ADIOLOGY '11111 NCOLOGY March 2005 Vol. 39 No. 1 Ljubljana ISSN 1318-2099 ADIOLOGY ANO NCOLOGY Edi to rial office RadiologtJ and OncologtJ March 2005 Institute of Oncology Vol. 39 No. 1 Zaloška 2 Pages 1-89 SI-1000 Ljubljana ISSN 1318-2099 Slovenia UDC 616-006 Phone: +386 1 5879 369 CODEN: RONCEM Phone/Fax: +386 1 5879 434 E-mail: gsersa@onko-i.si Aims and scope Radiologij and Oncologi; is a journal devoted to publication of original contributions in diagnostic and interventional radiologi;, computerized tomography, ultrasound, magnetic resonance, nuclear medicine, radiotherapy, clinical and experimental oncology, rndiobiologi;, radiophysics and radiation protection. Editor-in-Chief Editor-in-Chief Emeritus Gregor Serša Tomaž Benulic Ljubljana, Slovenia Ljubljana, Slovenia Executive Editor Editor Viljem Kovac Uroš Smrdel Ljubljana, Slovenia Ljubljana, Slovenia Editorial board Marija Auersperg Valentin Fidler Maja Osmak Ljubljana, Slovenia Ljubljana, Slovenia Zagreb, Croatia Nada Bešenski Be1a Fornet Branko Palcic Zagreb, Croatia Budapest, Hungary Vancouver, Canada Karl H. Bohuslavizki Tullio Giraldi Jurica Papa Hamburg, Germany Trieste, Italy Zagreb, Croatia Haris Boko Andrija Hebrang Dušan Pavcnik Zagreb, Croatia Zagreb, Croatia Portland, USA Nataša V. Budihna Ltiszl6 Horvtith Stojan Plesnicar Ljubljana, Slovenia Pecs, Hungary Ljubljana, Slovenia Marjan Budihna Berta Jereb Ervin B. Podgoršak Ljubljana, Slovenia Ljubljana, S/ovenia Montreal, Canada Malte Clausen Vladimir Jevtic Jan C. Roos Hamburg, Germany Ljubljana, Slovenia Amsterdam, Netherlands Christoph Clemm H. Dieter Kogelnik Slavko Šimunic Miinchen, Germany Salzburg, Austria Zagreb, Croatia Mario Corsi Jurij Lindtner Lojze Šmid Udine, Italy Ljubljana, Slovenia Ljublja7:.a,Slovenia Ljubomir Diankov Ivan Lovasic BonitStabuc So fia, Bulgaria Rijeka, Croatia Ljubljana, Slovenia Christian Dittrich Marijan Lovrencic Andrea Veronesi Vienna, Austria Zagreb, Croatia Aviano, Italy Ivan Drinkovic LukaMilas Živa Zupancic Zagreb, Croatia Houston, USA Ljubljana, Slovenia Gillian Duchesne Metka Milcinski Melbourne, Australia Ljubljana, Slovenia Publisher Association of Radiology and Oncology Affiliated with Slovenian Medica/ Association -Slovenian Association of Radiology, Nuc/ear Medicine SociehJ, Slovenian SociehJ far Radiotherapy and OncologiJ, and S/ovenian Cancer Society Croatian Medica/ Association. -Croatian Society of Radiologi; Societas Radiologorum Hungarorum Friuli-Venezia Giulia regional groups of S.I.R.M. (Italian Society of Medica/ Radiology) Copyright © Radiologi; and OncologiJ-Ali rights reserved. Reader for English Mojca Cakš Key words Eva Klemencic Secretaries Milica Harisch Mira Klemencic Design Monika Fink-Serša Printed by Imprint d.o.o., Ljubljana, Slovenia Published quarterly in 700 copies Beneficiary name: DRUŠTVO RADIOLOGIJE IN ONKOLOGIJE Zaloška cesta 2, 1000 Ljubljana S/ovenia Beneficiary bank account number: SI56 02010-0090006751 IBAN: SI56020100090006751 Our bank name: Nova Ljubljanska banka, d.d., Ljubljana, Trg republike 2, 1520 Ljubljana; S/ovenia SWIFT: LJBASI2X Subscription fee far institutions EUR 100 (16000 SIT), individuals EUR 50 (5000 SIT) The publication of this journal is subsidized by the Minisfry of Education, Science and Spori of the Republic of Slovenia. Indexed and abstracted by: BIOMEDICINA SLOVENICA CHEMICAL ABSTRACTS EMBASE / Excerpta Medica Sci Base This journal is printed on acid-free paper Radiologi; and Oncology is available on the internet at: http://www.onko-i.si/radiolog/rno.hl:ml ISSN 1581-3207 COLOGY Ljubljana, Slovenia ISSN 1318-2099 March 2005 UDC 616-006 Vol. 39 No. 1 CODEN: RONCEM CONTENTS DIAGNOSTIC RADIOLOGY Symptomatic imperforate Cowper' s syringocele in a 5-year-old boy 1 Roic G, Boric I, Posaric V, Bastic M, Župancic B SONOGRAPHY Sonography of pleural space in healthy pregnants -preliminary results Kocijancic I 5 lnjury of the axillary artery: duplex ultrasound detects postoperative occlusion of the artery with the establishment of the collateral network Krnic A, Sucic Z, Vucic N, Bilic A 9 Ultrasound signs of acute appendicitis in children -clinical application Vegar-Zubovic S, Lincender L, Dizdarevic S, Sefic I, Dalagija F 15 MAGNETIC RESONANCE The MR imaging as a one-way shopping tool for detecting and staging renal tumours Kirova G ONCOLOGY Is quadrant biopsy adequate as first-line sampling scheme in men likely to have non-organ-confined prostate cancer: comparison to extended biopsy protocol Brnic Z, Anic P, Gašparov S, Radovic N, Kucan D, Vidas Ž, Zeijko Ž, Lozo P, Ramljak V 37 Multiple primary malignancies in patients with lung cancer Kurishima K, Satoh H, Homma S, Kagohashi K, Ishikawa H, Ohtsuka M, Sekizawa K 49 Cranium eroding sweat gland carcinoma: a case report Arslan M, Karadeniz AN, Aksu G, Giiveli M 55 The dimethylhydrazine induced colorectal tumours in rat -experimental colorectal carcinogenesis Perše M, Cerar A 61 RADIATION PHYSICS IMRT point dose measurements with a diamond detector 71 Barnett E, MacKenzie M, Fallone BG SLOVENIAN ABSTRACTS 79 NOTICES case report Symptomatic imperforate Cowper’s syringocele in a 5-year-old boy Goran Roic1, Igor Boric1, Vesna Posaric1, Mislav Bastic2, Božidar Župancic2 1Department of Pediatric Radiology, 2Department of Pediatric Surgery, Children’s Hospital Zagreb, Zagreb, Croatia Background. Cowper’s syringocele is a rare anomaly in childhood. It is caused by the obstruction of the duct of Cowper’s gland. Depending of the type and size of the syringocele, and the age of the patient, the treatment for symptomatic lesions could be endoscopic deroofing or open perineal surgery. Case report. We report a case of symptomatic imperforate syringocele in a 5-year-old boy. Although the syringocele are usually best shown on voiding cysto-urethrography, there was not any detectable extrinsic impression or filling defect in the bulbar urethra. Ultrasonography guided perineal puncture with contrast filling of the cystic lesion was used to detect the connection of the Cowper’s duct to the ventral surface of bulbar urethra. Conclusions. In imperforate syringocele, ultrasonography could be useful imaging technique especially in young patients, to evaluate urethra and perineal lesions and for percutaneous guided procedures. Key words: bulbourethral glands-abnormalities; child; preschool Introduction Cowper gland is an accessory sexual organ that contributes to semen coagulation and urethral lubrication.1 The two main Cowper’s glands are situated within the urogenital di­aphragm, with a second pair of accessory glands situated in the bulbous spongiosal tis- Received 30 June 2004 Accepted 20 July 2004 Correspondence to: Goran Roic, MD, Department of Pediatric Radiology, Children’s Hospital Zagreb, Klaiceva 16, 10 000 Zagreb, Croatia; Phone: +385 1 46 00 231; Fax: +385 1 46 00 228; E-mail: goran.roic@ zg.htnet.hr sue. The main Cowper’s ducts enter the ven­tral surface of the bulbar urethra near the midline by piercing the spongiosum. The accessory ducts can enter the urethra directly or drain into the main duct. A retention cyst of a Cowper gland duct (syringocele) is caused by the obstruction of the duct of the gland; it causes a smooth rounded filling defect in the bulbous urethra just proximal to the expected site of the Cowper duct insertion. The true aetiology of Cowper’s duct cysts remains uncertain; most Cowper’s gland duct lesions are congenital; they are present in boys with reports of cys­tograms and have an incidence of 1.5%.2,3 Although usually asymptomatic, large reten­tion cysts may cause urethral obstruction, uri­nary infection and hematuria.4,5 The differen­tial diagnosis of a Cowper’s duct retention cyst includes urethral diverticulum, urethral duplication, fistula and Mullerian duct rem­nant.6 Depending of the type and size of the syringocele, and the age of the patient, the treatment for symptomatic lesions could be endoscopic deroofing or open perineal sur­gery.3,4 Case report A 5-year old boy presented with a one-month history of scrotal and perineal pain and dis­comfort, without dysuria or haematuria. On physical examination, fullness and medially protruding mass in the perineum were ob­served. The patient’s urinary flow rate, blood and urinary profiles were normal. Scrotal and perineal ultrasonography revealed a well de­lineated thin-walled cystic lesion located in the lower scrotum and perineum; no clear communication with urethra could be detect­ed (Figures 1a, 1b). There was not any detectable extrinsic im­pression or filling defect in the bulbar urethra during the voiding cysto-uretrography (Figure 2). Because of these findings, we decided to perform ultrasonography guided perineal puncture with contrast filling of the cystic le­sion instead of cystourethroscopy; there was a small duct emerging from the proximal end of the cyst towards the bulbous urethra (Figure 3). Due to the age of the patient and type of the syringocele, an open perineal surgery was carried out with complete resection of the sy­ringocele. During the dissection of the cyst, there was a small duct emerging from the proximal end of the cyst towards the pelvic diaphragm, which was mostly resected after cannulation. During the follow-up period there was complete relief of perineal pain with normal urine profile and flow rate. Discussion According to urethrographic and endoscopic findings, the lesions of the Cowper’s gland have been classified by Maizels et al7 into four groups: (1) simple syringocele - minimal­ly dilated duct; (2) perforate syringocele - a bulbous duct that drain into the urethra via the patulous ostium and appears as a diver-ticulum; (3) imperforate syringocele - a bul­bous duct that resembles a submucosal cyst and appears as a radiolucent mass; and (4) ruptured syringocele - the fragile membrane that remains in the urethra after dilated duct ruptures. Furthermore, syringoceles can be either within the corpus spongiosum (bulbar) or outside, lying posteriorly to it (perineal).8 The diagnosis of Cowper’s syringocele is based on the voiding cysto-urethrography, cystourethroscopy and ultrasonography. Schultheiss et al8 reported MRI appearance of imperforate syringocele. Although the sy­ringocele are usually best shown on voiding cysto-urethrography, if imperforate, there shouldn’t be any filling defect in the bulbous urethra or reflux into the Cowper’s gland ducts. In such cases, ultrasonography could be a useful imaging technique especially in young patients, to evaluate urethra and per-ineal lesions and for percutaneous guided procedures.9 References 1. Moskowitz PS, Newton NA, Lewotiz RL. Retention cyst of Cowper’s duct. Radiology 1976; 120: 377-80. 2. Brock WA, Kaplan GW. Lesion of Cowper’s glands in children. J Ural 1979; 122: 121-3. 3. Bevers RFM, Abbekerk EM, Boon TM. Cowper’s syringocele: Symptoms, classification and treat­ment of unappreciated problem. J Urol 2000; 163: 782-4. 4. Salinas Sanchez AS, Segura Martin M, Lorenzo Romero J, Hernandez Millan I, Ruiz Mondejar R, Virseda Rodriguez JA. [Ruptured syringocele of the Cowper’s gland. Report of a case]. [Spanish]. Actas Urol Esp 1998; 22: 712-5. 5. Pastor NJ, Liegro GJ, Garcia GF, Ros TM, Galiano RJL, Gutierrez SA, et al. Syringocele of the Cowper’s gland. Report of 2 cases diagnosed in adulthood. Arch Esp Urol 2002; 55: 322-4. 6. Barnewolt CE, Harriet JP, Lebowitz RL, Kirks DR. Genitourinary Tract. In: Kirks RD, editor. Practical pediatric imaging. Philadelphia: Lippincot-Raven Publishers; 1998. p. 1086-7. 7. Maizels M, Stephens FD, King Lr, Firlit CF. Cowper’s syringocele: Classification of dilatations of Cowper’s gland duct based on clinical charac­teristics of 8 boys. J Urol 1983; 129: 111-4. 8. Schultheiss D, Loty J, Hofner K, Jonas U. Symptomatic imperforate Cowper’s syringocele in an adult. BJU International 2000; 86: 4-6. 9. Pavlica P, Barozzi L, Stasi G, Viglietta G. Ultrasonography in syringocele of the male ure­thra (ultrasound-urethrography). Radiol Med 1989; 78: 348-50. Sonography of pleural space in healthy pregnants - preliminary results Igor Kocijancic Department of Radiology, Institute of Oncology, Ljubljana, Slovenia Background. The purpose of our study was to determine the incidence of sonographically visible normal pleural fluid finding in healthy pregnants. Methods. Chest sonography was performed in 47 pregnant volunteers, searching for pleural fluid, first lean­ing on the elbow and than in a sitting position. 9-12 MHz linear probe was used. If the result of the first ex­amination was positive (at least 2 mm thick anechoic layer), we repeated the procedure with 3-6 MHz large radius convex probe. Results. The fluid layer of typical wedge-shaped appearance was visible in the pleural space of 28/47 (59.5%) pregnant volunteers, on both sides in 18/47 (38.3%) and unilaterally in 10/47 (21.2%). The mean thickness of fluid layer (mean of positive results in both positions) was 2.86 mm (SD 1.09 mm, range from 1.8 mm to 6.4 mm). More than 3 mm thick fluid layer was easily detected with 3-6 MHz abdominal convex probe in 7/47 (15%). Conclusions. Small amounts of pleural fluid can sometimes be detected by chest sonography, and hence al­so by abdominal sonography, in otherwise healthy pregnants. Such a positive result, if isolated, should not be taken as a sign of occult thoracic disease. Key words: pleura-ultrasonography; pregnancy Introduction A small amount of fluid (5-15 ml) is often present in the pleural space of healthy indi­viduals.1 No data could be found in the liter- Received 28 November 2004 Accepted 15 December 2004 Corespondence to: Igor Kocijancic, MD, PhD, Department of Radiology, Institute of Oncology, Zaloška 2, SI - 1000 Ljubljana, Slovenia; Phone: + 386 1 587 9 505; Fax. + 386 1 587 9 400; E-mail: ikocijan­cic@onko-i.si ature on imaging of normal pleural fluid in healthy individuals. Only an older textbook by Felson2 reports that »in some normal indi­viduals a small amount of free fluid, as little as 5 to 10 cc, can be demonstrated and even aspirated«, basing the claim on 50 to 70 year old references. He continues that »the inci­dence is higher during pregnancy« without providing a reference. Data on the smallest amount of pleural flu­id detectable by imaging methods vary con­siderably, but they are essentially within the same broad range whether computed tomog­raphy, sonography or X-ray examination are used.3-8 Cadaveric studies9 have shown that volumes of pleural fluid as little as 5 ml may be detected with chest radiographs taken in lateral decubitus position. Recent reports have proved that minute pleural effusions can be easily detected using chest ultrasonog­raphy.4,10 The latest study, comparing chest sonography with expiratory lateral decubitus radiography in the diagnosis of very small pleural effusions, showed that sonography appears to assess the fluid layer more accu­rately than radiography.11 We undertook this study to determine the possibility of sonographic detection of nor­mal pleural fluid in healthy pregnants and to assess the frequency of this finding. Patients and methods Chest sonography was performed in 47 healthy pregnant volunteers, searching for pleural fluid. They had no signs of respirato­ry infects and normal results of laboratory tests. They were found healthy throughout regularly check-ups with their obstetrician. They all delivered healthy babies on term. The sonographic criterion for the presence of pleural fluid was detection of an anechoic zone between the parietal and visceral pleura, at least 2 mm thick (in the elbow position), changing appearance between inspiration and expiration and/or changing appearance with different positions during examina­ tion.4,6,12 The subject was placed in the lateral decu­bitus position for 5 minutes; sonography of the lower pleural space was performed with the subject leaning on her elbow11 and then in a sitting position. An SSA-390 ultrasound scanner (Toshiba, Tokyo, Japan) was used, initially with a 9-12 MHz linear, 5.7 cm long transducer. If pleural fluid was observed, we repeated the examination of the pleural space with 3-6 MHz large convex transducer, com­monly used during abdominal examinations. Maximal fluid layer thickness was measured, with the position of the probe perpendicular to the thoracic wall.13 Descriptive statistics were calculated for all the studied parameters. Mean differences were tested using t-test (for independent or paired samples, as appropriate), correlation was assessed using Pearson’s correlation co- Figure 1. Wedge shaped echofree fluid layer measuring 3 mm (between arrows) represents normal pleural fluid accumulation; L=liver. efficient and Fisher’s exact test was used for analyzing contingency tables. The study was approved by the Medical Ethics Committee of the Republic of Slovenia, and written informed consent was obtained from each subject prior to inclusion in the study. Results We examined 47 healthy pregnant volunteers with mean gestational age of 24.4 weeks (SD 4.6 weeks, range from 16 to 32 weeks) and we sonographically detected anechoic fluid layer in the pleural space in 28 subjects (59.5%). Fluid was observed bilaterally in 18 subjects (38.3%) and unilaterally in 10 subjects (21.2%), 9 of those on the left-hand side. The mean fluid layer thickness was 2.95 mm (SD 0.99, range from 2.0 mm to 6.0 mm) in patients leaning on the elbow. In sitting po­sition the mean thickness was 2.66 mm (SD 0.97, range from 1.8 mm to 6.4 mm). The dif­ference between the two positions proved to be statistically significant (t-test: p=0.001). Fluid layer detected with the linear probe was clearly visible with the large radius convex probe if it measured 3 mm or more, which was the case in 7 subjects (15% of all subjects, 25% of subjects with visible fluid layer). In the total sample, there were 24 male and 23 female fetuses. Among the pregnants with visible pleural fluid there was also an equal number (14) of male and female fetuses. Fluid layer thickness (mean of positive results in both positions) in pregnants carrying male fe­tuses was 3.18 mm (SD 1.12, range from 2.0 mm to 6.4 mm) while in pregnants carrying female fetuses the mean fluid layer was 2.44 mm (SD 0.58, range from 1.8 mm to 4.5 mm). The difference in mean fluid layer thickness proved to be statistically significant (t-test: p=0.041). Association between fetus gender and mean fluid layer thickness equal to or above 3 mm was marginally significant (Fisher exact test: p=0.077) in our sample, whereby 6 out of 7 mothers with visible fluid layer at least 3 mm thick carried male fetuses. We found no correlation between age of pregnant woman and mean fluid layer thick­ness (r=0.044; p=0.823), no correlation be­tween gestation age of the fetus and mean flu­id layer thickness (r=-0.189; p=0.335), as well Figure 2. Detection of pleural fluid using 6 MHz abdominal large radius convex probe (between arrows); L=liver. as no difference in mean fluid layer thickness between left and right pleural space (t-test: p=0.451). Discussion Parietal and visceral pleura and the space in-between usually measure only 0.3 to 0.4 mm.10 On sonograms, normal pleural fluid accumulation typically appears as a wedge-shaped echofree layer with the base oriented towards frenicocostal sulcus (Figure 1). Since our examination revealed pleural fluid in both elbow and sitting position in almost 60% of subjects, we believe that there is a possi­bility to observe pleural fluid during routine sonographic examination of abdominal or­gans in perfectly healthy pregnant women. Fluid layer at least 3 mm thick was easily de­tectable with large convex 3-6 MHz probe (Figure 2) in 25% of the pregnants with visible pleural fluid. If one misinterprets this as a pathologic condition (sign of occult thoracic disease), it can lead to unnecessary diagnostic examinations, such as X-ray, potentially harmful to the fetus. In our group of 16 - 32 weeks pregnancies results showed no association between gesta­tion age of the fetus and mean fluid layer thickness. However the value of this finding is limited as the sample was relatively small and early/late pregnancies were not exam­ined. As expected, we found a statistically significant difference in mean fluid layer thickness regarding the subject’s position during examination (on the elbow vs. sitting). Unexpectedly, we found male fetuses corre­sponding to thicker fluid layer on average. References 1. Black LF. The pleural space and pleural fluid. Mayo Clin Proc 1972; 47: 493-506. 2. Felson B. Chest roentgenology. Philadelphia: W.B. Saunders; 1973. p. 352. 3. Hessen I. Roentgen examination of pleural fluid. A study of the localisation of free effusions, the potentialities of diagnosing minimal quantities of fluid and its existence under physiological condi­tions. Acta Radiol 1951; 86(Suppl): 1-80. 4. Mathis G. Thoraxsonography-part I. Chest wall and pleura. Ultrasound Med Biol 1997; 23: 1131-39. 5. Eibenberger KL, Dock WI, Ammann ME, Dorffner R, Hörmann MF, Grabenwörger F. Quantification of pleural effussions: sonography versus radiogra­phy. Radiology 1994; 191: 681-84. 6. Mc Loud TC, Flower CDR. Imaging of the pleura: sonography, CT and MR imaging. AJR Am J Roentgenol 1991; 156: 1145-53. 7. Leung AN, Muller NL, Miller RR. CT in the differ­ential diagnosis of pleural disease. AJR Am J Roentgenol 1990; 154: 487-92. 8. Maffesanti M, Tommasi M, Pellegrini P. Computed tomography of free pleural effusions. Europ J Radiol 1987; 7: 87-90. 