f· L -. RADIOLOGY • • . . 1 Vol. 29 No. 4 Ljubljana 1 SSN 1318-2099 U DC 616-00(1 CODEN:RONCEM PREPRECEVANJE Ena sama intravenska injekcija po 4mg pri uvajanju v anestezijo POOPERATIVNA SLABOST IN BRUHANJE NELAGODJE IN STISKA OGROŽATA USPEH OPERATIVNEGA POSEGA e ZDRAVLJENJE Ena sama intravenska injekcija po 4mg ondansetron G/axo Podrobnejše informacije dobite pri: Glaxo Export Limited Podružnica Ljubljana, Cesta v Mestni log 55, 61115 Ljubljana, p.p. 17, Slovenija Telefon: (38661) 1231070, 1232097 , 1232319 Telefax: (386 61) 123 25 97 RADIOLOGY AND ONCOLOGY Radiology and Oncology is a journal devoted to publication of original contributions in diagnostic and interventional radiology, computerized tomography, ultrasound, magnetic resonance, nuclear medicine, radiotherapy, clinical and experimental oncology, radiophysics and radiation protection. Editor in chief Tomaž Benulic Ljubljana, Slovenia Associate editors Gregor Serša Ljubljana, Slovenia Viljem Kovac Ljubljana, Slovenia Editorial board Bela Pomet Maja Osmak Budapest, Hungary Zagreb, Croatia Marija Auersperg Tullio Giraldi Branko Palcic Ljubljana, Slovenia Udine, ltaly Vancouver, Canada Matija Bistrovic Andrija Hebrang Jurica Papa Zagreb, Croatia Zagreb, Croatia Zagreb, Croatia Haris Boko fJurtla Horvat Dušan Pavcnik Zagreb, Croatia Zagreb, Croatia Ljubljana, Slovenia Nataša V. Budilma Laszlo Horvati, Stojan Plesnicar Ljubljana, Slovenia Pecs, Hungary Ljubljana, Slovenia Malte Clausen Berta Jereb Ervin B. Podgoršak Kiel, Germany Ljubljana, Slovenia Montreal, Canada Christoph Clemm Vladimir Jevtic Jan C. Roos Miinchen, Germany Ljubljana, Slovenia Amsterdam, The Netherlands Mario Corsi H. Dieter Kogelnik Horst Sack Udine, Italy Salzburg, Austria Essen, Germany Christian Dittrich Ivan Lovasic Slavko Šimunic Vienna, Austria Rijeka, Croatia Zagreb, Croatia Ivan Drinkovic Marijan Lovrencic Lojze Šmid Zagreb, Croatia Zagreb, Croatia Ljubljana, Slovenia Gillian Duchesne Luka Milas Andrea V eronesi London, Great Britain Houston, USA Gorizia, ltaly Publishers Slovenim, Medica[ Society -Section of Radiology, Croatian Medica[ Association -Croatian Society of Radiology Affiliated with Societas Radiologorum Hungarorum Friuli-Venezia Giulia regional groups of S.l.R.M. (Italian Society of Medica! Radiology) Correspondence address Radiology and Oncology Institute of Oncology Vrazav trg 4 61000 Ljubljana Slovenia Phone: + 386 61 1320 068 Fax: +38661 1314 18 0 Reader far English Olga Shrestha pesign Monika Fink-Serša Key words und UDC Eva Klemencic Secretaries Milica Harisch Betka Savski Printed by Tiskarna Tone Tomšic, Ljubljana, Slovenia Published quarterly Bank account number 5010167 848454 Foreign currency account number 50100-620-133-27620-5130/6 Nova Ljubljanska banka d.d. -Ljubljana Subscription fee far institutions 100 USD, individuals 50 USD. Single issue far institutions 30 USD, individuals 20 USD. According to the opinion of the Government of the Republic of Slovenia, Pub/je Relation and Media Office, the journal RADIOLOGY AND ONCOLOGY is a publication of informative value, and as such subject to taxation by 5 % sales tax. lndexed and abstracted by BIOMEDICINA SLOVENICA CHEMICAL ABSTRACTS EXCERPTA MEDICA!ELECTRONIC PUBLISHING DIV/SION · CONTENTS DIAGNOSTIC AND INTERVENTIONAL RADIOLOGY Albuminuria after selective renal angiography: Influence of contrast media Lugonja M, Marolti M, Lovrencic M 267 Imaging modalities in diagnosis of cystic neoplasms of pancreas: Review of the literature and a case report of pancreatic cystadenoma Brnic Z, Brkljacic B, Drinkovic I, Januš D, Dolencic P, Hebrang A 272 ULTRASOUND Interventional, diagnostic and therapeutic use of chest ultrasonography Mažuranic I, Ivanovi-Herceg Z, Gorecan M, Petrak A, Pongrac I 279 Percutaneous transhepatic biliary drainage under ultrasonic guidance in the therapy of cholangitis due to biliary malignant obstruction Rustemovic N, Opacic M, Pulanic R, Vucelic B, Korac B, Frkovic M 283 Ultrasonic preoperative staging of rectal cancer lvaniš N, Glavaš R, Mozetic V, Šustic A, Uravic M, Peric R, Banic D, Vcev A, Fuckar Ž 286 Ultrasonography in the staging of urinary bladder tumors Radovic N 291 NUCLEAR MEDICINE Normal data base for quantitative salivary gland scintigraphy Bohuslavizki KH, Brenner W, Tinnemeyer S, Wolf H, Sippel C, Tonshoff G, Karde P, Stauch C, Clausen M, Henze E 297 Bone scintigraphy as a diagnostic tool in chronic inflammation of paranasal sinuses Cvetnic V, Kovacic K, Munitic A 306 ONCOLOGY Prognostic factors in breast cancer Cufer T 311 Clinical features as a predictor of Iaparotomy findings in supradiaphragmatic stage I and II Hodgkin's disease Vovk M, Šumi-Križnik T, Jenko-Fidler M, Petric-Grabnar G, Kremžar M, Novak J, Sencar M, Zakotnik B, Vodnik-Cerar A, Jakši(; B 318 Conservative surgery and irradiation in early lung cancer: Local control and survival Khartchenko VP, Kouzmine IV 326 Standardized immunohistochemistry of estrogen receptors in human breast carcinoma in routinely processed tissue Golouh R, Kljun A 330 REPORTS Sixth World Congress of the International Society for Diseases of the Esophagus Benulic T 338 News of the EAR Blery M 342 NOTICES 344 AUTHOR INDEX and SUBJECT INDEX, 1995 346 The publication of the journal is subsidized by the Ministry of Science and Technology of the Republic Slovenia. Fundacija doc. dr. J. Cholewa, Ljubljana; Inštitut za diagnosticno in intervencijsko radiologijo, KC Ljubljana; Klinika za otorinolaringologijo in maksilofacialno kirurgijo, KC Ljubljana; Klinicki zavod za dijagnosticku i interventnu radiologiju, KBC Rebro, Zagreb; Onkološki inštitut, Ljubljana Radio! Oncol 1995; 29: 267-71. Albuminuria after selective renal angiography: influence of contrast media Miljenko Lugonja, 1 Miljenko Marotti,2 Marijan Lovrencic2 1 2 RMC "Dr. Safet Mujic" Mostar, Zavod za radiologiju, University Hospital "Sestre Milosrdnice", Department of Diagnostic and Interventional Radiology, Zagreb, Croatia The purpose of the stucly was to evaluate the influence of various urotropic contrast meclia on albuminuria after selective rerzal angiography. We testecl ionic ancl non-ionic contrast meclia of low ancl high osmolarity. Influence of clifferent contrast meclia on albuminuria frequency, after selective renal angiography proceeclure, with various physical ancl chemical properties was evaluatecl. The contrast meclia were also testecl in vitro with 20 % sulphosalicilyc acicl to exclucle positive reaction on contrast meclia alone. The contrast meclia we testecl were: a.) ioxithalamat meglumin, b.) cliatrizoat meglumin, c.) iohexol ancl d.) meglumin ioxaglate. Presence of albuminuria was cleterminecl by precipitation methocl with 20 % sulphosalicyl acyd in urine samples afier 6, 12, 24 and 48 hours. Results were statisticaly evaluated by Fisher-Exact test. Albuminuria was often presen! after use of ionic contrast meclia with high osmolarity. Results of the in vitro stucly demonstrated that early positive urin reaction (6 and 12 hours) with sulphosalicil acyd is unspecific. Comparison of albuminuria frequency for two high-osmolal ionic contrast media (ioxithalamat meglumin, cliatrizoat meglumin) demonstratecl statisticaly significant difference (P>0.05) 48 hours after procechire. Comparison of albuminuria fi·equency between two low-osmolal contrast media (iohexol, meglumin ioxaglat) did not demonstrate statistical clifference. Comparison of albuminuria frequency between high-osmolal and low-osmolal contrast media demonstrated statisticaly significant difference in all time sequences stucliecl. Key worcls: renal artery -radiography; albuminuria Introduction Urotropic intravenous contrast media are wa­ter-soluble iodin preparations bound with ben- Correspondence to: Prof. dr. Miljenko Marotti, K.B. "Sestre Milosrdnice", Klinicki zavod za dijagnosticku i interventnu radiologiju, Vinogradska 29, 41000 Za­greb, Croatia. UDC 616.136.7-073.75:616.633.962.3 zen ring, and have renal excretion. 1 The phar­macology and chemistry of the water-soluble 23 contrast agents have been widely reviewed.• Previous contrast media have high osmolality and cause adverse reactions,4 while the recent ones demonstrate lower toxicity in animal expe­riment, 5 as well as better tolerance in everyday 6 use. The study published by Committee for contrast media at International Society of Ra­diology found that there were 4,73 % adverse Lugonja M et al. reactions after use of intravenous contrast me­dia in 302.083 patients. 