heating proceeded until total HT treatment tirne of 60 minutes elapsed. In ali 7 patients treated simultaneously TRT was not repeated. 
Combined percutaneous HT and RT was per­formed in 32 patients. After a TD of l0-20 Gy had been reached, the first HT treatment was performed. A single session of HT during the RT course was performed in 13 patients whereas 19 patients re­ceived 2-3 HT treatments. Repeated HT was ap­plied once weekly. The total heating tiine depended on maximum and minimum temperature measured inside the heated volume and lasted 45 -60 minutes for each HT session. Owing to technical problems, in 5/32 patients the tirne interval between the appli­cation of both modalities exceeded one hour. In 3 patients HT was performed immediately before ir­radiation while in the remaining 29 patients HT followed RT. 
Altogether, there were 23 patients treated with HT preceding RT, and 29 patients in whom HT followed RT treatment. 
Invasive thermometry was performed in 20 pa­tients treated by interstitial HT using five-point manganin-constantan thermocouple probes which were moved stepwise through 2-3 (depending on tumor volume) plastic tubes inserted perpendicular­ly to the implant. It was considered that HT treat­ment started when intratumoral temperature of >=42.5°C was obtained at the tumor periphery. Temperatures were registered every five minutes during the heating session; minimum and maxi­mum temperatures were recorded. 
In 32 patients heated with an external HT device, 

2-3 (depending on tumor volume) plastic tubes were 
inserted through the heated volume, and tempera­ture measurements performed by means of a one­point non-conducting temperature probe. The same protocol for temperature monitoring as in invasive HT treatments was used. with the exception of an extra thermal probe on the skin surface. 
Tmin i.e., mean minimum temperature measured in 3-5 measurement points at the tumor periphery during entire heating session was taken as a refer­ence for estimation of HT treatment quality. In patients with multiple HT treatments, the highest Tmin observed was recorded. The mean value of maximum temperatures measured intratumorally and/or on skin surface was expressed as Tmax and was used for treatment toxicity estimation. 
Estimation oj response to treatment and toxicity 
Only complete clinical disappearance of the treat­ed tumors (CR-complete response) 2 -3 months after completion of TRT was estimated as a thera­peutic success. Ali other responses were considered as treatment failures. The results were analyzed using Biomedical Statistical Software Package (BMDP);32 the survival was calculated from the end of treatment using Kaplan-Meier's method.33 A log-rank, X2-test, and Fisher exact tests were used to analyze the difference between groups. Sigma-plot computer program was used for the dose-response curves drawing. In order to estimate treatment re­lated toxicity RTOG/EORTC system was used,34 introducing HT related formati on of blisters as grade 3 early toxicity. Only the most severe grade of toxicity for each patient was recorded. 
Results 

In ali 52 patients treated with TRT at the Institute of Oncology, Ljubljana, Slovenia, a CR rate of 60% and a 2-year recurrence-free survival of 43% were achieved. The observation tirne ranged from 3 -42 months (median 11 months). The prognostic signif­icance of some tumoral characteristics is evident from Table 1 while the prognostic importance of the observed therapeutic parameters is apparent from Table 2. Next to tumor histology, tumor vol­ume was found to be the most prominent prognostic factor among tumoral parameters. The only signifi­cant parameter among hyperthermic factors was T ;n while neither the type of HT used nor the 
111

number of HT treatments showed any prognostic significance. Among radiotherapeutic treatment pa­rameters, except for the type of RT used, ali three 
Lešnicar H and Budihna M 
Table l. Prognostic importance of patients' and/or tumor characteristics. 
Tested N° ofpts. CR(o/o) p-value parameter 
Sex  Men  42  23 (55%)  
Women  10  8 (80%)  0.11  
Tumor site  Head & neck  34  19 (56%)  
Other  18  12 (67%)  0.65  
Histology  scc  38  19 (50%)  
Other  14  12 (86%)  0.045  
Tumor  
volume  < 55 ccm  31  23 (74%)  
~ 55 ccm  21  8 (38%)  0.02  
Previous RT Yes  39  24 (62%)  
No  13  7 (54%)  0.8  
s;50 Gy  22  15 (68%)  
>50Gy  17  9 (53%)  0.5  

CR -complete response, SCC -squamous celi carcinoma, RT -radiotherapy 
Table 2. Prognostic significance of therapeutic parameters 
Tested N° ofpts. CR(o/o) p-value parameter 
Type ofHT  Interstitial  20  10 (50%)  
Percutaneous  32  21 (66%)  0.4  
Type ofRT  Interstitial  13  6 (46%)  
Percutaneous  39  25 (64%)  0.1  
N°ofHT  1  33  23 (70%)  
> 1  19  8 (42%)  0.1  
Tmin  ~ 42.s0 c <42.5°C  43 9  29 (67%) 2 (22%)  0.015  
TTDofRT  ~45Gy <45 Gy  30 22  21 (70%) 10 (45%)  0.048  
Fraction  
size/HT  > 3 Gy s;3 Gy  28 24  21 (75 %) 10 (42%)  0.03  
Sequence  RT+HT  29  21 (72%)  
HT+RT  23  10 (43%)  0.026  

CR-complete response, RT -radiotherapy, HT-hyperther­mia, T . -minimum intratumoral temperature, TTD -total tumor ct'ose, Fraction size/HT -fraction size of RT concur­rent to HT 
remaining tested parameters, i.e. total dose of RT, fraction size of immediate irradiation, and sequence of RT showed a significant influence on local treat­ment outcome. While, ali patients in RT + HT group were treated by external TRT (ETRT) only, CR rates in HT + RT group differed regarding the type of TRT applied. There were 6/13 (46%) CR recorded in patients using ITRT, 4/7 (57%) using STRT, while no CR was obtained in 3 patients treated by ETRT. Figure 1 presents a 2-year recur­
100 
l (N=20) 
.., tl ............... 
················· .. ······ 
~ 80 > j 
a: 1'7 N=29 
::, 
"' 60 
w 
w 
a: 
1 7 N=23 
: 40 
o 
(>3Gy RT+ HT) > 
J 
z -RT+HT'-_ p=0.03 

120 
-HT+RT/p-o.o7 

a: o o 10 
20 30 
MONTHS 
Figure l. A 2-year recurrence-free survival (RFS) of 38% achived in 23 patients treated by TRT using HT prior to an immediate irradiation is compared to 66% for 29 patients in whom HT followed RT (p=0.07). Among those 29 patients in the latter group, there were 20 patients, refered in brack­ets, receiving a fraction size of > 3 Gy immediately before the heating. A significantly better RFS of 84% achieved in this subgroup of patients is presented by a dotted line (p=0.03). 

rence-free survival of 66% for the patients in whom RT was used immediately before HT, vs. 38% achieved in patients where RT followed HT (p=0.07). For 20 patients in whom an immediate fraction size of >3 Gy preceded HT, a recurrence­free survival of 84% was achieved (p=0.03). In Table 3 the two groups of patients treated with different sequence of the two modalities are com­pared regarding some prognostic parameters. It is shown that both treatment groups are acceptably comparable. Figure 2 presents dose response curves for the two groups of patients in whom different sequencing of both modalities was used. An en­hancement ratio of 1.7 was found for the group of 29 patients in whom RT was used immediately prior to HT when plotted against those 23 patients in whom RT followed HT. 
The majority of our patients tolerated TRT treat­ment well, and there was no reason to terminate the therapeutic session before 45-60 min of HT treat­ment was reached. In 39 interstitial and/or percuta­neous HT treatments, where no general anesthesia was used, generous infiltration of the heated vol­ume with 2% Xylocain was employed. In a few patients pressure over the heated area was used in order to diminish the cooling effect of enhanced blood flow. Using RTOG/EORTC system, there were 29% of acute and 23% of late toxicities grade 3-4 recorded in our patients. Tables 4 and 5 present the prevalence of tested tumor and/or therapeutic 


Supe1:ficial thermoradiotherapy 
Table 3. The prevalence of prognostic parameters within the two groups of patients treated by different sequencing of the two treatment modalities. 
Sequence T. Volume TTDofRT Fr.size/HT N°ofHT Histology ofRT & HT ~2.58C (%) <55 ccm (%) <'.40 Gy (%) >3Gy(%) > 1 (%) noSCC (%) 
RT+HT 24/29 (83%) 19/29 (66%) 16/29 (55%) 19/29 (66%) 13/29 (45%) 8/29 (28%) HT+RT 19/23 (83%) 12/23 (52%) 18/23 (78%) 9/23 (39%) 6/23 (26%) 6/23 (26%) 
p-value 0.9 0.5 
RT -radiotherapy, HT -hyperthermia, T . minimum intratumoral temperature, TTD of RT -totafiumor <lose, N° of HT -number of HT treatments, SCC -squamous celi carcinoma 
41• ¦ Y.SII 
100 
"' 
... 
80 
~ 

?E 70 
:Jl 
e " '° 
8. 
50 

I .(O 
o. E 30 
8 
20 
II RT+HT 
10 
G HT+RT 
o~-~--~-~-~--~-~--.L...-~-~ 
'° .. 
TD(Gy) 

Figure 2. An enhancement ratio of 1.7 was found when the dose-response curve calculated for 29 patients receiving an immediate fraction of radiotherapy prior to the heat treat­ment had been compared to the dose-response curve for 23 patients in whom irradiation followed hyperthermia imme­diately. 
Table 4. The influence of tumor and/or therapeutic parame­ters on acute toxicity grade. 
.. 
50 

Tested N° of pts. Grade 3-4 p-value parameter 
Tumor  
volume  <'.55 ccm  24  10  
< 55 ccm  28  5  0.04  
T nrnx  <'.45°C  30  13  
<45°C  22  2  0.006  
N° ofHT  > 1  19  7  
1  33  8  0.2  
TTD ofRT  >45 Gy  30  11  
:::;45 Gy  22  4  0.1  
Rcsporn:ic  CR  31  9  
noCR  21  6  0.2  

T maximum temperature measured in heated volume, I-if' hyperthermia, TTD -total tumor <lose, RT -radio­therapy, CR-complete response 0.2 0.12 0.3 0.8 
Table 5. The influence of tumor and /or therapeutic para­meters on late toxicity grade. 
Tested N° of pts.* Grade 3-4 p-value parameter 
Tumor  
volume  <'.55 ccm  23  9  
< 55 ccm  26  3  0.02  
T m"'  >45°C <45°C  28 21  8 4  0.2  
TTDofRT  >45 Gy  27  7  
:::;45 Gy  22  5  0.3  
Cumulative  
TTD  <'.85 Gy  29  10  
<85 Gy  20  2  0.04  

* In 3 patients evaluation of late toxicity was not possible because they died shortly after 3 months following TRT. 
T . , -maximum temperature measured inside the heated vofume, TTD-total tumor <lose, RT -radiotherapy 
parameters at risk for the expression of higher grade toxicity. Tumor volume of 55 ccm was found equal­ly significant for the appearance of both acute and late toxicity, T""' showed an important influence on acute toxicity rate, while higher cumulative TTD of RT was found to be responsible for a significant expression of high-grade late toxicity. There was no relation found in our patients between CR rate and the expression of either acute or late higher toxicity grade. 
Discussion 

Although, different treatment schedules of TRT were used at the Institute of Oncology, Ljubljana, it was possible to detect some important prognostic parameters with significant influence on local re­sponse rate. Next to tumor volume, TTD of RT, and Tmin which has been previously recognized as prog­nostically important16• 19• 35· 36 in our analysis also tumor histology, fraction size of RT concurrent to HT, and sequence of RT and HT were found of prognostic significance regarding CR rate (Tables 1 
Lešnicar H and Budihna M 
and 2). On the other side, tumor site, previous RT, type of RT and/or HT used, and more than one HT treatments showed no significant influence on re­sponse rate. 
On basis of preclinical21 and clinical data37-38 referring to the effects of HT treatment when com­bined with RT, it is possible to conclude that only appropriate heating should result in improvement of therapeutic effect when compared to RT alone. For multiple heatings used in clinical trials it was shown that CR rate, although strongly dependent of TTD of RT, is directly proportional to the cumula­tive equivalent tirne (CEM) at 43°C.39· 40 Unfortu­nately, it is impossible to predict the sufficiency of heat treatment in clinical HT. In recently published randomized studies18• 19 the planned intratumoral temperatures were reached only in a minority of treated patients. Although both trials failed regard­ing the planned threshold of minimum intratumoral temperatures, a significant influence of TRT over RT alone on CR rate (62% vs. 35%) was shown in a multicentric melanoma tria! using ETRT,19 while no benefit (57% vs. 54%) of combined treatment was recorded in RTOG study using ITRT. 18 From these data, regardless the differences in tumor his­tology, tumor volume, and TTD of RT for the pa­tients treated in both series, two conclusions can be derived as follows: First, in external TRT where RT using a higher fraction size had been followed by an immediate heating, even "mild HT" significant­ly enhanced the treatment results. Second, "mild HT" followed by an interstitial low dose-rate brach­yradiotherapy did not enhance already acceptable results achieved by RT alone. In meta analysis of clinical ETRT trials 15 it was found that the thermal enhancement ratios (TER) for different tumor types were similar regardless their response to RT alone. In the majority of published non-randomized series of head & neck tumors treated by TRT, the mean CR rate of 64% for ETRT15 and 55% for ITRT41 achieved were similar to the results of the two above mentioned randomized studies. In summary, although the heating in the majority of clinical tri­als has been equally inadequate, a constant superi­ority of ETRT over ITRT was recorded. It is hard to believe that thermal enhancement was more pro­nounced in ETRT trials, simply due to inferior re­sults obtained by fractionated irradiation alone when compared to continual low-dose irradiation. It is more likely, that some other (presumably radiother­aputic) treatment parameters are responsible for the loss of thermal enhancement in ITRT. 
In our treatments Tmin of 42.5°C, measured at the tumor periphery throughout the 45 -60 minutes of HT treatment course has been chosen as a therapeu­tic goal. 12 With respect to our HT strategy as much as 83% of patients (43/52) were adequately heated. Surprisingly, our overall CR rate of 60% was not found any better when compared to previously pub­lished TRT treatment series. 15• 42 However, when two groups of equally heated patients treated with different sequencing (i.e., RT + HT vs. HT + RT) (Table 3) were tested, a CR rates of 72% vs. 43% were estimated, respectively (p=0.025). RFS was significantly better for those 20 patients in whom >3 Gy of RT was used immediately before the heating (p=0.03) (Figure 1). When the <lose re­sponse curves for the same two groups of equally heated patients has been drawn (Figure 2), the shape of the curve obtained in 23 patients in whom RT followed HT strongly resembled the curves for RT alone published in previous clinical trials. 15 Accord­ing to the published data, similar effect are to be expected when HT is employed either before or after RT,43 however in our patients an enhancement ratio of 1.7 was calculated in favor of TRT using RT immediately prior to HT. In one published ani­mal study using ITRT,44 the opposite findings were recorded, however, neither hyperthermic nor radio­therapeutic conditions used in aforementioned ex­periment are clinically obtainable. 
The prediction that mild HT combined with low­dose rate RT would yield the best response45 clini­cally failed. 18 On the other side, the possibility of tumor reoxygenation during mild HT46 most likely does not affect tumors bigger than only few ccm.26 If it would, the number of HT treatments should , by the process of reoxygenation, significantly im­prove the therapeutic results, not only in small ex­perimental animal tumors,47 but also in substantial­ly larger human tumors.48• 49 Though, in most of our patients cytotoxic leve! of intratumoral tempera­tures has been reached, stili, practically no benefit of HT was recorded in patients in whom RT fol­lowed HT. The same observation was reported from animal experiments, when HT preceded RT.50 It should be stressed that in a majority of our suffi­ciently heated patients the signs of circulatory col­lapse have been observed 30 minutes after T min of 42.5°C at the tumor periphery has been reached. It is impossible to expect an enhancement of radiation damage in such a hypoxic situation. This is also a probable explanation for the achievement of only average treatment results (57% CR rate) achieved 
Supe1ficial thermoradiotherapy 
in 7 patients in whom a really simultaneous TRT was employed, introducing the irradiation 30 min­utes after HT treatment has been started. The fact, that in the majority of clinical trials an enhance­ment of TRT over RT alone was proved, although intratumoral temperatures achieved were far below from those proposed by results achieved from in vitro and in vivo experiments, is leading to a rea­sonable conclusion that in clinical circumstances tumors are more sensitive to HT. However, accord­ing to CEM,40 it is not understandable that even more than 30 minutes of an "adequate heating" (i.e., Tmin > 42.5°C), achieved in the majority of our patients, the therapeutic effect, obtained by HT + RT sequence, yielded the treatment results compa­rable only to those achieved by RT alone. The pos­sible explanation for these findings is that the mech­anism of thermal efficiency in clinical TRT most probably acts prevalently by inhibiting the ability of repair system for radiation induced damage. Be­cause of somewhat greater sensibility of human tumors, in clinical conditions, to the heat, even non-cytotoxic HT could enhance an immediately preexisting radiation damage, however, sufficient heating probably results in better enhancement. Therefore, it looks like, it is not HT itself to be blamed for the disappointing treatment results ob­tained by ITRT, but more likely the placement and the amount of immediate irradiation used concur­rently with HT. Our CR rate achieved in patients, where RT + HT sequencing has been used (i.e., CR rate of 72%), were even slightly better when com­pared to other randomized trials with similar se­quencing employed. 15 Except for malignant melano­ma, the positive influence of a higher fraction size of immediate RT, which in our case resulted in CR rate of 84%, in former clinical trials had not been found relevant. If radiosensitization induced by HT is a consequence of disturbances in DNA repair,51 then only irradiation applied immediately before HT could result in the potentiation of radiation damage. A larger fraction size of RT should, there­fore, result in more expressed potentiation of in­duced radiation damage. It is likely that higher intratumoral temperatures, rather than mild, inter­fere with the ability of repairing processes more effectively. Presumably, the recorded influence of somewhat higher fraction size on CR rate in our report is also related to the substantially higher leve! of intratumoral temperatures achieved in our HT treatments. Taking into account that in our re­port fairly good treatment results were achieved 
when RT was used immediately prior to somewhat more intense HT, even our higher rate of toxicity reported (Tables 4 and 5) could stili be acceptable, considering the fact that the treatment by TRT was the only chance of prolonged survival due to a local cure in our patients. 
It is true that a variety of tumor types and differ­ent treatment schedules used in our report can bias the fina! results. However, it is also true that by using strict protocols the differences would proba­bly never show up. 
It is our conclusion, that in the treatment of su­perficial human tumors by HT, either "mild" or "sufficient" heating, could be an important additive to RT, when appropriately employed. In our pa­tients a significant influence of reasonably higher fraction size of RT on treatment results, when ap­plied immediately before the heating session, was detected. Most likely, the low-dose irradiation, by having no ability to provide a productive amount of instant radiation damage to be increased by heat, rather than insufficient heating, was responsible for a poor expression of thermal enhancement in ITRT clinical trials. 
Acknowledgements 