9. Moskowitz H, Platt RT, Schachar R, Mellins H. Roentgen visualization of minute pleural effusion. Radiology 1973; 109: 33-5. 10. Reuß J. Sonographic imaging of the pleura: nearly 30 years experience. Eur J Ultrasound 1996; 3: 125­39. 11. Kocijancic I, Vidmar K, Ivanovi-Herceg Z. Chest sonography versus lateral decubitus radiography in the diagnosis of small pleural effusions. J Clin Ultrasound 2003, 31: 69-74. 12. Targhetta R, Bourgeois JM, Marty - Double C Chavagneux, Proust A, Coste E, Balmes P. Towards another diagnostic approach of peripher­al lung masses. Ultrasonically guided needle aspi­ration. [French]. J Radiol 1992; 73: 159-64. 13. Marks WM, Filly RA, Callen PW. Real - time eval­uation of pleural lesions: New observations re­garding the probability of obtaining free fluid. Radiology 1982; 142: 163-4. case report Injury of the axillary artery: duplex ultrasound detects postoperative occlusion of the artery with the establishment of the collateral network Anton Krnic1, Zvonimir Sucic1, Niksa Vucic2, Ante Bilic2 1Department of Radiology, 2Internal Medicine Clinic, Sveti Duh General Hospital, Zagreb, Croatia Background. Injury of the axillary artery is a life-threatening condition. The injury requires immediate, on-place treatment (compression) and a number of patients require prompt explorative surgery. Whenever a vascular injury is suspected, radiological follow-up (angiography), intra-operative or post-operative, should be performed. Case report. We report a case of axillary artery injury in 28-year- old woman. Though postoperative du­plex ultrasound gave an accurate finding, i.e. pre-stenotic, high resistant Doppler wave spectrum proximal to and post-stenotic, monophasic distal to the injury, angiography was performed. It showed extensive col­lateral network in the axilla and the blocked perfusion in the axillary artery. The patient underwent re-op­eration. Thrombectomy in the axillary artery was performed, with a subsequent radical improvement of the arm perfusion. Conclusions. In these particular circumstances, duplex ultrasound displayed a characteristic pattern and the angiography might even be avoided. Key words: axillary artery-injuries-ultrasonography-surgery; thrombosis; thrombectomy Introduction Injury of the axillary artery is a life threaten­ing condition. Seventy-five percent of the pa­tients die before being deported to the hospi- Received 19 May 2004 Accepted 20 June 2004 Correspondence to: Anton Krnic, M.D., Department of Radiology, Sveti Duh General Hospital, Andrije Hebranga 9, 10 000 Zagreb, Croatia; Phone: +385 1 48 56 209; Fax: +385 1 37 72 136; Fax: +385 1 37 72 136; E-mail: anton.krnic@zg.t-com.hr or luka.krnic@zg.ht-net.hr tal.1 Out of the rest, 82% are deported to the hospital within 24 hours, and others between 24 and 48 hours or more.1 The injury requires immediate, on-place treatment (compression) and many patients (38%) require prompt ex-plorative surgery.1 In reports, some 85% of axillary artery traumas are caused by pene­trating (stab) injuries and 15% by blunt in­juries.2 Some 40-50% of the patients suffer from brachial plexus trauma: 2/3 from direct injury (partial or complete resection), 1/3 from com­pression due to enlarging haematoma.2,3 Unlike in cases of compression due to haematoma, in cases in which a direct injury of the brachial plexus occur, most patients do not have subsequent neurological improve­ment.2,3 Arterial repair is usually successful.4 However, even if it fails, a severe ischemia is a rarity and the amputation rate is low.4,5 In cases of ischemia of the upper extremity, the patients usually undergo saphenous vein in­terposition grafting that generally yields good results.4 The most frequently recurring symptoms are motor and sensitive deficiencies and dis­tal ischemia, which, in some cases, may not occur, owing to an extensive collateral net­work.3 However, whenever vascular injury is sus­pected, radiological follow-up (angiography), intra-operative or post-operative, should be performed.1,3,6 Our case reports a very syn­chronous cooperation between surgeons and radiologists, which led to a high-quality eval­uation of the patient. Case report A 28-year-old woman fell through a glass door in a nightclub. An hour later, she was deported to the hospital in shock due to pro­fuse bleeding in the left axillary fossa. Her pe­ripheral pulses where not palpable, and her pupils where dilated. The breathing was very shallow, barely registered. She underwent an immediate explorative surgery of the axilla. The axillary artery, vein and the brachial plexus were resected and the surgeons performed the reconstruction with an end-to-end anasthomoses of the vein and artery and tried to repair the brachial plexus. However, after the operation, the pulsa­tions of the arteries of the left arm were not palpable, although the arm was not pale, but warm and blushing. The surgeons decided to refer the patient for radiological evaluation. First, she under­went duplex ultrasound scanning. The exam­iner found a pre-stenotic high resistant spec- Figure 1a. Duplex ultrasound: high resistant, pre-stenotic attenuated spectra in the subclavian artery. trum in the subclavian artery and a post-stenotic, monophasic spectra in all left arm arteries (brachial, ulnar, radial), (Figures 1a, 1b). The axillary artery was not examined be­cause the patient complained of heavy pain and the arm could not be elevated. The ve­nous circulation, however, was satisfactory. The next day, she underwent selective an­giography. Using Seldinger technique, the sublcavian artery was reached with the catheter and the contrast was injected. The subclavian and the proximal portion of the axillary artery were opacified, but the other two portions of the axillary artery were not. The brachial artery was filled with a delay, through the network of collateral vessels. The distal arteries of the left arm were later also opacified (Figure 2). These findings con­firmed the Doppler findings that there was an obstruction in the axillary artery. The patient was planned to undergo saphe-nous vein grafting, but during the second op­eration, exploration with the Fogarty catheter through the incision in the brachial artery was performed and thrombi were found prox­imal to the incision, and so, she was success­fully thrombectomised. Immediately after­wards, the reperfusion was established: the previously thin artery, very poorly filled with Figure 1b. Duplex ultrasound: low resistant, post-stenotic monophasic spectrum in the ulnar artery. blood and initially very hard to find, started to inject blood through the hole of the inci­sion and became obviously much better filled after the arterial wall was sewed. Congruen­tly, its diameter was considerably increased afterwards. The follow-up after this, second, operation proved almost normal (lightly attenuated) Doppler spectra in left arm arteries, almost symmetric to the contra-lateral one and the surgeons did not indicate the second angiog­raphy (they did not find it necessary any more). Discussion Due to the trauma of the axillary fossa and postoperative thromboembolism of the axil­lary artery in our patient, the blood perfusion through the axillary artery was blocked and collateral perfusion network was established. Duplex ultrasound showed a characteristic pattern, pre-stenotic, high resistant spectra in the subclavian artery, and post-stenotic, »parvus-tardus« spectra in the left arm arter­ies. These findings seemed to be almost pathognomonic. Despite the very convincing duplex ultrasound findings, angiography was performed to confirm the findings. Angiography is highly invasive; some pa­tients often refuse it. It has a 1-2-percent risk for complications and may be expensive.1,7,8 However, in circumstances when angiogra­phy is not possible or not preferable for vari­ous reasons, the duplex scanning, as it seems, might be sufficient to set up the diagnosis.9,10 Some data report the overall accuracy of 98% of Doppler ultrasonography in the detection of vascular trauma.5 Besides, duplex scanning equipment is portable, the test is non-inva­sive and relatively easy to perform and no contrast is required.8 When the examinations are correctly per­formed, there should be, as in this case, high concordance between clinical presentation, radiological findings and surgical, intra oper­ative findings.6 With such concordance, the duplex ultrasound may be a gold standard for the evaluation of this kind of patients. On the other hand, according to some re­ports, in case of axillary artery trauma the sensitivity of duplex ultrasound examination is usually low and therefore, the examiner has to be very cautious.8 We thereby recom­mend the examiner to compare the findings of the subclavian and arm arteries of the in­jured body side to the contra-lateral to make sure the Doppler wave spectra differ highly in its morphology and resistance index. When postoperative thromboembolism of the axillary artery develops, collateral axillary network might be established,3,4 although it may provide, as is shown here, only attenuat­ed, temporary sufficient arterial perfusion of the arm. In such cases, re-operation is re­quired in order to establish normal, fully functional perfusion. As seen here, explo­ration with the Fogarty catheter and throm­bectomy may be sufficient, and the saphe-nous vein interposition grafting may not be needed. In this very case, though the surgeons tried to repair the resected brachial plexus, the left arm is still under palsy (»flail limb«).1 Although reperfusion initially worsened the nerve function and aggravated the fibre de­generation, it allowed the fibre regeneration to occur in the longer time frame.11 Though the necessary condition for a possible recov­ery of the nervous function, i.e. normal blood supply, was fulfilled, the patient still had to undergo a long-term rehabilitation with neu­rological follow-up (electromyography) and with uncertain and probably only partial im­provement of the nervous function.3 Further duplex ultrasound follow-up was also neces­sary. Since the injuries of the subclavian-axil­lary arteries have taken many lives,1 and, as shown here, can happen in relatively benign, peaceful circumstances, we highlight the im-portance of prompt reaction on-place, as well as prompt hospital admittance and surgical exploration whenever the vascular and/or nervous injury is suspected.1 This way, many lives could be saved and disabilities prevent­ed.1,5 We assume that the experience from the war in Croatia (1991-1995) of the surgeon on duty was probably beneficial in this situa­tion, since these kinds of injuries are uncom­mon and most surgeons lack familiarity with their management and few are able to gain significant experience (operative mortality rate ranges between 5 and 30%).1 The importance of radiology in such cases is high.1,3,6 It is applicable for possible intra-operative and is necessary for postoperative evaluation and follow-up.1,3,6 Although the angiography is considered to be a »gold stan-dard«,3,6-8 a correctly performed duplex ultra­sound should give sufficient information and can even exclude the need for angiogra­phy.5,8-10 We offer our duplex ultrasound findings as an example of that. In these, particular circumstances (postop­erative thromboembolism in the axillary ar­tery and establishment of the axillary collat­eral perfusion network), duplex ultrasound gave a highly typical and recognizable pattern (Figure 1). It is also the method we recom­mend for postoperative follow-up. References 1. McKinley AG, Carrim AT, Robbs JV. Management of proximal axillary and subclavian artery injuries. Br J Surg 2000; 87: 79-85. 2. McCready RA, Procter CD, Hyde GL. Subclavian-axillary vascular trauma. J Vasc Surg 1986; 3: 24-31. 3. Adovasio R, Visintin E, Sgarbi G. Arterial injury of the axilla: an unusual case after blunt trauma of the shoulder. J Trauma 1996; 41: 754-6. 4. Bastounis E, Pikoulis E, Leppaniemi AK, Michail P, Alexiou D. Revascularization of the limbs using vein grafts after vascular injuries. Injury 1998; 29: 105-8. 5. Nanobashvili J, Kopadze T, Tvaladze M, Buachidze T, Nazvlishvili G. War injuries of major extremity arteries. World J Surg 2003; 27: 134-9. 6. Julia J, Lozano P, Gomez F, Corominas C. Traumatic pseudoaneurysm of the axillary artery following anterior dislocation of the shoulder. Case report. J Cardiovasc Surg (Torino) 1998; 39: 167-9. 7. Ofer A, Nitecki SS, Braun J, Daitzchman M, Goldsher D, et al. CT angiography of the carotid arteries in trauma to the neck. Eur J Vasc Endovasc Surg 2001; 21: 401-7. 8. Bergstein JM, Blair JF, Edwards J, Towne JB, Wittmann DH, Aprahamian C, et al. Pitfalls in the use of color-flow duplex ultrasound for screening of suspected arterial injuries in penetrated ex­tremities. J Trauma 1992; 33: 395-402. 9. Bynoe RP, Miles WS, Bell RM, Greenwold DR, Sessions G, Haynes JL, et al. Noninvasive diagno­sis of vascular trauma by duplex ultrasonography. J Vasc Surg 1991; 14: 346-52. 10. Schwartz M, Weaver F, Yellin A, Ralls P. The util­ity of color flow Doppler examination in penetrat­ing extremity arterial trauma. Am Surg 1993; 59: 375-8. 11. Iida H, Schmelzer JD, Schmeichel AM, Wang Y, Low PA. Peripheral nerve ischemia: reperfusion injury and fiber regeneration. Exp Neurol 2003; 184: 997-1002. Ultrasound signs of acute appendicitis in children - clinical application Sandra Vegar-Zubovic1, Lidija Lincender1, Salahudin Dizdarevic2, Irmina Sefic1, Faruk Dalagija1 1Institute of Radiology, 2Pediatric Surgery, Clinical Center of University in Sarajevo, Bosnia and Herzegovina Background. Acute appendicitis is a leading cause of the abdominal pain in children that need an urgent surgical treatment. Neither of individually clinical variables doesn’t have a real discriminational nor pre­dictive strength to be used as the only diagnostic test. A goal of this study is to define ultrasound criteria of the acute appendicitis by appointing of ultrasound parameters for this pathological condition, determine the relation between ultrasound signs and pathohistological finding, determine the connection of several ultra­sound signs with a degree of the inflammation of the acute appendicitis. Methods. In the prospective study with an ultrasound method we examine 50 patients with clinical signs of the acute abdomen. In these patients, the sonographic diagnosis is confirmed by the surgical finding, in fact with a pathohistological diagnosis. A basic, positive sonograph finding of the acute appendicitis was the identification of tubular, noncompresive, aperistaltic bowel which demonstrates a connection with coecum and blind terminal. In our work we analysed the lasting of the symptoms until the hospital intervention in patients stratified according to the pathohistological finding. We used ultrasound equipment- Toshiba Sonolayer with convex 3.75 MHz and linear 8 MHz probes. Results. From 8 ultrasound signs of the acute appendicitis, only an anterior-posterior (AP) diameter of ap­pendices, FAT (width of periappendicular fat tissue) and a peristaltic absence are positive ultrasound signs of the acute appendicitis. Appendicitis phlegmonosa is the most common pathohistological finding in our study (44%). Perforate gangrenous appendicitis and gangrenous appendicitis are represented in more than half of patients (30% + 22%), which suggests a long period of persisting symptoms until a hospital treat­ment. A statistic analysis shows a great possibility for using values of AP diameter, width of periapendicu­lar fat tissue, just like the values of mural thickness in the evaluation of the appendix inflammation level. Conclusions. Ultrasound is an absolute method of choice in the eventual doubt of the existing state of acute appendicitis, with 8 ultrasound signs that defined this pathological condition. AP appendix diameter, mural thickness and width of periapendicular fat tissue represents highly significant ultrasound criteria in the evaluation of the appendix inflammation level. Key words: appendicitis-ultrasonography; child Correspondence to: Sandra Vegar-Zubovic, MD, Institute of Radiology, Clinical Center of University in Received 7 June 2004 Sarajevo, Bosnia and Herzegovina; E-mail: denin@ Accepted 23 August 2004 bih.net.ba Introduction Acute abdomen is characterized by appearing of a sudden pain in the abdomen with a dys­function; it appears suddenly and unexpec­tantly and it is caused with large number of changes on different abdomen organs. A clin­ical picture of the acute abdomen is one of the most divert and most complex conditions in the human body because of the beginning and course of the illness which is dependent o a large number of different organs in the abdomen. Acute appendicitis is a leading cause of an abdominal pain in children which demands an urgent surgical treatment. Clinical symptoms and signs depend, in the first place, on children’s age, as well as on the pathological phase of appendicitis during the clinical examine. Beside the abdominal pain the acute inflammation of appendix is char­acterized with nausea, vomiting, anorexia, fever, diarrhoea, constipation, face blushing and tachycardia. Little patients preferred ly­ing on the back in the supinatory position or on the right decubitus, quietly, because every motion causes pains. Cope made a list of 34 illnesses which lead to acute abdominal pains, and those conditions, according to signs and symptoms, which imitate the acute appendicitis. This list could be a longer, if we include immunodeficiency syndromes and another immunodeficiency states.1 The differential diagnosis of an abdominal pain is one of the fascinating, but mysterious questions for the clinical surgery. Reginald Fitz (1886) gave his own historical session de­scribing a new pathological entity - appen­dicitis. And after 100 years, the exact diagno­sis of this mysterious disease is still a huge problem.1,2 A diagnostic imaging of an acute abdomi­nal pain in children is very hard, because lit­tle patients are not capable to give us relevant data. Besides, an acute, non-specific abdomi­nal pain, which is very common in children, these little patients with an abdominal pain usually have symptoms that last longer than 24 hours (2/3 patients). If diagnosis and treat­ment are delayed, the morbidity and mortali­ty of little patients increase. A diagnosis of typical clinical picture of the acute appendici­tis is relatively easy, but in 30-45% of little pa­tients it is presented with atypical clinical signs and symptoms which implicates the ad­ditional diagnostic imaging.3,4 Neither diagnostic variable individually (clinical and laboratory parameters) doesn’t have significant discriminating nor predictive strength to be used as a relevant diagnostic test. There is a high risk of the incorrect diag­nosis in some populations, especially in chil­dren without the existence of a relevant diag­nostic test. The exact and prompt diagnosis is essential for minimizing of morbidity. The goal of a modern surgical approach es­sentially is the same as in the 19th century, but today it is focused between percent of false negative appendectomy and percent of perforation in the time of the surgical obser­vation. Introducing of ultrasound in the diag­nosis of acute appendicitis, as this study shows, represents our aspect in leading of a modern medical protocol for young patients in this condition. Methods In the prospective study we analysed the pos­sibilities of ultrasound in diagnosis of the acute appendicitis in children. The research compassed 50 children in age from 0 to 16 years in whom ultrasound find­ings are confirmed with an operative, respec­tively, with a pathohistological finding (verifi­cation). These patients are observed and treated in the Clinic for Children’s Surgery of Clinical Center Sarajevo initiated from Dom zdravlja Sarajevo. The study includes patients with both genders, with a clinical picture of the acute abdomen with its symptoms that occurred for the first time. All patients are initially examined by the children’s surgeon who, after clinical and lab­oratory findings, referred children to the ul­trasound examination. After the examination of the pelvis minor abdomen - the area of a maximum pain which a patient pointed with his/her finger (self-lo­calisation) - the ileocoecal area was examined with a systematic ultrasound approach be­cause of the possibility of the aberrant locali­sation of appendix. A definition of the positive acute appen­dicitis sonograph finding was based on the identification of tubular, non-compressed, aperistaltic bowel which demonstrates a con­nection with caecum and clearly visible bow­el blind terminal. By a careful approach, on the basis of eight ultrasound signs of acute appendicitis, we determined a connection be­tween some US signs and a degree of the in­flammation of the acute appendicitis. In the study we tried to analyse the lasting of symp­toms until the hospital intervention in pa­tients divided according to the pathohistolog­ical finding. All examinations were done with the ultra­sound unit Toshiba Sonolayer SAL 77 with convex (3.7 MHz) and linear (8 MHz) probes. Little patients were coming to be ultrasound examined as the urgent cases during the day or in the evening hours after they had been examined by their surgeon. A dosed com­pression in the ileocaecal area with a linear probe enabled the approach of ultrasound waves by gaping bowels with its content. Patients can suffer moderate compression as long as it is gentle, and according to the in­tensity it is identical to moderate deep palpa­tion of the physical examination. For the identification of appendix it is necessary to find essential constraints: identify coecum and right colon in the transversal and longi­tudinal plane, identify musculus psoas and external iliac artery, and also identify termi­nal ileum. Results Table 1 shows basic demographic data of all patients. There is no significant statistical dif­ference of the mean value (using age frequen­cies) between two groups of patients (p>0.05). Table 2 shows eight ultrasound signs of acute appendicitis that are individually analysed in each patient. Figure 1 shows pathohistological findings of the examined group of little patients. From these data we can see that appendicitis fleg­monosa is the most common pathohistologi-cal finding (44%) (Figures 2a, 2b). In more than half of examined patients gangrenous appendicitis and perforate gangrenous ap­pendicitis (30% + 22%) were found, which suggests a long existence of symptoms until the hospital treatment. Table 3 analysed the lasting of symptoms until the hospital inter- Table 1. Basic demographic data in the examined group of patients Table 2. Ultrasound signs in the examined group of patients Group I Total Male Female Age interval 3-16 4-16 3-16 N 26 24 50 X 9.864 11.083 10.440 S 3.518 3.900 3.721 Sx 0.690 0.796 0.526 Mediana 9.5 11.5 11 X2= 0.0801; p=0.777 Anterior-posterior Mural Air in Inflame Lack of Intra- Persistence of Local diameter (AP) wall lumen surrounding peristaltic luminal lymphonodes pericoecal thickness (AIR) fat tissue appendicolitis in appendix fluid in (MWT) (FAT) region abdomen NegativeUS signs 0 0 0 0 0 15 (30%) 4 (8%) 29 (78%) Uncertain signs 0 6 (12%) 10 (20%) 0 0 9 (18%) 11 (22%) 0 Positive US 50 44 (88%) 40 (80%) 50 (100%) 50 (100%) 26 (52%) 35 (70%) 11 (22%) signs (100%) Table 3. Existing of symptoms until hospital intervention Appendicitis Appendicitis Appendicitis Appendicitis catharalis flegmonosa gangrenosa gangrenosa perforata N 2 22 11 15 Interval 4-8 4-48 10-48 14-72 X 6 20.091 24.909 34.067 S 2.828 12.641 12.661 19.073 Sx 2 2.695 3.817 4.925 Mediana 6 16 20 24 Mann-Whitney test t = 5.00 , p= 0.042 Figure 1. Patohistological findings in the examined group of patients. 