7 Intravenous contrast agents possess toxicity because of hyperosmola­rity, 8 chemotoxicity3 and additives.9• 10 Nephro­toxicity is a well known fact, while intravenous urotropic contrast media are excreted by kid­ney. As 90 % of applicated dose is excreted by kidney it can result in various degree of kidney damage.11-14 The patients with diabetes, multi­ple myeloma, oliguria and advance stage of arteriosclerosis are in high risk group of deve­loping damage to renal function. Patients and methods We tested urine with 20 % sulphosalicilyc acid from forty patients (19 female and 21 male) with normal renal function who underwent se­lective renal angiography with Seldinger techni­que. The contrast media we tested were: a.) ioxithalamat meglumin, b.) diatrizoat meglu­min, c.) iohexol and d.) meglumin ioxalat. The contrast media were also tested in vitro with 20 % sulphosalicilyc acid to exclude posi­tive reaction on contrast media alone. The patients were divided in to four groups, according to contrast media used. Every group had ten patients. In each group we administrat­ed different intravenous contrast media. The patients with albuminuria, diabetic patients, patients with history of previous adverse reac­tions, patients with paraproteinemia, as well patients under eighteen years were exluded from the study. The tip of the chateter was placed in to the renal artery. The choice of contrast media which were included in the study was done by random scheme. Automatic injector with flow of 5 mll/sec. and total 0.05) 48 hours after proccedure. Comparison of albuminuria frequency bet­ ween two low-osmolal contrast media (iohexol, meglumin ioxalat) did not demonstrate statisti­ cal difference. Comparison of albuminuria fre­ quency between high-osmolal and low-osmolal contrast media demonstrated statisticaly signifi­ cant difference in ali tirne sequences studied in Figure 3. Discussion Difference of albuminuria frequency between high and low-osmolal contrast media in our results demonstrated statistic significance at 24 Albuminuria after selective renal angiography (/) 8 a: :J o J: 7 60 yrs. No further age dependent differences could be detected as far as uptake and EF is concerned, therefore, all patients were pooled. Uptake was 0.42±0.I6 %ID, and 0.36±0./3 %ID in parotid gland and submandibular gland, and EF of parotid gland and submandibular gland amounted to 47.4±1/.7% and 37.4±9.8%, respectively. In conclusion, a reliable normal data base for quantitative salivary gland scintigraphy is now available. Key words: salivary glands-radionuclide imaging; quantitative salivary gland scintigraphy; normal data base, uptake, excretion fraction Introduction Salivary gland scintigraphy has been an estab­lished method in clinical practice to investigate both parenchymatous and excretory function of parotid and of submandibular glands for almost 30 years. 1 --12 N umerous investigators established normal values for the excretion fraction13--19 in order to quantitatively describe impaired saliva Correspondencc to: Dr. Karl H. Bohuslavizki, Chri­stian-Albrechts-University of Kiel, Arnold-Heller-Str. 9, D-24105 Kicl, Gcrmany; Tel.: + 49431 597-3147, Fax.: + 49431 597-3150. flow due to obstruction. On the other hand, parenchymatous function is much more difficult to quantify. Therefore, various (semi)quantita­tive methods were described, i.e. scoring the 12• 20--23 shape of time-activity curves, time-to­ 25 maximum uptake,24• ratios of salivary gland uptake calculated either to background activi­ 18 26 28 ty, • to serum activity27 • or to the uptake of the thyroid glanct,20 slope of the time-activity 2529 25 curves, • or calculation of rate constants.None of these methods gained relevance in routine salivary gland scintigraphy today possi­bly due to their sophisticated nature. However, there are reports of a simple clini­ UDC 616.316:539.163 cally feasable method in analogy to thyroid Bohuslavizki KH et al. quantitative scintigraphy. Tracer uptake as a measure for parenchymatous function is expres­sed in percent of the injected dose.13-17• 3o-33 Unfortunately, neither inclusion nor exclusion criteria for patient selection are given in these papers. Moreover, their number of patients is rather limited. Therefore, the purpose of this study was to quantitatively establish a normal data base re­garding both uptake and excretion fraction in quantitative salivary gland scintigraphy in per­cent of injected dose form a large number of carefully selected normal patients. Parts of the results have been presented orally. 34 Materials and rnethods Patients Prior to routine thyroid imaging, 485 patients underwent salivary gland scintigraphy. Infor­med written consent was obtained from ali subjects. To rule out any influence on salivary gland function, patients were excluded for seve­ra! reasons: xerostomia (n = 45), sialolithiasis (n = 78), history of either radioiodine therapy (n = 32), external radiation of the head/neck (n = 4), salivary gland tumour (n = 5), acute or chronic inflammation (n = 16), rheumatic disease (n = 58), perchlorate medication (n = 7), neuroleptic or antidepressant drugs with anticholinergic effects (n = 21), either so­nographic (n = 46) or radiographic (n = 23) signs of obstruction or parenchymatous impair­ment. The accepted 166 patients were conside­red normal of which 39 were male, and 127 were female ranging from 18 to 81 years. Pa­tients were divided into three age subsets. Pa­tient characteristics are shown in Table 1. Table l. Patient eharactcristics. Group range age mean ± SD n f/m I 18-40 31.5±6.4 28 21/7 II 41-60 51.9±5.2 69 52/17 III 61-81 69.4±4.8 69 54/15 Tota! 18-81 55.8±14.5 166 127/39 Salivary gland scintigraphy After intravenous injection of 53.9±10.5 MBq Tc-99m-pertechnetate, ranging from 31.0 to 83.8 MBq sequential images of 1 min each were acquired for 25 min with a conventional large field-of-view gamma camera (Searle Pho/Gam­ma, Nuclear Chicago Division, Chicago, USA) with a parallel hole LEAP collimator in anterior position as close as possible to the patients head, which was slightly reclined. Images were stored in a 128 x 128 matrix. Excretion of saliva was caused by 3 ml of diluted lemon juice given perorally 15 min p.i. from the patients left side. Five regions of interest (ROI) were used (Figure 1): one rectangular ROI in the brain, which served as backround ROI, and four irre­gular ROis over the respective parotid and submandibular salivary glands. In each patient uptake of parotid and submandibular glands was calculated in percent of the dose injected (%ID), using a calibration factor between gamma camera ( counts per minute) and activi­meter (MBq). For compensation of noise and, thus for stabilization of data, uptake was calcu­lated as mean of uptake from 12-14 min after Figure l. Illustration of the ROI technique used for quantitative salivary gland scintigraphy. Observe, four irregular salivary gland ROis and a single, common rectangular background ROi over the brain. Salivary gland scintigraphy subtraction of background activity from a ROi in the brain, and excretion fraction (EF) was calculated from mean activity at 17-19 min p.i., and was expressed as percent of the uptake measured. From both uptake and EF 50 and Lilliefors modification of the Kolmogoroff-Smirnoff test for n < 50.35 In ali subsets normal distribution could be shown, consequently, results are given as mean ± one standard deviation. Two-tailed unpaired stu­dents t-test was used to evaluate statistical differences between subsets, with p < 0.05 considered to be statistical significant. Results Uptake There was no sex difference in tracer uptake. Therefore, ali patients were pooled. Original data of Tc-99m-pertechnetate uptake in major salivary glands is shown in Figure 2. After pooling data of ali patients uptake was about 0.42 %ID and 0.36 %ID in parotid and subman­dibular glands, respectively. Visually, uptake seemed to be somewhat higher in elderly peo­ple. Therefore, uptake was calculated separa­tely for three subsets as given in Table 2, and uptake data was tested for statistical significant differences. In fact, a significant difference in Right Parotid Gland 1.5 Left Parotid Gland BI.O BI.O . ... . .. . "'• .. . • •• i o f//lJIJ:» ••• • ... i •. . . •• :•_,,,.!. .. • , . - • C\,I • . • :. ,_,.;ia.'\: : • . . ::O 0,5 .. ::o 0.5 • . 8 .. ...... . "I. - .q, • ... • o • .. . . ... 0.0-1-----.--.--.---.------, lO 30 50 70 90 10 30 o.o+-------.-.---.,.....-,...-.-----. 90 Age [years] Age [years] 1.5 L5 Right Submandibular Gland Left Submandibular Gland I.O BI.O B . . . . i .,,,,. • &g' .. •9.. . . ::o 0.5 ::O 0.5 • e • • • _,.a •• : ••4-.... .,. .... ,e.; .'\._ . •II">• •• lifi. • .. • o . • _. •o • 111-..I 0 --•• • • 0 0 • ••,i1 o--:-0 • , • o ··"""· • ·= 0.0-1-----.-----.-----.------, o.o+-----.-.---...-----.-----. 30 50 70 50 70 90 10 Age [years] Age [years] Figure 2. Original 60 yrs. as compared to younger patients in age less than 60yrs. (II vs. III). Patients being younger than 40yrs. showed less pertechnetate uptake than patients aged > 60 yrs. (I vs. III) detected between subsets I and II, their uptake values being almost identical. Excretion fraction Original data of excretion fraction in major salivary glands is shown in Figure 3. No diffe­rences could be detected between subsets as . indicated by EF data given in Table 3. EF was about 47 % in parotid glands, and 37 % in submandibular glands when pooling ali data. Left-to-right ratio Detailed data of LIR ratios of uptake and EF as calculated for the subsets and for ali patients pooled is given in Table 4. In ali subsets the marginally higher uptake in the right parotid glands was statistically insignificant. In contrast, LIR ratios of almost exact one were determined for the uptake in submandibular glands. As far as well, but no significant differences could be as EF is concerned, LIR of parotid and subman­ 901 90 Right Parotid Gland Left Parotid Gland . .. . . . . . .. •. .. o .. . . . . . . . . -·.· .. . 60 . . . . . . •• • -. . •· -..; . -,c: .• • . "It . . . . .-. . .. r-:­ . . . . -.'-, ,,, _ . . .• ... •.a.-•·;. ·.·. : ..,,. ....... j . . . . ....·• .. .... :. . .,. ,, • • •. ... ,. ... .. · cA.·, lle,:8 • ··• • ·· • fu 0 • • •• • • ... • . • 1 fu • • • ••:• a • •• ­ • •• • • -, • IS. • . \· . • . . • • s • • o 30 •• • •• 1 • : • • •• • 30 . • • • j i o+-.-.--.--.---..-.--.-----. JO 30 50 70 90 JO 30 50 70 90 Age [years] Age [years] 901 90 Left Submandibular Gland Right Submandibular Gland .. • •• .. ., • 60 • . •. • .a:.,;-;. .... •a• •• •11:, .. ,_ .:S::• -. • '4• ·-­ • , . . . ... . . ., .. _ . . • .. :. :-· 11: ....