This work was supported by grant J3-5254 from the Ministry of Science and Technology, Slovenia. We are much obliged to Othmar Handl, his wife Le­onore Handl-Zeller and Kurt Schreier from Vienna, Austria, for ali the technical support and collabora­tion during our experimental work. Special thanks to Maja Cemažar for estimation of Sigma-plot curves. 
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Lešnicar H and Budihna M 
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6. 
Seegenschmiedt MH, Sauer R, Fietkau R, Karlsson UL, Brady LW. Primary advanced and recurrent head and neck tumors: effective management with interstitial thermal radiation therapy. Radiology 1990; 176: 267­74. 

7. 
Vora N, Forell B, Joseph C, Lipsett J, Archambeau JO. Interstitial implant with interstitial hyperthermia. Can­cer 1982; 50: 2518-23. 

8. 
Gonzalez Gonzalez D, van Dijk JDP, Blank LECM. Chestwall recurrences of brest cancer: results of com­bined treatment with radiation and hyperthermia. Radi­other Oncol 1988; 12: 95-103. 

9. 
Gonzalez Gonzalez D, van Dijk JDP, Blank LECM, Rumke P. Combined treatment with radiation and hyperthermia in metastatic malignant melanoma. Radi­other Oncol 1986; 6: 105-13. 


10. 
Hiraoka M, Nishimura Y, Nagata Y, Mitsumori M, Okuno Y, Li PY, Takahashi M, et al. Clinical results of thermoradiotherapy for soft tissue tumors. lnt J Hyper­thermia 1995; 11: 365-77. 

11. 
Masunaga S, Hiraoka M, Takahashi M, Jo S, Akuta K, Nishimura Y, Nagata Y, and Abe M. Clinical results of thermoradiotherapy for locally advanced and/or recur­rent breast cancer-comparison of results with radio­therapy alone. lnt J Hyperthermia 1990; 6: 487-97. 

12. 
Van der Zee J, Treurniet-Donker AD, The SK, Helle PA, Seldenrath JJ, Meerwaldt JH et al. Low dose reira­diation in combination with hyperthermia: a palliative treatment for patients with breast cancer recurring in previously irradiated areas. Int J Radiat Onco/ Biol Phys 1988; 15: 1407-13. 

13. 
Engin K, Tupchong L, Waterman FM, Nerlinger RT, Hoh LL, McFarlane JD et al. Thermoradiotherapy with combined interstitial and external hyperthermia an ad­vanced tumours in the head and neck with depth 3 cm. lnt J Hyperthermia 1993; 9: 645-54. 

14. 
Lindholm CE, Kjellen E, Nilsson P, Hartzman S. Mi­crowave-induced hyperthermia and radiotherapy in human superficial tumors: clinical results with a com­parative study of combined treatment versus radiother­apy alone. lnt J Hyperthermia 1987; 3: 393-411. 

15. 
Overgaard J, Horsman MR Hyperthermia. In: Steel GG, ed. Basic Clinical Radiobiology. London: Edward Ar­nold, 1993: 173-84. 

16. 
Perez CA, Kuske RR, Emami B, Fineberg B. Irradia­tion alone or combined with hyperthermia in the treat­ment of recurrent carcinoma of the breast in the chest wall: a nonrandomized comparison. lnt J Hyperther­mia 1986; 2: 179-87. 

17. 
Datta NR, Bose AK, Gupta S. Head and neck cancers: results of thermoradiotherapy versus radiotherapy. lnt J Hyperthermia 1990; 6: 479-86. 


18. 
Emami, B, Scott C, Perez CA, Asbell S, Swift P, Grigs­by P, et al. Phase III study of interstitial thermoradio­therapy compared with interstitial radiotherapy alone in the treatment of recurrent or persistent human tu­mors: a prospectively controlled randomized study by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1996; 34: 1097-104. 

19. 
Overgaard J, Gonzalez Gonzalez D, Hulshof MCCM, Arcangeli G, Dah! O, Mella O et al. Randomised tria! of hyperthermia as adjuvant to radiotherapy for recur­rent or metastatic melanoma. Lancet 1995; 345: 540-3. 

20. 
Valdagni R, Amichetti M, Pani G. Radical radiation versus radical radiation plus microwave hyperthermia for N3 (TNM-UICC) neck nodes: a prospective rand­omized clinical t1ial. /nt J Radiat Oncol Biol Phys 1988; 15: 13-24. 

21. 
Dewey WC, Hopwood LE, Sapareto SA, Gerweck LE. Cellular responses to combination of hyperthermia and radiation. Radiology 1977; 123: 463-74. 

22. 
Field SB, Bleehan NM. Hyperthermia in the treatment of cancer. Cancer Treat Rev 1979; 6: 63-94. 

23. 
Overgaard J. The cmrnnt and potential role of hyper­thermia and radiotherapy. /111 J Radiat Onco/ Biol Phys 1989; 16: 535-549. 

24. 
Overgaard J, Nielsen OS, Lindegaard JC. Biological basis for rational design of clinical treatment with com­bined hyperthermia and radiation. In: Field SB and Franconi C, ed. An lntroduction to the Practical As­pects oj Clinical Hyperthermia, NA TO ASI Series E: Applied Sciences, No 127, Dordrecht, Boston: Marti­nus Nijhoff Publishers, 1987: 54-79. 

25. 
Streffer C.Biological basis of thermotherapy. In: Gauthrie M. Biological Basis oj Oncologic Thermo­therapy, Berlin: Springer, 1990: 1-7 l. 

26. 
Stanley JA, Shipley WU, Steel GG. Influence oftumor size on hypoxic fraction and therapeutic sensitivity of Lewis Jung tumor. BrJ Cancer 1977; 6:105-13. 

27. 
Budihna M, Lesnicar H, Handl-Zeller L, Schreier K. Animal experiments with interstitial water hyperther­mia. In: Handl-Zeller L, ed. lllferstitial Hyperthermia, Wien: Springer, 1992: 155-63. 

28. 
Schreier K, Budihna M, Lesnicar H, Handl-Zeller L., Hand, JW, Clegg ST, et al. Preliminary studies of inter­stitial hypertherrnia using hot water. Int J Hyperther­mia 1990; 6: 431-44. 

29. 
Lesnicar H, Budihna M, Handl-Zeller L, Schreier K. Clinical experience with water-heated interstitial hyper­thermia systern. Acta Chir Austriaca 1992; 24: 214-6. 

30. 
Steucklschweiger G, Arian-Schad KS, Kapp DS, Han­dl-Zeller L, Hackl AG. Analysis of temperature distri­bution of interstitial hyperthermia using hot water sys­tern. lili J Radiat Oncol Biol Phys 1993; 26: 891-5. 

31. 
Lešnicar H, Budihna M. Clinical treatrnent with sirnul­taneous hypertherrnia and irradiation. In: Gerner EW, ed. Proceedings oj the 6"' lnternational Congress on Hyperthermic Onco/ogy (ICHO ), Tucson: Arizona Board of Regents, 1992: 382. 

32. 
BMDP statistical software. University of California Press, Berkley, 1990. 


Superficial thermoradiotherapy 
33. 
Kaplan EL and Meier P. Nonparametric estimation from incomplete observations. JASA 1958; 53: 457-81. 

34. 
Perez CA, Brady LW. Overview. In: Perez CA and Brady LW, ed. Principles and Practice oj Radiation Oncology, Philadelphia: Lippincott, 1992: l-63. 

35. 
Arcangeli G, Benassi M, Cividalli A, Lovisolo GA, Mauro F. Radiotherapy and hyperthermia: analysis of clinical results and indentification of prognostic varia­bles. Cancer 1987; 60: 950-65. 

36. 
Valdagni R, Lin FF, Kapp D. Important prognostic factors influencing outcome of combined radiation and hype1thermia. lnt J Radiat Oncol Biol Phys 1988; 15: 959-972. 

37. 
Cox RS, Kapp DS. Correlation of thermal parameters with treatment outcome in combined radiation therapy­hyperthermia trials. Int .1 Hyperthennia 1992; 8: 719-32. 

38. 
Leopold KA, Dewhirst MW, Samulski TV, Dodge RK, George SL, Blivin JL, et al. Cumulative minutes with T90 greater than temp.index is predictive of response of superficial malignancies to hyperthermia and adia­tion. Int J Radia/ Oncol Biol Phys 1993; 25: 841-7. 

39. 
Oleson JR. Hype1thermia from the clinic to the laborato­ry: a hypothesis. Int J Hyperthermia 1995; 11: 315-22. 

40. 
Oleson JR, Samulski TD, Leopold KA, Clegg ST, Dewihirst MW, Dodge RK, et al. Sensitivity of hyper­thermia tria! outcomes to temperature and tirne: impli­cation for thermal goals of treatment. lnt J Radiat. Oncol Biol Phys 1993; 25: 289-97. 

41. 
Seegenschmiedt MH, Sauer R, Fietkau R, Iro H, Brady LW. Interstitial thermoradiotherapy for head and neck tumors: results of a cooperative phase 1-2 study. In: Seegenschmiedt MH, Sauer R, ed. Interstitial and lnt­racavitary Thennoradiotherapy, Berlin: Springer, 1993: 241-56. 

42. 
Overgaard J. Hyperthermia as an adjuvant to radiother­apy. Strahlenther Onco/ 1987; 163: 453-7. 

43. 
Horsman MR, Overgaard J. Simultaneous and sequen­tial treatment with radiation and hyperthermia: com­


parative assesment. In: Handl-Zeller L, ed. Interstitial Hyperthermia, Wien:: Springer, 1992: 11-33. 

44. 
Van Geel CAJF, Visser AG, van Hooije CMC, van den Aardweg GJMJ, Kolkman-Deurloo IKK, Kaatee RSJP, et al. Interstitial hyperthermia and interstitial radiotherapy of a rat rhabdomyosarcoma; effect of sequential treatment and consequences for clono­genic repopulation. Jnt J Hyperthermia 1994; 10: 835-44. 

45. 
Konings A WT Interaction of heat and radiation in vitro and in vivo. In: Seegenschmiedt MH, Fessenden P, Vernon CC, ed. Thermoradiotherapy a,u/ Thermoche­motherapy, Vol.l, Berlin Springer, 1995: 103-21. 

46. 
Song CW, Shakil A, Osborn JL, Iwata K. Tumor oxy­genation is increased by hyperthermia at mild tempera­tures. lnt J Hyperthermia 1996; 12: 367-73. 

47. 
Marino C, Cividalli A. Combined radiation and hyper­thermia: effects of the number of heat fractions and their interval on normal and tumour tissues. lnt J Hyper­thermia 1992; 8: 771-81. 

48. 
Engin K, Tupchong L, Moylan DJ, Alexander GA, Waterman FM, Komarrnicky L, et al. Randomized tria! of one versus two adjuvant hyperthermia treatment per week in patients with superficial tumors. lnt .1 Hyper­thermia 1993; 9: 327-40. 

49. 
Kapp DS, Petersen IA, Cox RS, Hahn GM, Fessenden P, Prionas SD, et al. Two or six hyperthermia treat­ments as an adjunct to radiation therapy yield similar tumor responses: results of a randomized tria!. lnt J Radiat Oncol Biol Phys 1990; 19: 1481-95. 

50. 
Nishimura Y, Urano M. The effect of hyperthermia on reoxygenation during the fractionated radiotherapy of two murine tumors FSA-II and MCA. Int J Radiat On­col Biol Phys 1994; 29: 141-8. 

51. 
Iliakis G, Seaner R, Okayasu R. Effect of hyperthennia on the repair of radiation-induced DNA single-and double-strand breaks in DNA double-strand break re­pair-defficient and repair-proficient celi lines. lnt .1 Hyperthermia 1990; 6: 813-33. 


Radio! Oncol 1997; 31: 48-53. 