1 apendicitis gangrenosa perforata; 2 apendicitis flegmonosa; 3 apendicitis catharalis; 4. apendicitis gangrenosa. vention in all patients divided according to the pathohistological finding. Using a suma range test we can see that 2/3 of patients with acute appendicitis have symptoms which last more than 24 h. There is a direct correlation between the percent of perforations and the period of lasting symp­toms; and also time of delay of the hospital treatment and time of the observation before admitting to hospital have a significant influ­ence. In the following tables, using suma range test, we tested the possibility of using values Table 4. Anterior-posterior (AP) diameter of appendix in the examined group of patients (n=48), except appen­dicitis catharalis (n=2) Appendicitis flegmonosa Appendicitis gangrenosa Appendicitis gangrenosa perforata N 22 11 15 Interval AP diameter 7-12 10-18 9-14 X 9.318 13.455 11.067 S 1.427 2.659 1.534 Sx 0.304 0.802 0.396 Mediana 9 13 11 T=-5,854; p<0,001 T=2.894; p=0,008 Mann-Whitney P=0,003 test (app.flegmonosa vs app. perforata gangrenosa) Table 5. Mural wall thickness (MWT) of appendix in the examined group of patients (n=48), except appen­dicitis catharralis (n=2) Pathohistological finding Appendicitis. flegmonosa Appendicitis gangrenosa App. gangrenosa perforata N 22 11 15 MWT interval 2.5-4 3-5 2.8-5 X 3.145 3.664 4.056 S 0.436 0.612 0.816 Sx 0.093 0.185 0.204 Mediana 3 3.5 4 p = 0.012* p = 0.217* Mann-Whitney p = 0.001* test (app.flegmonosa vs. app. perforata gangrenosa) Table 6. Inflame surrounding fat tissue (FAT) around appendix in the examined group of patients (n=48) except appendicitis catharralis (n=2) Pathohistological finding Appendicitis. flegmonosa Appendicitis gangrenosa App. gangrenosa perforata n 22 11 15 MWT interval 7-13 9-15 11-20 X 10.045 12.182 14.200 S 1.430 2.272 2.426 Sx 0.305 0.685 0.626 mediana 10 12 14 p = 0.013 p = 0.042 Mann-Whitney p < 0.001 test (app.flegmonosa vs. app. perforata gangrenosa) of: Anterior-posterior diameter (AP), Mural wall thickness (MWT), Inflame surrounding fat tissue (FAT) (Tables 4, 5, 6) in estimating of degree of appendix inflammation. Statistic analysis shows a great potential and possibil­ities of using AP and FAT in estimation of the inflammation degree in everyday practice. A statistical analysis shows the limited possibil­ity of using mural wall thickness values in gangrenous appendicitis and perforate gan­grenous appendicitis. In that case we use oth­er ultrasound signs that can determinate these pathological conditions. Sensitivity of ultrasound method in our study is 85%. Discussion The incidence of appendicitis appearance is usually between 5-10 years of age. Homogeneity of the group is showed with mean value where it is proved that there is no significant difference in the examined age fre­quency (p> 0.05). Homogeneity of our group also showed that the appearance of acute ap­pendicitis will be most common in age be­tween 5 and 10 years, without gender pre­dominance. Until puberty, the incidence of appendicitis is the same at boys and girls, and in the puberty prevalence is in male popula­tion with rate 2:1.5 There is no significant connection between life style, taking some specific food or genetic predispose for arising of the acute inflammation of appendix.6 Until 1986, the conventional radiography, includ­ing standard abdomen radiography and iri­gography, represents the only radiological methods, beside clinical and laboratory find­ings, that tried to limit the differential diag­nosis of the acute appendicitis. Detailed clas­sifying of the clinical examination can in cer­tain percent reduced the differential diagno­sis and constrains it to possible acute appen­dicitis: pain migration to lower right quad­rant, pain deterioration because of motion, cough, anorexia and vomiting and indirect tenderness (Rovsing sign). Children with an »uncertain« diagnosis deserved further diag­nostic imaging or observation depending to aspect and lasting of symptoms. High percent of acute gangrenous appen­dicitis and perforate gangrenous appendici­tis, which our study shows, suggests a long period of persisting symptoms until the hos­pital treatment. Unfortunately, only two pa­tients had appendicitis catharalis. Percent of perforations and complications of the acute appendicitis in children’s age is still very high. The reasons for that are because little patients don’t recognise and don’t show signs and symptoms of the disease, appearance of clinically atypical picture of the acute appen­dicitis, quick evaluation of disease in these patients, health ignorance of parents. Worell S et al. in its study on 200 patients offered on­ly four criteria for the analysis of acute ap­pendicitis: 1. visualisation of appendix, 2. an­terior-posterior diameter AP > 6 mm, 3. mural thickness of appendix MWT > 3 mm, 4. ap­pearance of complex mass in ileocaecal area. Because of limiting factors that characterized this study, its sensitivity was only 68%.7 Our study offered eight ultrasound signs of the acute appendicitis. Results showed that AP diameter, FAT and peristaltic absence are certain ultrasound signs of the acute ap­pendicitis, and also FAT and AP have a great potential in defining the appendix inflamma­tion degree, while MWT have a limited possi­bility in that case. According to the experi­ence in our study, in patients without the pos­sibility of visualisation of appendix, and with the appearance of good and clearly visible pericaecal fluid and changed pericaecal fat tissue, we can make a conclusion that it is perforate appendicitis. Most common mistakes in US imaging of appendicitis compassed the commutation be­tween appendix and terminal ileum, and also between normal and inflame appendix.8 Terminal ileum doesn’t rise from caecum base, doesn’t have blind terminal but shows very accelerating peristaltic, and in transver­sal scanning it is oval describing to appendix which is clearly round as a »target«. False negative results in the ultrasound examina­tion can appear in overweight patients and in atypical localisation of appendix.9 Conclusions The initiation of ultrasound in diagnostic im­aging of the acute abdomen allowed a high percent of diagnostic assurance in little pa­tients. With the experience true continuous work with an ultrasound technique and by understanding of criteria of acute appendici­tis, the improvement of diagnostic assurance can be achieved. The continuation of hospital observation and treatment increase the mor­bidity and mortality of patients with the acute abdomen. Concretely, the persistence of symptoms from beginning of the disease un­til the initial ultrasound examinations and surgical treatment is in a direct proportional relation with the degree of appendix inflam­mation. Anterior-posterior diameter (AP), mural thickness (MWT), periapendicular fat tissue width (FAT) represent highly reliable US signs in the evaluation of degree of the acute appendicitis inflammation. Ultrasound is a cheap method, without a harmful effect, quick and simple, and using a real-time inter­active technique. The aim of a modern surgical approach is essentially the same as in the 19th century, but today, it is focused between the percent of false negative appendectomies and the one of the perforation during the time of the sur­gical observation. The initiation of ultrasound in imaging of specific cases of the acute ap­pendicitis, as this study shows, represents a modern (up to date) surgical approach and qualifies a modern medical protocol for little patients in this condition. References 1. Tarjan Z, Jaray B. What are the sonographic sing of appendicitis? European Congress of Radiology 2000; 10(2 Suppl 1): 115. 2. Wilson EB, Cole JC, Nipper ML, Cooney DR, Smith RW. Computed tomography and ultra-sonography in the diagnosis of appendicitis: when are they indicated? Arch Surg 2001; 136: 670-5. 3. Sivit CJ, Siegel MJ, Applegate KE, Newman KD. When appendicitis is suspected in children. Radiographics 2001; 21: 247-62. 4. Pena BM, Taylor GA, Fisheman SJ, Mandl KD. Cost and effectiveness of ultra sonography and limited computed tomography for diagnosing ap­pendicitis in children. Pediatrics 2000; 106: 672-6. 5. Rettenbacher T, Hollerweger A, Macheiner P, Rettenbacher L, Tomaselli F, Schneider B, et al. Outer diametar of the verifirm appendix as a sign of acute appendicitis: evaluation at US. Radiology 2001; 218: 757-62. 6. Hartamn GE. Acute Appendicitis. In: Jensen BK, editor. Text book of pediatric.16th edition. Philadelphia: W.B. Saunders Company; 2000. p. 1178-81. 7. Rettenbacher T, Hollerweger A, Macheiner P, Rottenbacher L, Frass R, Schneider B, et al. Presence or absence of gas in appendix: Additional criteria to rule out of confirm acute ap­pendicitis - evaluation with US. Radiology 2000; 214: 183-7. 8. Gutierrez CJ, Mariano MC, Faddis DM, Sullivan RR, Wong RS, Lourie DJ, et al Doppler ultrasound accurately screens patients with appendicitis. Am Surg 1999; 65: 1015-7. 9. Velanovich V, Harkabus MA, Tapia FV, Gusz JR, Vallance SR. When its not appendicitis. Am Surg 1998; 64: 7-11. review The MR imaging as a one-way shopping tool for detecting and staging renal tumours Galina Kirova Department of Radiology, University Hospital Lozenetz, Sofia, Bulgaria Background. Magnetic resonance imaging is one of the most attractive approaches: the technology is wide­ly available, it is not associated with the exposure to ionizing radiation, and does not require the injection of iodinated contrast agent. High-field strength clinical magnets, high-performance gradient hardware, and ul­trafast pulse sequence technology are rapidly making the vision of a comprehensive »one-stop shop« uro-logic MR imaging examination a reality. Conclusions. Difficulties that remain are related to the variable protocols of the examination and, therefore, it is mandatory to standardize as much as possible the techniques that are used in order to obtain repro­ducible information. Key words: kidney neoplasms - diagnosis; magnetic resonance imaging; neoplasms staging Introduction Since the only successful curative treatment of renal tumours is surgery, accurate radio­logical information is crucial during the initial tumour staging for an optimal operative plan­ning. The preoperative assessment of renal carcinoma includes tumour size, tumour ex­tent, in particular capsule invasion with tu­mour spread to perinephric fat with or with­out direct invasion of adjacent organs outside Received 5 July 2004 Accepted 10 September 2004 Correspondence to: Galina Kirova, MD. PhD, Department of Radiology, University Hospital Lozenetz, 1 Koziak st, 1407 Sofia, Bulgaria; Phone: +359 888 401 678; E-mail: kirovag@yahoo.com Gerota’s fascia, regional lymph node metasta­sis, venous tumour thrombosis, and distant metastases.1 Intravenous urography, angiog­raphy and ultrasound have been the main in­vestigations for a long period of time. All these methods are complementary and each has advantages and disadvantages. None of these single methods are sufficient for the evaluation of all aspects involved in oncolog­ic urologic pathology. Nowadays the prether­apeutic planning of renal carcinoma has dra­matically improved in the use of cross-sec­tional imaging, in particular CT and MRI. Magnetic resonance imaging is one of the most attractive approaches: the technology is widely available, it is not associated with the exposure to ionizing radiation, and does not require the injection of iodinated contrast agent.2 In recent years a number of reports on dy­namic MRI have evaluated renal functioning and morphological changes. Dynamic MRI has proven able to integrate renal scintigra­phy in documenting functional impairment and to supplement the information acquired by other imaging techniques on the morphol­ogy of the kidney.3 Stimulated by the philos­ophy and results of the all-in-one examina­tion for pancreatic neoplastic disease, Verswijvel et al invade a similar approach for the evaluation of urologic disease. Cross-sec­tional sequences, MR angiography in the ar­terial and venous phase, evaluation of the re­nal parenchymal and lesional perfusion, and contrast-enhanced MR urography were com­bined in one imaging session.4 The method gained a widespread acceptance as a stan­dard for patients in which several conven­tional complementary modalities must be performed and is fairly well illustrated for pa­tients with neoplasms of the renal parenchy-ma or urothelium. The aim of the paper is to describe an all-in-one approach protocol for MR examination of patients with suspected or proved renal tu­mours in order to achieve all necessary pre­operative (pretreatment) information. Some explications of the possibilities and clinical usefulness of each one MR series will be done. Paramagnetic contrast materials Advances in the application of MRI in kid­ney’s pathology depend predominantly on the use of magnetic resonance contrast Table 1. Example of order of the sequences for an all-in-one approach protocol 1. AX T1 WI 2. AX T2 FSE WI 3. COR T2 FSE WI double echo half-Fourier acquisition single-shot turbo spin echo + FAT SAT + IN/OUT Phase T1 4. Furosemide+Gd (Gd-DTPA 0,2mmol/kg body weight, injection rate 2,5ml/s and Furosemide 0,1mg/kg body weight) Breath-hold 3D gradient echo MRA Breath-hold 3D gradient echo MRU 5. Postprocessing Table 2. Parameters of the MR sequences (for GE 1.5T Signa). Phased-array torso coil. (TE-echo time, TR-repeti­tion time, FA-flip angle, ST-slice thickness, FOV-field of view) Pulse TR(ms) TE(ms) FA(’) ST(mm) FOV(mm) Matrix(mm) orientation Scan time sequence COR T2 SSFSF 2300 80 -8 36 256/256 coronal 48s COR T2 SSFSE 1300 200 -3 36 256/160 obl 16s AX T1 BH dual 160 2,2/4,4 80 8 36 256/128 axial 33s echo AX T2 FRFSE 3000 85 -8 36 256/256 axial 4,07min AX 3D SPGR 4,6 1,8 15 5 36 256/160 axial 20sec/phase Dyn+CM URO COR 3D SPGR 150 6 80 8 36 256/128 coronal 20s agents to enhance both parenchyma and tu­mours. The most widely used contrast agents are chelates of gadolinium (Gd). Its chemical structure comprises a Gd-ion with a triple positive charge combined with a DTPA de­rivate, forming a very stable complex. The strongly paramagnetic gadolinium has sever­al effects. It can change (relax) the magnetic state of hydrogen atoms in water molecules; this markedly changes the appearance of tis­sues, with a high contrast agent uptake in T1­weighted images, causing tissues to appear bright. High concentrations of gadolinium chelates can also induce local changes in the magnetic field (magnetic susceptibility). This is most apparent during the first pass of a bo­lus of contrast agent after the rapid intra­venous injection. On gradient echo T2*­weighted images, this effect is apparent as a darkening of the image in well-perfused areas of tissue. Gadolinium-DTPA is eliminated rapidly and completely by the renal excretion with­out tubular reabsorbtion. The half-time of Gd-DTPA in blood is ~90 minutes. More than 91% of the administrated dose is eliminated after 24 hours. The elimination depends only upon the glomerular filtration rate. The renal insufficiency is not a contraindication for the contrast material administration. The recommended contrast dosage for magnetic resonance imaging of the kidneys is 0.1 mmol Gd-DTPA/kg BW. The administra­tion of contrast material should be mechani­cal with the use of automatic injector after the correct timing of the bolus injection in order to synchronize the moment of the peak renal artery enhancement with the acquisition of central k-space data.5 The intravenous administration of an ex­tracellular paramagnetic contrast material provides a means for imaging the circulation. Dynamic measurements, in which the uptake and washout of contrast in tissues is moni­tored with time, can assist in the diagnosis and can provide information on vascular per­meability and perfusion, by quantifying and analyzing image intensity changes, and fit­ting these to analytical or model functions. Dynamic information shows the rate at which tissue enhances, and subsequently the rate at which contrast agent washes out. This de­pends on the delivery of the agent (perfu­sion), the ability of the agent to leak out of the vasculature (vascular permeability), and the extracellular volume. Usually, a region of in­terest (ROI) is selected within the tumour, and the software that is provided with the magnetic resonance scanner is used to evalu­ate the change in signal intensity with time in that ROI. Technique of MR imaging of the kidneys Patient positioning and coils The patient is examined in supine position with both arms lying flat against the body, us­ing a phased-array torso coil to optimize sig­nal-to-noise ratio. Prior the examination pa­tients would be informed about the necessity of breath-holding in some sequences. Field strength Presently recommended systems for the per­formance of MRI of the kidneys with contrast material have the field strength of 0.5 to 1.5T and most published studies using fast GE se­quences have been performed on higher field strength systems. The advantage is that the paramagnetic contrast material has a greater effect on the signal due to the increased T1 re­laxation time of enhancing tissues at higher field strengths. At the same time the high-field strength machines allow to perform fast techniques, required for the angiographic and dynamic studies. Imaging protocol The imaging protocol should be designed for the evaluation of the kidney and the entire upper urinary tract and should include unen­hanced and enhanced phases. Morphological assessment The imaging protocol for renal tumour stag­ing should include conventional or fast-spin echo sequences in axial and coronal projec­tions for assessing the morphology of both kidney and tumour parenchyma.6 T2-weighted sequences In T2-weighted sequences, hydrous or oede­matous structures emit an intense signal. Spin-echo (SE) or fast-spin-echo (FSE) se­quences are the T2-weighted sequences most commonly used in MR imaging of the ab­domen. COR T2 weighted images using the half-Fourier acquisition single-shot turbo spin echo technique permits in a very short exam­ination time to visualize kidneys, ureters and urinary bladder, giving the possibility for the rough orientation. Usually they are acquired before performing contrast enhanced dynam­ic measurements (Figures 1, 2a, 2b, 2c). T2-weighted images are useful in recogniz­ing small cysts only a few millimetres in di­ameter with high sensitivity.7 This is an ad­vantage of MR imaging compared with the CT, where the partial volume effect leads to confusion in such kind lesion characteriza­tion. T1-weighted images The axial T1WI focused at the kidney gives an excellent T1 contrast independent of patient breathing. If »bright« spots (hyperintense le­sions in T1) are detected, breath-hold T1 fat suppressed gradient echo pulse sequences should be obtained to exclude or confirm the pres­ence of fat lesion. This technique is especial­ly useful in cases of the suspected intratu­moural haemorrhage or fat-containing le­sions.8 Chemical shift can be used as a tool for delin­eating structures that are surrounded by fat. Out-of phase images can aid in the demarca­tion of the renal contour, the margin of the adrenal glands, and the liver edge. Gradient-echo images that use out-of phase chemical shift demonstrate dark lines around organs embedded in fat. Those dark lines are created by the phase cancellation of the fat and water signals that exist within the voxels of the lipid-water interface. The width of the dark lines can be accentuated by increasing the field of view. The use of a narrower band­width will also increase the chemical sift banding seen on the images (Figures 3a, 3b, 3c).9 Chemical shift MR imaging has become a popular technique for diagnosing adrenal adenomas. Benign adrenal adenomas, which are typically composed of approximately 16% lipid based on in vivo studies,10 can demon-strate measurable differences in signal inten­sity when their appearance on in-phase gradi­ent-echo images is compared with that on the Figures 3a, 3b, 3c. COR and Ax T2WI of a 34 years old man with renal cancer demonstrate round high-inten­sity renal tumour, protruding the renal contours and invading the perirenal space (arrow in a and b). AX out-of phase T1 image of the same patient shows a mass invading into the inferior aspect of the liver, as evidenced by the interruption of the dark cortical line (arrow in c.) that demarcates the liver margin (c). ab out-of-phase counterparts. A decrease in the signal intensity of greater than 20% within an adrenal mass on out-of-phase images helps to confirm the diagnosis of an adrenal adeno­ma.11 Adrenal metastases, on the other hand, typically do not contain any significant lipid elements and will not demonstrate an appre­ciable change in the signal intensity with in-phase and out-of-phase chemical shift imag­ing (Figures 4a, 4b). Combined morphological and functional assessment Contrast-enhanced MRI Multi-phase breath-hold 3D volume acquisi­tion is the technique of choice for evaluating renal vessels and dynamic changes in renal parenchyma.12,13 Two technical developments are essential to the successful use of fast 3D MR sequence: the availability of high-performance gradient systems as well as dedicated surface coils. The implementation of high-performance gra­dient has enabled the acquisition of complex 3D sets with ultrashort repetition (TR) and echo (TE) times within a comfortable breath-hold period. The ultrashort TR in conjunction with a relatively high flip angle minimizes the signal of all abdominal tissues. Against this background, structures containing T1-short­ening contrast agents can be made selectively visible.14 In the 3D technique, the entire part of the body is exited as a volume. This volume can be divided into the so-called partitions, or slices of variable thickness, in any desired plane. 