• . •• • . • . ,:, j . . fu 30 30 • • . . • ·­ ·1:·• • • ... • ·· · • : •• '9•·· . .• . • • C • •t'. r. •'l.o . • o . . ,C .. 1 • . . 50 70 90 o 10 50 70 lO Age [years] Age [years] Figure 3. Original data of excretion fraction of major salivary glands expressed in percent as refcrrcd to the uptake. Pooled data of 166 patients. Salivary gland scintigraphy Table 3. Normal valucs of cxcrction fraction cxprcssccl in pcrccnt as rcfcrrccl to thc uptakc in salivary glancls. Data is givcn both for subscts ancl for ali paticnts poolccl (total). I: l8-40 yrs, II: 41-60 yrs, III: 6l-81 yrs. ExcrctiClfl_fraction [%] Group RPG LPG RSG LSG I 44.2±11.0 46.2± l2.0 34.3± 9.7 35.3±l0.3 II 45.6±10.3 47.1±10.0 36.9± 8.9 38.4± 9.1 III 46.9±12.7 51.5±12.6 36.9±10.1 39.2±10.4 Tota! 46.0±11.5 48.8±11.7 36.5± 9.6 38.3± 9.9 RPG, LPG: right, lcft paroticl glancl. RSG, LSG: right, lcft submanclibular glancl. dibular glands was found to be above 1 in ali subsets with a tendency to somewhat higher values both in elderly people and in parotid glands, i.e. LIR of EF was calculated as 1.15 in parotid glands of patients aged > 60 yrs., while LIR of EF in submandibular glands in patients less than 40 yrs. was about 1.04. Howe­ o.3 Right Paroticl Glancl Table 4. Lcft-to-right ratios (LIR) both of uptakc ancl of cxcrction fraction givcn scparatcly for paroticl glancl (PG) ancl submanclibular glancl (SG). Data is givcn both for subscts ancl for ali paticnts poolccl ( total). I: 18-40 yrs, II: 41-60 yrs, III: 61-81 yrs. Uptakc Excrction fraction Group LIR PG LIR SG LIR PG LIR SG I 0.95±0.12 1.01±0.13 1.06±0.21 1.04±0.18 II 0.96±0.15 1.00±0.16 1.06±0.23 1.06±0.18 III 0.94±0.14 1.00±0.16 1.15±0.38 1.10±0.29 Tota! 0.95±0.14 1.00±0.15 1.10±0.30 1.07±0.23 ver, statistical differences of EF in right and left parotid gland could be shown for EF in subgroup III (61-81 yrs.) only. In subgroup II (41-60 yrs.) we just failed to show a difference with p = 0.053. In no other subgroup statistical differences between right and left glands could be shown concerning EF. Time-activity-curves Time activity curves of major salivary glands 0.8 Left Parotid Gland 5' i ::, 1 JI 1 1 1 l I l 1 111 l l !!I ll l 111 8 1 o.o I I , , , , , O.O O 5 10 15 20 25 O 5 lO 15 20 25 Time [min] Time [min] o.31 0.8 Right Submanclibular Glancl Left Submandibular Gland 5' 5' . 0.6 . 0.6 ! ::. ! 1 I ! i 11 l ! l l l l l l ! l l l l l l l ll o.oT"'......,-----.----...... --....... -----, o.o-i--.-.-,----.----...... --......,----, O 5 10 15 20 25 O 5 10 15 20 Time [min] Time [min] Figure 4. Time-activity-curves of Tc-99m-pertechnetate uptake of major salivary glancls. Mean ± one standard deviation of 166 patients. 302 Bohuslavizki KH et al. showing mean ± one standard deviation of ali patients pooled are shown in Figure 4. Discussion Methodology Basically, there are two methods to obtain normal values, i.e. the inductive and the deduc­tive way.36 When determining normal values in an inductive way, healthy normal subjects have to be selected for investigation out of the whole population. Both for ethical reasons and for reasons of radiation protection radioactive sub­stances must not be injected in healthy subjects without thorough clinical indication. Therefore, in this study normal values were obtained in a deductive way. In patients who were referred for thyroid imaging salivary gland scintigraphy was performed prior to thyroid scintigraphy. However, ali patients who were suspected to have impaired salivary gland function had to be excluded from statistical evaluation. This was done for following reasons: xerosto­ 12 22 31 37 4 11, 18 37 mia,2· 9. , 20, , , sialolithiasis,, , hi­ story of either radioiodine therapy, 3 external radiation of head/neck, 10 salivary gland tu­4 5• 811• 38 mour , · · acute or chronic inflamma­ 29 12 tion,7· 13 rheumatic disease,· · perchlorate medication, 1· 37 either neuroleptic or antidepres­sant drugs with anticholinergic effects,37· 39--41 eit­her sonographic or radiographic signs of obs­ 4 8· 1823 truction· · or parenchymatous impair­ment. 2· 8· 9· 12 Therefore, quantitative values ob­tained in this study reflect salivary gland func­tion of normals, and thus, can be ascribed to be a reliable normal data base. The background ROi was positioned close to the salivary glands by others.16· 31 The advan­tage might be a more accurate estimation of the trne background activity. However, this ROi technique is rather difficult to standardize during routine patient management. For simpli­city, we selected a single, common background ROi for ali four salivary glands (see Figure 1). In patients with complete destruction of paren­chymatous salivary gland function the uptake values amounted to approximately zero, as shown elsewhere.42 Thus, this ROi located in the brain seems to be appropriate for back­ground estimation of the salivary glands. Excretion of saliva can be stimulated by the application of severa! drugs, e.g. subcutaneous injection of carbamoylchloride, 18· 25 or by pero­ral application of either tartraic acid, 12 pilocar­ 14 ts pin as a parasympathomimetic drug· or even by sugar.38 However, for patient's convenience and due to both its Jack of undesired side effects and its equal efficacy as compared to parasympathomimetics we chose diluted lemon 29 juice to increase excretion of saliva. LIR ratio of pertechnetate uptake in parotid and submandibular glands was calculated as of approximately one, whereas LIR ratio of EF was systematically above 1. This was more pronounced in elderly people as given in table 4. In case of sufficient patient selection a LIR ratio near unity is expected, however, LIR ratios of up to 2.5 were observed by others. 16 In our study, lemon juice was given by the technologist from the patient's left side. Patients were told to turn the lemon juice around in the oral cavity in order to reach a homogenous excretion in ali four major salivary glands. However, this obviously depends on patient's compliance. Therefore, this artifact, observed especially in elderly people, should be kept in mind in routine salivary gland scintigraphy. Normal data base Quantitative measurement of parenchymatous function has been performed in various way, e.g. calculation of time-to-maximum up­take,24 · 25 ratios of salivary gland uptake calcu­lated either to background activity, t3, 26 to se­rum activity27 · 28 or to the uptake of the thyroid gland,20 obtaining the slope of the time-activity 2529 25 curves, · or calculation of rate constants.None of these methods is easy to handle, and in consequence none of them has become a relevant method in routine salivary gland scin­tigraphy today. Therefore, salivary gland scinti­graphy in work-up of patients suffering from impaired parenchymatous function, e.g. Sjo­gren's syndrome is performed usually in a qua­litative manner. However, a reliable quantita­ Salivary gland scintigraphy tive measure of parenchymatous function would be helpful for the clinician especially when impairment is just beginning. In addition, this measure should be easy to handle. In analogy to well established state-of-the-art quantitative thyroid scintigraphy43• 45 some authors reported on quantitative salivary gland scintigraphy cal­culating the uptake of pertechnetate expressed in percent of the injected dose. Details of their data are given in Table 5. However, none of them reported in detail on their criteria of patient selection. This could be the reason for varying uptake values ranging from 0.30 % ID16 up to 0.83 %ID.14• 15 Most authors evaluated somewhat higher uptake values than calculated in this study. However, in these studies 13-15, 17• 32 salivary gland scintigraphy was performed in an one hour protocol, thus, uptake was calcula­ted between 40 and 50 min post injection. It is known that uptake in salivary glands depends on the interval from injection to calculation. Therefore, their data is not quite comparable to the uptake values obtained in this study. In two studies a 30 min protocol was used, and uptake was calculated at 13 min post injection yielding uptake values of 0.30 %ID16 and 0.31 %ID31 for parotid glands and 0.17 %ID and 0.18 % ID for submandibular glands, re­spectively. These data were based on 36 and 25 patients, and no detail can be found whether their scatter data indicate standard error or ­most probably -standard error of mean. In our study at 13 min post injection uptake values of 0.42 % ID and 0.36 %ID were obtained for parotid and submandibular gland, respectively, basing on data of 166 clearly defined normals. Scatter of uptake data varied in the literature from 0.10 % ID up to 0.45 %ID with numbers of patients ranging from 8 to 45 as given in table 5. Nevertheless, after reducing systematic scatter by well defined selection of patients reliable uptake data with reduced standard de­viation can be obtained by an increased number of patients only. 35 Scatter data of pertechnetate uptake expressed as one standard deviation in our study based on 166 normals and amounted to 0.16 %ID and 0.13 %ID for parotid and submandibular glands, respectively. As could be expected, standard deviation of our data is less than observed from other authors. l4-l7, 30-32 The value of this reduced standard deviation of our normal data base has already been praven by the detection of mild parenchymatous im­pairment in early Sjogren's syndrome.42 Many authors reported normal values for the exctretion fraction. EF is an established mea­sure of functional obstruction of the salivary gland ducts, which can be used conveniently in daily clinical nuclear medicine_ 13-t9 Therefore, even lithothriptic treatment of lithiasis can be Table S. Quantitative salivary gland seintigraphy, as reported in the literature. Data represent mean of left and right gland expressed as mean ± one SD. min: tirne after injection of measurement of tracer uptake given in minutes. Parotid glands Submandibular glands Reference n Uptake [%ID] EF[%] Uptake [%ID] EF[%] min [13]* n.g. 0.70±0.10 =50 n.g. n.g. 50 [15] 11 0.83±0.40 =20* n.g. n.g. [16] 36 0.30±0.02§ 0.17±0. 