Radiotherapy in nephroblastoma. Pre-and postoperative combina­tion treatment. Radiotherapy in localized (stage II, III, IV) and metastatic disease. Acute and long-term side effects. * 
Berta Jereb 
Institute of Oncology, Ljubljana, Slovenia 
Nephroblastoma, an embryonic type of malignant tumor in the kidney found in infancy and early childhood is sometimes associated with congenital anomalies. In recent years the research in genetics of this tumor has been extremely active. For decades radiation has generally been accepted as a valuable supplement to surgery in the treatment of nephroblastoma. Unfortunately it may produce undesirable late effects. With the survival rates steadily improving from about 25% before up to 80% and more, the problem of late sequelae is becoming the most important one. With the aim to diminish late sequelae with adjustment of treatment to known variables severa! clinical trials have been conducted in Europe, USA and Great Britain. The results of these are presented together with adverse e.ffects and second malignancies. Further prospects are discussed. The success of therapy for children with nephroblastoma has resulted in growth to adulthood of a large population of former patients. Radiation therapy is considered responsible for a great deal of early and late toxicities. However, the number of children at risk for this has certainly diminished. 
Key words: nephroblastoma-radiotherapy 
General aspects 
Nephroblastoma is a term used for an embryonic type of malignant tumor in the kidney, found in infancy and early childhood, seldom seen beyond the age of 10 and very rarely in adult life. 
Wilms suggested in 1899 that the tumor arises from undifferentiated mesoderm. This was accept­ed and his name has been associated with the tumor ever since. Nephroblastoma comprises 10% of ma­lignant diseases in children and afflicts one in 
10.000 children. 
* Presented at ESTRO/SIOP teaching course on paediatric radiooncology, AKH Vienna University, Vienna, Austria. 27-28 September, 1996. 
Correspondence to: Berta Jereb M.D., Ph.D. Institute of Oncology, Zaloška 2, 1105 Ljubljana, Slovenia. Tei: +386 61 323 063, Fax: +386 61 131 41 80. 
UDC: 616.61-006.85:615.849 
Nephroblastoma is sometimes associated with congenital anomalies. Children with aniridia, geni­to-urinary malformations and mental retardation (W AGR), Denys-Drash syndroma or Beckwith­Wiederman syndroma are considered to run a high­er risk for nephroblastoma. 1 
In Wilms' tumor associated with specifical con­genital syndromes, WT 1 germ-line mutations are frequently detected, while in sporadic Wilms' tu­mor WT 1 -DNA mutations are present only in 6% of the cases. Possible molecular markers for prog­nosis, using DNA techniques, are being developed. The loss of heterozygosity for chromosomes in Wilms' was seen for chromosomes 11 p, 16 q and 1 p in 33,17 and 12% respectively. Patients with loss of heterozygosity for chromosome 16 q had mortal­ity rates 12 times higher than those without it. How­ever, the correlation of chromosome 16 q and poor prognosis seems related to tumor progression rather than initiation, as there is no constitutional deletion 

Radiotherapy in nephrob/astoma 
of the chromosome in Wilms' tumor. Whether IGF binding protein -2-levels will be a useful serum marker of Wilms' tumor activity is no yet estab­lished.2·3 
Radiation treatment -development 

The first cure of a child with nephroblastoma was reported in 1894, the report on the first child treated for nephroblastoma by radiation therapy (RT) alone in 1916 and in 1945 the first cures of children with nephroblastoma treated with RT were reported. It has since then been generally agreed upon that RT is a valuable supplement to surgery for nephroblas­toma. 
A beneficial effect of preoperative radiation has been first shown in 194 7 and later by many others. Opponents, however, warned of the delayed sur­gery and thereby risk for metastases. They also denied that preoperative shrinkage of the tumor was of importance for the surgeon. The discussion on whether radiation should be used preoperatively or postoperatively has been continued until 2 decades ago, when more systematical studies provided evi­dence of the value of preoperative radiation and of the value of preoperative treatment of nephroblast­oma in general. This expeiience is stili not general­ly used outside Europe, preoperative chemotherapy (ChT) is at present widely accepted as a mode of treatment for the great majority of children with malignant solid tumors. 
The optimal dose of radiation for nephroblasto­ma was also a matter of discussion for decades. It was shown more than 20 years ago that 20 Gy to the tumor bed postoperatively was sufficient for tumor control. The decision, that in the great majority of cases not more than that is necessary, was made only after the introduction of Actinomycin D. A significant influence of preoperative RT in locally advanced tumors on the cure rate was shown in a retrospective multivariate analysis in 1973 and was the basis for the first study to determine whether preoperative radiation improves survival as com­pared to postoperative radiation, in a prospective randomized trial.4 Postoperative radiation was stili much more in use. 
The technique of RT as regard the design of the 

treatment volume, frnctionation schemes, daily dose 
and planning has not changed much during the dec­
ades. Two opposing fields are used to cover the 
tumor bed. After recognizing the risk for scoliosis, when irradiating only one half of the vertebral body, the 2 opposing fields were enlarged to cover the whole vertebral bodies. Fields for treatment of the whole abdomen or the whole Jung in disseminated tumors have also remained essentially the same, although the dose had to be reduced because of additional ChT. Nephroblastoma being a rare con­dition; studies have been conducted in cooperative groups: The National Wilms' Tumor Study (NWTS) 5 started in 1969 in the USA by the Children Cancer Study Group (CCSG). The Nephroblastoma SIOP 1 in Europe in 1971 6 and in 1979 the United Kingdom Children's' Cancer Study Group Wilms' tria! (UKW) in Great Britain and Norway.7 
The stage of the tumor and its histological type have been recognized as the most important factors for the prognosis in nephroblastoma. Consequently, the criteria applied for randomization were mainly the same in the thrce trials, the questions asked, however, varied, as they wcre based on previous experiences and traditions at the 3 different re­gions. Recognizing the importance of lymph node involvement for prognosis8, the staging has been slightly modified, from that which was first accept­ed by the NWTS 1, and in the SIOP 1 Study tria!. 
The significant difference in the outcome of tu­mors with favourable histology (FH) and unfavour­able histology (UH) (10% of all cases), has been confirmed in the trials.9 For further randomization, only localized stages with FH were included; in­fants and stage IV, Stage V and ali tumors with UH were dealt with in other ways. 10 In the course of these studies severa! histological subtypes have been recognized e.g. the Stockholm histological classifi­cation of nephroblastoma (Table 1). 
Table l. The Stockholm working classification of renal tumors of childhood (1994). 
I. LOW RISK TUMOURS ("FAVOURABLE") 
-Cystic partially differentiated nephroblastoma Nephroblastoma with fibroadenomatous-like structures Ncphroblastoma of highly differcntiated epithelial type 
-Nephroblastoma -completely necrotic (after preopera­tive chemotherapy) -Mesoblastic nephroma 
II. INTERMEDIATE RISK TUMOURS ("STANDARD") -Non-anaplastic nephroblastoma with its variants -Nephroblastoma -necrotic but some features left ( < 10%) 
III. HIGH RISK TUMOURS ("UNFAVOURABLE") -Nephroblastoma with anaplasia -Clear celi sarcoma ofthe kidney 
Rhabdoid twnour of the kidney 

50 Jereb B 
Groups of patients with very good prognosis have been identified; e.g. children younger tban 2 years witb tumors of FH, not greater tban 550 ccm (NWTS) or stage I tumors 11 in wbicb after preoper­ative cbemotberapy no vita! tumor cells were found (SIOP). In such cases postoperative treatment could possibly be omitted. Also, groups witb very poor prognosis bave been identified; tbose with advanced tumors and UH. For tbose, more aggressive treat­ment schemes were designed. 12 
By increasing the rate of Stage I tumors witb preoperative cbemotherapy in the ongoing SIOP tria!, postoperative radiation is given only to 20% of ebildren as eompared to 80% in tbe first SIOP study. 13 The number of ebildren reeeiving postoper­ative RT has diminisbed in the UKW when tbe study eonfirmed that omittanee of postoperative RT for Stage I tumor is safe and RT was given to Stage II and Stage III tumors only if at tbe second look operation no residual tumor was found. Fewer ebil­dren reeeive RT in the NWTS as well and also the doses in general are lower. 
After tbe most important questions were resolved: on tbe value of preoperative treatment in the SIOP, on tbe effeet of cbemotherapy combinations VCR, VCR -AMD, VCR + AMD + Doxo in tbe NWTS, on tbe safe omittance of postoperative RT for Stage I tumors in tbe UKW, tbe main goal, tbat is, to decrease tbe number of ebildren reeeiving postop­erative radiation seemed to be acbieved. 
Tbe experienee of tbe different trials was con­stantly exchanged and incorporated into treatment scbemes. Preoperative treatment is used in tbe on­going SIOP tria! for ali eases, in tbe USA it is given to cbildren witb "unresectable" tumors and its ben­eficial effect is reported in selected groups of pa­tients witb intracaval and intraatrial tumor exten­sion. 14 Also, in the UKW study, preoperative treat­ment is given to individually considered unresecta­ble tumors. The main drawback, aecording to the opponents of preoperative ehemotherapy, is the dif­ficulty of histological elassification. Tbey accept, however, a 100% tumor response to preoperati ve chemotherapy as a good prognostic sign. There is stili no known effeetive treatment for some of the tumors of UH, especially if disseminated. For these children with poor prognosis, RT is stili used to reduce the risk of abdominal recurrence, while new chemotherapeutic agents or new combinations are being introduced to reduce the risk for metastases. 
In the majority of cases, radiotherapy has been replaced by ehemotherapy. For advanced tumors and those with UH, Doxorubicin is usually added. It has also been a part of treatment for UH and recurrent tumors, often in eombination with RT. Fatal late effects of eardiotoxicity have been ob­served after treatment with Doxorubicin. The an­swer to the question how best to balance the merits and demerits of ehemotberapy vis-a-vis tbose of RT has yet to be found. 


Adverse ef'fects of treatment 
With the survival ratcs of Wilms' tumor steadily improving from about 25% before the introduetion of chemotherapy, with the amounting knowledge and treatment tailored to age, stage, histology type, tbe survival rates are now up to 80% and more in some good risk groups; tbe problems of late seque­lae are becoming the most important ones. 
The tolerance for RT of different organs has been agreed upon after deeades of experienee and obser­vation, the late effects of ebemotherapy are stili being recognized and the effeets of combination of chemotherapy and RT are a rather new ehapter of radiobiology. 
Radiation nephrotoxicity 
In general, the tolerance to radiation of the kidney in the child is similar to tbat in the adult. It is about 
20.0 Gy when radiation has been delivered to both kidneys in 3-5 weeks, using redueed daily fractions, wben delivered without chemotherapy. The dura­tion of follow-up is eritical, signs and symptoms of late radiation damage to tbe kidney may not devel­op for years. The underlying process of late radia­tion damage is progressive nephrosclerosis. 
It bas been suggested that renal function compat­ible with clinieal health in nephrectomised patients can be preserved as long as the remaining kidney bas received less the 12.0 Gy. It bas been reported tbat one ebild out of four, who received 14-15 Gy, experieneed transient nephropathy, and one ehild in tbe NWTS has developed fatal nephropathy. Tbus, tbe dose of 14 Gy appears relatively safe even ona long-term basis. An exeess of diastolic hyperten­sion has been reported in the long-term survivors (5 years from diagnosis) of the NWTS, notably among younger children. The results of this retrospective study bave to be taken witb caution for severa] 
15 
reasons. It has been suggested tbat moderate doses of radiation (14.5 -20.0) may reduee or eliminate the 

Radiotherapy in 11ephrohlasto111a 
ability of a remaining kidney to hypertrophy. The enhancing effect of AMD on radiation ncphropathy is controversial, but in animal experiments BCNU, cisplatinum and Doxorubicin showcd this effect. Iphosphamide may produce nephropathy, but it is not clear if it enhances the effects of RT. 1" 
Radiation hepatotoxicity 
Hepatotoxicity is one of the major acute rcactions to combined postoperative treatment in nephroblas­toma patients. 30.0 Gy is considered a safe RT dose to the whole ]iver. The tolerance of the Iiver varies a great deal depending on the volume irradiated and on additional chemotherapy. Hcpatotoxicity identi­cal in prcsentation and course to radiation hepatitis occurred in children who received postoperative chemotherapy only, in about 10%. In the SIOP group of patients who received postoperative radia­tion and AMD it occurred in 11 out of 58 children (19%) who had major parts of the Iiver or whole ]iver within the irradiation fields. Four of them had veno-occlusive discase (VOD). The dosc range was 
12.0 -22.5 Gy with a few who had a boost up to 30 Gy. Ali four patients who had VOD had received doses > 20 Gy and AMD on 5 consecutive days (15 y/kg). None of the patients who received a singlc dose of AMD (0/13) developed ]iver toxicity but 11/24 with AMD on 5 consecutive days dicl. Ali children recovered from toxicity with conscrvative treatment and dosc reduction of AMD. 17• 18 
Radiation pnewnonitis 
Radiation induced interstitial pneumonitis and pul­monary fibrosis are common complications of treat­ment for Jung metastases in Wilms' tumor patients. A safc dose to the whole Jung is considered to be 20 Gy when given in convcntional fractionation and without chemotherapy; 1400 Gy in 10 fraction in combination with ChT havc resulted in no compli­cations. In the NWTS, however, with 14 Gy to the wholc Jung plus AMD and VCR, pneumopathy was foundin 10-13%. 
Whether Doxorubicin addition increased the rate of late pulmonary dysfunction is not clear. Radia­tion pneumonitis has been seen as a "rccall effect" of AMD after RT. 19 
Cardiac toxicity 
Congestive heart failure is a known complication of therapy with antracyclines. lts frequcncy is directly proportional to thc cumulativc dose of doxorubicin, with a reported incidence of congestive heart fail­ure of about 5% in patients who received a cumula­tive dose of 400-500 mg/m2 or more. Although the initial reports of cardiac failurc were Iimited to the first year after completion of therapy, rcports of heart failurc and dysarrhytmias, leading in some cases to sudden death, are now appearing in pa­tients trcated 4-20 years earlier. In patients from the NWTS 1, 2 and 3, 8 cases ( 1.7%) were found of congestive heart failure after doxorubicin treatment. Additional risk factors included whole Jung irradia­tion and concurrent thcrapy with cyclophosphamide. Only further follow-up will define the magnitude of the risk for different combinations of chemotherapy and RT.20 
Reproductive syslem 
Damage to the male and female reproductive sys­tem caused by cancer therapy may result in infertil­ity or hormona] dysfunction. Up to 12% of female survivors of childhood cancer who received abdom­inal radiation have ovarian failure. In males, gonad­al radiation may result in temporary azoospermia and elevated levels of follicle stimulating and lutci­nizing hormones. A study of pubertal development in children treated for Wilms' tumor found that 3 out of 1 O girls and I out of 6 boys had delayed development associated with elevated hormone lev­els. Thc relative fertility of the 20 Wilms' tumor survivors was 1.49%. Serious adverse pregnancy outcomes have been observed in women who had received abdominal radiation for Wilms' tumor. Perinatal mortality has been cstimated to be eight limes higher than among USA whitc women in general and thc rates of low births weight 4 limes higher. Similar observations regarding the effect of abdominal radiation on low birth weight have been made in babics born to other childhood cancer sur­vivors. Thc risk for children born to Wilms' tumor patients who had chemothcrapy, but no RT, is not known. 
Second malignancies 
Children trcatcd for cancer are at increased risk for both malignant and bcnign second tumors. Cyclo­phosphamide, doxorubicin and cisplatin currently used to treat high risk Wilms' tumor patients, or those who had recurrences, have been implicated in leukemogenesis and carcinogenesis. Radiation and chemotherapy in combination may be more onco­
52 Jereb B 
genic than either agent alone. Studies of second malignant neoplasms in Wilms' tumor survivors have documented a 1 % cumulative incidence at 10 years from diagnosis and rising thereafter. Ali but 2 of the 26 SMN identified in 2 studies occurred in iITadiated patients, most within the radiation field. 
In the NWTS, among 5415 patients treated, 46 developed SMNs, 34 of these had RT and 12 had no RT. Radiation, doxorubicin and recurrence, alone or in combination appear to account for 86% of the SMN cases recorded.21 These 46 cases represent a 
8.5 times higher rate than excepted. One possible cause of SMN might also be related to genetic predisposition; there are some observation that sug­gest such correlation: patients with congenital anom­alies have an increased risk of SMN, the patients who experienced SMN were relatively young (5 out of 7 less the 2 years old and in one study of 36 patients with SMN after Wilms', eight had first degree relatives with Wilms' tumor or congenital anomalies associated with Wilms' tumor.22 
How much the risk for SMNs has decreased by decreasing the use of RT only tirne will show. Much work is stili needed to define the risks depending on treatment modality, doses of RT and particular chemotherapy agents. 
The success of therapy for children with Wilms' tumor has resulted in growth to adulthood of a large population of former patients. The quality of their lives and the lives of their offspring must be our first concern after saving their lives. 
RT is considered responsible for a great deal of early and late toxicities and the most serious late sequelae -second malignant tumors. The number of children at risk for this has certainly diminished. 
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13. 
Tournade MF, Com-Nougue C, Vofite PA, et al.. Re­sults of the Sixth Internati ona! Society of Pediatric On­cology Wilms' Tumor tria! and study: A risk-adapted therapeutic approach in Wilms' tumor. J Ciin Oncol 1993; 11: 1014-23. 