3D imaging allows the depiction of thin slices without gaps in a defined slice pro­file. Generally a volume block of 150mm with, for example, 30 partitions is used for an examination with axial angulation. The re­sulting slice thickness is 5mm. The coronal angulation permits the use of a rectangular FOV. The resulting time gain allows the ac­quisition of a greater number of partitions, optimizing the spatial resolution. For the purpose of tumor staging MRA is performed in the axial plane, with the top of the volume at the diaphragmatic level and the base below the level of lower renal poles. The volume should extend posteriorly to encom­pass both kidneys. This large field of view combined with an acquisition matrix of 512 Figures 4a, 4b. AX in-phase (a) and out-of phase (b) T1 images of a 56-years-old man with metastatic clear cell re­nal carcinoma in the left adrenal glad. No differences in signal are seen on the two images. Metastases generally do not contain fat and do not exhibit the signal loss by chemical shift effects. in frequency and 128-256 in phase-encoding direction is typically used. The use of multi­phase sequence gives the possibility to repeat the series from three to ten times, depending on the suspected pathology.5 Angiography for preoperative arterial and venous mapping The determination of the extent of intra­venous tumour growth is of paramount im­portance, since it affects the operative ap­proach in many cases. Venous involvement is one of the cornerstones of the surgical plan­ning in renal tumours. A few studies have re­ported the usefulness of MR angiography in the preoperative assessment of venous in­volvement in patient with renal cell carcino­ma, as well in tumour characterization. In the study of J.P. Laissay et al venous diameter en­largement was the hallmark of tumour throm­bus, with a sensitivity of 84% and a specifici­ty of 94%. At the same time the use of Gd-en­hanced imaging improved the diagnostic yield of morphological data by additional in­formation upon the thrombus enhancement (Figures 5, 6, 7a, 7b).15 Serial MR imaging for evaluation of renal parenchyma and tumour vascularity Regarding the functional evaluation, the ki­netics of gadolinium chelates during passage through the kidneys has been described in many reports. In the normal kidney four phases can be distinguished in the transit of the paramagnetic contrast agent through the parenchyma: the cortical, corticomedullary, medullary and excretory phases. For these reasons, the generally accepted guidelines re­quire that dynamic measurements (at least five measurements after CM administration) have a temporal resolution of 20-25sec per se­quence. This makes possible the discrimina­tion between pathological processes and sur­rounding parenchyma, as well as the acquisi-tion of a sufficiently accurate dynamic curve. Researches in this field have established the way in which changes in the kinetics of the Figures 7a, 7b. Postcontrast MR imaging of a patient with large left renal cell carcinoma with thrombus within the left renal vein and IVC. Ax image shows thrombus within IVC (arrow in a.) resulting in a filling defect. Reconstructive image in coronal plane in the same patient shows the large thrombus extending in­to the vena cava up to the level of hepatic veins (punc­tuate arrow in b.). contrast agents in the kidney reflect alter­ations in the renal function.16-19 Admini­stration of gadolinium compounds is not con­traindicated in patients with the impaired re­nal function, and it is therefore possible to study renal perfusion and excretion in pa­tients with a chronic renal failure by dynamic MRI.20 Assessing the corticomedullary phase alone may result in clinically significant er­rors, since small hypovascular tumours of the renal medulla may be missed since they are not sufficiently enhanced and hypervascular cortical renal cell carcinomas may enhance to the same degree as the normal cortex. During the early nephrographic phase inhomoge­neous enhancement of the medulla may be al­so misinterpreted as a mass lesion. This arti­fact disappears later in the nephrographic phase.21 Advantages of the corticomedullary phase include the differentiation of the nor­mal variants of renal parenchyma from renal masses and the better depiction of tumour hypervascularity improving the characteriza­tion of solid renal mass lesions.22 The nephrographic phase is considered the optimal phase for the detection and charac­terization of renal masses, in particular of small renal masses, providing both homoge­neous enhancement of cortex and medulla and lesion enhancement (Figures 8a, 8b). In principle, it is possible to perform MRI examinations at any angulation. For dynamic MRU, the coronal slice orientation is general­ly preferred. The main advantage of the coro­nal slice orientation is that it permits the se­lection of a rectangular FOV, which makes to allow the reduction of the slice thickness and the optimization of the spatial resolution to 2mm. The disadvantages are that the whole ~volume of the slab is reduced and it is not al­ways possible to visualize the whole ab­domen. This is very important in cases of abundant collateral vessels (after CVI throm­bosis) or in cases of tumour staging, when the condition of the liver is crucial. The axial slice orientation is that it makes a good assessment of the whole abdomen, which is of great importance in case of onco-logic disease. The sagittal and parasagittal orientation is not routinely recommended for use. They are, however, employed in the examination of pyelo-ureteral junction pathology and ob- Figures 8a, 8b. Angiographic phase in a patient with relapsed Wilm’s tumour (the same patient as in pic­ture 2) showing a strengthed and displaced right renal artery (arrow in a.). Axial image of the same patient in the parenchymal phase, demonstrating the possibility of comparing the signal intensity levels in different tu­mor levels and the spared part of the kidney (b). tained for each individual excretory system having the major advantage of data acquisi­tion of nearly isovolumetric voxels. This is due to the fact that the effective slice thick­ness can significantly be reduced which in­creases the image resolution both in the na­tive and MIP images. MRU for evaluation of collecting system The term MRU is used for a MR examination which combines different techniques for vi­sualizing the urinary tract.23 This can be per­formed with the so-called heavy T2 tech­niques receiving a signal from fluid-field structures or at the end of contrast-enhanced MR of the kidneys.24,25 Later the collecting system and the ureters are visualized during the excretory phase as reformatted 3D im­ages. MRU in the excretory phase provides the volume scanning of the kidney and the upper urinary tract within one breath hold. The visualization of the renal collecting sys­tem and ureter is significantly improved due to the avoidance of respiratory data misregis­tration improved resolution and data sets suitable for 2D and 3D reconstructions. The multiplanar reformation creates images simi­lar in appearance to IVU. For this purpose the measurement volume should extend as far posteriorly as possible to encompass the pelvic segment of the ureters and anteriorly to encompass the anterior bladder wall. The top of the coronal volume should be set above the upper pole of the kidneys at the one end and just inferior of the bladder base at the other. In particular cases sagitally oriented images for each kidney could be performed using smaller field of view, reduced effective slice thickness and respective generating, more detailed images. The latter is obtained for each individual excretory system and has the major advantage of data acquisition of nearly isovolumetric voxels, which has a ma­jor benefit in the MIP images. The lumen, the wall, the structures adja­cent to the collecting system and ureter as well as the contrast enhancement are as­sessed on axial and MPR views. When pathology is depicted on axial images the re­formatted images are of additional diagnostic value to the axial ones being not only a means to present an abnormality in an easily under­standable manner. MRU has the potential to become a primary investigation in the evalua­tion on the upper urinary tract; however, its sensitivity for the diagnosis of subtle urothe­lial lesions is unknown and needs to be eval­uated by clinical validation studies (Figures 9, 10). The evaluation of the images could be done on the original images (a), or on the ed­ited MIP images (b) (Figures 11a, 11b, 11c). Figures 11a, 11b, 11c. Coronal and axial images in a patient with left renal cell carcinoma and retroperi­toneal lymph nodes, leading to an obstruction of the right pyelo-ureteral system (arrow in a). Note the necrotic parailiac lymph node on the right side (arrow in b). Edited maximum intensity projection (MIP) of the MR urogram of the same patient (c). Post processing Conclusions Postprocedure processing of the MRA and MRU data could be supplementary obtained by means of a maximum intensity projection algorithm. MIP technique yields a three-di­mensional comprehensive view of both kid­neys and their vessels. Based on post processed subtraction images in which only image pixels having at least a certain signal intensity are taken into account (threshold value algorithm), the representation of image information gives the impression of a real 3­dimensional angiographic or urographic views.26 The resultant MIP images with sub­traction techniques allow the adequate visu­alization of the renal vessels - renal arteries, renal veins and inferior vena cava. This form of imaging allows a simpler spatial orienta­tion and is especially suitable for the presen­tation of suspicious findings. MPR images allow the three-dimensional view of partial volumes within the abdomen. These are also based on postprocessed sub­traction images. In special cases, these clarify the topographic relationship between a suspi­cious lesion and defined anatomical struc­tures. 3D imaging of tumours using VRT and 3D data sets allow the ascertainment of the size (T1 and T2 staging) and the precise location of the tumour within the kidney as well of re­lation to the major vessels and the renal col­lecting system. This influences the decision as to whether nephron-sparing surgery can be performed. In case of tumour resection, the depth of incision can be calculated, the con­servation of normal renal parenchyma is en­sured and complications are minimized.27,28 In case of tumoural lesion, the time-re­solved perfusion of the cortex of the lesion could be compared in a curve to the perfusion of the normal cortical parenchyma of the same kidney. The concept of a comprehensive imaging evaluation has been an evolving theme dur­ing the past decade, with the vision of a com­plete examination that could be performed in a relatively short time. Advances in the rapid MRI technology and its application to oncolo­gy imaging have shown that MRI has a tremendous potential for the evaluation of re­nal tumours and renal disease in general. A comprehensive MR examination including CE 3D MRA, MRU and MR nephrogram of­fers several potential advantages compared with conventional X-ray studies. By combin­ing all three techniques into an all in one pro­tocol the same information can be obtained as with conventional studies; however, the patient convenience will be improved, the po­tential morbidity is lower and the substantial costs decrease. The use of contrast-enhanced dynamically collected multiplanar acquisi­tions permits local, lymph node, and hepatic staging, all within the same examination. At the same time the use of Gadolinium chelates are considered to be safe and can be per­formed in patients with the impaired renal function. The combination of different MR tech­niques in one examination with the simulta­neous morphologic and functional analysis appears to be the »Holly Grail« of Magnetic Resonance Imaging. Such kind of technique has several advantages: 1. The duration of the combined MR exami­nation is approximately 30-40min. 2. The all-in one approach examination based on MR imaging provides the good visuali­zation of the renal parenchyma, the renal vascular supply and the collecting system, irrespective of the renal function. 3. The combination of nonenhanced and en­hanced MRU gives the possibility of the evaluation of both dilated and nondilated collecting systems. 4. The combination of standard MRI, MRA and MRU expands the MR evaluation of patients with the oncologic disease of the urinary tract, which is probably the major current indication for the complex exami­nation References 1. Reznek RH. Imaging in the staging of renal cell carcinoma. Eur Radiol 1996; 6: 120-8. 2. McClennan BL, Deyoe LA. The imaging evaluation of renal cell carcinoma; diagnosis and staging. Radiol Clin North Am 1994; 32: 55-69. 3. Frank JA, Choyke PL, Austin HA 3rd, Girton ME, Weiss G. Gadopentetate Dimeglumine as a mark­er of renal function. Magnetic resonance imaging to glomerular filtration rates. Invest Radiol 1991; 26(Suppl 1): S134-6. 4. Verswijvel GA, Oyen RH, Van Poppel HP, Goethuys H, Maes B, Vaninbrouckx J, et al. Magnetic resonance imaging in the assessment of urologic disease: an all-in one approach. Eur Radiol 2000; 10: 1614-9. 5. Dong Q, Schoenberg SO, Carlos RC, Neimatallah M, Cho KJ, Williams DM, et al. Diagnosis of renal vascular disease with MR angiography. Radio-graphics 1999; 19: 1535-54. 6. Jeong JY, Kim SH, Lee HJ, Sim JS. Atypical low-signal-intensity renal parenchyma: causes and pat­terns. Radiographics 2002; 22: 833-46. 7. Levine E. Acquired cystic kidney disease. Radiol Clin North Am 1996; 34: 947-64. 8. Helenon O, Merran S, Paraf F, Melki P, Correas JM, Chretien Y, et al. Unusual fat-containing tu­mors of the kidney: a diagnostic dilemma. Radiographics 1997; 17: 129-44. 9. Hood MN, Ho VB, Smirniotopoulos JG, Szumowski J. Chemical shift: the artifact and clin­ical tool revisited. Radiographics 1999; 19: 357-71. 10. Leroy-Willig A, Bittoun J, Luton JP, Louvel A, Lefevre JE, Bonnin A, et al. In vivo MR spectro­scopic imaging of the adrenal glands: distinction between adenomas and carcinomas larger than 15mm based on lipid content. AJR Am J Roentgenol 1989; 153: 771-3. 11. Reinig JW, Stutley JE, Leonhardt CM, Spicer KM, Margolis M, Caldwell CB. Differentiation of adre­ nal masses with MRI: comparison of techniques. Radiology 1994; 192: 41-6. 12. Halpern EJ, Mitchell DG, Wechsler RJ, Outwater EK, Moritz MJ, Wilson GA. Preoperative evalua­tion of living renal donors: comparison of CT an­giography and MR angiography. Radiology 2000; 216: 434-9. 13. Glockner JF. 3D Gadolinium enhanced MR an­giography: applications for abdominal imaging. Radiographics 2001; 21: 357-70. 14. Vosshenrich R, Fischer U. Contrast-enhanced MRA of abdominal vessels: is there still a role for angiography? Eur Radiol 2002; 12: 218-30. 15. Laissy JP, Menegazzo D, Debray MP, Toublanc M, Ravery V, Dumont E, et al. Renal carcinoma: diag­nosis of venous invasion with Gd-enhanced MR venography. Eur Radiol 2000; 10: 1138-43. 16. Schoenberg SO, Bock M, Aumann S, Just A, Essig M, Floemer F, et al. [Quantitative recording of re­nal function with MR tomography]. [German]. Radiologe 2000; 40: 925-37. 17. Baumann D, Rudin M. Quantitative assessment of rat kidney function by measuring the clearance of the contrast agent Gd(DOTA) using dynamic MRI. Magn Reson Imaging 2000; 18: 587-95. 18. Prasad PV, Priatna A. Functional imaging of the kidneys with fast MRI techniques. Eur J Radiol 1999; 29: 133-48. 19. Katzberg RW, Buonocore MH, Ivanovic M, Pellot-Barakat C, Ryan JM, Whang K, et al. Functional, dynamic, and anatomic MRU: feasibility and pre­liminary findings. Acad Radiol 2001; 8: 1083-99. 20. Dalla-Palma L, Panzetta G, Pozzi-Mucelli RS, Galli G, Cova M, Meduri S. Dynamic magnetic reso­nance imaging in the assessment of chronic nephropathies with impaired renal function. Eur Radiol 2000; 10: 280-6. 21. Birnbaum BA, Jacobs JE, Ramchandani P. Mutiphasic renal CT: comparison of renal mass enhancement during the corticomedullary and nephrograohic phases. Radiology 1996; 200: 753-8. 22. Knesplova L, Krestin GP. Magnetic resonance in the assessment of renal function. Eur Radiol 1998; 8: 201-11. 23. Nolte-Ernstin CCA, Adam GB, Gunter RW. MRU: examination techniques and clinical applications. Eur Radiol 2000; 11: 355-72. 24. O’Malley ME, Soto JA, Yucel EK, Hussain S. MR Urography: evaluation of a three-dimensional Fast Spin-Echo technique in patients with hy­dronephrosis. AJR Am J Roentgenol 1997; 168: 387­92. 25. Nolte-Ernsting CC, Tacke J, Adam GB, Haage P, Jung P, Jakse G, et al. Diuretic-enhanced Gd ex­cretory MRU: comparison of conventional gradi­ent-echo sequences and echo-planar imaging. Eur Radiol 2001; 11: 18-27. 26. Stringer WA. MRA image production and display. Clin Neurosci 1997: 4: 110-6. 27. Coll DM, Herts BR, Davros WJ, Uzzo RG, Novick AC. Preoperative use of 3D volume rendering to demonstrate renal tumors and renal anatomy. Radiograpics 2000; 20: 431-8. 