01§ =8* [17] 0.56±0.29 81.7±15.9 0.36±0. 15 75.0±19.5 (30] 8 0.35±0.11§ 0.34±0.1§ n.g. n.g. [31] 25 0.31±0.02. n.g. 0.18±0.02. n.g. 13 [32] 9 0.75±0.45* n.g. n.g. n.g. 40 [33] 44 0.40±0.15* 0.38±0.10* =50* own 0.1 No.of Ig! areas involved 1 36 20 15 1 23 11 o 32 Trend 19 16 3 o 16 1.521 1 0.2175 ?4 6 4 2 o 30 No.of Ig\ areas involved 1 44 1 36 20 ?2 16 o 27 2.2789 1 >0.1 * Histologically unelassified (5/95) are not included. CS = elinical stage, PS = pathologica\ stage, LP/ND = Lymphocyte predominant and Nodular selerosis, MC/ LD = Mixed cellularity and Lymphocyte depleted CS I but not in CS II. 6 The lowest percentages I and LP histological type: O% ,7 5 %5 and of positive SLs were found in patients with CS 16%.6 Clinical features of Hodgkin's disease Table 3. Hodgkin's disease clinical stage 1-II (n = 95): Laparotomy findings by laboratory rcsults. Clinical fcatures CS 1-II No. Postlaparotomy stage PS 1-II PS III PS IV No. No. No. Stage change % Chi2 df p SR 0-15 29 20 8 1 28 9 6 o 27 Trend 31-50 21 18 3 o 51-70 15 lO 5 o 0.747 1 0.3873 ?70 15 6 9 o 60 Hb 0.1 SR: mm/hr; range 2-132; X = 38.5; Median = 33; SD = 29.3 135; Median = 132; SD = 16.5 Copper (in 89/95 pts): µ,mol/!; normal 11-26.7; range 10-48; X 27.9, Median= 26.8; SD Albumins (in 90/95 pts): g/1; normal 35; range 21-58; X = 35.8; Median = 36; SD = 6.4 CS = clinical stagc, PS = pathological stagc Table 4. Hodgkin's diseasc clinical stage I (n = 36): Laparotomy findings by site. Site CS I No. Stage ehange No. % Chi2 df p Neek L R 12 13 6112 4/13 50 31 0.3272 1 >0.1 Axilla L R 1 2 1/1 1/2 100 50 Neck or L 7/13 54 0.5056 1 >0.1 axilla R 15 5/15 33 yes 8 2/8 25 Mediastinum 0.2526 1 >0.1 no 28 12/28 43 Neek R+L 25 10/25 40 Axilla R+L 3 2/3 67 1.634 2 >0.1 Mediastinum 8 2/8 25 Compared to patients with CS I, in those the number of regions involved. Other authors6 with CS II subdiaphragmatic disease is reported have not confirmed those findings, possibly due 58 to be significantly more frequent;4 • • more-to the fact that only patients with less that three over, the rate of positive SLs is increasing by involved regions were included into the study. Vovk Metal. Table S. Hodgkin's disease clinieal stage II (n = 59): Laparotomy findings by site. CS II Site No. II, Stage change No. % Chi2 df p Neck bilat. 2 1/2 50 Neck unilat. + mediastinum 26 Neck bilat. + 8/26 31 0.0037 1 >0.1 mediastinum 9 2/9 22 no 14 Mediastinum yes 45 4/14 29 12/45 27 0.0417 1 >0.l bulky 11 Mediastinum not bulky 29 size undefined 8 1/11 9 8/26 31 3/8 37 2.442 2 >0.1 CS = clinical stage Table 6. Hodgkin's disease clinical stage I-II (n = 95): pos1tive SL (Tab le 2) than those w ith CS Predicted risk of positive laparotomy, based on sex* though the differ ence is insi gnifican t. The rea­ and age*. son may be in o ur definition of supradiaphrag­ Stage change Age Sex Observed Predicted yrs No. %% Males: .20 2/6 33 28 21-39 11/27 41 matic lymph node areas (see Patients and Met­hods). Opinions on the influence of B-symptoms on SL outcome are also controversial. We -as well as some other authors,5 could not prove a 40-59 10/16 63 62 significantly higher percentage of positive SL in ?,60 2/2 100 77 patients with B-symptoms while others did.4• 7• 8• 10 We also did not confirm the in­ Females: .20 14 8 fluence of sedimentation rate, serum hemoglo­ bin, copper and albumins on the outcome of 21-39 5/31 16 15 40-59 0/5 o 27 ?,60 1/1 100 43 SL (Table 3). Only one such study8 has been found in the available literature, which also * derived from logistic regression analysis. Table 7. Hodgkin's disease clinical stae I-II (n 95): Predicted risk of positive laparotomy, based on sex* and age.* Stage change Risk Risk factor Observed Predicted degree No. %% High male + ?,40 yrs 12/18 67 62-77 (69.5) male + <40 yrs 13/33 28-44 (36) Medium or 36 female + ?,40 yrs 1/6 27-43 (35) Low female + <40 yrs 6/38 16 8-15 (11.5) * derived from logistic regression analysis · Our results also fail to confirm the above cited failed to prove any influence of sedimentation findings; on the contrary, we have found that rate, serum copper and LDH values on the patients with CS I have higher percentage of outcome of SL. Clinical features of Hodgkin's disease The results of some investigations4-6 reveal an interesting observation that none of the patients with a single localization of HD in the mediastinum (CS I) had positive SL (in one of the previously mentioned studies4 this applies only to females). Therefore, in Stanford (U.S.A.) SL has not been performed in such patients since 1973. Ours (Table 4) as well as the findings of other investigators8• 10• 11 support this observation since the percentage of positive SLs was lower in patients with a single media­stinal HD site than in those without mediastinal involvement, though in our case the difference was not statistically significant. In patients with CS I the side of localization, i.e. either left of right, did not influence the outcome of SL (Table 4) which is in accordance with the results of other studies.4-6 We did not evaluate the influence of the size and localization of cervical lymph nodes on the outcome of SL since these data were not available. The results of some studies6-8 lead to an interesting conclusion that patients with CS I and lymph node involvement above the hyoid cartilage have statistically sig­nificantly less positive SLs than those with localizations under the hyoid cartilage, and that patients with lymph nodes >5 cm in diameter have subdiaphragmatic disease more frequently than those with smaller lymph nodes;6 the latter observation, however, has not been confirmed by other authors. 8 In patients with CS II the situation is diffe­rent. As evident from our study (Table 5) and those of others,6 the outcome of SL is neither influenced by the size of lymph nodes6• 8 nor by the presence or absence of HD in the mediastinum. By LRA, sex and age were the only indepen­dent significant predictors of positive laparo­tomy in our CS I-II patients. On the basis of these factors the predicted risk estimates for positive SL are shown (Tables 6 and 7). The higher risk in males is particularly evident in those exceeding 40 years of age, with a pre­dicted chance of positive laparotomy of 69.5 % . At the other end of the spectrum, females under 40 years of age have a predicted risk of 11.5%. To our knowledge, there are only four stu­dies4-6 , 8 where the predictors of positive Iaparo­tomy have been analysed by means of multiva­riate analysis. On the basis of these factors some authors predicted risk estimates for posi­tive SL. Summarising ours and the above four studies, we can draw the following two conclusions: 1) Clinical features predicting a Iow risk of positive SL in CS I are as follows: female sex, and irrespective of sex: mediastinal site, non­bulky upper neck nodes, and LP histological type. 2) Clinical features associated with a high risk of positive SL in CS I-II are as follows: male sex ( confirmed by all studies), age ( the evidence for that is controversial: <20 years,6 >27 years,5 ;c,40 yearsour reSults), a greater num­ber of involved regions (inconsistent evidence: 4 2 or more,3 or more,8 4 or more5), mixed cellularity and lymphocite depleted histological type,8 and B-symptoms.4• 8 Conclusion Our study and the review of existing literature were aimed to identify the patients who do not require SL, i.e. those in whom the selection of treatment metod can be based solely on the evaluation of risk of abdominal HD involve­ment. Patients with low risk would require radiotherapy alone, and high-risk patients che­motherapy. The objective to de fine high-and low-risk patients on the basis of clinical features has been only partly realized. The above findings have shown that the de­finitions of risk groups are unreliable due to incomplete agreement between different stu­dies, which could be attributed to the following reasons: 1) Most of the studies were done on a small number of patients. 2) In some studies, CS I and CS II were analysed separately, which is correct, while in others CS I-II were pooled together owing to the small number of patients in a particular center. Vovk M et al. 3) The clinical features analysed were not always the same. Nevertheless, the most reliably definable is the group of patients at a low risk of positive SL. A prospective multicentric study on a larger number of patients would be required to allow more rigorous statistical analysis, which howe­ver seems hardly feasible as SL has been mostly abandoned nowadays. References l. Lukes RJ, Oraver LF, Hall TC, et al. Report of the Nomenklature Commitee, Cancer Res 1966; 26: 1311--6. 2. Lister TA, Crowther D, Sutcliffe SB, et al. Report of a Committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. J Ciin Oncol 1989; 7: 1630--6. 