14. 
Ritchey ML, Kelalis PP, Haase GM, Shochat SJ, Green DM, D' Angio G. Preoperative therapy for intracaval and atrial extension of Wilms Tumor. Cancer I 993; 71: 4104-IO. 

15. 
Finklestein JZ, Norkool P, Green DM, Breslow N, D' Angio GJ. Diastolic hypertension in Wilms' tumor survivors: a late effect of treatment? A report from the National Wilms' Tumor Study Group. Am J Ciin Oncol 1993; 16: 201-5. 

16. 
Cassady JR. Clinical radiation nephropathy. /nt J Radi­at Oncol Biol Phys 1995; 31:1249-56. 

17. 
Flentje M, Weirich A, Potter R, Ludwig R. Hepatotox­icity in irradiated nephroblastoma patients during post­operative treatment according to SIOP9/GPOH. Radi­other Oncol 1994; 31: 222-8. 

18. 
Raine J, Bowman A, Wallendszus K, et al. Hepatopath­ythrombocytopenia syndrome -a complication of ac­tinomycin-D therapy for Wilms' tumour. J Ciin Oncol 1991; 9: 268-73. 

19. 
Green DM, Finklestein JZ, Breslow NE, et al.. Remain­ing problems in the treatment of patients with Wilms' tumor. Pediatr Ciin North Am 1991; 38: 475-88. 


20. 
Green DM, Breslow NE, Moksness J. Congestive heart failure following initial therapy for Wilms tumor: a report from the National Wilms Tumor Study. Pediatr Res 1994; 35:161A. 


Radiotherapy in nephrob/astoma 
21. Breslow NE, Takashima JR, Whitton JA, Moksness J, 22. Hartley AL, Birch JM, Blair V, Morris Jones P, Gatta­D' Angio GJ, Green DM. Second malignant neoplasms maneni HR, Kelsey AM. Second primary neoplasms in following treatment for Wilms' tumor: a report from a population-based series of patients diagnosed with the National Wilms' Tumor Study Group. J Ciin Oncol renal tumours in childhood. Med Pediclfr Oncol 1994; 1995, 13: 1851-9. 22: 318-24. 
Radio/ Oncol l 997; 31: 54-5. 

Three-layer template for low-dose-rate remote afterload transperineal interstitial brachytherapy 


Janez Kuhelj, Primož Strojan, Janez Burger 
Institute of Oncology, ˝iuh(jana, Slovenia 
Our experience with a low-dose-rate ( LDR) remote qfierload device (RAD) for transperineal interstitial brachytherapy with 192lr wires has shown that in commercially available templates the smallest distance between individual need/e guides is JO mm due to the fixation teclmique used; the JZxation of the guides also turnecl out inadequate since these tended to move uncontrollably when attached to the LDR RAD. Therefore, a special three-layer template was developed at our Institute. The two outer plates of the device are _joined to form a rigid unit; there is a third, longitudinally movable plate placed in between the other two. The distribution c~l holes for guides insertion is identical in ali three plates, and can be adjusted as required. By 
tightening two screws mounted on the outer plates, the mediwn plate is moved longitudinally, thus simultane­ously _fixing ali the guides inserted. We believe that this device proves ve,y useful, thanks to the simplicity of technical solution, more suitable distribution of ho/es for guides as well as firm and simultaneous jixation of ali guides. 
Key words: brachytherapy-methods; interstitial brachytherapy, transperineal template 
Introduction 
According to the rules of Paris system for dose calculation, 1• 2 a template for needle guides fixation in the interstitial brachytherapy using low-dose-rate (LDR) remote afterloading device (RAD) with 192Ir wires should provide a geometrically correct distri­bution of needle guides in the treated volume, and also ensure strong fixation of the guides during implantation. 
Evaluating our previous work,3 we found com­mercially available templates imperfect as a result of the guide fixation method used.4·6 The distribu­tion of holes for guides in these templates permit­ted for a minimum distance of 10 mm between guides. Taking into account the irregular shape of 
Correspondence to: Janez Kuhelj, M.D., Ph. D., Institute of Oncology, Dept. of Brachytherapy, Zaloška 2, l 105 Ljubljana, Slovenia; Fax: +386 61 1314180. 
UDC: 615.849.5 
tumors implanted, this would not always enable an optimum distribution of guides in the implanted area. Besides, the fixation of guides in these tem­plates was insufficient as they would move uncon­trollably while attached to RAD during implanta­tion. 
Therefore, at the Department of Brachytherapy of the Institute of Oncology in Ljubljana, we have made a template which is devoid of the previously mentioned drawbacks. 
Design 
We have cleveloped ancl constructed a three-layer template presented in Figure 1. The two thinner, 3 mm thick outer plates are joined in four corners with screws and distance washers to form a rigid unit. The third, median 5 mm thick plate is movable longitudinally with respect to the outer plates. Ali three plates have identical perforations, the bole diameter being the same as the outer diameter of 

Template for transperineal brachytherapy 
the guides. The guides are inserted through the three plates and fixed by tightening of the two screws mountecl on the outer plates. At cloing this, the median plate slicles longituclinally; the movement is gradual which allows precise exertion of pressure on the guicles ancl thus simultaneously fixing ali the guicles insertecl. This is necessary to prevent guicle clistortion ancl at the same time ensure sufficient shear forces required for stable fixation of the guides inserted. Generally, we use a template with regular 5-mm square hole clistribution pattern which en­sures goocl coverage of the treated volume. Its low weight, simple construction ancl solicl fixation of conveniently clistributed guicles solve the problems associated with massiveness, elaborate construction, ancl inadequate distribution of holes which results in inappropriate clistribution of guicles in the exist­
ing commercially available templates. 
Conclusion 

Our experience with the presented template indi­cates that this meets the requirements for LDR re­mote afterload interstitial brachytherapy. It enables greater flexibility as to the selection of distance between guicles, and their clistribution with respect to the shape ancl size of the volume treatecl. Also, the fixation of the guicles insertecl is simultaneous, whieh prevents the guides from being clistortecl. Accordingly, when attached to RAD tubes, no un­controllable movements may occur during implan­tation. 

Figure lA. Template assembly for LDR RAD interstitial brachytherapy with 1'J2lr wires designed and worked out in the Institute of Oncology, Ljubljana, Slovenia. 
@ 
@ 

o r ? 
~ 

~ o 
jP------------! 
~ 

Figure 1 B. Schematic dcscription of template. 
We believe that the template clesigned ancl worked out in the Institute promotes the quality of work with LDR RAD in our transperineal interstitial brachytherapy. 
Acknowledgment 

The authors thank Mrs. O. Shrestha, E.A., for her English translation. 
Referenccs 

1. 
Dutrcix A, Marineilo G. The Paris system. In: Picrquin B, Wilson JF, Chassagnc D, eds. Modem brachythera­py. New York: Masson Publishing, 1987: 25-42. 

2. 
Dutreix A, Marincilo G, Wambersie A. Dosimetric du systeme de Paris. In: Dutreix A, Marineilo G, Wamber­sie A, eds. Dosimetrie en curietherapie. Paris: Masson Publishing, 1982: 109-61. 

3. 
Kovac V, Kuhelj J. Complications at interstitial raclio­thcrapy of gynecological carcinoma. Radio/ lugos/ 1990; 24: 181-5. 

4. 
Martinez A, Cox RS, Edmunclson GK. A multiple-site perineal applicator (MUPIT) for the treatment of pros­tatic, anorectal and gynecologic malignancies. !nt J Radia/ Oncol Bio/ Phys 1984; 10: 297-305. 

5. 
Fleming P, Nisar Syed AM, Neblett D, Puthawala A, George FW, Townsencl D. Description of an afterload­ing l 92lr interstitial-intracavitary technique in the treat­mcnt of carcinorna of the vagina. Obstet Gyneco/ 1980; 50: 525-30. 

6. 
John B, Scarbrough EC, Nguyen PD. A diverging gyne­cological template for radioactive interstitial/intracavi­tary implants of the ccrvix. lnt J Radia/ Onco/ Biol Phys 1988; 15: 461-5. 


Radio/ Oncol 1997; 31: 56-9. 


ESTRO teaching course in Basic Clinical Radiobiology 
November 24-28, 1996, lsmir, Turkey 
This year ESTRO Teaching course in Basic Clini­cal Radiobiology was organized in co-operation with the Dukuz Eylul University of Ismir and The Turkish Radiation Oncology Society. Almost 150 medica! doctors, physicists and biologists from different European countries and also from Japan, the United States of America and Australia attend­ed this very well prepared teaching course. The course provided an introduction to radiation biolo­gy as applied to radiotherapy. 
The first day of the course was dedicated to the basic lectures introducing radiobiology. Prof. Dr. 

A. van der Kogel from Institute for Radiotherapy, the Netherlands described the concept of clonogen­ic cells and celi survival. The clonogenic cells could be ascribed as the cells that form colonies exceed­ing 50 cells (5-6 divisions) within a defined growth environment. He gave an overview of different as­says of clonogenic tumor and normal tissue cells. By these assays one can detect the stem cells since they have the ability to form a colony. Models of radiation celi killing were mathematically explained by Dr. M. C. Joiner from the CRC Gray laboratory, United Kingdom. Three models were explained as follows: 
a) 
Single target single hit model; the idea of this model is that just one hit by radiation on a single sensitive target leads to celi death. The survi val curve is exponential and the probability of survival can be calculated by means of Poisson statistics. 

b) 
Multi-target single-hit model. This model as­sumes that there is more than one sensitive target and again a Poison statistics can be applied to de­termine the probability of celi survival. 

c) 
Linear-quadratic model gives a better descrip­tion of radiation response in the low-dose region (0-3 Gy). The shape of the curve is deterrnined by the a/fJ ratio; the <lose at which the linear contribution to the damage equals the quadratic contribution. Linear component of the equation might be due to a single trnek event while the quadratic component might arise from two-track events. A high a/{J ratio is char­acteristic of response of cells to densely-ionizing 


radiations such as neutrons and a-particles, while a low a/{J ratio is characteristic of X-rays. 

Dr. F. A. Stewart from the Netherlands Cancer Institute presented the lecture entitled "Celi Prolif­eration in Normal Tissues". Normal tissues can be divided into two categories: hierarchical tissues with a clear separation between the stem cell compart­ment, an amplification compartment and post-rni­totic compartrnent of mature functional cells (bone marrow, epiderrnis, intestine ... ) and flexible tissues, where ali cells are capable of celi division (Jung, kidney, spina! cord ... ). The hierarchical tissues are rapidly responding tissues where the amount of darnage and the tirne to repair the damage caused by radiation are <lose dependent while the tirne to response is not. In contrast, in the flexible tissues it takes weeks to see the damage, and the rate of damage expression is strongly <lose dependent. 
Dr. M. Baumann from Carl Gustav Carus Uni­versity Clinic, Germany listed in his lecture on clinical radiobiology the radiosensitive and radiore­sistant tumors. He also stressed the importance of <lose per fraction and overall treatment tirne for tumor response and normal tissue damage. A more accurate description of how changing the <lose per fraction influences the shape of isoeffecti ve curves for radiation damage to normal tissues was given by Dr. S. M. Bentzen from Cancer Research Insti­tute, Denmark. The sensitivity to large fraction siz­es is much higher for late responding than for early responding normal tissues. He also explained short­comings of Ellis NSD formula and strongly op­posed its further use. Growth kinetics of tumors were explained by Prof. Dr. G. G. Steel. He pre­sented the method of measuring tumor celi prolifer­ation by using flow cytometry and described the parameters: growth fraction (the proportion of cells that are proliferating), population doubling tirne (tirne required for a celi population to double its number), potential doubling tirne (the predicted celi population doubling tirne in the assumed absence of celi loss), celi cycle tirne (tirne between two mi­toses) and celi loss factor (the rate of celi loss from 
Report 57 
a tumor, as a proportion of the rale at which cells are being added to the tumor by mitosis). 
The second day of the curse dealt with radiobiol­ogy of normal tissues, re-treatment tolerance of normal tissues, the linear-quadratic approach to frac­tionation and hyperfractionation, and accelerated therapy. Prof. Dr. A. van der Kogel held a lecture about radiobiology of normal tissues, focused on radiation effects on the central nervous system. In the central nervous system where the turnover of the cells is very long, the early radiation damage (white matter necrosis) is expressed after 4-6 months, while late vascular damage is detectable only after 7 months. These results were obtained from the studies of radiation effects on rat spina! cord. In general, a high, alf] ratio is characteristic for early radiation effects, and a low one for late effects. This year, a new lecture on re-treatment tolerance of normal tissues was given by Dr. F. A. Stewart. Ali prospective studies on this topic were done on animal models. Rapidly renewing tissues such as the skin or intestine have full reirradiation tolerance within 2-3 months, since they show al­most complete recovery within 1-2 months after the first treatment. In slowly renewing tissues (central nervous system, lung ... ) recovery is much slower and depends on the size of the initial radiation dose. 
The lecture on use of linear-quadratic model in fractionation was presented by Dr. M. C. Joiner. The linear-quadratic model describes the relation­ship between a total isoeffeetive dose and dose per fraction more satisfactory than Ellis NSD formula. For late responding normal tissues a low alf] ratio (0.5-6.0 Gy) is characteristic indieating that for the same effect you must increase the lota! dose if you decrease dose per fraetion. A higher alf] ratio (7-20 Gy) is characteristie for early responding tissues and tumors, which indicates a less rapid increase in total dose with decreasing dosc per fraction. The bcnefits and disadvantage of hyperfractionation (usc of a reduced dose pcr fraction over a conventional overall trcatrnent tirne using rnultiple fractions per day) ancl acceleratecl radiotherapy (use of a conven­tional dose per fraction over a recluced overall treat­ment tirne using rnultiplc fractions per day) were explaincd by Dr. M. Baumann. In hyperfractiona­tion the gain is that late reactions are recluced, while keeping the early racliation damage to normal tis­sues ancl the cffect on tumor in same range as in conventional racliotherapy. The benefit of acceler­ated radiotherapy is that the tumor control curve in dose response plot is shi fted to the left as a conse­quence of reclucing the protective effect of tumor celi repopulation cluring radiotherapy. The radia­tion effects on normal tissue clamage based on the data of three clinical trials are constant or even increasecl. The problems associatecl with the dose response curves for tumor response were explained in detail by Dr. S. M. Bentzen. His lecture was focusecl prirnarily on the problems of estimating the close response relationship ancl on the prescriptions bias which could bc very srnall but could lead to enorrnous changc in tumor response to radiation therapy. 
The first leeture on the thircl clay was devotecl to radiobiology of tumors. Prof. Dr. G.G. Steel ex­plained the advantages and clisaclvantages of differ­ent experimental systems for studying the radiation effects on tumors frorn in vitro tumor celi lines and rnulti spheroids to in vivo transplanted and primary tumors of animal ancl also human tumor xenografts. The basics, and when to use the different end points 
e.g. growth clelay, tumor eontrol and celi survival for measuring radiation effeets on tumors were also explainecl. Tumor growth delay is appliecl when the treatment performecl is not a eurative one. Tumor growth delay is defined as the tirne in the treated group minus the tirne in control group to reach the given size. The parameter most often used in tumor control assay is tumor control close (TCD50); i.c. the radiation dose that controls 50% of tumors. The advantage of celi survival assay is that by removing of cells into growth environrnent that is uniform ancl unaffectecl by the treatrncnt there is less arte­fact due to effects of treatrnent to the host animal. 
The antitumor effectiveness of racliotherapy is strongly dependent upon oxygen. The enhancernent of radiation clamage by oxygen is close rnodifying ancl is constant at ali levels of celi survival curve. Cells in turnors could be either chronically or acute­ly hypoxic. Chronically hypoxic cells are the cells that are situated on the edge of the viable tumor cells that smrnund bloocl vessels. Acute hypoxia occurs when blood vessels in the tumor are tran­siently occludecl. The rnechanfsms for this type of perfusion-limitecl hypoxia are not yet known, but could be due to the plugging of vessels by bloocl cells or by circulating tumor cells; collapse of the vessels in the regions of high interstitial pressure; or by spontaneous vasomotion in incorporatecl host arterioles affecting blood llow in tumors (presented by Dr. M. C. Joiner). Since hypoxic celi are resist­ant to racliation severa! attempts were made to re­cluce hypoxic cells in the tumors, inclucling: 
Cemažar M 
a) 
Chemical radiosensitizing of hypoxic cells us­ing drugs such as misonidazole or nimorazol; 