28. Winterer JT, Strey C, Wolffram C, Paul G, Einert A, Altehoefer C, et al. [Preoperative examination of potential kidney transplantation donors: value of gadolinium-enhanced 3D MR angiography in comparison with DSA and urography]. [German]. Rofo 2000; 172: 449-57. Is quadrant biopsy adequate as first-line sampling scheme in men likely to have non-organ-confined prostate cancer: comparison to extended biopsy protocol Zoran Brnic 1, Petar Anic 1, Slavko Gašparov 2, Nikola Radovic 3, Damir Kucan 3, Željko Vidas 3, Žarko Zeljko 3, Petar Lozo 5, Vesna Ramljak 6 1Department of Diagnostic and Interventional Radiology, 2Department of Pathology, 3Department of Urology; University Hospital Merkur, Zagreb, Croatia; 4Poliklinika Lozo, Department of Ultrasound, Zadar, Croatia; 5University Hospital for Tumors, Zagreb, Croatia Background. While extensive prostate biopsy (PB) in the patients with early prostate cancer (PC) provides better sensitivity and more precise tumour staging, in the patients with advanced PC, it is virtually only a confirmation of malignancy. The purpose of our study was to find out whether the quadrant prostate biop­sy (QPB) provides a sufficient first-line pathological evaluation in the patients likely to have advanced PC, and whether the reduction of core number impairs the competence of PB through missing quantitative his­tology information. Methods. We studied 84 men who underwent PB and classified into groups »H« (highly-) and »L« (low likely to have advanced PC). Pathological results of 5-12 cores PB and simulated QPB were retrospectively compared, particularly for the presence of PC, tumour volume, Gleason score (GS), and the presence of high-grade prostatic intraepithelial neoplasia (HGPIN). Results. The PC detection rate was not impaired in group H, but dropped significantly in group L, while the percentage of positive cores was insignificantly changed in group H (p=0.39), but significantly decreased in group L (p=0.04) due to the sampling scheme reduction. No HGPIN was missed with QBP in group H, while 2 HGPIN were missed in group L. Insignificant GS changes resulted in both groups as a consequence of the limitation to QPB. Conclusions. QPB is an appropriate first-line scheme in the patients with advanced PC as the information lost due to the core number reduction is mainly not critical for patient management. Key words: prostatic neoplasms - pathology; biopsy, needle; prostate-specific antigen Received 26 July 2004 Accepted 9 August 2004 Correspondence to: Zoran Brnic, MD, PhD, University Hospital "Merkur", Department of Diagnostic and Interventional Radiology, Zajceva 19, 10000 Zagreb, Croatia. Phone: +385 98 199 12 26; Fax: +385 1 243 14 14; E-mail: zoran.brnic@zg.htnet.hr Introduction Standard sextant prostate biopsy (PB) is proved to be of limited sensitivity in prostate cancer (PC) detection. An increase of the num­ber of tissue cores per PB session improves the PC detection rate,1-5 and contributes to a better preoperative staging accuracy.6-8 Recently, many urologists abandoned biopsy­ing hypoechoic focal lesions, and focused on systematic sampling of the gland with as much cores as possible. Although even he ex­tensive PB was proved to be relatively safe, discomfort and minor complications occur in many patients;9-11 it is therefore sensible to avoid them if possible. In the patients with pre­sumed high tumour burden, with regard to PSA level, suspicious digital rectal examination (DRE) or transrectal ultrasound (TRUS), and suspicion of metastases,12-15 it does not seem reasonable to take large number of cores in initial PB because PC has very probably spread all over the gland volume, and exact as­sessment of intraprostatic tumour distribution is of minor importance. As these men are at high risk to have a non-organ-confined (NOC) PC, they are rarely candidates for radical prostatectomy (RP); hence only histological confirmation of the diagnosis of prostatic ma­lignancy is virtually needed. There is scant lit­erature16 dealing with the possibility to reduce the PB protocols when an extensive sampling is not strictly necessary in order to spare the invasiveness of the procedure and its costs. We hypothesized that the extensive first-line PB is redundant in the patients with pre­sumed high tumour burden, and that the quad­rant PB (QPB) can fulfil the task of preopera­tive pathological evaluation in the patients likely to have NOC PC. The purpose of the present study was to investigate whether the reduction of core number from 5-12 to 4 in the patients in whom PSA and/or clinical evaluation indicate high likelihood to have NOC PC, would impair the diagnostic com­petence of PB through missing clinically rele­vant information usually obtained by this procedure. Patients and methods Patients We retrospectively studied 84 consecutive pa­tients (mean age 71.8 years, range 50-89) in whom systematic PB was performed during one-year period. The men were previously untreated for PC and biopsied for the first time. The patients were classified into two study groups according to serum PSA, DRE and TRUS findings, the factors which can Table 1. Selection criteria for stratifying the patients into two categories according to probability of the presence of advanced (non-organ confined) PC. Number of patients in each sub-category is given. Likelihood for the presence of advanced PC PSAa level TRUSb and DREc finding Number of patients Low <4 ng/mL TRUS suspect or DRE suspect 5 Low 4-10 ng/mL TRUSP non-suspect and DRE non-suspect 24 High <4 ng/mL TRUSP suspect and DRE suspect 4 High 4-10 ng/mL TRUSP suspect and/or DRE suspect 12 High >10 ng/mL Irrespective of TRUS and DRE-finding 39 Total 84 a PSA test (Elecsys 1010, Roche Diagnostics GmbH, Manheim, Germany) was done prior to any prostate manipu­lation, to avoid false positive findings; no patients in our series had acute prostatitis (possible cause of elevated PSA); mean prostate size was similar in groups H and L. b TRUS was considered suspicious of malignancy if hypoechogenic sector or nodule in peripheral zone was de­tectable, if the prostate was inhomogeneous without zonal discrimination, or if unsharp prostate margins or infil­tration of extraprostatic tissues was seen. c DRE was considered suspicious of malignancy if considerable irregularity of the prostate surface, »rocky hard« induration/nodule or considerable asymmetry is detected on palpation. Abbreviations: PC = prostate cancer, PSA = prostate-specific antigen, TRUS = transrectal ultrasound, DRE = digi­tal rectal examination predict the PC burden in a patient.12-15 The group more likely to have NOC PC (high tu­mour burden) is assigned »H«, while other patients (with presumed low tumour burden) are classified in »group L«. The selection cri­teria for the groups are listed in Table 1. Prostate biopsy protocol We perform US-guided PB by transrectal ap­proach, routinely taking 6-8 tissue cores from <50 cm3 of prostate glands, and 8-12 cores from >50 cm3 of glands at the first-line PB. Six cores are taken from the very lateral parts of peripheral zone at the base, mid-gland and apex bilaterally, followed by additional cores from the posterolateral parts of peripheral zone, similarly to protocols used in the stud­ies.17,18 The number of cores intended to be taken in a particular patient is dependent ex­clusively upon the prostatic size, irrespective of the parameters of suspicion for PC. However, we occasionally reduce the number of cores ad hoc if bleeding from haemorrhoids occurs, or on the patient’s demand due to pain. We usually obviate more medial cores, as also those less expected to be positive.1,2 As a consequence of such approach, the ma­terial in the present study consists of 5-12 cores per biopsy session. Equipment and technique HP ImagePoint ultrasound system (Hewlett-Packard Company, Andover, MA, USA) with 5.0-7.5 MHz sector endorectal probe and plastic biopsy needle guide was used to assist PB, performed with spring-loaded Bard Magnum device (Bard Urological Division, Covington, GA, USA) coupled with 18-G-nee­dles. A new needle was taken for every 3 - 4 tissue cores. Biopsy cores from different sites of the prostate were submitted for analysis in individually labelled separate containers,19 and core sites were charted on a dedicated form. Pathologist (G.S.) who analysed the specimens was unaware of the aims of this study. Methods Pathological report for the entire set of PB samples (5-12 cores) was available for each patient. We verified each individual tissue core whether it was positive for PC, and whether high-grade prostatic intraepithelial neoplasia (HGPIN) was present. Gleason score (GS) was determined on the basis of the complete 5-12 PB set. With the evidence of pathohistology of the complete set of biopsies (5-12 cores) for each patient, we simulated the situation as if only 4 biopsy cores would have been taken (quadrant PB, QPB). In the hypothetical biopsy scheme the apical and medial cores were eliminated. For each pa­tient, we retrospectively compared the patho­logical results of the actual complete 5-12 PB with the presumed results of QBP. The two compared sampling schemes are shown in Figure 1. The following relevant pathologic parameters were considered in comparison of the two PB schemes: presence of PC in the prostate, presence of HGPIN and percentage of positive cores. Additionally, for the pur­pose of the study only, the same pathologist (G.S.), unaware of previously reported GS, determined GS for each patient on the basis of the set of 4 cores, which matched the sites of QBP. GS was then compared with that de­termined from 5-12 PB. T-test was used in sta­tistical analysis. Oral and written informed consent was ob­tained from each patient before PB, and in­formation on possible complications of sys­tematic PB was given. Our study did not in­fluence the patient management in any way, as QPB was only an imaginatively rather than really applied procedure. Local Medical Ethics Committee approved this investiga­tion. Results The mean age of patients was 71.8 years (range, 50-89), and did not differ significantly between the groups H and L (71.2 vs. 72.9 years, p=0.86). The mean PSA for the whole series was 36.3 ng/mL (range, 0.03-346); sig­nificant difference (p=0.0002) was observed between group H (52.9 ng/mL, range 1-346) and group L (5.8 ng/mL, range 0.03-9). Prostate volume ranged 16-192 cm3, and did not differ significantly between the groups H and L (63.2 vs. 63.7 cm3, p=0.19). GS deter­mined from the 5-12 BP and QPB material are given in Table 2. Positive correlation between GS and PSA (c=0.39), and between GS and the percentage of positive cores (c=0.53) was shown in the 5-12 PB material. GS deter­mined from the QPB material did not differ significantly from GS determined from the material of 5-12 PB, either for the whole se­ries, or for each particular study groups H (p=0.13) and L (p=0.12), with a maximum in­dividual difference of 2 points. In one L-pa­tient, GS=4 was overgraded as GS=6 from the QPB material, while in one H-patient GS=8 was undergraded as GS=6 also from the QPB material. In 22/46 (47.8%) patients, GS de­fined by both PB sets was identical, while in 20/46 (43.5%), it was undergraded, and in 2/46 (4.4%) overgraded by 1 point by QPB. Overall results of 5-12 PB and QBP for groups H and L are shown in Tables 3 and 4. Total number of cores taken from 84 patients was 605. Median number of cores per PB was 8 (range 5-12). Of all cores, 54.5% were positive for PC: 69.3% in group H, and 14.1% in group L. The percentage of positive cores in the 5-12 PB and QPB material in both compared study groups are shown in Tables 5 and 6. In 19/84 (22.6%) patients, all cores in the 5-12 PB ma­terial were positive for malignancy (1 patient in group L, 18 patients in group H). The num­ber of patients with PC detected in only one tissue core in both PB materials is shown in Tables 3 and 4. Pathological results allowing for the following parameters, presence of PC, presence of HGPIN, and percentage of posi­tive cores for two different PB schemes are shown in Tables 5 and 6. The data, which Table 2. Gleason scores determined from 5-12 PB and QPB material. Gleason score 5-12 PB QPB Difference observed Overall series median 6 median 6 0 mean 6.59 mean 6.32 p=0.13 (NS) range 3-9 range 3-9 Group H median 7 median 6 -1 point mean 6.79 mean 6.36 p=0.13 (NS) range 4-9 range 3-9 Group L median 4 median 5 +1 point mean 4.50 mean 5.50 p=0.12 (NS) range 3-5 range 4-6 Abbreaviations: PB=prostate biopsy, QPB=quadrant prostate biopsy, NS=non-significant would have been missed if only QPB were done, are given in the last column. Discussion The two fundamental shortages of systematic PB - its sampling error and invasiveness, lie in reciprocity: sampling extensiveness decreas­es sampling error at the cost of higher patient discomfort and postbiopsy morbidity. The re­cent tendency to increase the number of cores per one PB session is based on the evi­dence that an extensive sampling yields a higher PC detection rate and staging accura­cy.2-4,6-8,17,19,20 To balance the diagnostic yield and risk, the PB protocol needs to be individ­ualized for each patient according to his PSA level, TRUS and DRE findings, prostate vol­ume, age and life expectancy. In the present Table 3. Overall results of 5-12 PB outcome: the number of patients in each study group with respect to the pres­ence of PC and PIN Patient group 5-12 PB positive for PC 5-12 PB negative for PC Total >1 core positive 1 core positive no PIN HGPIN+LGPIN L 3 5 10 4+7 29 H 43 1 3 5+3 55 Total 46 6 13 9+10 84 Abbreviations: PB=prostate biopsy, PC=prostate cancer, LGPIN = low-grade prostatic intraepithelial neoplasia, HGPIN = high-grade prostatic intraepithelial neoplasia Table 4. Overall results of QPB outcome: the number of patients in each study group with respect to the presence of PC and PIN Patient group QPB positive for PC QPB negative for PC Total >1 core positive 1 core positive no PIN HGPIN+LGPIN L 1 4 15 2+5 27 H 42 2 65+2 57 Total 43 6 21 7+7 84 Abbreviations: PB=prostate biopsy, PC=prostate cancer, LGPIN = low-grade prostatic intraepithelial neoplasia, HGPIN = high-grade prostatic intraepithelial neoplasia Table 5. Comparative results of different PB schemes in group H Parameter analysed 5-12 PB QPB Missed with QPB Presence of PC 44 44 0 Presence of PIN 5 HGPIN 5 HGPIN 0 3 LGPIN 2 LGPIN 1 LGPIN Percentage of positive cores 69.3% 63.1% 6.2%, p=0.39 (NS) Abbreviations: PB=prostate biopsy, QPB=quadrant prostate biopsy, HGPIN=high-grade prostatic intraepithelial neoplasia, LGPIN=low-grade prostatic intraepithelial neoplasia, NS=non-significant Table 6. Comparative results of different PB schemes in group L Parameter analysed 5-12 PB QPB Missed with QBP presence of PC 8 5 3 presence of PIN 4 HGPIN 2 HGPIN 2 HGPIN 7 LGPIN 5 LGPIN 2 LGPIN percentage of positive cores 14.1% 9.8% 4.3%, p=0.04 Abbreviations: PB=prostate biopsy, QPB=quadrant prostate biopsy, HGPIN=high-grade prostatic intraepithelial neoplasia, LGPIN=low-grade prostatic intraepithelial neoplasia, NS=non-significant study, we focused our attention to the pa­tients with high laboratory and clinical suspi­cion of advanced PC. Despite the presump­tive diagnosis of PC, most of these men have to undergo PB to obtain the tissue diagnosis before treatment with androgen ablation. A very accurate staging is mostly not critical for the therapy, which is rarely radical. Extensive sampling protocols do not seem to be reason­able in the first-line BP in such patients, be­cause the confirmation of prostate malignan­cy and orientation on tumour biology could be reached even with few biopsy cores, and unnecessary discomfort, risks and costs may be avoided by such an approach. Cancer detection rate (sensitivity) can de­crease due to PB scheme reduction for two reasons: overall sampling density reduction and eliminating the gland areas, in which PC is frequently located, from sampling. The im­pact of sampling density on the sensitivity of PB is well known.2-5,17,20 It is particularly ex­pressed in the patients with negative DRE and TRUS, and PSA<10 ng/mL,3,4 correspon­ding to patient population similar to our group L. Thus, the strategy of reducing PB protocol does not seem convenient for the men with presumed low tumour burden because only the extensive sampling provides a prop­er sensitivity for the early detection of a po­tentially curable malignancy.4 This is concor­dant to our results: using QBP in group L, 3 of 8 PC would have remained undetected, which is a considerable drop of sensitivity. How­ever, in the men with presumed high tumour bur­den, the risk that PC will remain undetected with limited number of cores is little because their tumour is probably not small, and can-cer-free areas in prostate are less likely to ex­ist. Moreover, as many PC are predominantly infiltrating rather than only expansive, even the finding of cancer-free cores does not war­rant that this part of the prostate is not in­volved. Our results reassured these assump­tions: QPB would detect malignancy in all 44 men with PC detected with 5-12 PB protocol in group H, with neither significant nor in­significant PC missed due to sampling scheme reduction. Other authors similarly showed that PC detection rate is less affected by the core number increase in the patients with PSA>10 ng/mL, while significantly im­proved in those with PSA<10 ng/mL.1,3,20 Aus et al. showed that the reduction of sextant PB protocol to QPB resulted in the decrease of sensitivity for PC by only 4% in the patients with elevated PSA and positive DRE and/or TRUS.1 Damiano et al have recently demon­strated that the reduction of 14- to 8-cores regimen resulted in only 3.1% lower PC de­tection rate, and concluded that 8-cores PB may be appropriate as initial PB for general male population.16 A question arises whether, in the series larger than our, some H-patients positive for PC on 5-12 PB would have appeared negative on QPB. As a rule, any patient with high sus­picion of PC and negative initial PB have to be rebiopsied, and rebiopsy need to be more ex­tensive than the first-line PB.2 In such a way, a part of false-negative H-patients on QPB will be correctly detected as positive. Thus, adhering to QPB as the first-line BP in H-pa­tients, we spare discomfort and costs in at least 98% of positives on initial QBP, paying the price of rebiopsy in <2.2% (theoretically 1 of =45) false negatives on QPB. This »price« is considerably lower than unnecessary exten­sive sampling in every H-patient, which yields no clinically relevant information for these patients. Excluding different prostate areas from sampling will yield in the same sensitivity de­crease because the likelihood to be an origin of PC varies. We eliminated medial biopsies in our reduced PB because the medial cores are less frequently positive for PC than the lateral ones,1,2,4,17 and the lateral parts of pe­ripheral zone can be sampled by transrectal approach more efficiently than the medial parts. As the biopsy needle passes more or­thogonally across the posteromedial periph-eral zone and more longitudinally through the lateral parts of peripheral zone, the later­al tissue cores almost completely include pe­ripheral zone, while the medial cores usually include also a considerable part of transition­al zone. Finally, it is our impression that me­dial passes cause bleeding more frequently than lateral ones and that they are more painful. It seems harder to argument apical biopsies elimination from the first-line PB protocol. Quite a lot of PC are localized near the midline at the prostate apex,2,17 which may remain undetected after the exclusion of apical biopsies from the first-line PB. Two apical biopsies added to 2 middle lobar later­al biopsies increase the sensitivity by 13%,1 and most tumours missed on the initial BP were located just in apico-dorsal region.2 Nevertheless, the apex-directed PB have su­perior sensitivity compared with the sextant PB in the patients with PSA<10 (comparable to our group L), but the sensitivity was lower than in the sextant PB in the patients with PSA>10 (comparable to our group H).21 This may indicate that the sampling of the apex is unavoidable only for the detection of early stage PC, while less critical when an ad­vanced PC is more probable. Therefore, when searching for PC in general population or population similar to our group L, it would not be advisable to obviate apical cores. In H-patients, however, even if originated in the apex, PC would probably have infiltrated into the majority of the gland, with positive basal and mid-gland cores, and would possibly be NOC. Obviating the apical cores in such pa­tients would consequently not be critical for PC detection rate, as we have confirmed in our results. »One-core« prostate tumours. In men with limited life expectancy, it is important to de­termine whether T1c PC is clinically signifi­cant and needs treatment at all. As tumour significance is related to its volume (>0.5 mL), hence to the number of cores that contain neoplastic tissue,22 PC detected as only one positive core may be insignificant. A dilemma arises of how many biopsies should be per­formed to increase the overall PC detection rate without over-diagnosing clinically in­significant neoplasms,5,22 and whether a less extensive sampling decreases that risk. In our group L, 5 of 8 tumours were detect­ed as »one-core tumours« on 5-12 PB. On QPB, 1 of 5 »one core CP« would have been missed. In low range PSA patients, many PCs are detected by chance, being not responsible for patient’s clinical presentation, and missing such an insignificant PC is not detrimental, particularly if PC tumour is of low aggressive­ness. However, in group L, 2 of 3 significant CP would have also been missed on QPB - a considerable drop of overall PC detection rate. In group H, the number of »one-core PC« increased from 1 to 2. One PC with GS=8, which was detected in 2 adjacent cores on 5­12 PB, would have become »one-core PC« on QPB. This patient would have been managed similarly, irrespective of the number of posi­tive cores, due to its high GS. Even if some insignificant PC would remain undetected on QPB in group H (if our series were larger), this would not be a serious shortcoming as such small PC is not likely to be responsible for clinical and laboratory presentation, which, indeed, prompted PB in group H. Such a small PC could be detected in many H-patients on an extensive rebiopsy, and its sig­nificance would be estimated from the com­plete set of cores. Organ confinement of the tumour. The ability of pre-treatment variables to identify the pa­tients with organ-confined PC (OCPC) is a challenging issue. The presence of extrapro-static extension (EPE) is a feature of T3-stage, unfavouring radical treatment. The tumour volume is an important independent predict­ing parameter of the margin status and dis­ease progression after RP, and underestima­tion of tumour volume may result in overindi-cation of RP. Number, percentage and bilat­erality of positive cores in PB are valuable predictors of tumour volume, EPE and prog­nosis.5-8,19 Ipsilateral EPE is more likely, as the number of positive biopsies on that