3. Dixon WJ, Brown MB, Engelman L, Jennrich RI, eds. BMDP statistical software manual. Vol 1, 2. Berkeley: University of California Press, 1990. 4. Mauch P, Larson D, Osteen R, et al. Prognostic factors for positive surgical staging in patients with Hodgkin's disease. J Clin Oncol 1990; S: 257--65. 5. Leibenhaut MH, Hoppe RT, Efron B, Halpern J, Nelsen T, Rosenberg SA. Prognostie indicators of Iaparotomy findings in clinical stage 1-11 supra­ diaphragmatic Hodgkin's disease. J Clin Oncol 1989; 7: 81-9. 6. Brada M, Easton DF, Horowtch A, Peckham MJ. Clinical presentation as a predictor of Iaparotomy findings in supradiaphragmatie stage I and II Hod­gkin's disease. Radiother Oncol 1986; 5: 13-22. 7. Hagemeister FB, Vlasak M, Fuller LM, et al. Factors predicting abdominal disease in patients with Hodgkin's disease following negative lym­phangiograpy, Proc Am Soc Ciin Oncol 1983; 2: 214. 8. Aragon de la Cruz G, Cardenes H, Otero J, et al. lndividual risk of abdominal disease in patients with stages I and II supradiaphragmatic Hodgkin's disease: A rule index based on 341 Iaparotomized patients. Cancer 1989; 63: 1799-803. 9. Kaplan HS, Dorfman RF, Nelsen TS, Rosenberg SA. Staging Iaparotomy and splenectomy in Hod­gkin's disease: analysis of indications and patterns of involvement in 285 cosecutive unselected pa­tients. Natl Cancer lnst Monogr 1973; 36: 291-301. 10. Vlasak MC, Martin RG, Fuller LM, Hagemeister FB, Da Cunha MF, Shullenberger CC. Clinical staging of Hodgkin 's disease: results of staging laparotomy. Cancer Bull 1983; 35: 209-17. 11. Castellino RA, Hoppe RT, Blank N, et al. Com­puted tomography, lymphography, and staging laparotomy: correlations in initial staging of Hodg­kin's disease. Am J Radio! 1984; 143: 37-41. Radio! Oncol 1995; 29: 325-9. Conservative surgery and irradiation in early lung cancer: Local control and survival Vladimir P. Khartchenko and Igor V. Kouzmine Department of Thoracic Surgery, Moscow Research Institute of Diagnosis and Surgery, Russia 1041 patients underwent complete resection far peripheral lung cancer prior to 1990. In 230 (22 %) cases tumor was less or equal to 30 mm and metastases were absent (pTIN0M0). Tumorectomy was carried out in 7 cases, wedge resection in 57, segmentectomy in 40, standard curative operations in 126. In 5 cases microinvasion at the specimen margin or malignant complexes in lymphatic (blood) vessels oj adjoining lung structures was detected. In 63 cases (from 1983) prospective randomization was used. Preoperative (59 patients) and postoperative (123) radiation therapy completed according to 4 protocols. After tumorectomy 5-year survival was 60,0 %, after wedge resection -69,1 %, after segmentectomy -72,5 % (p>0.05). Local relapse after lung-preserving resections were proved in 7, 7 % patients and correlated with type oj operation and regimen of radiation therapy. Key words: Jung neoplasms-surgery; radiotherapy; survival rate Introduction Radiation therapy was added to organ-preser­ving operations in order to reduce the risk of local recurrences. In Jung oncology this adju­vant method is not desirable for it compensates the curability but disturbs the Jung function. So the profit of lobe conservation becomes du­bious. However, the advantage of Jung irradia­tion has been proven in some institutions. Sup­pression of occult regional metastases and crea­tion of unfavorable conditions for malignant Corrcspondencc to: Prof. Vladimir P. Khartchenko, M. D., Department of Thoracic Surgery, Moscow Research Institute of Diagnosis and Surgery, 117837, GSP7, Profsojuznaya str. 86, Moscow, Russia. Fax: + (095) 334 79 24. Enail: dircctor@ mniidih. msk. su. UDC: 616.24-006.6-08-036 elements growth in adjoining structures had been shown in the course of experience. In the year 1982 we retrospectively studied the results of occasional conservative resections with postoperative irradiation and found that combined treatment provides the best survival.1 Material and methods Pilot study of lung-preserving resection and radiation therapy began in 1980. 1041 patients underwent complete resection for peripheral Jung cancer prior to 1990. In 230 (22 % ) cases tumor was less or equal to 30 mm and meta­stases were absent (pTlN0M0). Before the year 1980 no more than one organ-preserving resection had been expe­rienced annually. In the years 1986-1988 the treatment in association with irradiation was Khartchenko VP and Kouzmine IV Conservative surgery vs lobectomy resection, in 1 (14,2 % ) case of tumorectomy and in 1 (2,5 % ) case of segmentectomy. Ali patients survived conservative resections. Fol­ 26 20 16 10 6 1980 1981 1982 1983 1984 1986 1986 1987 1988 1989 1990 Year Figure l. Annual numbcr of conservative ancl raclical rcsections of TI NO Jung canccr. executed on more than 20 patients in a year (Figure 1). Diagnosis of primitive lung lesion was verified histologically. Tumor localization and other prognostic factors were essentially similar. Wedge resection was carried out with staplers that applied on the lung tissue at distance more than 2 cm from tumor margin. Segmentectomy technique with original automatic suture was presented elsewhere.2 Following surgery 98 pa­tients were observed more than 3 years, 71-5 years and 11-ten years after treatment. Survival was according Kaplan-Meier and Fisher met­hods with the use of computerized data base (FoxPro). Tumorectomy was carried out in 7 cases, wedge resection in 57, segmentectomy in 40, lobectomy or pneumonectomy in 126. In 63 cases (from the year 1983) prospective randomi­zation was used. Conservative surgery seemed to be curative but after careful histologic inspection of the resected tissues in 5 cases microinvasion at the specimen margin or malignant complexes in lymphatic (blood) vessels of adjoining Jung structures was detected. Agressive tumor growth was found in 3 (5,25 % ) cases of wedge lowing lobectomy or pneumonectomy 4 (3,2 % ) patients died. Preoperative radiation therapy (PreRT) with betatrone 25 Me V or telecobaltherapy was com­pleted in 59 cases according to 3 protocols: TD = 40-45 Gy (2-2,5 Gy daily fractions); TD 36 Gy (3 Gy in 12 fractions); single dose 7,5 Gy with thoracotomy on the next day. The irradiated volume included hilus, bifurcation and paratracheal zone on the side of the lesion. Following multiple fractionation of PreRT Jung resection was practiced in 3-4 weeks at comple­tion of radia ti on therapy. Methods of treatment are given in Table l. Postoperative radiation therapy (PostRT) in 123 cases. In 18 cases PreRT (single dose 7,5 Gy) and PostRT (30 Gy in 3 Gy fractions) were utilized. Results Risk of surgical complications increased with excised Jung parenchyma volume. However, the lowest morbidity registered after segmentec­tomy -12 % . Following tumorectomies minor complications were seen in one patient (14 % ); the difference was not significant (p > 0.05). Following lob-, pneumonectomy complications were observed in 33 % of cases (p < 0.005). There were no lethal complications connected with conservative resections. Actuarial 5-year survival following conserva­tive surgery -73,1 % , lobectomy or pneumo­nectomy -63,4 % (p > 0.05; Figure 2). The rate in females was 82,1 % in male -71,6 % (after radical operations respectively 71.0 and Table l. Periphcral TlNO Jung cancer. Methocls of rcscction ancl irracliation. Racliation therapy Type of resection Tota] Tumorectomy Weclge resection 10 5 32 10 Segmentectomy 10 10 17 3 40 Lob-Pneumonectomy 46 26 52 2 124 Conservative surgery and irradiation in early lung cancer PERIFERAL LUNG CANCER TlN0M0 Figure 2. Survival after conservative surgcry and adju­vant radiation thcrapy in pcriphcral T1 NOMO Jung cancer. 61.7 % ). The difference was statistically insigni­ficatlt. The trend for better prognosis in women we could trace in ali groups of patients that underw;nt different .ethods of surgery. Long-term results of organ-preserving sur­gery correlated with size of primary tumor. Ali the patients who had the primary Iesion dimne­ter less then 1.5 cm were alive for 5 years. If the diameter of the tumor was 1.5 cm or more 5-year survival was 71.5-74.1 % depending ofmethod of resection (p < 0.005). Lobectomyand pneumonectomy Iong term results were notsignificantly correlated with the size of theIesion. The best prognosis observed in adenocarci­noma and adenosquamous cancer, 5 years after organ-preserving treatment respectively 85. 7 and 73.8 % patients were alive. We cannot properly explain good Iong term results of con­servative resections in TINO adenosquamous carcinoma. Following lobectomy 5-year survival was 54. 