b) 
Preferential killing of hypoxic cells using bi­oreductive drugs that are activated under hypoxic conditions; 

c) 
Increasing oxygen availability by using hypcr­baric oxygen (in this case you need a lower dose to control the tumors, but the studies on patients were stopped because this method was very inconven­ient); 

d) 
By introducing perfluorochemical emulsions into vessels to increase the oxygen-carrying capaci­ty; 

e) 
By using drugs that increase tumor blood per­fusion; 

f) 
By using carbogen (95% 0 + 5% C0) under 



2 2
the normobaring conditions (Dr. M. Baumann). 
The lecture on different classifications of normal tissue damage used in clinical practice was held by Dr. S. M. Bentzen. It is essential to score the nor­mal tissue damage and treatment-related mortality in any study of cancer treatment. He also presented basic features and limitations of RTOG/EORTC, WHO, French/Italian and European systems for re­porting and grading of treatment-related morbidity after radiotherapy. 
The fourth day of the course was dedicated to clinical implications of volume effect, brachythera­PY (dose-rate effect) and combination of radiother­apy and chemotherapy. The volume effect is de­scribed as dependence of the radiation damage to normal tissues on the voltnne of tissue irradiated. The radiosensitivity of the tissue depends largely on its organization into separate functional units and on the potential of the surviving stem cells to migrate and repopulate in irradiated part of the tissue. Prof. Dr. A. van der Kogel presented the volt11ne effect on the spina! cord, lung, kidney and skin. He also pointed out that Ellis NSD formula is not suitable for the evaluation of volume effect. Mechanisms underlying the dose-rate effect are re­population, cell-cycle progression (reassortment) and repair. Repair is the fastest (half tirne is approx. 1 hour) of these processes and modifies the radia­tion effects over the dose range in between I Gy/ min and I cGy/min. Reassortment is a slower proc­ess and modifies the radiation effects over an inter­mediate range of dose rates. Repopulation is the slowest process; doubling times of tumors and nor­mal tissues range from few days to severa! weeks or even months, therefore the repopulation affects cel­lular response at very low dose rates (below 2 cGy/ min) depending on celi proliferation. 

The combination of radiotherapy and chemother­apy was the subject of lecture given by Dr. F. A. Stewart. Aims of combined modality treatments are improvement of local control, eradication of distant metastases and avoiding mutilating surgery. Inter­action between radio and chemotherapy eould be either short-term interaction (sensitization), medi­um-term interaction or long-term modification. Short-term interaction comprises alterations in the shape of drug/radiation survival curve. The mecha­nism underlying the short term interactions is re­pair inhibition. Medium-term interactions are alter­ations of repopulation kinetics, oxygenation and pH status of the tumors and celi cycle distribution. In long-term interactions residual damage to tumors is a consequence of one modality that influences the response of the other. 
Chemotherapeutic drugs could be given either concomitantly, before (neoadjuvant chemothera­py) or after radiotherapy (adjuvant chemothera­py). A disadvantage of concomitant radiotherapy is that normal tissue toxicity is increased. The rationale for neoadjuvant chemotherapy is the use of chemotherapy to debulk the· primary tumor and eradicate distant metastases, however, a disadvan­tage of this therapy is that radiotherapy (which is more effective than chemotherapy) started with delay. A rationale for adjuvant chemotherapy is an additive local tumor effect and eradication of dis­tant metastases. Alternating use of chemo/radio­therapy was also discussed. There are severa! rationales for this therapy, including early admin­istration of both treatment approaches, reduced risk for developing resistance, and tempom! sepa­ration of both modalities, which results in in­creased normal tissue tolerance. Clinical trials for non-Hodgkin lymphomas, small celi Jung carcino­mas, breast cancers and severa! others conducted in the Institute Gustave Roussy in Villejuif dem­onstrate excellent response. In view of radiothera­py, the future perspectives of chemotherapy are in the search for new, more effective drugs, develop­ment of methods for drug targeting, and predic­tion/identification of patients likely to benefit from this treatment modality. 
The use of predictive assays for tumor responsc to radiotherapy was prcsented by Dr. S.M. Bentzcn. One of the assays is the measurement of potcntial doubling time using flow cytometry, which is prob­ably not a very good predictor, because of intratu­moral celi variability, celi loss and problems asso­

Repc>rt 59 
ciated with differentiation between normal and tu­mor eells. Another assay is the measurement of survival at 2 Gy. The disadvantage of this assay is its long duration and a lot of cxperimental noise due to the presence of fibroblasts. The measure­ment of pO2 shows in general a positive correlation with outcome, but is suitable only for aecessible (and large) tumors only. Severa] new methods, in­cluding the use of PET, NMR, and p53 mutations, are foreseen as predicti ve assays for tumor response to radiotherapy. 
On the last day of the course Dr. M. C. Joiner held a lecture on linear energy transfer (LET) and relative biological cffcctiveness (RBE). LET is a term used to dcscribe the density of ionization in particle traeks. LET is defined as the average ener­gy (in keV) released by a charged particle travers­ing a distance of 1 µm. X and y-rays have a low LET while some particle radiations (ncutrons, a­particles) have a high LET. High-LET radiations are biologically more cffeetive than low-LET radi­ations. Biological effectiveness is measured by RBE, which is defined as the ratio of dose of the reference low-LET radiation (usually 250 kV X­rays) and the dose of tested radiation that produce equal effect. RBE is not constant, but depends on the leve! of biological damage (dose Jevci). RBE dependcnce on radiation dose is different in differ­ent tissucs. 
Stages in process of damage produced by radia­tion was presented by Prof. G.G. Steci in his lecture on "Molecular Aspects of Radiation Biology''. These processes can be divided into induction (ion­ization and formation of free radicals), processing (initial DNA damage and fixation/misrepair on these damages) and manifestation (chromosomal aberra­tions, fragment loss, micronuclci and celi death). 
During the course, some practical ealculations based on the linear-quadratic model and clinical examples were discussed. A particular attention was paid to unplanned gaps that could occur during ongoing fractionated radiotherapy. It was stressed that an increased dose per fraction in order to deli v­er the same total dose, as well as adding an addi­tional dose at the end of therapy, are not satisfacto­ry solutions. The best way to overcome an un­planned gap is to accelerate radiotherapy by treat­ing the patient twice per day till the planned schedule is obtained. It is important that the overall treatment time is not changed. 
This very educational course ended with course cvaluation, examination and announcement that a new edition of "Basic Clinical Radiobiology" with some new chapters and the !atest devclopments in radiothcrapy will be published next year ( 1997). 
Maja Cemažar M.Se. Institute of Oncology, Ljubljana 
Radio! Oncol 1997; 31: 60-1. 

Study tour in Cambridge: A report 
With the help of Cambridge Colleges Hospitality Scheme for Central and Eastern European Scholars I spent a month at the Department of Radiology of the Cambridge University Teaching Hospital in July, 1996. 
There are over 5000 people employed in the hos­pital, daily treating 900-1000 patients, which makes about 60 000 patients, and 290 000 outpatients per year. The hospital has approximately 30 depart­ments and clinics, one of them is the Department of Radiology dealing with medica! imaging. Within the hospital complex there are also Blood Transfu­sion Centre, Clinical School with Medica! Library, Molecular Biological Laboratory and Ambulance Station. 
The Department of Radiology has the following units: conventional radiology, angiography, US-, CT-, MR-unit and a department of Nuclear Medi­cine. Sixten consultants and twenty junior radiolo­gists (registrar, senior registrar) work in the Depart­ment together with fifty radiographers (including ultrasonographers). The radiotherapeutical depart­ment works independently of the department of ra­diology. The Brain lmaging Centre which houses the PET Unit is a Neurosurgery collaborative unit. 
At the Department of Radiology the work with the patients starts at 9 a.m., but the radiologists come one hour earlier to attend conferences, meet the consultants, demonstrate new techniques and tutor their junior colleagues. 
I spent the majority of my tirne in CT-, MR-, US­units. In the US-unit there are 5 US-machines avail­able, ali suitable to perform color, Doppler investi­gation and facilities for intracavitary examinations. Comparable to the Hungarian US routine, this hos­pital did not perform "total abdominal" investiga­tions, but smaller regions were investigated (e.g. !iver + biliary tract, kidneys + bladder; thoracic fluid, child hip, neck). The US investigations were performed by three-four persons, some radiologists, some ultrasonographers. In the CT-unit there are two CT-scanners, a scanner for head and spine (Ge­neral Electric High Speed Advantage GE 9800), and another body-scanner (Siemens Somatom plus4 spiral CT). In both units interventional radiological procedures were performed, e.g. biopsy, abscess and empyema drainage, etc. In the MR-unit there are 2 General Electric Signa machines (0.5, 1.5 T). The main indication fields were the nervous sys­tem, the abdomen, the joints. These machines are capable MR spectroscopy also. I had the opportuni­ty to see for the first time MR investigation of the biliary and pancreatic ducts, MRCP and the 3D-box technique. Computers are used extensively being the part of the information system within the hospi­tal. Each unit has a reception; part of the adminis­trative work is made by the reception staff. The application of the computer is very useful in admin­istrative work. Comparable to the Hungarian prac­tice, this hospital has many more radiographers and nursed, therefore the physicians do not waste tirne with non-medical work. 
Aboute the Cambridge Colleges Hospitality Scheme for Central and Eastern European Scholars: in the beginning of the l 980's a linquist of the Uni­versity of Cambridge originating from Hungary de­cided to promote the study tour of scientists and teachers from universities of Central and Eastern Europe. Since 1984 there bas been an opportunity to spend a month in Cambridge during summer for 7 countries from this region. The University and the Colleges provide free accommodation, food and tu­toring. The applicant can apply for a trave! grant at the Soros Foundation. Visitors get a bursary from the Soros Foundation and the British Council for profes­sional purposes (xeroxing, books). In 1996 the number of the visitors from Central and Eastern Eu­rope was approx. 20, and 4 or 5 of us from Hungary. The majority of the visitors deal with human scienc­es and arts, I was the only one spending my time in the Cambridge University Teaching Hospital. I was there as an observer, it was necessary to avoid the clinical contact with the patients, but nevertheless, I was able to increase my expertise. 

Report 61 
I'm very grateful to professor Dixon and his col­visit (the Cambridge Colleges Hospitality Scheme leagues for the kind welcome and permission to for Central and Eastern European Scholars). participate in the work of the Department of Radio­logy; to Sir John Meurig Thomas, The Master of Scaba Weniger M. D. radiologist Peterhouse for his invitation to live in his House Department of Radiology University and to Mrs. M. Ferguson-Smith for organizing my Medica! School, Pecs 
Radio/ 011co/ 1997; 31: 62-6. 

Ali je kvantitativna scintigrafija pri žlezah slinavkah primerna preiskava pred in po radiojodnem zdravljenju? 
Bohuslavizki KH, Brenner W, Tinnemeyer S, Lassmann S, Kalina S, Mester J, Clausen M, Henze E 
Namen pricujoce preiskave je bil s kvantitativno scintigrqfijo ugotoviti zmanj.fonje .fimkcije pri žlezah slinavkah, ki lahko nastane zaradi nizkodoznega radic~jodnega zdravlje11ja. Prav tako smo ugotavljali pogostnost okvar žlez slinavk pri .//citnicnih bolnikih. Kvantitativno scintigrafijo pri žlezah slinavkah smo delali pred rutinsko §citnicno scintigrqfijo. b1jicirali smo intravenozno 36-126 MBq Tc-99m-pertehnetata in s kopice1;je111 izotopa v slinavkah izracunali paren/zimsko funkcijo. Preiskavo smo naredili pred radiojodnim zdravlje11je111 in 3 mesece po njem pri 144 bolnikih. Pri 674 drugih bolnikih, ki so bili napoteni na §citnicno scintigrqfijo, pa smo s predhodno kvantitativno scintigra.fijo ugotavljali pogostnost okvar žlez slinavk. Kljub spodbujanju delovw1ja žlez slinavk med radioiodnim zdravlje1;jem z askorbinsko kislino, smo izmerili 15­90% parenhimske okvare žlez slinavk pri bol11ikih, ki so z radiojod11im zdravljenjem prejeli 0,4-24 GBq J­
131. Pogostnost okvar žlez slinavk pa smo na§li v l 1,4% (771674) v eni ali dveh žlezah in 7,7% (52/674) pri treh ali §tirih žlezah. Menimo, da je kvantitativna scintigra.fija pred in po radir~jodnem zdrav(jenju primerna preiskava za kvantitativno ugotavljanje .fimkcijskih okvar žlez slinavk -tako predhodnih okvar kot okvar zaradi zdrav(jenja, kar je pomembno tudi pri uporabi nizkih doz J-13 l. Posebc(j priporocamo kvantitativno scintigrq/ijo pri žlezah slinavkah zaradi forenžicnih razlogov. 
Radio/ 011co/ 1997; 31: 5-12. 