side increases, while the patients with >3 and bi­laterally positive cores had greater likelihood of EPE.8 It was demonstrated that such quan­titative histology data are especially valuable in the men with presumed low tumour burden (similar to our group L), thus better predict­ing the final pathological stage.19 Therefore, the information on the percentage of positive cores in PB must not be sacrificed in any re­duced sampling scheme, particularly in group L in which RP is often considered as a treat­ment option. In only one patient in group H, PC was de­tected with one instead of =2 positive cores, and in only one patient with 2 instead of 3 positive cores, as a consequence of scheme reduction to QPB. This does not preclude the use of QPB as the first-line PB scheme in H-patients. Grossklaus et al. compared <6 vs. >6 cores PB and concluded that the reduction of core number could impair the PC detection rate, but not other information, particularly the percentage of positive cores and bilaterality of PC.5 In our study, the percentage of posi­tive cores decreased significantly (14.1% to 9.8%, p=0,04) in group L, but insignificantly in the whole series (54.5% to 45.1%, p=0.17), and in group H (69.3% to 63.1%, p=0.39), due to the limitation to QPB. Maximum individ­ual differences in the percentage were 20% and 25% in two H-patients, respectively. Therefore, considering the parameter »per­centage of positive cores«, the use of QPB as the first-line PB scheme is not appropriate in group L, while acceptable in group H. Although the conclusions by Grossklaus et al5 and ours are similar for the overall series, the patient populations are not quite compa­rable as Grossklaus et al studied two different groups of men with different sampling schemes, while we compared two PB schemes on the same bioptic material. The association of high-grade prostatic in-traepithelial neoplasia (HGPIN) on PB specimen with concurrent invasive PC next to it or else­where in the gland is evident,23 and a signifi­cant proportion of patients with HGPIN de­tected on initial PB will be found to have PC on repeat PB.24,25 Thus, the identification of HGPIN on PB is an imperative as it may prompt further search for coexistent or sub­sequent invasive PC in the patient.23 The number of cores with HGPIN was an inde­pendent predictor of the risk for PC.25 It was shown that the extensive »five-region PB« de­tected significantly more HGPIN compared to the sextant BP.24 Thus, the reduction of core number in PB can decrease the HGPIN detection sensitivity, which can in conse­quence decrease the CP detection rate. The detection of HGPIN on the first-line PB is an imperative, particularly in L-patients, in whom the finding of HGPIN may be decisive for rebiopsy; had this information been missed, a number of rebiopsies would not have been ordered and early PCs could have remained undetected. QPB would miss 2 HG­PIN lesions in 21 PC negative L-patients (9.5%); thus, QPB is not appropriate as the first-line PB regimen in L-patients. On the contrary, none HGPIN was missed with QPB in group H. In larger H-population, some HG­PIN theoretically could have been missed, but this lack would not have been critical, as every PC-negative H-patient has to be rebiop­sied also for reasons other than HGPIN, mainly for persistent clinical and biochemical suspicion. Proper estimation of Gleason score (GS) from PB specimens is essential in making treatment decision as high GS precludes rad­ical treatment even when CP seems to be or­gan-confined.26 GS determined from a PB specimen may be discordant to that deter­mined from a surgical specimen.27-30 GS as­signed to PB material were identical to RP specimen in 51-67% of cases, greater in 4­15%, and lower in 22-54%. The magnitude of discrepancy was directly related to the quan­tity of tissue in PB specimen, being greater among specimens with GS<7 than among those with higher GS.27,28 GS defined by 18­cores BP speciment exactly matched that of surgical specimen in 37-57% of cases,27,29 be­ing within the interval of +1 point in 93% of cases.29 Undergrading is particularly precari­ous as it may lead the clinician to underesti­mate falsely the true biological potential of PC and to proceed to RP in the patient with great likelihood to have NOC PC; of most concern are the patients with GS>6 detected as GS<6 on QPB. As predisposing factors for errors in histological grading by needle PB were limited core length and limited number of biopsy cores.30 PB is to be repeated when low-grade PC was initially diagnosed on only lim­ited quantities of neoplastic tissue to reduce the risk of underestimation the GS. In our study, GS of group H was not significantly in­fluenced by the core number limitation to 4, but the accuracy was decreased in group L (more low grade PC-higher grading error ac­cording to).28 In group H, in which less pa­tients may be 50 ng/mL indicates PC with a positive prediction value of 98.5%.12 Another advantages of re­duced PB are higher safety for performance on an out-patient basis, less patients’ anxiety for future PB, lower time consumption and workload to pathologists, lower costs (one needle per patient), and lower risk of seeding tumour cells. Our study may have limitations. Although PSA level and DRE finding may, to some ex­tent, indicate statistical risk of PC in a de­fined population,2-14 our study groups H and L were defined arbitrarily, with the aim of sorting out patients with significantly differ­ent likelihood to have PC. We can estimate that the likelihood of L- and H-patients to have PC is <30% and >60%, respectively.13 These rates are, however, only for orienta­tion, as our classification does not match strictly the criteria.13,14 Thus, H- vs. L- classi­fication is a provisional tool for rapid estima­tion of the likelihood for the presence of PC and tumour burden, but not an attempt to stage the tumour or give a prognosis. It is aimed only to serve for identifying the pa­tients who might benefit from PB reduction. We conclude that in the patients with high likelihood to have NOC PC, the reduction of the number of cores does not impair the over­all sensitivity, and minimally changes the staging accuracy. In the patients likely to have an early PC, the reduction of the num­ber of cores significantly impairs the overall sensitivity. QPB can be an appropriate first-line sampling scheme in H-patients, as the in­formation lost due to the core number reduc­tion is mainly not critical for the patient man­agement; a more extensive PB is necessary for other patients, for proper sensitivity and stag­ing accuracy. References 1. Aus G, Bergdahl S, Hugosson J, Lodding P, Pihl CG, Pileblad E. Outcome of laterally directed sex­tant biopsies of the prostate in screened males aged 50-66 years. Implications for sampling order. Eur Urol 2001; 39:655-61. 2. Chon CH, Lai FC, McNeal JE, Presti JC Jr. Use of extended systematic sampling in patients with a prior negative prostate needle biopsy. J Urol 2002; 167:2457-60. 3. Nava L, Montorsi F, Consonni P, Scattoni V, Guazzoni G, Rigatti P. Results of a prospective randomised study comparing 6, 12, 18 transrectal ultrasound guided sextant biopsies in patients with elevated PSA, normal DRE and normal pro-static ultrasound. J Urol 1997; 157(Suppl): 59A. 4. Babaian RJ, Toi A, Kamoi K, Troncoso P, Sweet J, Ewans R, et al. A comparative analysis of sextant and an extended 11-core directed biopsy strategy. J Urol 2000; 163: 152-7. 5. Grossklaus DJ, Coffey CS, Shappell SB, Jack GS, Cookson MS. Prediction of tumour volume and pathological stage in radical prostatectomy speci­mens is not improved by taking more prostate needle-biopsy cores. BJU Int 2001; 88: 722-6. 6. Grossklaus DJ, Coffey CS, Shappell SB, Jack GS, Chang SS, Cookson MS. Percent of cancer in the biopsy set predicts pathological finding after prostatectomy. J Urol 2002; 67: 2032-5. 7. Borboroglu PG, Amling CL. Correlation of positive sextant biopsy locations to site of positive surgical margins in radical prostatectomy specimens. Eur Urol 2001; 39: 648-53. 8. Tigrani VS, Bhargava V, Shinohara K, Presti JC Jr. Number of positive systematic sextant biopsies predicts surgical margin status at radical prostate-ctomy. Urology 1999; 54:689-93. 9. Djavan B, Waldert M, Zlotta AR, Dobronski P, Seitz C, Remzi M, et al. Safety and morbidity of first and repeat transrectal ultrasound-guided prostate needle biopsies: results of the prospective European Prostate Cancer Detection Study. J Urol 2001; 166: 856-60. 10. Peyromaure M, Ravery V, Messas A, Toublanc M, Boccon-Gibod L. Pain and morbidity of an exten­sive prostate 10-biopsy protocol: a prospective study of 289 patients. J Urol 2002; 167: 218-21. 11. Naughton CK, Ornstein DK, Smith DS, Catalona WJ. Pain and morbidity of transrectal ultrasound guided prostate biopsy: a prospective randomized trial of 6 versus 12 cores. J Urol 2000; 163: 168-71. 12. Gerstenbluth RE, Seftel AD, Hampel N, Oefelein MG, Resnick MI. The accuracy of the increased prostate specific antigen level (greater than or equal to 20 ng./ml.) in predicting prostate cancer: is biopsy always required? J Urol 2002; 168: 1990­93. 13. Potter SR, Horniger W, Tinzl M, Bartsch G, Partin AW. Age, prostate-specific antigen, and digital rectal examination as determinants of the proba­bility of having prostate cancer. Urology 2001; 57: 1100-4. 14. Eastham JA, May R, Robertson JL, Sartor O, Kattan MW. Development of a nomogram that predicts the probability of positive prostate biopsy in men with an abnormal digital rectal examina­tion and a prostate-specific antigen between 0 and 4 ng/mL. Urology 1999; 54: 709-13. 15. Yamamoto T, Ito K, Ohi M, Kubota Y, Suzuki K, Fukabori Y, et al. Diagnostic significance of digital rectal examination and transrectal ultrasonogra­phy in men with prostate-specific antigen levels of 4 ng/mL or less. Urology 2001; 58: 994-8. 16. Damiano R, Autorino R, Perdona S, De Sio M, Oliva A, Esposito C et al. Are extended biopsies really necessary to improve prostate cancer detec­tion? Prostate Cancer Prostatic Dis 2003; 6: 250-5. 17. Gore JL, Shariat SF, Miles BJ, Kadmon D, Jiang N, Wheeler TM, et al. Optimal combinations of sys­tematic sextant and laterally directed biopsies for the detection of prostate cancer. J Urol 2001; 165: 1554-9. 18. Ravery V, Goldblatt L, Royer B, Blanc E, Toublanc M, Boccon-Gibod L. Extensive biopsy protocol im­proves the detection rates of prostate cancer. J Urol 2000; 164: 393-6. 19. Tombal B, Tajeddine N, Cosins JP, Feyaerts A, Opsomer R, Wese FX, et al. Does site-specific la-belling and individual processing of sextant biop­sies improve the accuracy of prostate biopsy in predicting pathological stage in patients with T1c prostate cancer? BJU Int 2002; 89: 543-8. 20. Aus G, Ahlgren G, Hugosson J, Pedersen KV, Rensfeldt K, Soderberg R. Diagnosis of prostate cancer: optimal number of prostate biopsies relat­ed to serum prostate-specific antigen and findings on digital rectal examination. Scand J Urol Nephrol 1997; 31: 541-4. 21. Brossner C, Madersbacher S, Bayer G, Pycha A, Klingler HC, Maier U. Comparative study of two different TRUS-guided sextant biopsy techniques in detecting prostate cancer in one biopsy session. Eur Urol 2000; 37: 65-71. 22. Furuya Y, Fuse H, Nagakawa O, Masai M. Preoperative parameters to predict tumor volume in Japanese patients with nonpalpable prostate cancer. Int J Clin Oncol 2002; 7: 109-13. 23. Ellis WJ, Brawer MK. Repeat prostate needle biop­sy: who needs it? J Urol 1995; 153: 1496-8. 24. Rosser CJ, Broberg J, Case D, Eskew LA, McCullough D. Detection of high-grade prostatic intraepithelial neoplasia with the five-region biop­sy technique. Urology 1999; 54: 853-6. 25. Kronz JD, Allan CH, Shaikh AA, Epstein JI. Predicting cancer following a diagnosis of high-grade prostate intraepithelial neoplasia on needle biopsy: data on men with more than one follow-up biopsy. Am J Surg Pathol 2001; 25: 1079-85. 26. Manoharan M, Bird VG, Kim SS, Civantos F, Soloway MS. Outcome after radical prostatectomy with a pretreatment prostate biopsy Gleason score of >/=8. BJU Int 2003; 92: 539-44. 27. Djavan B, Kadesky K, Klopukh B, Marberger M, Roehrborn CG. Gleason scores from prostate biopsies obtained with 18-gauge biopsy needles poorly predict Gleason scores of radical prostatec­tomy specimens. Eur Radiol 1998; 33: 261-70. 28. San Francisco IF, DeWolf WC, Rosen S, Upton M, Olumi AF. Extended prostate needle biopsy im­proves concordance of Gleason grading between prostate needle biopsy and radical prostatectomy. J Urol 2003; 169: 136-40. 29. King CR, Long JP. Prostate biopsy grading errors: a sampling problem? Int J Cancer 2000; 90: 326-30. 30. Ruijter E, van Leenders G, Miller G, Debruyne F, van de Kaa C. Errors in histologic grading by pro-static needle biopsy specimens: frequency and predisposing factors. J Pathol 2000; 192: 229-33. Multiple primary malignancies in patients with lung cancer Koichi Kurishima1, Hiroaki Satoh1, Shinsuke Homma1, Katsunori Kagohashi1, Hiroichi Ishikawa2, Morio Ohtsuka1, Kiyohisa Sekizawa1 1Division of Respiratory Medicine, Institute of Clinical Medicine, University of Tsukuba; 2Department of Internal Medicine, Tsukuba Medical Center Hospital, Japan Background. To evaluate the incidence of multiple primary malignancies in lung cancer patients, we sum­marized our experience in lung cancer patients with multiple primary malignancies. Methods. A total of 1194 consecutive lung cancer patients, who were admitted to our division over a 29­year period up to August 2004, were retrospectively analyzed. Results. Ninety-eight (8.2%) of 1194 lung cancer patients had multiple primary malignancies. Metachronous malignant disease comprised 77.6% and synchronous 21.4%. Multiple primary tumours in our patients were detected more frequent in the advanced stage of lung cancer (IIIA-IV 67.3%) than in the early stage (IA-IIB 32.7%). The histological examination of lung cancer revealed a preponderance of squa­mous cell carcinoma (40 patients, 40.8%). First primary tumours developed most commonly in gastroin­testinal tract, followed by lung and uterus. Fifty-seven (85.1%) of 67 patients with aerogastrointestinal and head and neck cancers had a smoking habit. In 98 patients with multiple primary cancers, forty (40.8%) pa­tients had stage IA-IIIA lung cancer, however, 26 (26.5%) had a surgical resection. Conclusions. Existing metachronous primary tumours proved to be a worse prognostic factor in non-small cell lung cancer patients (p=0.0480), while synchronous primary tumours were not, as well as there was not proven that multiple primary tumours were worse prognostic factors in patients with small cell lung cancer. Key words: lung neoplasms; neoplasms, multiple primary Introduction Nearly one hundred years ago, Billroth1 first reported on synchronous cancers in various Received 23 September 2004 Accepted 20 October 2004 Correspondence to: Hiroaki Satoh, M.D., Division of Respiratory Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba-City, Ibaraki, 305­8575, Japan; Fax: +81-29-853-3320; E-mail: hirosato@ md.tsukuba.ac.jp organs. About 40 years later, Warren and Gated established the criteria for the diagno­sis of multiple primary tumours.2 According to the criteria, such tumours occurring at dif­ferent locations must be histologically malig­nant and separated by normal mucosa, and one tumour must not be a metastasis of an­other. Thereafter, a greater awareness, im­proved diagnostic techniques and facilities account for the observed increase in the inci­dence of metachronous and synchronous ma­lignancies. Of patients with lung cancer, 3.2 ­9.7% are considered to have a metachronous or synchronous malignancy in various sites at presentation.3-5 This article summarizes our experience in lung cancer patients with metachronous or synchronous malignancies at various sites. Methods A total of 1194 consecutive lung cancer pa­tients, who were admitted to our division over a 29-year period up to August 2004, were retrospectively analyzed. In all patients, the diagnosis of lung cancer was confirmed Table 1. Characteristics of lung cancer patients with multiple primary malignancies (n=98) Number of patients Gender Male 78 Female 20 Age in years Range; median 45-85; 70 Histology Adenocarcinoma 35 Squamous cell carcinoma 40 Small cell carcinoma 19 Large cell carcinoma 3 Others 1 Performance status (ECOG) 0-1 / 2-3 / 4 76/20/1 Clinical stage IA-B/IIA-B/IIIA/IIIB/IV 20/12/8/24/34 Malignant diseases Synchronous/matachronous/both 21/76/1 Gastrointestinal 49 Urogenital 15 Lung 9 Head and neck 9 Others 19 Treatment Chemotherapy 37 Surgery 26 Radiation 20 Best supportive care 15 pathologically. Patients were classified using the International System for Staging Lung Cancer.6 The following criteria have been used for the designation of synchronous can­cers: (1) the tumours were anatomically sepa­rate; (2) the tumours were histologically dif­ferent. If the tumours were histologically the same ones, the gross appearance of each tu­mour was strongly suggestive of the primary cancer.7 The criteria that we have used to deter­mine metachronous cancers were related: (1) the tumours were anatomically separated; (2) tumour-free interval was at least 2 years. At the time of admission, the past medical history including malignancies was taken from all patients. Staging procedures includ­ing physical examination, brain magnetic res­onance imaging (MRI), chest computed tomo­graphic (CT) scan, abdominal CT scan or ul­trasonography, and bone scintigraphy were performed in all patients. A Cox's proportional hazard model8 was used for the multivariate regression analysis to clarify the independent prognostic impor­tance of the following variables: gender, age, stage, performance status (PS), resectability at surgery, and existing multiple primary tu­mours. Results Among the 1194 patients with lung cancer, 98 (8.2%) patients were diagnosed as having metachronous and synchronous malignan­cies. All relevant data relating to the patients who had metachronous and synchronous ma­lignancies are shown in Table 1. The mean age at presentation of lung cancer was 70 years (range 45-85). Eighty-six (87.8%) of pa­tients were 60 years of age or more. There were 78 men and 20 women. Among 98 pa­tients, 76 had metachronous malignancies, 21 had synchronous malignancies, and 1 had both. As metachronous or synchronous ma-lignancy, gastric cancer found in 32 patients, colon and rectal cancers in 10, lung cancer in 9, uterus cancer in 6, and prostate cancer in 5, respectively. A histological examination of lung cancer revealed a preponderance of squamous cell carcinoma (40 patients, 40.8%). There were 35 patients (35.7%) with adenocarcinoma, 19 pa­tients (19.4%) with small cell carcinoma and 3 patients (3.1%) with large cell carcinoma. This distribution of pathologic types is in striking contrast to that found in patients without multiple primary tumours, in whom there was a lower frequency of squamous cell car­cinomas (29.5%) and a higher frequency of adenocarcinomas (47.1%). With regard to tobacco smoking, 77.6% of patients with multiple primary tumours were habitual smokers including 68 patients (69.4%) with 30 pack year or more history of smoking. Fifty-seven (85.1%) of 67 patients with aerogastrointestinal and head and neck cancers were smokers. On the other hand, 76.3% of patients without multiple primary tumours were smokers including 65.1% of pa­tients with 30-pack year or more history of smoking. There was no significant difference in smoking habit between the two groups (p = 0.3510). However, there was a significant difference in 30 pack year or more history of smoking in the two groups (p=0.0005). In 98 patients with multiple primary can­cers, forty (40.8%) patients had stage IA-IIIA lung cancer, however, 26 (26.5%) had a surgi­cal resection. Twenty (20.4%) received chest irradiation, and 15 (15.3%) had only the best supportive care. A Cox's proportional hazard model was used for the multivariate regression analysis to clarify the independent prognostic impor­tance of the following variables: gender, age, stage, PS, resectability at surgery, and exist­ing multiple primary tumours. For each vari­able, the proportional hazard assumption was examined graphically. In 1194 patients with lung cancer, gender (p<0.0001), stage (p<0.0001), PS (p<0.0001), and resectability at surgery (p<0.0001) were significantly related to the survival. In these patients, the existing multiple primary tumours were not proved to be a worse prognostic factor for the survival (p=0.1919). However, in 1018 patients with non-small cell lung cancer, the existing metachronous primary tumours were a sig­nificant prognostic factor for survival (p=0.0480) (Table 2). Discussion The criteria of double primary cancers enun­ciated by Warren and Gates2 are now gener­ally accepted. Of patients with lung cancer, an incidence for multiple primary tumours of 3.2 - 9.7% has been reported in the litera­ture.3-5 Cahan reported the incidence of sec­ond malignancies was 3.2% of patients with lung cancer.3 Antakli et al4 demonstrated 4.1% incidence of the second primary lung cancer in 1572 cases of cancer patients, the metachronous cancer comprised 60% and the synchronous are 40%. Reynolds et al5 found an unusually high association of another pri­mary cancer (9.7%) in cases of lung cancer, Table 2. Prognostic factors in 1018 patients with non-small cell lung cancer determined by the Cox proportional hazard model Variables Coefficient Standard error p-value Age - 0.095 0.236 0.6884 Performance status 0. 