7 % (p < 0.005). Some other important factors are to be included into analysis. On the other hand, one can appreciate rather good results of conservative resections in early scar cancer, 3 years 91.7 % patients were alive, 5 and 10 years -80.3 % . The most important long term results we got in monitoring of 9 patients with histologically disclosed tumor growth near resection margin (5 cases) or malignant celi complexes in lympha­tic (blood) vessels in the excised preparation. After such a "relatively curative" resections in two cases developed Iocal recurrences and in 2 -early distant metastases, 3-year survival inthis group of patients was 77 .8 % , 5-year survi­val -38.9 % (p < 0.001; Figure 3). Five-year survival following tumorectomy was 60 % , wedge resection -69 .1 % and seg­mentectomy -72.5 % . However, inspite of an apparent trend in prognosis, statistical diffe­rence is not significant. The reason for that is insufficient number of patients. But we cut down on tumorectomy after experience in the years 1985-1986. Neither PreRT nor PostRT improved in long-term results. It is not worth to repeat this reduced operation even with adjuvant therapy in early primary lung cancer. Three years following 20 conservative resec­tions lived 77.3 % of patients, 5 year -68.7 % . Radiation therapy improved long term results: these rates were respectively 81 and 70.5 % . The most effective method appeared to be PostRT. In the group of patients that were subjected to Iobectomy 5-year survival was 63 % , after combined treatment depending of the method -59.5-65.3 (p > 0.05). With PostRT the results are somewhat better but the difference is not significant. We studied the effect of radiation therapy depending on Iocal doses. In 8 of 68 cases PreRT was completed in single dose of 7.5 Gy the day before conservative surgery. In 60 cases the equivalent dose attained 44 Gy. In 1st group Khartchenko VP and Kouzmine IV Table 3. Type of resection and survivaJ in TlN0 Jung cancer. Type of resection Number of patients NoRT 5-year survivaJ (%) PreRT PostRT Random Tumorectomy 7 50 75 60 Wedge resection 57 66.7 25 73.l 69.1 Segmentectomy 40 67.5 80 76.5 72.5 Lob-, Pncumoncctomy 124 66.9 57.9 65.3 63.7 Iocal recurrences developed in 25 % cases (2 in 8 patients), in 2nd -8.3 % (5 in 60). When the dose of PreRT was 36 or 44 Gy, the rate of recurrences decreased to 7. 7 % . The same re­sults were observed following "sandwich" use of both PreRT and PostRT. So radiation therapy with low leve! of Iocal doses in association with conservative surgery proved to be ineffective. Tota! doses of 44 Gy reduced the risk of local recurrences. Decre­asing of the irradiated volume of the Jung have not influenced the effect of local treatment. It is important to state that equivalent doses PreRT and PostRT produced the similar local effect. In 7 (5.5 % ) cases following lobectomy and in 4 (3.8 % ) after conservative surgery patients developed severe radiation pneumonitis with clinical symptoms (p > 0.05). In all of them in zone of radiation included a large volume of Jung parenchyma, lymph nodes of hilus and mediastinum. Tota! dose was not les than 44 Gy. Single dose of PreRT 7.5 Gy or decreased zone of irradiation have not developed sympto­matic pneumonitis. Asymptomatic radiological changes in Jung tissue were observed more frequently either after conservative or radical resections. But the impairments of general Jung function following combined organ-preserving treatment were less significant than after lobec­tomy with adjuvant irradiation. Discussion It is rather a problem to compare our data with published reports. Sometimes complete condi­tions and important prognostic factors are lack­ing, other authors do not properly compare the results of conservative and radical resections. Some of them use the former versions of TNM. In the Table 4 we compare the rates of the most relevant reports. However, there are some significant differences, one can find the trend to better results of conservative surgery in early (TlN0) and stage I peripheral Jung cancer. We presume that combined organ-preserving treat­ment of the tumor will be the alternative met­hod of treatment at least in some groups of patients with favorable prognostic factors. Special importance was attached to quality of life after combined organ-preserving treat­ment of lung cancer. Usually the main objec­tions to combined organ-preserving treatment was radiation pneumonitis that brings to naught all the efforts to save the functioning lung tissue. The same point of view expressed some authors in opposition to radiation therapy be- Table 4. Conservative and standard reseetions in TlN0 Jung cancer. Reference Number of conservative 5-year survivaJ (%) resections Conserv. surg. Lobectomy MenneW.4 95 56.3 53.6 Windheim K.5 88 40 39 Jensik R.6 274 55 DobrovoJsky S.7 41 67.5 64.5 Khartchenko V. 104 74.8 68.1 Conservative surgery and irradiation in early lung cancer fore of after bronchoplastic procedures. The problem of adjuvant therapy complications is real but seems to be exaggerated.3 The results of this study are preliminary findings but the analysis of immediate and delayed data offers the possibility to suggest the acceptable organ-preserving method in early (TINO) lung cancer. The combined treatment of peripheral lesion must be an alternative method not only in elderly patients with limited Jung function but in ali TINO cases with favora­ble prognostic factors (tumor diameter less than 1.5 cm, scar cancer). It is preferable to carry out segmentectomy and PostRT in total dose 40-44 Gy. Conclusion l. Conservative resections with radiation the­rapy are justified in peripheral TINO Jung can­cer, 5 year following combined organ-pre­serving treatment 70.5 % patients, after stan­dard radical resections 63.4 % (p > 0.05) sur­vived. 2. The less the volume of excised lung tissue, the greater becomes the risk of local recurren­ces, but limited experience is not enough to make a significant conclusion. 3. The best remote results of organ-preserv­ing treatment were observed after segmentec­tomy with PostRT: 5-year survival -77.2 % . 4. Unlike standard resection in conservative surgery, size and histologic type of the tumor influenced the survival. The best prognosis is observed in scar carcinoma and early adenocar­cinoma. Organ-preserving treatment is defini­tely justified when the diameter of primary lesion is less than 1.5 cm. 5. Tumorectomy in patients with early Jung carcinoma is not an adequate procedure even with adjuvant therapy. Wedge resection is ad­missible only in cases of favorable prognosis and subpleural minute Iesions. 6. PreRT in association with conservative surgery does not seem to be sufficient to pro­vide the stabilization of malignant cells in pri­mary lesion and to prevent the dissemination of distant metastases during surgery. The possi­ble mechanism is connected with immune sup­pression. 7. Changes of Jung tissue following irradia­tion and conservative surgery are not frequent and grave in comparison with standard combin­ed treatment. In 5.5 % lobectomy cases and in 3.8 % organ-preserving resections severe radia­tion pneumonitis that demands repeated hospi­talizations and unspecified treatment is to be found. References l. Khartchenko VP, Galil-Ogly GA, Chkhikvadze VD, et al. Role of conservative rescctions in Jung cancer. Vopr. Oncologii (Rus) 1987; 33: 110-1. 2. Khartchenko VP, Chkhikvadze VD, Eltyshev NA, Kouzmine IV. Segmenta! Jung resection with sta­pler. Grudnaja i sred.-sosud. Khir. (Rus) 1993; 6: 57-60. 3. Khartchenko VP, Galil-Ogly GA, Chkhikvadze VD et al. Surgical and combined treatment of Jung cancer. Vesin Chirurg (Rus) 1989; 5: 3-6. 4. Menne W, EuJe E. Unsere Erfahrungen mit der sparsamen Keilresektion bei der Behandlung des Bronchialkarzinoms Berlin: Abh. Akad. Wiss. DDR, JRG, 1974: 95-100. 5. Windheim KV. Sind gewebserhaJtendene Resek­tions verfaren bei bronchopulmonalen Krebser­krankungen vcrterbar? Thoraxchirurgie 1978; 26 (4): 304-5. 6. Jesnik RJ. The role of segmenta! resection in Jung cancer. Chest 1986; 89: (Suppl.-4): 588. 7. Dobrovolsky SP, Grigorjeva SG. Surgery of stage I Jung cancer. Khirurgia (Moscow) 1991: 53-9. Radio! Oncol 1995; 29: 330-7. Standardized immunohistochemistry of estrogen receptors in human breast carcinoma in routinely processed tissue Golouh R and Kljun A Institute of Oncology, Department of Pathology, Ljubljana The aim of this study was to determine the optimal method for estrogen receptor (ER) staining on routinely processed breast tumors. We tested different commercially available primary antibodies, different methods for tissue digestion and severa! detection systems on formalin-fixed, paraffin embedded tissue under conditions of our laboratory. All antibodies to ER tested (H222, ERJD5, D75, NCL-ER-P31, and 1D5), gave positive results at least under some conditions of retrieval andlor heavy salt enhancement. Proteolytic enzyme pretreatment, microwave irradiation and heavy metal ions had varions influence on intensity of fina! color products depending mostly on primary antibody tested. We have found that immunohistochemical assessment of estrogen receptor status using Dako JD5 primary antibody, microwave heat induced epitope retrieval, and Streptavidin-pe­roxidase protocol, performed by an automatic immunostainer has many advantages over other antibodies and methods tested. Key words: breast neoplasms; receptors, estrogen; immunohistochemistry Introduction require substantial amount of fresh tissue, that The value of the estrogen receptor (ER) assay to predict breast cancer response to therapy and overall survival has been established by an extensive literature on the subject over last few decades (1,2,3). The widely used biochemical assay is based on the ligand binding, dextran­coated charcoal (DCC) using tissue homogena­tes. This method is generally regarded as the standard against which new methods are measu­red (4,5). Unfortunately, biochemical methods Correspondcncc to: Prof Golouh Rastko, M. D., Ph. D. Thc Institute of Oncology, Zaloška c. 2, 61000 Ljubljana, Slovcnia. has to be collected immediately after surgery and transported on ice. As the method is de­structive of the tissue, the assessment of actual tumor content of the specimen is not possible (6). Furthermore, biochemical assay in very small tumors and retrospective analyses of fixed material are impossible. The first step to