Relativna koncentracija DNK v tirocitih scintigrafsko vrocih nodusov 
Budihna NV, Zupanc M, Zorc-Pleskovic R, Porenta M, Vraspin-Porenta O 
Cilj na.ve raziskave je ugotoviti citolo§ko sliko in izmeriti relativno koncentracijo DNK v tirocitih dominantno scintigrqf.i·ko vrocih nodusov §citnice. Metode: Preiskali smo 67 bolnikov z hipertirozo zaradi lokaliziranega avtonomnega tkiva (vrocih nodusov). Relativno koncentracijo DNK v vrocih nodusih smo dolocili s pomocjo celicne citofotometrije in jo primerjali z rezultati citologije, sci11tigrqfije, TT4, TT3, TSH in tiroglobulinom v serumu bolnikov. Rezultati: Modalna vrednost relativne koncentracije DNK v tirocitih je bila v 16 vrocih nodusih diploidna (tip J), v 21 hiperdiploidna (tip 2). 12 nodusov v diploidno (tip 3) in 18 z hiperdiploidno (tip 4) modalno vrednostjo relativne koncentracije DNK je imelo hkrati znake povec'ane prol(feracije celic. Tirociti 4 normalnih .fcitnic so bili diploidni. Citom01/olo§ki znaki atipije in degenerativne spremembe so bili signifikantno boU pogosti pri tipih DNK distribucije 3 in 4 kot pri tipih l in 2. Sklepi: Dominantni scintigrajs·ko vroci nodusi v §citnici so diploidni ali hiperdiploidni. Nekateri vroc'i nodusi so v fazi proliferacije. DNK cito.fotometrija je lahko koristna kot pomožna diagnosticna metoda v primerih, ľier citolo.ška slika (vrocih) .šcitnicnih nodusov ni zanes(iiva, zlasti kadar nacrtujemo radiojodno zdrav(ie11je hipertiroze z lokaliziranim avtonomnim tkivom. 
Radio/ Oncol 1997; 31: 13-7. 

Abstracts 
Diagnosticna vrednost razpoložljivih tumorskih oznacevalcev pri 
šcitnicnem karcinomu 

Brenner W, Bohuslavizki KH, Klutmann S, Henze E 
Pri sledenju onkolo.'iikih bolnikov so tumorski oznacevalci pomembno sredstvo -tako za zgodnje ugotavljanje napredovanja ali ponovitve bolezni in za ugotavUmije oddaljenih metastaz, kot tudi za ugotavljanje ucinkovitosti zdravljenja. Za najbolj pogoste vrste .'iicitnicnih karcinomov so na razpolago preizku.frni twrwrski oznacevalci. Uporab!jamo jih pri papilarnem in folikulamem. karcinomu, ki izhqjata iz .'iicitnicnega epitela ter pri medularnem karcinomu, ki nastane iz parqfblikularnih C-celic žleze šcitnice. V c<lanku so predstav!jeni tumorski oz1wcevalci tireoglobulin, kalcitonin in karcinoembrionalni antigen ter njihova uporaba v obicajni klinicni praksi. Avto1:ji obravnavajo tudi tkivni polipeptidni antigen in neuron specificno enolaw kot možna tumorska oznacevalca pri .'iicitnicnem karcinomu. 
Radio/ Onco/ 1997; 31: 18-20. 
Vrednost scintigrafije s FDG-PET pri odkrivanju tumorjev trebušne slinavke 
Bohuslavizki KH, Mestner J, Brenner W, Buchert R, Klutmann S, Clausen M, Henze E 
Zgodnje odkrivw;je tu11w1:jev trebu/ine slinavke predstavlja v diagnosticni radiologiji velik izziv. Odkrivarije teh tu11101:jev z mm:fiJlo.š:kimi metodami, kot so ultrazvok, racunalni.fka to1110grqff:ia in slikovna magnetna resonanca, je še vedno težavno. Twnor:je trebušne slinavke so poiz/wfoli odkrivati tudi z imunoscintigrqfijo, receptorsko scintigrqfijo in nespecif1cno pe,:fuzijsko scintigrqfijo, vendar se nobena od teh diagnosticnih metod ni pokazala primerna za obicqjno klinicno prakso. Nqjbolj uspefoi so bili z uporabo F-18~fluorodeoksi­glukozno pozitronsko emisijsko tomogrqfijo (F-18-FDG-PET), kier so dosegli 80% natancnost. Zaradi tehnicnih omejetiv pozitronske tomogrq/(je pa ne moremo odkriti 111w1j§ilz sprememb od 1 O do 15 111111, tudi ce uporabljamo visoko resolutivni PET citalec. Tako se tudi ta metoda kaže kol mwii primerna za zgodnje odkrivc117:je raka trebufoe slinavke in ni jasno, ali lahko uporaba FDG-PET zmanjfo pogostnost diagnosticnih laparotomij. Še vedno so potrebne prospektivne prime,:jalne raziskave z ultrazvokom, racunalni§ko tomogrq/1)0, retrogradno kontrastno pankreatikogrqfUo in magnetno resonanco, da bi doloc:ili najprimernej.fr zaporeclje preiskav. FDG-PET illla posebno vrednost, ker nam poleg odkrivcuija sprellle111b v trebufoi slinavki daje tudi podatke o naravi tumorskih mas v trebu.vni slinavki in o ucinkovitosti zdravlje11ja. Seveda so potrebni še nadalj,yi napori, da bomo tocno doloc'ili, kak.\'en pomen imqjo nuklearno medicinske metode pri obravnavi raka trebufoe slinavke. 
Radio/ Oncol 1997; 31: 21-6. 
64 Abstracts 


Nuklearno medicinski IBM PC PIP-GAMMA-PF racunalniški sistem 
Fidler V, Prepadnik M, Fettich J, Hojker S 
Lasten razvoj racunalniškega sistema za zajemanje in obdelavo nuklearno medicinskih slik temelji na naših bogatih izkušnjah pri razvoju nuklearno medicinske strojne in programske opreme ter visokih cenah komercialnih sistemov. Projekt smo zaceli pred petimi leti na cenenem IBM PC z razvojem lastnega zajemalnega modula (GAMMA-PF), ki je v koncni profesionalni obliki izdelan v štiriplastni tehnologiji z avtomatiziranimi funkcijami kontrole kvalitete slike ter analize klinicnih preiskav. V sedanjifazije programska oprema izdelana za DOS okolje v programskem jeziku C++. Sistem je zelo lahko vgraditi ter poganjati in ne potrebuje veliko specializiranega znanja. Poleg avtomatske prilagoditve ojacanja in odmika vhodnih pozicijskih signalov z gama kamere na racunalniški matriki, velikosti posameznega matricnega elementa, izbire preddefiniranega klinicnega protokola in registriranja interventnih posegov med snemanjem omogoca sistem tudi analizo razlicnih klinicnih preiskav na avtomatski nacin z možnostmi korekcije. Prav tako omogoca arhiviranje in izpis rezultatov obdelave z racunalni.~kem mrežnem sistemu na centralno arhivno in izpisno enoto. Pri izgradnji sistema sodelujemo z londonsko univerzo (razvoj PIP -portable image process­ing sistema), mednarodno agencijo za atomsko energijo in ministrstvom za znanost in tehnologijo RS. Do sedaj je bil sistem uspešno uveden na kliniki za nuklearno medicino v Ljubljani, v nuklearno medicinskem laboratoriju v Mariboru ter v tridesetih laboratorijih po svetu. 
Radio! Oncol 1997; 31: 27-32. 



Študij prekrvljenosti fibrosarkoma LPB po elektroterapiji z enosmernim tokom pri imuno-kompetentnih in golih miših z metodo barvanja tkiva s Patent modrim barvilom 
Jarm T, An DJ, Belehradek Jr J, Mir LM, Serša G, Cemažar M, Kotnik T, Pušenjak J, Miklavcic D 
Z elektroterapijo s .~ibkim elektricnim tokom lahko ucinkovito zmanjšamo velikost tumo1jev tako v eksperimentalnih kot klinicnih tumorskih modelih. Proucevali smo ucinke elektroterapije na prekrvljenost trdnih podkožnih tumorjev fibrosarkoma LPB pri imuno-kompetentnih miših C57Bl/6 in pri golih miših z zmanjšanim imunskim odzivom. Uporabili smo enourno terapijo s tokom jakosti 0.6 mA in !.O mA, ki smo ga dovajali preko igelnih elektrod iz zlitine platine in iridija. Elektrode so bile vstavljene podkožno na dveh nasprotnih straneh tumorjev. Upocasnitev• rasti tumorjev pri miših C57Bl/6 je bila po enkratni terapiji statisticno znacilna. Ucinek na rast tumorjev pri golih mWh je bil neznacilen. Z metodo barvanja tkiva s Patent modrovijolicnim barvilom smo ocenjevali ucinek elektroterapije na prekrv!Jenost tumo1jev, ki je eden od možnih mehanizmov elektricnega protitumorskega delovanja. Prekrvljenost smo ocenjevali takoj po terapiji in 24 ur po terapiji. Prekrvljenost tumorjev pri miših C57Bl/6 se je po elektroterapiji nekoliko zmanjšala, medtem ko pri golih miših prakticno nismo zaznali nobenega ucinka. Razlicen odziv v rasti tum01jev na elektroterapijo pri obeh tumorskih modelih kaže na to, da po.~kodba napajalnega ožilja v neposredni bližini vstavljenih elektrod, do katere pride zaradi produktov elektrolize, ve,jetno ni glavni vzrok za zavoro v rasti tumorjev pri imuno-kompetentnih mi.ših. 
Radio! Oncol 1997; 31: 33-8. 

Abstracts 
Površinska termoradioterapija: klinicne izkušnje kažejo na prednost obsevanja neposredno pred pregrevanjem 
Lešnicar Budihna M 
V poglm:j11 s1110 razclenili nekatere pmnemlmej.fo /1111wrske in terapevlske dejavnike, ki so vplivali 11a mpeh /erapije pri bolnikih zdravljenih z lokalno hiperter111ijo. V obdobju 111ed 1989-1995 smo na Onkolo:<:kem in!itillllu v [,j11bijani s termoradiolerapijo zdravili 52 bolnikov z napredovalimi malignimi tu11101ji. Pri 39 (75%) bolnikih smo se za tak nac'in zdravije11ja odlocili, ker predhod110 zdrav(jenje s standardno radio/erapijo ni bilo uspeKno, pri 13 (2Yi'o) bolnikih pa je lermoradiolerapija predslav(iala primamo zdravlje11je. Pri 32 (62'fo) bolnikih smo uporabili perkuta11i nacin, pri 20 (38%;) bolnikih pa i111ersticial11i nac'in zdrav(ie11ja. Popoln odgci\'or 11a terapijo s1110 dosegli pri 60% bolnikov, 2-lelno prežive(je brez ponovitve bolez11i pri 51%, 2-letno za bolezen specificno prežive(ie pa pri 45% bolnikov. Na koncno 11speKnost zdravlje11ia so znac'ilno vplivali: vrsta histologije, t11111orski volu111en, minimalne illlratwnorske temperature, skupna 111111orska doza obsevmija, neposredni odmerek obsevmtja ob pregrevm1ju ter vrstni red obsevm1ja in pregrevm1ja. Ponav(jcmje pregrevwija ni vplivalo 1w izid zdravlje11ja. Znahlno bolj.ve 2-letno prežive(je brez ponovi/ve bolezni (85%) smo v pri111e1javi z bolniki, ki s1110 jih najprej pregrevali in na/o obsevali (38'.1/o), ugolovili pri bo/11ikih, l\jer je obsevmiju ob UJIOrabi nekoliko vi,~jega enkratnega odmerka neposredno sledilo pregrevwije (p=0.03). Krivulji dozne odvis11osli, izractmani za JH1smrwzni skupini bol11ikov z razlicnim zaporec(jem obsevanja in pregrevwija, sta doda11w pokazali, da je ob enakem ucinku zdravlje11ja celokup11a obseval11a doza pri uporabi obsevwija tik pred pregrevmijem lahko bislve110 nižja. Izracunani kolicnik izboU.vm1ja zdravlje11ja ( cnlw11ce111ent rcllio) med skupinama je znafol 1.7. lzrazitej.ve akutne in kronicne posledice zdravljenja smo opažali pri 28% oziroma 23% bolnikov. Stra11ski 11ci11ki zdrav/je1iia so bili z.1w6l11c_j.vi pri bolnikih z vifjo maksimalno izme1:jeno temperaturo v ogrevanem podro(ju, pri bolnikih z ve(jim tw11orski111 vo/111111wm in pri uporabi vi,~je celokupne lllnwrske obsevalne doze. Na.vi klinih1i izsledki nakazt(jejo pomemlmo vrednos/ llJIOrabe vitjih odmerkov obsevc11ija 11ej1osred110 pred pregreva11je111. Tak nac'in kombiniranega zdravlje11ja lahko privede do zadovo(iivih rezulwlov 
že pri razmeroma 11izki celokupni dozi obsevanja, wlo je uporaba ter111oradio1erapije smiselna tudi pri predhodno že obsevanih ho/11ikih. 
Radio/ Oncol 1997; 31: 39-47. 
Radioterapija nefroblastoma. Pred-in pooperativno kombinirano zdravljenje. Radioterapija pri lokalizirani (stadij II, III, IV) in diseminirani bolezni. Akutne in kasne posledice. 
JerebB 
Ne.fi'oblas1m11 embrio11al11i maligni t1111wr ledvice se pr1javUa nqjpogoslcjJie v z.god1;ji o/ro,vki dobi, nelw/eri bol11iki imqjo wdi prirqje11e m1011w!ije. V zadnjih letih so se mocno razvile genetske raziskave lega tw11m:ja. Pri zdrav/jenju 11e.fi-r1/Jlaslon1a se je obsevmije uveUavilo že Jlred deset/e(ji kot tl('i11kovit doda1ek kirnrg!ji, žal pa pov::.roca 11eza".ele11e kasne posledice. Preživetje se je trqjno iz.bolj.veva/o od prvotnih 25%1 pa do 80% ali vec'. S lem je problelll kasnih posledic poslal !ie bo!j po111e111be11. V Evropi, ZDA i11 Veliki Britaniji so s iitevil11i111i rando111iziruni111i klinicnimi !ilud!jami poskufo/i preclvse111 ::.mmij:foti kasne posledice na ta nacin, da so 6111 bo/j prilagodili ::.dro1'/je1iic ::.nc111i111 prognostic'!tim cli:jav11iko111. Re::.11ltati teh ra11do111i::.iranilt kli11ic'11ilz fotdij so opisani, pa tudi kon1plikac!je ::.drav!je11ja in sekundarni tw1w1ji. Zaradi uspe:Vnosti zdmvije1;ja otrok z ll('./i·ob/as/011w111 se je 111oh10 povdala poptilacija biviih bolnikov, ki so odrasli. Menijo, da je obscwmjc nqjpogostejii vzrok zgod11jih in kasnih komplikacij z.drav/jenja. Vsekakor se je .'itevilo rmlrav!jenih otrok s t\'l'g<ll(jem za kasne posledice zadnja dPsellelja hislveno zmanj.valo. 
Radio/ Onco/ 1997; 31: 48-53. 
Abstracts 
Trislojna šablona za transperinealno intersticijsko brahiterapijo 
pri obsevanju z nizko hitrostjo 
Kuhelj J, Strojan P, Burger J 
Pri obsevariju z 11izko hitros;jo (low-dose-rate LDR) in remote qfierload aparatom (RAA) za transperinealno intersticžjsko brahiterapžjo z 192lr žicami smo ugotovili, da je zaradi na6na fiksac(ie vodil pri komercialno dostopnih ?iablo11alz nqjmariFfo medsebojna razdalja med vodili suma 10 111111; sama fiksacija vodil pa je neustrezna, sqj je ob njihovi prikljucitvi 11a LDR RAA prihajalo do nekontroliranih premikov le-teh. Zato smo v na:fi ustanovi izdelali novo, troslojno fob/0110. Zunanji dve ploXci sta med seboj spojeni in tvorita rigidno celoto; med 1;ji111a je tretja, vzdolžno pomicna p/oh'a. Razpored odprtin za vnaJic111je vodil je v vseh treh plo§cah e11ak in je lahko poljube11. S privijanjem dveh vijakov, prit1jenih na zunanji/z ploJicah, vzdolžno pomikamo sreclrijo, ki s striž110 silo pritrdi naenkrat vsa vstavljena vodila. Menimo, da tehnicna enostavnost rditve, primernej.fo razporeditev odprtin za vodila ter cvrsta i11 hkratna pritrditev vodil poveczUe uporabnost opisane :<:ablone. 
Radio! Oncol 1997; 31: 54-5. 
Radio/ Onco/ 1997; 31: 67-70. 
Notices 
Notice.1· submittedfor publication should contain a mailing address, phone and/orfax number and/or e-mail qf a contact person or department. 
Oncology 