752 0.100 <0.0001 Stage - 0.633 0.122 <0.0001 Existing metachronous primary tumours - 0.381 0.193 0.0480 Resectability at surgery 1.019 0.122 <0.0001 and the analysis by the stage of lung cancer as the second primary cancer showed a higher incidence of associated malignancies in the early stage lung cancer than in the advanced stage. In our 1194 lung cancer patients, 98 (8.2%) of them had multiple primary malig­nancies; the metachronous malignant disease comprised 77.6% and the synchronous one 21.4%. Inconsistent with the report by Reynolds et al,5 more multiple primary tu­mours in our patients were detected in the ad­vanced stage of lung cancer (in stage IIIA-IV 67.3%) than in the early stage(in IA-IIB 32.7%). We cannot explain the reason why the difference in incidence with regard to the stage was derived from. The precise inci­dence varies from series to series and might also be related to the length of the follow-up. Moreover, greater awareness and improved diagnostic techniques account for the appar­ent increase in incidence. All retrospective studies published so far have revealed that multiple primary tumours occur more frequently than it would be ex­pected by chance in patients who have pri­mary lung cancer. Several environmental fac­tors are thought to play a role in the develop­ment of primary and second malignancies. The role of tobacco and/or alcohol use in sus­ceptible tissues of the upper aerodigestive tract is of major importance in multiple pri­mary tumours including lung cancer. In our patients, 85.1% of patients with aerogastroin­testinal and head and neck cancers had a smoking habit. The possible roles of immuni­ty, heredity, nutrition are not completely known. The development of the second pri­mary cancer has been well known following the chemotherapy,9-11 but in this series no pa­tients received chemotherapy for the first pri­mary cancers. There have been reported that a grater per­centage of multiple primary cancers occur in the same organ or in the organs of the same system than in the unrelated organs.12 The as­sociation between unrelated organs, such as lung, stomach and kidney may indicate the circulation of carcinogenic metabolites.13 Our study showed that the first primary tumours occurred most commonly in gastrointestinal tract, followed by lung and uterus. Our re­sults also revealed that the existing multiple primary tumours were not proved to be a worse prognostic factor for the survival in 1194 patients with lung cancer. However, in 1018 patients with non-small cell lung cancer, the existing metachronous primary tumours were a significant prognostic factor for the survival. The second primary cancers may develop as much as 30 years later, and therefore, the possibility of a second cancer should be kept in mind in all cancer cases although the con­cept of a 5-year cure may be valid for the first cancer in most cases.14 Recognizing that the incidence of the development of the second malignant tumour depends on the exactitude of evaluation, length of follow-up, curability of the first primary tumour, and patterns of tobacco and alcohol use, we should approach the problem of the second malignancies in lung cancer from several angles in the future. When a second primary cancer appears, a careful search for the metastatic disease should be made and a consideration for the curative intervention should be given. An ag­gressive curative approach conserving as much organ function as possible still offers the greatest chance for the long-term survival. References 1. Billroth T. Die allgemeine chirurgische pathologie und therapie in 51 vorlesungen. In: Reimer G, ed­itor. Handbuch für studierende und ärzte. Berlin; 1882. p. 908. 2. Warren S, Gates O. Multiple primary malignant tumors. Am J Cancer 1932; 16: 1358-414. 3. Cahan WG. Lung cancer associated with cancer primary to other sites. Am J Surg 1955; 89: 494-514. 4. Antakli T, Schaefer RF, Rutherford JE, Reed RC. Second primary lung cancer. Ann Thorac Surg 1995; 59: 863-6. 5. Reynolds RD, Pajak TF, Greenberg BR, Shirley JH, Lucus RN, Hill RP, et al. Lung cancer as a second primary. Cancer 1978; 42: 2887-93. 6. Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997; 111: 1710-7. 7. Carter D, Eggleston JC. Tumours of the lower res­piratory tract. Washington, DC: Armed Forces Institute of Pathology; 1974. p. 70-94; p 113-27. 8. Cox DR. Regression models and life tables. J Royal Stat Soc B 1972; 34: 187-220. 9. Johnson BE, Linnoila RI, Williams JP, Venzon DJ, Okunieff P, Anderson GB, et al. Risk of second aerodigestive cancers increases in patients who survive free of small-cell lung cancer for more than 2 years. J Clin Oncol 1995; 13: 101-11. 10. Johnson BE. Second lung cancers in patients after treatment for an initial lung cancer. J Natl Cancer Inst 1998; 90: 1335-45. 11. Waller CF, Fetscher S, Lange W. Secondary chron­ic myelogenous leukemia after chemotherapy fol­lowed by adjuvant radiotherapy for small cell lung cancer. Leuk Res 1999; 23: 961-4. 12. Watanabe S, Kodama T, Shimosato Y, Arimoto H, Sugimura T, Suemasu K, et al. Multiple primary cancers in 5456 autopsy cases in the National Cancer Center of Japan. J Natl Cancer Inst 1984; 72: 1021-7. 13. Barbin A. Role of etheno DNA adducts in carcino-genesis induced by vinyl chloride in rats. IARC Sci Publ 1999; 150: 303-13. 14. Kogelnik HD, Fletcher GH, Jesse RH. Clinical course of patients with squamous cell carcinoma of the upper respiratory and digestive tracts with no evidence of disease 5 years after initial treat­ment. Radiology 1975; 115: 432-27. Cranium eroding sweat gland carcinoma: a case report Mehmet Arslan, Ahmet N. Karadeniz, Görkem Aksu, Murat Güveli Istanbul University, Institute of Oncology, Istanbul, Turkey Background. Sweat gland carcinomas are rare tumors. Eccrine sweat gland carcinomas are also very rare, with only about 200 cases reported in the world literature and only one of them was eroding the cranium. Treatment modalities of these carcinomas are not well known. Case report. Our patient was 47 years old female. Since 1989, she was operated on six times because of the tumour relapses. After each operation, the pathological results were: sweat gland adenoma, sweat gland tumour, cylindroma, turban tumour, malign cylindiroma. That was her seventh relapse. On examination, a lesion of the size 10 x 6 cm was observed in the left parietal region. Computed tomography showed the le­sion had the size of 11 x 5 cm, and was destroying the tabula externa, diploic region and tabula. The tumour was invading the dura and causing periost reaction. Surgery and postoperative radiotherapy treatment was planned because of malign transformation and risk of recurrence. Conclusions. Only one case with cranium erosion was reported in literature. In our case, also intracranial extension of the tumor was observed. Key words: sweat gland neoplasms; parietal bone; neoplasms invasiveness Introduction Little is known about these rare sweat gland carcinomas and their treatment modalities. We reviewed the literature on sweat gland carcinomas to elucidate the nature of these tumours and best treatment course. The mean patients' age is 57 years with equal male-to-female distribution. Tumour distribu- Received 24 March 2004 Accepted 14 May 2004 Correspondence to: Prof. Mehmet Arslan, MD, Institute of Oncology, Istanbul University, C,apa, 34390, Istanbul, Turkey; Phone: +90 532 686 4659; E­mail: marslan19@yahoo.com tion is: lower extremities, 32.9%; upper ex­tremities, 27.6%; trunk, 11.9%; head, 26.3%; neck, 1.3%. Metastasis sites are: lymph nodes, 30.2%; viscera, 22%. Malignant sweat gland carcinomas have a propensity for local and regional lymph node recurrence.1 The roles of lymph node dissection, radiation, and chemotherapy were reviewed. Apocrine gland carcinoma is a rare sweat gland neoplasm with distinctive cytological appearance. Although the region of the axilla remains the most common site for these tu­mours, apocrine gland carcinoma of the anogenital region, eyelid, ear, chest, wrist, lip, foot, toe, and finger have been reported. Classically, these slow-growing lesions pres­ent as painless, colourless or reddish, firm or cystic nodules. More than half of the reported patients with apocrine carcinoma had lymph node metastases at the time of diagnosis. Wide local excision is standard therapy for these lesions. A therapeutic lymph node dis­section is indicated if lymph node metastases are confirmed. It may be effective in the set­ting of a large or highly aggressive tumour with narrow surgical margins. As apocrine gland carcinoma responds poorly to chemotherapy, adjuvant radiotherapy may be applied in advanced, local, or regional dis­eases.2 Malignant eccrine sweat gland tumours are rare and usually develop from pre-exist­ing eccrine appendage tumour of lesser matu­rity.3-6 Clinical features of these tumours are non-specific, and final diagnosis is always based on histology. The tumours are usually located on the head, neck, or extremities and manifest as slow-growing nodules or infiltrat­ed plaques. These tumours are rare, with on­ly about 200 cases reported in the world liter­ature.7 A review of the literature reveals only 25 published reports of malignancies arising from eccrine spiradenoma. These tumours have a metastasis rate of >50 per cent in re­ported cases with high mortality rates as a re­sult.3 The case that is reported by Ritter et al is the only porocarcinoma eroding the crani­um. A review of the literature failed to reveal any other such case.4 Dermal eccrine cylindroma or turban tu­mour is a rare benign tumours of the eccrine sweat glands. Despite its histological benign behaviour, the disease process is distressing for the patients and cylindromas rarely progress to cylindrocarcinoma.8 Case report Our case is 47 years old women patient. She first visited the health care centre in 1989 for a solitary, colourless and painless lesion that she had on the scalp for a long time. On ex­amination, colourless and painless 2 cm solid scalp lesion was palpated. The lesion was ex­cised and not examined pathologically at that time. For about two years later, the lesion re­lapsed. It was excised and diagnosed patho­logically as sweat gland adenoma. Adjuvant therapy was not needed. For about two years later, the lesion relapsed again. It was excised thirdly and diagnosed pathologically as sweat gland tumour. For about two years later, the lesion relapsed thirdly; this time, it was red­dish. It was excised fourthly and diagnosed pathologically as sweat gland cylindroma. For about one year later, the lesion relapsed mul­tifocally. The largest lesion was 4 cm long, reddish and painful. Other lesions were colourless, painless and solitary. The lesion was excised again and diagnosed as turban tumour. Adjuvant therapy was not needed. Short time later, the lesion relapsed multi-focally again. Dimensions of the lesions were up to 5 x 6 cm (Figure 1). The excision of the lesions, increasing in number and diameter and changing physically each time, was per­formed again. Pathologically, it was diag­nosed as cylindroma with malign features (Figure 2). On physical examination of the patient with recurrence referred to our clinic, a mass of the size 10 x 6 cm was found on the left Figure 2. Pathological appearance of the lesion (H&E, X100). parietal region of the scalp. With cranial di­rect roentgen and computed tomography, a mass, measuring 11 x 5 cm, was destructing tabula, tabula externa, and diploic region, in­vading the dura and causing periost reaction was identified (Figure 3). Surgery and postop­erative radiotherapy with surgical consulta­tion was planned because of malign transfor­mation and risk of recurrence. Discussion Dermal eccrine cylindroma or turban tumour is a rare benign tumour of the eccrine sweat glands.9,10 Women are affected 4 times more frequently than men. About 10% of all cylin­dromas are hereditary, transmitted autoso­mally dominantly and with variable pene-trance. Papules, nodules, and tumours occur mainly on the scalp, but they may be found on the face and upper part of the trunk. If nodules of cylindromas cover the entire scalp and are heaped up, they resemble a turban. Despite its histological benign behaviour, the disease process is distressing for the pa­tients.8 Cylindromas rarely progress to cylin­drocarcinoma.11-13 Most of these cases of cylindrocarcinomas have developed from long persisting tumours of cylindroma. Histologically, the tumours are similar to cylindromas, but they are marked by large numbers of mitotic figures and atypical mi­toses. Cylindrocarcinomas are aggressive, with metastases to lymph nodes, bone, and visceral organs.6 In our case, despite its histo­logical benign features, the disease relapsed seven times and increased in dimension and number. Thus, despite its benign pathology, it was distressing for the patient. Some of them become malignant. Last pathological re­port of our case was cylindroma with malign features; so, it changed to a malign form from a long persisting cylindroma. A review of the literature reveals only 25 published reports of malignancy arising from eccrine spiradeno-ma. These tumours are rare tumours, with only about 200 cases reported in the world litera­ture.7 The case that was reported by Ritter et al is the only porocarcinoma eroding the cra­nium. A review of the literature failed to re­veal any other such case.4 Our case with cra­nial erosion, dural invasion, and intracranial extension is the first scalp eccrine sweat gland tumour, cylindroma. Multiple resec­tions were required for local control and, fi­nally, the lesion changed to a growth with malign histology. Wide local excision is standard therapy for these lesions. A therapeutic lymph node dis­section is indicated if lymph node metastases are confirmed, and it may be efficient in the setting of a large or highly aggressive tumour with narrow surgical margins. As sweat gland carcinoma responds poorly to chemotherapy, adjuvant radiotherapy may be used in ad­vanced local or regional diseases.2 The treat­ment plan for our patient comprised wide lo­cal excision and postoperative radiotherapy because of malign transformation and risk of recurrence. The tumour invaded the dura and extended intracranially. Adjuvant treatment such as chemotherapy and craniospinal irra­diation may be applied. But these tumours re­spond poorly to chemotherapy and there is no experience of craniospinal irradiation. Conclusions The reported case with cranial erosion, dural invasion, and intracranial extension is the first scalp eccrine sweat gland tumour, cylin­droma. Cylindromas rarely progress to cylin­drocarcinoma. Most of these cases of cylin­drocarcinomas have developed from long persisting tumours of cylindroma. In our case, it also changed to malign cylindroma. Wide local excision is standard therapy for these lesions. Multiple resections may be re­quired in order to obtain local control even if the lesion is benign. Therapeutic lymph node dissection and adjuvant radiotherapy may be used in advanced local or regional diseases. References 1. Asley I, Smith-Reed M; Chernys A. Sweat gland carcinoma. Dermatol Surg 1997; 23(2): 129-33. 2. Chamberlain RS, Huber K, White JC, Travaglino-Parda R. Apocrine gland carcinoma of the axilla. Am J Clin Oncol 1999; 22(2): 131-5. 3. Beekly AC, Brown TA, Porter C. Malignant eccrine spiradenoma. Am Surg 1999; 65(3): 236-40. 4. Ritter AM, Graham RS, Amaker B, Broaddus WC, Young HF. Intracranial extension of an eccrine porocarcinoma. J Neurosurg 1999; 90(1): 138-40. 5. Tay JS, Tapen EM, Solari PG. Malignant eccrine spiradenoma. Am J Clin Oncol 1997; 20(6): 552-7. 6. Shafer WF, Hine MK, Levy BM, editors. A textbook of oral pathology. Philadelphia: WB Saunders; 1983. p. 20. 7. Safai B, Brash DE. Tumors of eccrine glands. In: Vincent T, DeVita, editors. Cancer. Philadelphia: Lippincott-Raven; 1997. p. 40. 8. Irwin LR, Bainbridge LC, Reid CA, Piggot TA, Brown HG. Dermal eccrine cylindroma (turban tu­mour). Br J Plast Surg 1990; 43(6): 702-5. 9. Cotton DW, Braye SG. Dermal cylidromas origi­nate from the eccrine sweat gland. Br J Dermatol 1984; 111: 53-61. 10. Goette DK, McConnell MA, Fowler VR. Cylindroma and eccrine spiradenoma coexistent in the same lesion. Arch Dermatol 1982; 118: 273-4. 11. Urbanski SJ, From L, Abramowicz A, Joaquin A, Luk SC. Metamorphosis of dermal cylindroma: possible relation to malignant transformation. Case report of cutaneous cylindroma with direct intracranial invasion. J Am Acad Dermatol 1985; 12: 188-95. 12. Lyon JB, rouillard LM. Malignant degeneration of turban tumour of scalp. Trans St Johns Hosp Dermatol Soc 1961; 46: 74-7. 13. Bondeson L. Malignant dermal eccrine cylindro-ma. Acta Derm Venereol 1979; 59: 92-4. review The dimethylhydrazine induced colorectal tumours in rat - experimental colorectal carcinogenesis Martina Perše and Anton Cerar Institute of Pathology, Medical Experimental Centre, Medical Faculty, University of Ljubljana, Slovenia Animal models of colorectal carcinogenesis represent invaluable research tool for investigating colorectal cancer (CRC). Experimentally induced tumours in laboratory animals provide opportunity for studying cer­tain aspects of tumours that cannot be effectively studied in humans. Significant information on human CRC aetiology or factors influencing it has derived from studies using dimethylhydrazine (DMH) model that is one of the experimental models appreciated for its morphological similarity to human CRC. Today, DMH model represents useful research tool for the studies of colon carcinogens and chemopreventive agents. The review offers insight into morphogenesis and genetic alterations of DMH induced colorectal epithelial tu­mours in rats. Key words: colorectal neoplasms - chemically induced; azoxymethane; 1,2-dimethylhydrazine; disease models, animal; rats Introduction The beginnings of the first animal model ap­preciated for its macroscopic and histological similarity to human colorectal carcinoma (CRC) extend to 1963, when Laqueur discov­ered that rats fed cycasin, a plant product, developed intestinal cancer. The active sub­stance was identified and soon a similar com­pound, methylazoxymethanol acetate (MA- Received 29 October 2004 Accepted 20 November 2004 Correspondence to: Martina Perše, DVM, Institute of Pathology, Medical Experimental Centre, Medical Faculty, Korytkova 2, 1105 Ljubljana, Slovenia. Phone: +386 1 543-71-91; Fax: +386 1 543-71-81; E­mail: martina.perse@mf.uni-lj.si MA) was synthesized that was more effective than the natural product. In 1970 Druckrey found that two chemicals structurally related to MAMA, dimethylhydrazine (DMH) and azoxymethane (AOM), were even more po­tent intestinal carcinogens.1 Today, DMH and its metabolite AOM are the agents widely used in experimental mod­els of colorectal carcinogenesis in rodents. They are highly specific indirect colorectal car­cinogens that induce the initiation and promo­tion steps of colorectal carcinogenesis yielding colorectal tumour lesions in a dose-dependent manner in rats, mice and hamsters.2-4 In rats they can produce colorectal tumour lesions in almost 100% of treated animals.4-8 Nevertheless, various strains of rats differ in susceptibility to these carcinogens.8-10 Decreased susceptibility was reported also in female rats.11,12 In chemically induced colorec­tal studies mostly 6-10 weeks old male rats are used and most often-applied rat strains are Fisher, Sprague-Dawely and Wistar (Table 1). DMH metabolism DMH is highly specific colorectal carcinogen that is metabolically activated in liver by se­ ries of reactions through intermediates azo-methane, AOM and methylazoxymethanol (MAM) to the ultimate carcinogenic metabo­lite, highly reactive methyldiazonium ion.13 MAM is excreted into the bile and transport­ed to the colon or enter directly into epithelial cells of the colon from the blood circula­tion.2,13,14 Some studies have demonstrated that rat colon epithelial cells are capable of metabolising DMH into carcinogenic metabo­lite without previous metabolism by other tis- Table 1. Protocols used for chemical induction of colorectal lesions References C Strain, sex and Dose R N D initial age or weight Sprague-Dawley Rubio et al. 1986 DMH (male, 200g) 21 mg/kg s.c. 1 32 Sprague-Dawley McGarrity et al. 1988 DMH (male, 220-260g) 20 mg/kg s.c. 20 30 Wistar Park et al. 1997 DMH (male, 8-10 weeks) 15 mg/kg s.c. 19 24 Fischer 11 Onoue et al. 1997 DMH (male, 10 weeks) 20mg/kg i.p. 2 34 Fischer 6 Ghirardi et al. 1999 AOM (male, 6 weeks) 15 mg/kg s.c. 2 36 Sprague-Dawley Rubio et al. 1999 DMH (male, female, 200g) 21 mg/kg s.c. 27 32 Sprague-Dawley De Jong et al. 2000 DMH (male, 6 weeks) 30 mg/kg p.o. 5 24 Fischer Bissonnette et al. 2000 AOM (male, 80-100g) 15 mg/kg i.p. 2 37 Wistar Narahara et al. 2000 AOM (male, 6 weeks) 7,4 mg/kg s.c. 5 45 Wistar Ravnik-Glavac et al. 2000 DMH (male, 9 weeks) 20 mg/kg s.c. 15 25 Fischer Yamada et al. 2000 AOM (male, 6 weeks) 15 mg/kg s.c. 3 10 Fischer Takahashi et al. 2000 AOM (male, 6 weeks) 15 mg/kg s.c. 2 36 Fischer Kishimoto et al. 2002 AOM (male, 6 weeks) 15 mg/kg s.c. 3 4 Wistar 4 Rodrigues et al. 2002 DMH (male, 6 weeks) 40 mg/kg s.c. 2 30 Wistar, Fischer Veceric et al. 2004 DMH (male, 8-10 weeks) 25 mg/kg s.c. 20 25 Legend: C, carcinogen; R, route of application (s.c., subcutaneous; i.p., intra peritoneal; p.o., per oral); N, number