solve these problems was the development of monoclonal antibodies to ER that has allowed the use of immunohisto­chemical techniques to visualize the receptors in tissue sections. It should now be possible to perform the study on scant material that other­wise would be insufficient for biochemical assay and to evaluate the degree of intratumoral UDC: 618.19-006.6-07 heterogeneity. Standardized immunohistochemistry c.f estrogen receplors . .. Among the well defined antibodies, the rat monoclonal antibody H222 raised by Greene and coworkers and commercially available as a kit by Abbott Laboratories was recommend initially for use on frozen sections (7). As frozen section has its drawbacks, in second step, efforts have subsequently been made to make this antibody effective on paraffin-embed­ded tissue (8,9). So far, the Abbott H222 antibody is well characterized and immunohi­stochemical results have been found repeatedly to correlate well with biochemical methods of assessing ER status. However, this antibody requires an overnight incubation and in diffe­rent laboratories the results of staining were not reproducible. With the advent of new anti­bodies to ER, different techniques used, and diverse cut-off points established for evaluating the results, standardization of ER immunostain­ing protocol has been strongly advocated ( 4). The aim of this study was to test different approaches to ER immunostaining on routinely processed breast tumors and to determine the optimal method under conditions of our labora­tory. Material and methods Breast tumor tissue As routine fixation and processing are by defi­nition heterogeneous and may have unpredicta­ble effects on the immunohistochemical results (4) we tried to avoid this variability. In our institution, ali breast specimens were received fresh on the ice immediately after surgical re­moval, and examined by surgical pathologist. Table 1. ER primary antibodies tested Figure l. Immunostaining for estrogen receptors with Dako ID5. Note the intense nuclear staining in cells of both, infiltrating and intraductal eomponent of dueta! carcinoma and the absence of cytoplasmic stain­ing. Microwave pretreatment, automatic stainer. Routinely, and for the purpose of this study, a portion of tumor tissue was snap frozen in liquid nitrogen and submitted for DCC assay. At the same tirne, an additional piece of tumor was fixed for period not exceeding 24 hours, using 10 % neutral-buffered formalin at room temperature. In the tissue processor (Hypercen­ter, Shandon), the material underwent dehyclra­tion, clearing and paraffin infiltration. The tis­sue was then embeclded in blocks, and 3-micron sections were cut and mounted on Silane (Sig­ma) coated slides. ER staining procedure Monoclonal antibodies. Five different monoclo­nal antibodies to ER were tested (Table l). Preparation of paraffin-embeclcled sections. The slicles were di'iecl in a 56°C oven overnight; then they were depar.1ffinized ancl rehydrated in graded alcohols. Af,tt;r r e.y.,gration, enclogenous . Clone Source Dilution Incubation tirne Temperature H222 Abbot Prediluted Overnight RT* ERlD5 Immunotech 1: 10 Overnight 4 ° c D75 Courtesy of 1: 100 Overnight 4 ° C DrGLGreene NCL-ER-P31 Novocastra 1: 20 Overnight RT 1D5 Dako 1: 100 Overnight 4 ° c RT -room temperature * reincubation at 37 ° C, 2 hours Golouh R and Kljun A peroxidases were blocked by immersing the slides in 1 % H202 in methanol for 15 minutes and washed well with phosphate buffer solution (PBS) before enzymatic, and in distilled water before microwave pretreatment. Antigen retrieval The most controversial step in ER immunohistochemistry of paraffin-embed­ded tissue is, no doubt, the pretreatment of the sections. It is well known that many epitopes are sensitive to formalin fixation, often propor­tionally related to the duration of fixation, thus potentially causing unsuspected false-negative immunostains (10). For the purpose of this study we applied two different methods of antigen retrieval. The first one, proteolytic enzyme treatment of formalin­fixed tissue sections was found to enhance im­munoreactivity (11,12). In this study a series of enzymes was tested for enzymatic digestion (Tab 2). As enzymatic digestion is effective with only limited fraction of currently used diagnostic antibodies, the second method using microwave radiation of sections has been stated to improve immunostaining in a broader group of antigens (13). To this end, we have used a microwave Table 2. Tissue enzymatic digcstions testcd oven (M752, Miele, 850W). Slides in the citrate buffer, pH 6.0, were exposed to heating at power setting of 750 W in three intervals of 5 minutes. Completion of staining procedure. The remaind­er of the staining procedure followed our rou­tine procedure for different detection systems or a method supplied by manufacturer (Abbott) for ERICA kit. In this study, three immunohistochemical de­tection systems were tested in combination with different antibodies (Tab 3). As heavy metal ions have long been proposed as a means to increase intensity of final color products (12,14), we also tested the influence of copper, nickel, cobalt, and osmium salts on ER staining intensity. In the first part of the study, ali procedures tested were performed manually. Ideally, a single method should be adopted and standardi­zed for routine day-to-day staining within a laboratory. The chosen method should then be performed in identical fashion on every run. This is best achieved by automation, which offers levels of quality and consistency far better than that achievable by manual methods (15). Enzymc Source Dilution Timc, min Temperature Proteasc XIV Sigma 0.1 % 30 37 ° c Proteasc 1 Sigma 0.1 % 30 37 ° c Protcasc K Sigma 0.25 mg/ml 5 RT +DNase Sigma 5mg/ml 15 RT Ficin Sigma Undiluted 30 37 ° c RT -room temperature Table 3. Detection systems tested System Primary antibody Secondary antibody Chromogen PAP H222 Goat anti-mouse DAB ABC H222 Biotinylated rabbit anti-mousc DAB D75 ER 1D5 I D5 NCL-ER-P31 StrAP ID5 Biotinylated rabbit anti-mouse DAB P AP -peroxidase-antiperoxidase ABC avidin-biotin complex StrAP -streptavidin-peroxidase DAB -3,3'-diaminobenzidine tetrahydrochloride Standardized immunolzistochemistry o.f estrogen receptors . .. Table 4. ER Streptavidin-peroxidase protocol Step No. Step name Duration min: sec (Dako, modified) 56 Pad 3 00:29 Step No. Step name Duration min: sec 57 Buf3 00:10 58 Pad3 00:45 Buf 1 00:10 Chrom 05:00 Pad 1 00:29 60 Pad3 00:29 3 Buf 1 00:10 61 Buf3 00: 10 4 Pad 1 00:29 62 Pad4 00:29 5 Buf 1 00: lO 63 Buf3 00:10 Pad 1 00:29 Pad4 00:29 Buf 1 00:10 8 Pad l 00:45 65 Buf3 9 AB1 25:00 66 Pad4 10 Pad 1 00:29 67 Buf3 II Buf 1 00:10 68 Pad4 12 Pad 1 00:29 69 Buf3 01:00 00:29 00:10 00:29 01:00 70 Pad4 00:29 Buf 1 00:10 71 Buf2 01:00 14 Pad 1 00:29 72 Pad 4 00:29 15 Buf 1 00: 10 73 Buf2 00:10 16 Pad l 00:29 74 Pad4 00:29 17 Buf 1 00:IO 75 H20 00:10 18 Pad 1 00:29 76 Pad4 00:29 Buf 1 00:10 77 H20 00:10 20 Pad2 00:45 78 Pad4 00:29 21 AB2 25:00 79 HiO 00:29 22 Pad2 00:29 Buf l 00:10 Buf -buffcr 24 Pad2 00:29 Buf2 00:10 Chrom -chromogcn (DAB) Str AP -strcptavidin-peroxidasc 26 Pad2 00:29 27 HPblock 02:30 28 Pad2 00:29 HPblock 02:30 Thus, in the second part of the study, ER Pad2 00:29 immunostaining was performed on the DAKO HP block 02:30 TechMate 500 immunostainer. This system uses 32 Pad2 00:29 the capillary reaction to draw up reagents to 33 Buf2 00:IO 34 Pad2 00:29 cover the specimens on the specially prepared 35 Buf2 00:IO slides. Prior to staining, routinely fixed paraffin­36 Pad2 00:29 embedded tissue sections were subjected to Buf2 00:10 antigen retrieval in microwave oven. For the Pad2 00:45 StrAP 25:00 staining of ER, both the original DAKO rea­ Pad 3 00:29 gent kit and Streptavidin-peroxidase protocol 41 Buf2 00:10 were used. The step names, number of steps, Pad3 00:29 Buf2 00:10 reagents and incubation times for the individual Pad3 00:29 step are listed on Table 4. However, instead of Buf3 00:10 the original prediluted primary antibody, the Pad3 00:29 Buf 3 00:10 Pad3 00:29 antibody used was DAKO 1D5, 1: 150. Addi­ tionally, in the step 65, originally prescribed Buf3 00:10 hematoxylin was substituted by buffer 3. Fina! Pad3 00:45 counterstaining with hematoxylin was perfor­ Chrom 05:00 Pad 3 00:29 med manually. Controls. Only nuclear immunostaining was in­ Buf3 00:10 terpreted as positive result. Cytoplasmic reacti­ Pad3 00:45 Chrom 05:00 vity, if any, was ignored. As a positive control, Golouh R and Kljun A a case of invasive breast carcinoma of known positive ER reactivity determined by DCC as­say was included in ali batches of paraffin-em­bedded material to ensure consistency of stai­ning between batches. Cells in the same section, not expected to give positive reactivity with the antibody in question (stromal cells, lymphocy­tes, etc.), served as intrinsic negative controls. A specimen was considered "ER positive" by biochemical assay if the result was more than 10 pmol/g protein. For the purpose of this study, a series of "ER positive" tumors from different patients was tested. Scoring. The staining results were assessed se­miquantitatively according to the percentage of stained tumor cells and the intensity of the staining, using a scale of 1-3 for each of these two components (16). The resulting two figures were multiplied by each other, and the fina! result expressed as follows: negative (no stai­ning or only an occasional positive celi); weakly positive ( +, total score = 1-3); positive ( + +, score 4-6); strongly positive ( + + +, score more than 6). Results Positive immunostaining of nuclei was seen in both malignant and benign epithelial cells. Most cases show mild variation in staining intensity, but in few cases there was considerable hetero­geneity of staining both in tumor and in normal breast epithelium. Ali five antibodies to ER tested, gave positive results at least under some conditions of retrie­val and/or heavy salt enhancement. The inten­sity of nuclear staining, however, showed great variations depending on the antibody applied (Table 5). Analysis of our results confirmed the superio­rity of monoclonal antibody 1D5 for immunohi­stochemical determination of ER. In compari­son to other antibodies, done 1D5 not only produced the greatest intensity of staining, that was most extensive, but also gave no back­ground or any cytoplasmic staining. The results were even better when staining had been per­formed automatically (Fit. 1). The second best results were achieved by ER1D5 and H222. The staining with the latter was acceptable only after protease K+ DNase pretreatment. Gene­rally, unsatisfactory stainings showed negative or weak staining of nuclei and extensive back­ground staining of collagen and fat. Proteolytic enzyme pretreatment gave diffe­rent results. Protease K and DNase pretreat­ment resulted in notable enhancement of immu­nostaining with the antibody H222, whereas ER1D5, and NCL-ER-P31 proved to be less sensitive to this enzyme. Parallel to that, ficin pretreatment gave better staining with H222 compared to ER1D5 and D75. On the other band, the staining with NCL-ER-P31 and ficin Table 5: Results of ER staining in formalin-paraffin scctions Antibody H222 ER1D5 D75 NCL-ER-P31 1D5* 1D5** Proteasc K+ DNase ++ + ND + ND ND Protease K+ DNase + Os +++ ND neg + ND ND Protcasc K+ DNase + Ni ++ ND neg + ND ND Protease K+ DNase + Cu ND ND neg + ND ND Ficin ++ + ND neg ND ND Ficin+ Os +++ ND neg neg ND ND Ficin+ Ni ++ ND neg neg ND ND Ficin+ Cu ++ ND neg neg ND ND MW + ND ++ ++ +++ MW+Os ++ ND + ++ +++ ND MW+Ni ND ND + ++ +++ ND MW+Cu ND ND + ++ +++ ND * manually; ** automatically; Os -Osmium; Ni -Nicke!; Cu -Copper; MW -microwave; ND -not done Standardized immunohistochemistry of estrogen receptors . .. pretreatment proved to be completely negative. In our experiment, microwave irradiation produced intense staining with the ER1D5 and 1D5 antibody. However, it only enhanced stain­ing with NCL-ER-P31 and H222. Contrary to that, staining with D75 after microwave pre­treatment remained negative. Copper, nickel, cobalt, and osmium had va­rious influence on intensity of fina\ color pro­ducts. Among them, the nickel-DAB product provided the highest detection efficiency. Cop­ per-D AB product resulted an indistinct gray black color of nuclei thus providing insufficient contrast after subsequent hematoxylin counter­staining. Discussion The application of a suitable immunohistoche­mical method for assessing of ER in breast cancer on formalin-fixed tissue, contrary to more traditional method based on biochemical assay of estradiol binding in tissue homogena­tes, has been strongly advocated. The latter method has the disadvantage of being costly, requiring a fairly large amount of tissue homo­genate, and being affected by bound estrogen receptor from high endogenous levels of estra­diol in premenopausal women. Immunohistochemistry, on the other hand, would eliminate the need for fresh tissue and has severa! other advantages. This method is applicable to formalin-fixed, routinely proces­sed tissue and allows ER status to be assessed on the same blocks as those used for histopa­thologica\ assessment of tumor without prese\ection of tissue for separate frozen sec­tion. This is particularly important in increasin­gly more frequent small tumors where separate samples for tissue diagnosis and biochemical assessment of ER cannot be taken, as well as in impalpable mammographically detected or unexpected malignancy cases where the carci­noma may be grossly invisible and the only source for ER determination remains paraffin block with microscopically identified tumor tis­sue. This method also allows improved morpho­logy and better representation of the tumor, its use in archival material, not to mention the inclination of practicing pathologists to interpret the immunohistochemical findings on paraffin slides. As immunohistochemistry is extremely tech­nique-dependent, consistent quality can be sig­nificantly more difficult to achieve than with other staining techniques. The immunohisto­chemical ability to stain for cellular proteins is equally dependent on two factors: preservation of the proteins in tissue sections after fixation and processing and quality of the reagents, mainly antibodies, chosen for immunostaining. Pathologists are faced with the decision to ex­pend va\uable tiine and resources on in-house testing of different antibodies, processings and optimizing the procedures. The same holds for ER immunostaining, where the standardization of quality is stil! a problem even within indivi­dual \aboratories and reproducibility in general practice is poor. In this study we decided to compare different commercially available ER antiboies, different methods for tissue digestion, and different de­tection systems to determine the optimal me­thod for ER immunostaining on formalin-fixed, paraffin-embedded tumor tissue. The compari­son of our resu\ts showed that the best and most reproducible staining for ER can be achie­ved using standardized formalin fixation, toget­her with Dako 1D5 primary antibody, micro­wave antigen retrieval, and Streptavidin-peroxi­dase protocol performed by an automatic immu­nostainer. The method we have described is teclrnically easy and rapid to perform, not re­quiring overnight incubation procedure and gi­ves reproducible results. Indeed, at our Depar­tment this method has now been adopted for all cases of primary breast carcinoma, allowing inclusion of ER status as a part of surgical pathology report. It is beyond the scope of this study to identify a valid cut-off for positivity od ER status using Dako 1D5. Goulding et al found a good corre­lation in an assessment of ER using Dako 1D5 and Abbott H222 monoclonal antibody. How­ever, in some cases a marked discrepancy was Golouh R and Kljun A observed between the scores obtained. This may be attributed to the recognition of different epitopes by the two antibodies (17,18). Similar discrepancies have been observed by others. With the use of the 1D5 antibody a significant increase in the sensitivity of ER determination has been noted together with a more significant correlation with overall survival and disease­free survival than showed previous results with Abbott H222 (19,20). Moreover, recent rma1io11 i11 North Amcrica Co11wc1: /111ernatio11al reprinl Co1pora1io11 96R Admiral Callag­/11111 /.a,11', # 268 P. O. Box 12004, Val!ejo, CA 94590, "fd : 1 -07) 553 9230, h,x: /707) 552 9524. Nepotrebno je, da bolezen spremlja bolecina tramado! Moc opioidnega analgetika brez opioidnih stranskih ucinkov centralno delujoci analgetik za lajšanje zme1·nih in hudih bolecin ucinkovit ob sorazmerno malo stranskih ucinkih Indikacije: Srednje mocne do mocne akutne ali kronicne bolecine. Po tristopl!njski slu:mi StJetrwue zdmeswene c11:qanizac(fe za fajša11je l>oleG"in pri bolnihih z rnkal'fm obolenjem tmnwclol odprew(fa srednje hudo bulel'ino ali lwlf!l'irw drnge stup,vi•, Kontraindikacije: Zdravila ne smemo dajati otrokom, mlajšim od ] leta. Tramaclola ne smemo uporabljati pri akutni zastrupitvi z alkoholom, uspavali1 an.tlgctiki in drugimi zdravili, ki delujejo na osrednje živcevje. Med nosecnostjo predpišemo tramadol le pri nujni indikaciji. Pri zdravljenju med dojenjem moramo upoštevati, da O, 1 <:11 zdravib prehaja v materino mleko. Pri bolnikih z zvecano obcutljivostjo za opiate moramo tramadol uporabljati zelo previdno. Bolnike s krci centralnega izvora moramo med zdravljenjem skrbno nadzorovati. Interakcije: Tramaclola ne smemo uporabljati skupaj z inhibitorji MAO. Pri socasni uporabi zdravil, ki delujejo na osrednje živcevje, je možno sinergisticno delovanje v obliki povecane sedacijc, pa tudi ugodnejšega analgeticnega delovanja. Opozorila: Pri predoziranju lahko pride do depresije dihanja. Previdnost je potrebna pri bolnikih, ki so preobcutljivi za opiate, pri starejših osebah, pri mikseclemu in hipotiroidizmu. Pri okvari jeter in ledvic je potrebno odmerek zmanjšati. Bolniki med zdravljenjem ne smejo upravljali strojev in motornih vozil. Doziranje in nacin uporabe: Odrasli ;u o/rod, starejš; od 14 let: Injekcije: 50 do 100 mg i.v.,i.m .. s.c.; intravensko injiciramo pocasi ali infundiramo razredceno v infuzijski raztopini. Kapsule: 1 kapsula z malo tekocine. Kapljice: 20 kapljic z malo tekocine ali na kocki sladkorja; ce ni zadovoljivega ucinka, dozo ponovimo cez 30 do 60 minut. Svecke: 1 svecka; ce ni ucinka, dozo ponovimo po 3 clo 5 urah, Otroci od I do 11 let: 1 do 2 mg na kg telesne mase, Dnevna doza pri vseh oblikah ne bi smela biti višja od 400 mg. Stranski ucinki: Znojenje, vrtoglavica, slabost, bruhanje, suha usta in utrujenost. Redko lahko pride do palpitacij, onoslatske hipotenzije ali kardiovaskularnega kolapsa. Izjemoma se lahko pojavijo konvulzije. Oprema: 5 ampul po I ml (50 mg/ml), 5 ampul po 2 ml (100 mg/2 ml), 10 ml raztopine ( JOO mg/ml), 20 kapsul po 50 mg, 5 sveck po 100 mg. Podro/J11effo h?f'ormac(ie so Jla uo(io JJr; jJro;zuc{ialcu. ...KRK. SLOVENIJA