May 28-3 !, 1997. 
The lntcrnational Confcrence 1997 Comprehensive Can­cer Carc "Focus on Cancer Pain" will be offere<l in Limassol, Cyprus. 
Contact Congress Sccretariat, Options Eurocongress, P.O.Box 4723, Limassol, Cyprus; or call +357 5 399 722; or fax + 357 5 399 494. 
Hrachytherapy 

March 5-7. /997. 
Deutsche Brachytherapy Konfercnz '97 will be hcl<l in Lucbcck, Germany. 
Contact Prof. Dr. E. Richter, Med. Univ. zu Luebeck, Klinik fuer Strahlcntherapie, Ratzeburger Allee, 160, 23538 Lucbeck, Germany; or call +49 45 l 500 6660; or fax +49 45 l 500 3324. 
Familial cancer and cancer genetics 

April, 1997. 
The ESO training course "Familial Cancer and Cancer Genetics" will be offcrecl in Haifa, Israel. 
Contact ESO Balkans an<l Midclle East Oflice, c/o Egnatia Epirus Founclation, 7 A Tzavella St., 453 33 loannina, Grcecc; or call +30 651 72315/76992; or fax +30 651 36695. 
Radiotherapy 

May 11-12, 1997. 
The two clay teaching seminar "Stcrotactic Racliotherapy / Ra<liosurgery Using Linear Accclerator" will bc hclcl in London, U.K. 
Contact Mrs Chris Casscll, Neuro-oncology Unit, The Royal Marsden Hospital, Downs Roacl, Sutton, Surrey SM2 5PT, U.K.; or call +44 l 81 6426011 Ext. 3272; fax +44 181 643 5468. 
Asa service to our readers, notice.,· of meetings or courses 
will be inserted free t!/" charge. 
Radiation oncology 

Mav 9-IO, 1997. 
'foe "Second Annual Multi<lisciplinary Ra<liation Oncology Confcrencc" will be offered in Washington, DC, USA. 
Contact Tamara Gilmore, CMP; Every Last Detail, 14203 Woolen Oak Court, Suite 7, Si Iver Spring, MD 20906, USA; or call +l 800 592 8337; fax +l 800 994 8757; e-mail: Detail_erols.com 
Clinical trials 

June, /997. 
Thc EORTC course "Clinical Trials Statistics for non Statisticians" will be offered in Brussels, Belgium. 
Contact Ms. A.Marinus, EORTC E<lucation an<l Training Division, Av. E. Mounier 83, 1200 Brusscls, Bclgium; or call +32 2 7724621; or fax +32 2 772 6233. 
Prostate cancer 

.lune, 1997. 
The ESO training coursc will be helcl in Moscow, Russia. 

Contact ESO Russia ancl Community of Inclepenclcnt States, c/o CSC Lt<l., Mrs. Mira Vukclic, Heiligenstae<ltcr Strasse 395b, 1190 Vienna, Austria; or call +43 1 3188 466; or fax +431 3188 466-20 . 
Radiotherapy 

June 4-7, /997. 
The ''lnternational Congress of Racliation Oncology 1997 ([CRO'97)" will take place in Beijing, China. 
Contact Marleen Stevens, ISRO office, Racliotherapy Dc­partment, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium; or call +32 16 34 76 85; or fax +32 16 34 76 81. 
Peripheral stem celi transplantation 

J1111e 5-7, /997. 
The ESO training course will be offerecl in Delphi, Greece. 
Please sent iltformation to the Editorial ojjice, Radiology Contact ESO Balkans ancl Midclle East Office, c/o Egnatia and Oncology, Vrazov trg 4, SI-! 105 Ljubljana, S!ovenia. Epirus Foundation, 7A Tzavella St., 453 33 loannina, 
68 Notices 
Greece; or call +30 651 72315/76992; or fax +30 651 36695. 
Gastric and intestinal cancers 
.lune 10-11, I 997. 
The ESO training course will be held in Mexico DF, Mexico. 
Contact ESO Latin America, Dr.G.Fmallle, Yia Ripa­rnonti, 66, 20141 Milan, ltaly; or call +39 2 57 305 416; or fax +39 2 57 307 143 . 
Laenkemias and lymohomas 
.lune 10-J /, /997. 
The ESO training course will be held in Bogota, Colom­bia. 
Contact ESO Latin Arnerica, Dr.G.Farante, Yia Ripa­rnonti, 66, 20141 Milan, ltaly; or call +39 2 57 305 416; or fax +39 2 57 307 143 . 
Breast cancer 
.lune 10-11, 1997. 
The ESO training course will be held in Santiago, Chile. 
Contact ESO Latin Amcrica, Dr.G.Farante, Yia Ripa­monti, 66, 20141 Milan, Jtaly; or call +39 2 57 305 416; or fax +39 2 57 307 143 . 
Gynaecological oncology 
.lune JO-//, 1997. 
Thc ESO training coursc will be held in Buenos Aires, 
Argentina. 
Contact ESO LatinAmerica, Dr.A.Rancati,Av. Las I-leras 1666, 1018 Buenos Aires, Argentina; or call +54 1 8141 129; or fax +54 1 8141 129 . 
Headache 
.lune I 0-14, 1997. 
The "8th lnternational Headache Congress" will be of­fered in Amsterdam, The Nctherlands. Contact Lidy Groot, Congrcss Events, PO Box 83005, 1080-AA Amsterdam, The Netherlands . 
.lune 11-13, /997. 
The clinical seminar "Stratcgy on Mechanical Yentilation in Newborns ancl lnfant" will take placc in Bernriecl am Starnberger See (near Munich), Germany . 
Contact IPOKRaTES lnternational Hcacl Office, Rosen­gartenplatz 2, D-68161 Mannheim, Germany; or call +49 621 4106 134; or fax +49 6214106202. 
Digestive tract 
.lune 12-14, 1997. 
The ESO advanced course "Digestive Tract (part 1): Gas­troesophageal Tumours" will be offered in Milan, ltaly. 
Contact European School of Oncology, Yia Ripamonti, 66, 20141 Milan, ltaly; or call +39 2 57 305 416; or fax + 39 2 57 307 143. 
II Latin America edncation convention 
Ju11e 12-14, 1997. 
The ESO convcntion will be held in Sao Paul<), Brazil. 
Contact ESO Latin America, Dr.A.Frasson, Avc. lpiranga 6690, Porto Alegrc, Brazil; or call +55 51 3392 709; or fax +55 51 3392 709. 
Utrasonography 
.lune 23-25, /997. 
The clinical seminar "Neonatal & Pediatric Utrasono­graphy" will take placc in Bernricd am Starnbcrger Sce (near Munich}, Gerrnany . 
Contact IPOKRaTES International Head Office, Rosen­gartenplatz 2, D-68161 Mannheim, Germany; or call +49 6214106134; or fax +49 6214106202. 
Magnetic Resonance 
Ju11e 26-29, /997. 
Thc ·'Clinical Magnetic Resonance Society Annual Mcct­ing" will be offered in Orlando, USA. 
Contact Walt Disney World SWAN, Disney World/EPCOT Center, Orlando, Florida, USA; or call + 1 800 823 2677 / + 1 513 221 0()70; fax + 1 513 221 0825; e-mail: cmrs_one.net 
Asthma 
August 24-27, /997. 
Tile "2nd Annual Meeting of thc Central and Eastern European Regional INTERASMA organisation" will bc of­fercd in Budapest, Hungary. 
Contact Central and Eastern European Regional INTER­ASMA Conference, Dr. Endre Laszlo, MAV Gyermckgyo­gyhaz, Budapest, XII. ker .. Manyct u. 11., H-1121. Hungary. 

Augus1 3 I -September 4, I 997. Tile ESTRO and ERTED teaching course "Radiation Physics for Clinical Radiotherapy" will be offered in Lucven, Bclgium. 

Notices 69 
Contact the ESTRO office, Radiotherapy Department, Uni­versity Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium; or call +32 16 34 76 80; or fax +32 16 34 76 81. 
Clinical trials 

Autumn, 1997. 
The EORTC course "Data Management in Cancer Clini­cal Trials" will be held in Leuven, Belgium. 
Contact Ms. A.Marinus, EORTC Education and Training Division, Av. E. Mounier 83, 1200 Brussels, Belgium; or call +32 2 772 4621; or fax +32 2 772 6233. 
Clinical trials 

September, 1997. The EORTC course "One Day Introduction to EORTC Trials" will be held in Brussels, Belgium. 
Contact Ms. A.Marinus, EORTC Education and Training Division, Av. E. Mounier 83, 1200 Brussels, Belgium; or call +32 2 772 4621; or fax +32 2 772 6233. 
Cytokines 

Septembe1; 1997. 
The ESO training course "Cytokines" will be offered in Hofburg Conference Center, Vienna, Austria. 
Contact European School of Oncology, Office for Cen­tral and Eastern Europe, c/o Arztekammer fuer Wien, Fort­bildungsreforat Weihburggasse 10-12, 1010 Vienna, Aus­tria; or call +43 l 3188 466; or fax +43 l 3188 466 20. 
Breast reconstructive surgery 

Septembe1; 1997. 
The ESO training course will be held in Caracas, Venezuela. 
Contact ESO LatinAmerica, Dr.G.Farante, Via Ripamon­

ti, 66, 20141 Milan, Italy; or call +39 2 57 305 416; or fax 
+39 2 57 307 143. 
Neuropathology 

September 7-12, 1997. 
The 13th lnternational Congress of Neuropathology will 

be offered in Perth, Australia. 
Contact Ms Angela Schaefer, ICMS Conference Secre­

tariat, PO Box 8120, Hindley St., PO, Adelaide, SA 5000, 
Australia; or call +61 8 210 6776; fax +61 8 212 5101; e­
mail: icnp97 _icms.com.au 
Radiotherapy 

September 12-13, 1997. 
The ESTRO workshop on "3D Treatment Planning and Optimization for Clinical Radiotherapy" will take place in Nice, France. (It will be linked to the 4th Biennial ESTRO Physics Meeting). 
Contact the ESTRO office, Radiotherapy Department, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium; or call +32 16 34 76 80; or fax +32 16 34 76 81. 
Oncology 

September 14-19, /997. 
The ESTRO 16 / ECCO 9 Congress will be offered in Hamburg, Germany. 
Contact the ESTRO office, Radiotherapy Department, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium; or call +32 16 34 76 80; or fax +32 16 34 76 81. 
Radiotherapy 

September 14-19, 1997. 
The ESTRO teaching course "Radiotherapy in Integrated Cancer care will be held in Izmir, Turkey. 
Contact the ESTRO office, Radiotherapy Department, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium; or call +32 16 34 76 80; or fax +32 16 34 76 81. 
Radiobiology 

September 14-19, 1997. 
The ESTRO teaching course "Basic Clinical Radiobiol­ogy" will be offered in Como, ltaly. 
Contact the ESTRO office, Radiotherapy Department, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium; or call + 32 16 34 76 80; or fax +32 16 34 76 81. 
Medical physics and engineering 

September 15-19, 1997. 
The "11 th Internati ona! Conference on Medica! Physics" 

and "18th Internaional Conference on Medica! and Bio­
logical Engineering" will be offered in Nice, France. 
Contact Nice'97, SEE-48, rue de la Procession, F-75724 

Paris Cedex, France. 
Pediatric neurology 

September 18-20, 1997. 
The clinical seminar "Pediatric Neurology" will be held 

in Krems, Austria. 
Contact IPOKRaTES lnternational Head Office, Rosen­

gartenplatz 2, D-68161 Mannheim, Germany; or call +49 
6214106134; or fax +49 6214106202. 
70 Notices 
Neonatology 
September 22-25, 1997. 
The clinical seminar "Neonatology" will take place in Krems, Austria. 
Contact IPOKRaTES International Head Office, Rosen­gartenplatz 2, D-68161 Mannheim, Germany; or call +49 621 4106 134; or fax +49 621 4106 202. 
Melanoma and skin cancer 
September 24-25, 1997. 
The ESO training course "Melanoma and Skin Cancer" will be offered in Hofburg Conference Center, Vienna, Austria. 
Contact European School of Oncology, Office for Cen­tral and Eastern Europe, c/o Arztekammer fuer Wien, Fort­bildungsreferat Weihburggasse 10-12, 1010 Vienna, Aus­tria; or call +43 1 3188 466; or fax +43 1 3188 466 20. 
Good clinical practice 
September 24-25, 1997. 
The ESO training course "Good Clinical Practice" will be offered in Hofburg Conference Center, Vienna, Austria. 
Contact European School of Oncology, Office for Cen­tral and Eastern Europe, c/o Arztekammer fuer Wien, Fort­bildungsreferat Weihburggasse 10-12, 1010 Vienna, Aus­tria; or call +43 1 3188 466; or fax +43 1 3188 466 20. 
Oncology 
September 25-27, 1997. 
The ESO training course "New Approaches in Diagnosis and Treatment of Cancer" will be held in Belgrade, Yugo­slavia. 
Contact ESO Balkans and Middle East Office, c/o Egnatia Epirus Foundation, 7 A Tzavella St., 453 33 loannina, Gree­ce; or call +30 651 72315/76992; or fax +30 651 36695. 
Oncology 
September 26-27, 1997. 
The ESO training course "Modem Trends in Cancer Screening" will be held in Belgrade, Yugoslavia. 
Contact ESO Balkans and Middle East Office, c/o Egnatia Epirus Foundation, 7 A Tzavella St., 453 33 loannina, Gree­ce; or call +30 651 72315/76992; or fax +30 651 36695. 
Oncology 
September 26-28, 1997. 
The ESO training course "Myeloproliferative and Mye­lodysplastic disease" will take place in Patras, Greece. 
Contact ESO Balkans and Middle East Office, c/o Egna­tia Epiru s Foundation, 7 A Tzavella St., 453 33 loannina, Greece; or call + 30 651 72315/7 6992; or fax + 30 651 36695. 

International Conference 




LIFE Sc1ENCES 1997 
and 
SLOVENIAN -CROATIAN MEETING ON MoLECULAR ONCOLOGY ToDAY 
Gozd Martuljek, Slovenia 16th_ 19th Octobef'. 1997 
' 

0RGANIZED BY 
Slovenian Biophysical Society 
ancl 

Institute of Oncology, Ljubljana 
IN CooPERATION WITH: Physiological Society of Slovenia, Slovenian Genetic Society, Slovenian Immunological Socicty. Slovcnian Medica] Association, Oncology Section, Slovcnian Pharmaco­logical Society, Slovcnian Society for Medica! ancl Biological Engineering, Society for Stcrcology ancl Quantitativc lmage Analysis, Faculty of Elcctrical Engineering, University of 
Ljubljana, Institute Rucljer Boškovic, Zagreb 
CoNNECTING Tnmvm Biophysics and Biology of Tumors 
MAIN TOPICS 
Experimental Oncology Diagnostic ancl Prognostic Factors in Oncology Molecular Oncology Immune System ancl Biological Response Modifiers MR Imaging EPR Spectroscopy Functional Electrical Stimulation Physiology Membranes Image Analysis New Technologies 
0RGANIZING COMMITTEE ADDRESS 
Gregor Serša, Institute 01· Oncology, Dept. of Tumor Biology, Zaloška 2 SI-1105 Ljubljana, Slovenia ~: (+386 61) 133 74 10 or 323 063 ext. 29 33 Fax: (+386 61) 131 41 80 
gsersa@mail.onko-i.si 
Symposium on 

ORGAN SPARING TREATMENT IN ONCOLOGY 
Ljubljana, Slovenia 19-21 June 1997 
Organized by: 
Institute of Oncology, Ljubljana, Slovenia 
Under the auspices of: 
Alps Adriatic Working Community 
Design and Content 
The Symposium is designed for medica) doctors and other specialists involved in cancer treatment who wish to exchange experiences with oncologists and to contribute to upgrading the knowledge in organ sparing treatment. It will cover the following topics: • Breast Conserving Therapy • Bladder Sparing Treatment in Muscle Invasive Bladder Carcinoma • Organ Sparing Treatment in Head and Neck Carcinoma • Organ Sparing Treatment in Soft Tissue Tumors • Quality of Life after Organ Sparing Treatrnent 
Mailing Address 
Organizing Committee Institute of Oncology Zaloška 2, 1 105 Ljubljana SLOVENJA Phone: +386 61 131 42 25 Fax: +386 61 131 41 80 E-mail: mcaks@mail.onko-i.si 




DIFWCAN* 
(flukonazol) 
Glivicne 
okužbe kože 
Odmerki: 
50 mg/dan ali 150 mg/teden* 
· zatineoversicolorie priporocljiv odmerek 50 mg/dan 
Trajanje: 
2-4 tedne** 
"za lineo pedis je morda potrebno 6 tedensko zdravljenje 
Vaginalna kandidijaza 
Odmerek: 
150 mg 
Trajanje: 
Enkratni odmerek 

Kriptokoki meningitis 
Odmerki: 
400 mg (prvi dan) 200-400 mg/dan 
Trajanje: 
6-8 tednov 
Profilaksa: 
200 mg/dan 
Sistemska kandidijaza 
Odmerki: 
400 mg (prvi dan) 200-400 mg/dan 
Trajanje: 
Odvisno od klinicnega odziva 
Profilaksa: 
50 mg/dan 
Orofarin~ealna in sluzni na kandidijaza 
Odmerki: 
50 mg/dan* 

• pri zelo hudih okužbah sluznice je morda potrebno 100 mg/dan 
Trajanje: 
1-2 tedna** 
"pri okužbah sluznice je morda potrebno 30 dnevno zdravljenje 
Profilaksa: 
50 mg/dan 


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 odmen<i: obrni. Uporaba pri starejših: kot zgoraj, razen pri ljudeh z ledvicn i mi 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 pri porocljive odmerke za otroke starejše od enega leta. Bolniki z led vicnim i okvarami: morda so potrebni manjši odmerki -glej popolne inforlJ)acije za predpiso­vanje. Dajanje zdravila: DIFLUCAN lahko dajemo oralno ali v obliki intravenske infuzije. Odmerki so pri oben nac in ih enaki. Kontraindikacije: Znana preobcu tljivost 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. P o rocajo tudi o anafil akti cn ih reakcijah. Varnostni ukrepi: Ker so na voljo le omejeni podatki, odsvetuje­mo uporabo pri nosecn icah , razen kadar se zdi to l ececemu zdravniku nujno potrebno. Dojenje: ne p ri porocamo 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 uc inki so vezani na gastrointestinalni trakt: sla­bost, abdominalno nelagodje, diareja in vetrovi. Po rocajo tudi o kožnem izpu šcaju. Pri bolnikih s hudo osnovno boleznijo so med zdravljenjem z DIFLU­CANOM in primern imi ucinkovinam i opazili spremembe v testnih rezultatih l edvic ni h in hematoloških funkcij ter bolezenske spremembe jeter, vendar pa sta kl inicna 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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FONDACIJA 
DR. J. 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 15 91 277 FAKS 06 1 2 1 8 1 1 3 
:Ž:R: 50100-620-133-05-1033115-214779 


FONDACIJA DR.]. CHOLEWA 
Activity of "Dr. J. Cholewa Foundation" for cancer research and education -repo rt f or the second half of 1996 
"Dr. J. Cholewa Foundation" for cancer research and education continued its act1v1ty through the second half of 1996 as it was outlined at the meetings of the executive and scientific concils of the Foundation that took place at the end of 1995. One of the most important aspects of Foundation's activity is the support it lends to the publishing activity concerned with cancer research, education and treatment, that takes place in the Republic of Slovenia. 
The Foundation continues to give part of the support needed for the regular publication of the "Radiology and Oncology" scientific journal. A source of relevant information is thus provided in this way for physicians and nurses involved in the treatment of cancer patients and in cancer research, and for those that are involved in various levels of cancer education. "Radiology and Oncology" is an international scientific journal and therefore offers the possibility to serve to ali those interested as an important point of reference and scientific discussion. 
Support for the regular publication of "Challenge" is another important activity of "Dr. J. Cholewa Foundation" for cancer research and education. "Challenge" is the newsletter of the European School of Oncology distributed free of charge to health professionals working in countries with limited resources to deal with the issue of cancer diagnosis and treatment in these parts of the world. The scarcity of resources is not limited to the developing countries alone and "Challenge" thus provides interesting information to ali interested in this issue in the Republic of Slovenia and other countries as well. As one of the publications of European School of Oncology it is available on the Internet, together with the information concerning the activities and efforts of this important European scientific institution. In this way part of the activities of "Dr. J. Cholewa Foundation" appears regularly on the Internet. 
The Foundation is proud to be one of the supporters of the International Conference on Epithelial Hyperplastic Lesions of the Larynx that took place on October 28-30, 1996, in Ljubljana, Slovenia. The fact that a large number of attendants of the Conference from Slovenia fulfills one of the important goals of "Dr. J. Cholewa Foundation" for cancer research and education. 
The opening of "Dr. J. Cholewa Foundation" office is expected to take place in Ljubljana in the first quarter of 1997. This will enable the Foundation to further advance its activities in the future. 
Borut Štabuc, MD; PhD Andrej Plesnicar, MD Tomaž Benulic, MD 

TO JE DESETLETJE MAKROLIDOV 

azitromicin 



® 


injekcije, kapsule, kapljice, svecke tramadol 

Povrne mik življenja 

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 sinergisticno 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 s~rojev in motornih vozil. Med 
nosecnostjo in dojenjem predPišemo tramadol le pri nujni indikaciji. Bolnike s krci centralnega izvora skrbno nadzorujemo. Dozira,tje: Odrasli in otroci, star~ši od 14 let: 50 do 100 mg 3-do 4-krat na dan. Otrokom od 1 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 in utrujenost. Redko lahko pride do palpitacij, orto~taticne hipotenzije ali kardiovaskularnega kolapsa. Izjemoma se lahko pojavijo konvulzije. Oprema: 5 ampul po 1 ml (50 mg/ml), 5 ampul po 2 ml (100 mg/ 2 ml), 20 kapsul po 50 mg, 10 ml raztopine (100 mg/ml), 5 sveck po 100 mg. 

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Radio/ Oncol 1997; 31: 84. 
Instructions to authors 
Editorial policy o/' the journal Radiology and Onco/ogy isto publish original scientilic papers. professional papcrs. review articlcs. case rcporls and varia (cditorials. revicws. shorl con1munications. professional infonnation. book rc­views. lellers. elc.) pertinenl to diagnostic and interven­tional radiology. computerised tomography. magnetic reso­nance. ullrasound. nuclear medicine. radiotherapy. clinical and experimental oncology. radiobiology, radiophysics and radiation proteclion. The Editorial Board rcquires that thc paper has 11ot been published or sub1nitted for publicalion elsewherc: lhe authors are responsiblc for ali slalemenls in their papers. Acccplcd articlcs become thc properly of the journal and thereforc ca11not be publishcd clsewhere with­out wrillcn pcrmission fro111 tile cditorial hoard. Papers con­cerning thc work on humans. must comply wilh the princi­ples of thc dcclaration or Helsinki ( 1964). The approval of thc cthical commillcc must then be statcd on the manu­scripl. The editors reserve thc right to reject a paper with qucstionablc justi lication. 
Submission of manuscript: Manuscripts wrillcn in Eng­lish should bc submitted in triplicatc (the original and two copies). including the illustrations to the Editorial Onice: Radiologr and Onrnlog1·. Institute of Oncology. Vrazov trg 
4. Sl-1 105 Ljubljana. Slovenia: (Phonc: + 386 61 1320068, Fax: +386 61 13 14 180. c-mail: oshrestha@mail.onko-i.si). Authors are asked to submit their manuscripls also ona 3.5" 
1.44 Mb fonnalted diskelle. The type or computer and word­processing package should bc specilied (Word for Win­dows is prelerrcd). 
Ali a11iclcs are subjectcd to cdilorial review a11d rcvicw by two indepe11dcnt relerees selected by the editorial board. Manuscripls which do not co111ply with lhe lechnical rcquirc­ments stated herc will be returned to thc autl1ors for corrce­tion before thc rcview or thc rclerees. Rejected manuscripls are gencrally returned to authors. howevcr. the journal can­not bc hcld rcsponsible for lheir loss. The edilorial ho:1rd rescrves lhc righl to ask authors to make appropriate ehanges in the contenl as well as grammatical and slylistic corrcctions when nccessary. The expenses of addilional cditorial work and requesls ltir reprints will hc charged to the authors. 
General instructions: Radiology and Oncology will con­sider manuscripts prcpared according to the Vancouver Agrcement (N Engl .! Med 1991: 324: 424-8. BM.I 1991: 
302: 6772.). Typc the manuscript double spaced on one side with a 4 cm margin at the lop and len hand side or the shecl. Write the paper in grammatically and stylislically correct language, Avoid abbrcviations unless previously explained. The tech11ical data should conlinn to lhe SI syslcm. The manuscripl. including the refcrcnces may not exeeed l ."i type­writte11 pages. and thc numbcr of ligures a11d tables is limited to 4. lf appropriate. organise the text so that it includes: lntroduelion. Material and melhods, Rcsulls and Discussion. Exceptionally. the results and discussion can be cornbincd in a simde section. St:1r1 each scction ona new pagc and number these' consccutivcly with Arabic numerals. ' 
'fl1/e page should include a concise and descriplive litle for the paper: thc full namc(s) or thc author(s): the institu­tional aniliation or each author: thc name a11d address or the corresponding author (including telephone. fax and e-mail) and abbrcviated title. This should be followed by the ah­slracl page. sunHnarising in less than 200 words the reasons for the study. experimental approach. thc major lindings (with speci/ic dala if possible). and lhc principal conclu­sions. and providing 3-6 key words for indexing purposes. The text or thc reporl should ihen procecd as follows: 
l,1tmduclion should describc the background or lhe in­vcstigation, eiting only the essential relerenccs and slating the aim or the study. 
Ma1eria/ and me1/wds should provide enough informa­tion to enable cxperiments to be repeated. New methods should be deserihed in detail. Research on human and ani­mal subjeets should indicate that clhical approval of the study was oblained. 
Resul!s should be prescnted clearly and eoncisely wilh­out rcpcating the dala in lhe tables a11d ligures. Emphasis should be on clear and precise presentalion or results and their signilicancc in rclation to the aim of the investigation. 
Di.1·cu,l'sion should explain thc results, and not simply rcpeal thc1n, interpret their signif1cance and draw conclu­sions. It should review the results of the study in the light or previously published work. 
Illustrations and tahlcs: Ali illustrations and tables must be nurnbered and refcrred to in the test. with appropriate location indicated in tht: text rnargin. lllustrations must be labelled on lhe back with the author's name, figure number and orienlation, and should be accornpanied hy a descrip­tive legend on a separate pagc. Line drawings should be supplied in a form suitable for high-quality reproduetion. Photographs should be glossy prints or high quality with as much co11trasl as the subject allows. They should be cropped as close as possible to lhe arca or interesl. In photographs mask lhe identilies or the patienls. Tables should be typed with double spacing wilh descriptive title and. if appropri­ale, units of 11urnerical measurcments included in colunm heading. 
Refcrcnccs: Number thc relerences in the order in which they appear in thc texl and quotc their corresponding lllllll­bers in the text. Authors are responsible for thc aceuracy or their rcferences. Rclercnces to thc Abstracts and Letters to the Editor must be identilicd as such. Cilalion of papers in preparation. or submitted for publication. unpublished ob­servalions. and personal comnrnnicalions should not be in­cluded in the rcfcrcnce list. lf essential. sueh material 1nay be incorporated in lhe appropriate place in lhe text. The style or relerences is that of lndcx Medicus. Ali aulhors should be lisled whcn their number does 11ot exceed six: when therc are seve11 or more authors. the lirsl six listed are followed by "el al". The following are some examplcs of rcferences from articles. books and book chapters: 
Dent RAG, Cole P /11 vilro maluration of rnonoeytes in squamous carcinoma or thc lung. Br .! Cancer 198 l. 43: 486-95. 
Chapman S, Nakielny R. ;\ guide /o mdiologirnl f'/'/!Cl'­dure.1·. London: Bailliere Tindall. 1986. 
Evans R. Alexander P. Mcclianisms of exlraeellular kill­ing or nucleatcd mammalian cclls hy 1naerophages. In: Nel­son DS. ed. /111111111w/,io/ogy o( 11wcm1ihage. New York: Aeademic Prcss, 1976: ,+5-74. 
Page proofa will he raxed to lhe eorresponding aulhor whencver possiblc, It is their responsibilily to check the proofs carefully and fax a table or essential corrections to thc editorial orlice within 48 hours of rcceipt. If corrections are not reccived by the statcd deadline proof-reading will be carricd oul by the editors. 
For reJJrint i11/iimw1io11 in Norih Alllerica Con/acl: lll/er­

11a/io11a/ Hcpri1I1 Co1pmwi11n CJ081ld111iml Callaglhlll Lane, # 268 le O. Box 120/N. Val/ejo: C1\ 9./-590. 71'1.· (707) 553 9230. Fax: (707) 552 952./-. 

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