of applications; D, duration of experiment (weeks) sues or colon bacteria.15,16 Although intestin­al flora17,18 and bile acids19 have influence on the incidence of tumours, the latter were in­duced also in germ-free rats17 and function-isolated segments of rat colon.14 The ultimate carcinogenic metabolite of DMH is responsible for methylation of DNA of various rat organs including epithelial cells in the proliferative compartment of the intes­tinal crypts.20 Metabolically activated DMH modifies not only nucleic acids but also his-tones and other DNA-binding proteins in the target cells.21 Tumour lesions induced by DMH DMH is highly specific for colonic epithelium and induces tumours mostly in large bow­el.14,20,22 Colon specific susceptibility for this carcinogen is a result of a delayed or incom­plete repair of damaged DNA in the colon compared to other organs,20 leading to accu­mulation of mutations, and in a small propor­tion of cells giving rise to CRC. Higher sus­ceptibility to colon versus small intestine has been shown in experiment where segments of colon that were transposed to the middle part of small intestine developed tumours but segments of small intestine that were trans­posed to the colon did not.22 Tumours are dis­tributed in all parts of the colon, but in a ma­jority are observed in the distal part of colon.4,8,23,24 Gross tumours are initially de­tected in the distal colon at 16 weeks but in proximal colon after 22 weeks.23 The tumour incidence can be modulated by the amount of carcinogen administered and the number of applications. With increasing doses of the carcinogen, the latency period decreases and the tumour incidence increases.3,4 Usually carcinogen at a dosage of 15-25 mg/kg body weight per week is administered subcuta­neously (Table 1). In our studies DMH at a dosage of 15-25 mg/kg-body weight was in­jected subcutaneously once a week, for 15-20 weeks consecutively.8,11,25,26 Besides the colorectal tumours, the small bowel tumours are also induced but in much lower incidence.5,8,11 However, small bowel tumorigenesis is characteristic of high-dose regimens of DMH.27 Small intestinal tumours are mostly well or poorly differentiated ade­nocarcinomas.5,8,11 Well-differentiated ade­nocarcinomas only occasionally demonstrate invasion through the intestinal wall and into the adjacent tissues.5 On the other hand the poorly differentiated type is more aggressive and mostly metastasises to the mesenteric lymph nodes and in advanced stages fre­quently develops carcinosis of peritoneum or conglomerate tumours in the area between the duodenum, stomach, hilus of the liver and affected small intestine.5,6 Extraintestinal tumours may also be in­duced by DMH. Some rats develop tumours of Zymbal’s gland (auditory sebaceous glands), usually squamous cell carcino­ ma.5,11,28 Colorectal tumour lesions Aberrant crypt foci The first specific morphologically identifiable lesions for colonic carcinogenesis are aber­rant crypt foci (ACF). They were first identi­fied in the colon of carcinogen treated mice by the light microscopic examination of the mucosal surface of colons that had been stained with methylene blue.29 ACF are stereoscopically distinguished from normal crypts by their darker staining and larger size, elliptical shape, thicker epithelial lining, and larger perycriptal zone.30-34 They appear within two weeks after carcinogen injection as single crypts that expand by crypt branch­ing or multiplication. Sequential histologic analysis of ACF revealed that with time the number of ACF with increasing crypt multi­plicity increases and a higher number of ACF exhibit dysplasia.30,32 It was observed that ACF with increasing crypt multiplicity are more resistant to apoptotic cell death.31 Hyperplastic ACF (Figure 1A) are composed of mixture of goblet and absorptive cells with enlarged or sometimes crowded nuclei with­out stratification. The luminal opening of ACF is slightly elevated from the surrounding normal mucosa and the crypts are elongated and occasionally branching with partial mucin depletion. Mitotic figures are limited to the lower two-thirds of the crypts and are never observed on the surface of ACF.33,34 Dysplastic ACF (Figure 1B) are mostly com­posed of absorptive cells that display an un­ceasing proliferative activity.33 Histologically these cells manifest cytoplasmic basophilia, a high nuclear-cytoplasmic ratio, prominent nucleoli and loss of cell polarity to variable degrees. The number of goblet cells is de­creased and mucin depleted. The dysplastic crypt so formed tends to have an increased diameter, relatively smooth contour and di­lated cryptal lumen in the lower half, and some irregularity and tortuosity with occa­sional evagination of the lining epithelium in the upper half.33,34 Adenomas and carcinomas Two types of tumours can be distinguished grossly: polypoid (pedunculated or with a broad base) and non-polypoid (slightly elevat­ed, flat or depressed).5,35 Histologically, col-orectal epithelial tumours are divided into adenomas and carcinomas.36 Adenomas are characterized by hypercel­lularity with enlarged, hyperchromatic nu­clei, varying degrees of nuclear stratification, loss of polarity and decreased mucine excre­tion. Depending on the degree of glandular or villous complexity, extent of nuclear strat­ification and severity of abnormal nuclear morphology, dysplasia in adenomas can be divided into mild, moderate and severe (Figure 2A). Tumours that penetrate through the mus-cularis mucosa into the submucosa are classi­fied as carcinomas.36 When no clear evidence Figure 1. A. Hyperplastic aberrant crypt focus of colorectal mucosa. The focus is composed of three elongated crypts covered by slightly higher epithelium with nuclei at the base of cells. The luminal openings are elevated. B. Dysplastic aberrant crypt focus of colorectal mucosa. The focus is composed of epithelial cells with stratified, hy­perchromatic nuclei, and with a loss of cell polarity and mucin secretion E the signs of dysplasia. Displacement of the surrounding normal crypts is evident. of tumour growth through the muscularis mucosa is found additional criteria like sharp transition from unaltered epithelium to se­vere dysplasia, the presence of necrosis on the surface and desmoplastic stromal reac­tion are used.37 Carcinomas are divided into well, moder­ately and poorly differentiated adenocarcino-mas (Figure 2B), mucinous adenocarcinomas (Figure 3A) if more than 50% of the lesion is composed of mucin and signet-ring cell carci­nomas (Figure 3B) if more than 50% of tumour cells with prominent intracytoplasmic mucin are present.36 Most frequently observed carci­nomas in rat colorectal model are well-differ­entiated adenocarcinomas.8,25,26 Some inves­tigators8,11,25 classify the stage of carcinomas according to Dukes staging system: stage A if tumour is limited to the intestinal wall, stage B if tumour grows through the lamina muscu­laris propria, stage C if tumour grows through the lamina muscularis propria and dissemi­nates into the lymph nodes and stage D when carcinoma disseminates into distant organs. Metastases Metastases to the liver and lung are very un­common in rats. The tumours that are capa­ble of metastasis are almost exclusively the mucinous and signet ring cells carcinomas of the proximal colon. The adenocarcinomas of the distal colon have not been shown to metastasise. The metastases are generally Figure 2. A. Polypoid tubular adenoma of colorectal mucosa with moderate grade of dysplasia. Muscularis mucosa is intact. B. A well-differentiated adenocarcinoma of colorectal mucosa. Submucosal invasion and accompanying fibroplastic stromal reaction is evident. Stage Dukes A. Figure 3. A. A mucinous carcinoma with a wide infiltration of submucosa. Note abundant extracellular mucin se­cretion. B. Signet-ring cell carcinoma metastasis in regional lymph node. Stage Dukes C. found in regional lymph nodes (Figure 3B) or on the peritoneal surface.5,11 Tumour association with gut lymphoid tissue Often, the earliest dysplastic mucosa is found over a mucosal lymphoid aggregate.8,35,38,39 Significant association between tumour de­velopment, particularly non-polipoid adeno­mas35 and mucinous adenocarcinomas,38 and the presence of lymphoid aggregate have been observed. Hardman et al39 have demon­strated that the association is due to higher proliferative activity in colonic crypts over the lymphoid aggregates. Adenoma-carcinoma sequence and de novo formation of colorectal carcinoma investigators3,7,24,32,40,41 Several have ob­served differences in the histopathological findings of the carcinomas between the distal and the proximal colon in rats. The studies suggest that chemically induced carcinogene-sis in the rat colon follows two distinct path­ways: adenoma-carcinoma sequence, where histogenesis follows the ACF-adenoma-carci­noma sequences and de novo sequence where adenocarcinomas develop without passing through ACF stage.3,7,24,40 The former is char­acteristic for middle and distal colon whereas the latter leads to the development of poorly differentiated, mucin-secreting carcinomas in the proximal colon.3,7,24 Molecular alterations Mutations in the adenomatous polyposis coli gene (Apc), the gene coding for ß-catenin (Ctnnb1) and K-ras gene were detected in col-orectal tumours of rats administered DMH or AOM.42 Alterations of specific oncogenes and tumour suppressor genes play role at dif­ferent stages of carcinogenesis process. In rat carcinogenesis an extensive genomic instabil­ity was found, that is the necessary step for the generation of multiple mutations underly­ing the occurrence of cancer.25,43 Mutations in Apc gene were detected ex­clusively in the mutation cluster region of Apc44 and were found only in 18% of tumours and not in ACF, suggesting that mutations of the Apc gene are associated with the transi­tion from ACF to adenoma and adenocarci­noma and not from normal mucosa to ACF.45 In rat tumorigenesis ß-catenin mutations are more frequent event than Apc mutations,44 suggesting that consequent alterations in the stability and localisation of the protein may play an important role in this colorectal car-cinogenesis model.46 Mutation causes activa­tion of the ß-catenin-Tcf pathway resulting in the accumulation of ß-catenin in the cytosol and nucleus. Most of the mutations occur as single nucleotide substitution within func­tionally significant phosphorylation sites on exon 3. The most common mutation in the early lesions is G:C to A:T transitions that is recognised as the representative mutation in rat colorectal tumours.46,47 ß-catenin gene mutations were detected in tumours and dys-plastic ACF, none in hyperplastic ACF. Also alteration in expression and cellular localiza­tion of ß-catenin and inducible nitric oxide synthase were observed in all dysplastic ACF, adenomas and adenocarcinomas, but not in any hyperplastic ACF.48 K-ras mutations are important early event in the progression of chemically induced col-orectal carcinogenesis in rodents,49,50 fre­quently detected in tumours, dysplastic ACF51 and even in hyperplastic ACF.48 The majority of K-ras mutations are identified in codon 12 and 13.49,50 Constitutive activation of K-ras by point mutation occurs with a fre­quency of 40-60%. K-ras point mutations oc­cur mostly as G to A transitions.49 In carcinogen induced tumours elevated expression of c-myc,52 c-jun44 and c-fos30 were detected and increased expression of cy­clin D1 were observed, particularly by muta-tions in either K-ras or ß-catenin.42 In a subset of carcinogen induced rat col-orectal tumours without detectable K-ras mu­tations constitutively activated wild-type p21ras have been observed, presumably due to increased expression of c-erbB1 receptor and decreased expression of GTPase activat­ing protein. Mitogen-activated protein kinase (MAPK) activation and cyclooxygenase-2 ex­pression were increased in tumours with mu­tated or activated wild-type p21ras. Colonic tumours with activated wild type p21ras, like those with mutated p21ras, have increased activation of extracellular signal regulated ki­nase-1 and extracellular signal regulated ki­nase-2, presumably via the activation of Raf-1 and MAPK kinase.42 Long-term and short-term assays Repeated injections of DMH are needed to induce irreversible molecular and histological alterations in rat colons leading to develop­ment of ACF, adenomas and carcinomas. Based on duration of experiment assays can be divided into short-term and long-term. Short-term assays require 4-11 weeks to complete (Table 1). In that time only ACF are induced, which are identified by light micro­scopic examination of large bowel.29,30 They are precancerous lesions that are used as in­termediate biomarkers to predict the ability of a test agent to affect tumour outcome.29­34,53 Based on ability to retard or induce the appearance of ACF, compounds are classified as tumour inhibitors or tumour promot-ers.29,30,53 However, it is important to take in­to consideration that ACF are a heteroge­neous group of lesions33,34,53 not equally dis­tributed in colon. Ghirardi et al41 observed the majority of ACF in the middle colon. Also Rodrigues et al32 reported that majority of ACF were observed in the middle and distal colon and that induction of ACF by DMH in the short-term assay was correlated with de­velopment of well-differentiated adenocarci­nomas. Park et al24 demonstrated, that ACF are marker lesions for colorectal tumours, but only in distal colon where tumours follow the adenoma-carcinoma sequence. Therefore, compounds, which appear to be effective in the short-term, are usually examined in long­term experiments. In contrast to short-term assays, the long­term usually take 20-40 weeks to complete (Table 1). In that time ACF, adenomas and adenocarcinomas are induced, which are fur­ther examined to assess the effect of testing substances on colorectal tumorigenesis. Conclusions Studies on DMH model allow monitoring the step-wise development of CRC by examining the dissected colons of randomly selected an­imals from a group, at different time inter­vals, as the disease progresses and under de­fined experimental conditions. They have al­ready produced much important information on histology and biochemistry of tumour de­velopment as well as on factors that retard or enhance tumorigenesis. Even today, DMH model represents invaluable research tool for studying the molecular events of CRC and for developing and evaluating of a variety of nov­el cancer chemopreventive agents. 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Rofecoxib does not in­hibit aberrant crypt foci formation but inhibits lat­er steps in the development of experimental col-orectal cancer. Rofecoxib in experimental colon cancer. Scan J Gastroenterol 2005; 40: 61-7. 27. Ward JM, Yamamoto RS, Brown CA. Pathology of intestinal neoplasms and other lesions in rats ex­posed to azoxymethane. J Natl Cancer Inst 1973; 51: 1029-39. 28. Shetye J, Mathiesen T, Fagerberg J, Rubio C. Ear tumours induced by experimental carcinogenesis in the rat: excision prevents early death. Int J Colorectal Dis 1994; 9: 125-7. 29. Bird RP. Observation and quantification of aber­rant crypts in the murine colon treated with a colon carcinogen: preliminary findings. Cancer Lett 1987; 37: 147-51. 30. Bird RP, Good CK. The significance of aberrant crypt foci in understanding the pathogenesis of colon cancer. Toxicology Letters 2000; 112: 395-402. 31. Bird RP. Role of aberrant crypt foci in understand­ing the pathogenesis of colon cancer. Cancer Letters 1995; 93: 55-71. 32. Rodrigues MA, Silva LA, Salvadori DM, De Camargo JL, Montenegro MR. Aberrant crypt foci and colon cancer: comparison between a short-and medium-term bioassay for colon carcinogene-sis using dimethylhydrazine in Wistar rats. Braz J Med Biol Res 2002; 35: 351-5. 33. Shipitz B, Bomstein Y, Mekori Y, Cohen R, Kaufman Z, Neufeld D, et al. Aberrant crypt foci in human colons: distribution and histomorpho-logic characteristics. Hum Pathol 1998; 29: 469-75. 34. Cheng L, Lai MD. Aberrant crypt foci as micro­scopic precursors of colorectal cancer. World J Gastroenterol 2003; 9: 2642-9. 35. Rubio CA, Shetye J, Jaramillo E. Non-polypoid adenomas of the colon are associated with subja-cent lymphoid nodules. Scand J Gastroenterol 1999; 34: 504-8. 36. Hamilton SR, Vogelstein B, Kudo S, Riboli E, Nakamura S, Hainaut P, et al. Carcinoma of the colon and rectum. In: Hamilton SR, Aaltonen LA, editors. WHO Classification of Tumours. Pathology and Genetics of Tumours of the Digestive System. Lyon: IARC Press; 2000. p. 103­113. 37. Cerar A, Zidar N, Vodopivec B. Colorectal carci­noma in endoscopic biopsies; additional histolog­ic criteria for the diagnosis. Path Res Pract 2004; 200: 657-62. 38. Nauss KM, Locniskar M, Pavlina T, Newberne PM. Morphology and distribution of 1,2-dimethyl-hydrazine dihydrochloride- induced colon tumors and their relationship to gut-associated lymphoid tissue in the rat. J Natl Cancer Inst 1984; 73: 915-24. 39. Hardman WE, Cameron IL. Colonic crypts located over lymphoid nodules of 1,2-dimethylhydrazine-treated rats are hyperplastic and at high risk of forming adenocarcinomas. Carcinogenesis 1994; 15: 2353-61. 40. Rubio CA, Nylander G, Sveander M, Duvander A, Alun ML. Minimal invasive carcinoma of the colon in rats. An J Pathol 1986; 123: 161-5. 41. Ghirardi M, Nascimbeni R, Villanacci V, Fontana MG, Di Betta E, Salerni B. Azoxymethane-induced aberrant crypt foci and colorectal tumours in F344 rats: sequential analysis of growth. Eur Surg Res 1999; 31: 272-80. 42. Bissonnette M, Khare S, von Lintig FC, Wail RK, Nguyen L, Zhang Y, et al. Mutational and nonmu­tational activation of p21ras in rat colonic azoyxmethane-induced tumors: effects on mito-gen-activated protein kinase, cyclooxygenase-2, and cyclin D1. Cancer Res 2000; 60: 4602-9. 43. Luceri C, De Filippo C, Caderni G, Gambacciani L, Salvadori M, Giannini A, et al. Detection of somat­ic DNA alterations in azoxymethane-induced F344 rat colon tumors by random amplified polymor­phic DNA analysis. Carcinogenesis 2000; 21: 1753-6. 44. Blum CA, Tanaka T, Zhong X, Li Q, Dashwood WM, Pereira C, et al. Mutational analysis of Ctnnb1 and Apc in tumors from rats given 1,2-di­methylhydrazine or 2-amino-3-methylimidazo[4,5­f]quinoline: mutational »hotspots« and the relative expression of beta-catenin and c-jun. Mol Carcinog 2003; 36: 195-203. 45. De Filippo C, Caderni G, Bazzicalupo M, Briani C, Giannini A, Fazi M, et al. Mutations of the Apc gene in experimental colorectal carcinogenesis in­duced by azoxymethane in F344 rats. Br J Cancer 1998; 77: 2148-51. 46. Takahashi M, Fukuda K, Sugimura T, Wakabayashi K. Beta-catenin is frequently mutat­ed and demonstrates altered cellular location in azoxymethane-induced rat colon tumors. Cancer Res 1998; 58: 42-6. 47. Yamada Y, Yoshimi N, Hirose Y, Kawabata K, Matsunaga K, Shimizu M, et al. Frequent ?-catenin gene mutations and accumulations of the protein in the putative preneoplastic lesions lacking macroscopic aberrant crypt foci appearance in rat colon carcinogenesis. Cancer Res 2000; 60: 3323-7. 48. Takahashi M, Mutoh M, Kawamori T, Sugimura T, Wakabayashi K. Altered expression of beta-catenin, inducible nitric oxide synthase and cy­clooxygenase-2 in azoxymethane-induced rat colon carcinogenesis. Carcinogenesis 2000; 21: 1319-27. 49. De Jong TA, Skinner SA, Malcontenti-Wilson C, Vogiagis D, Bailey, van Driel IR, et al. Inhibition of rat colon tumors by sulindac and sulindac sulfone is independent of K-ras (codon 12) mutation. Am J Physiol Gastrointest Liver Physiol 2000; 278: G266­72. 50. Vivona AA, Shpitz B, Medline A, Bruce WR, Hay K, Ward MA, et al. K-ras mutations in aberrant crypt foci, adenomas and adenocarcinomas during azoxymethane-induced colon carcinogenesis. Carcinogenesis 1993; 14: 1777-81. 51. Caderni G, Dolara P, Fazi M, Luceri C, Geido E, Rapallo A, et al. Cell cycle variantions in azoxymethane-induced rat colorectal carcinogene-sis studied by flow cytometry. Oncol Rep 1999; 6: 1417-20. 52. Kishimoto Y, Morisawa T, Hosoda A, Shiota G, Kawasaki H, Hasegawa J. Molecular changes in the early stage of colon carcinogenesis in rats treated with azoxymethane. J Exp Clin Cancer Res 2002; 21: 203-11. 53. Ehrlich VA, Huber W, Grasl-Kraupp B, Nersesyan A, Knasmuller S. Use of preneoplastic lesions in colon and liver in experimental oncology. Radiol Oncol 2004; 38: 205-16. IMRT point dose measurements with a diamond detector Erin Barnett, Marc MacKenzie, B. Gino Fallone Department of Physics, University of Alberta, and Department of Medical Physics, Cross Cancer Institute, Edmonton, Alberta, USA Background. Radiation dose distribution calculations used in treatment planning systems (TPS) describe dose deposition well for large fields. For small fields encountered in Intensity Modulated Radiation Therapy (IMRT) these models may be less accurate. Dose verification of IMRT fields is therefore essential in IMRT implementation and quality assurance. For these smaller fields, lateral electronic equilibrium may not exist and volume averaging effects in ion chambers become increasingly problematic. For this reason, detectors with sensitive volumes smaller than that of conventional ion chambers are preferable in both small fields and high dose gradient region. Diamond detectors are capable of making such accurate dosimetric measurements. Methods. This study compares dosimetry measurements made with a PTW-Freiburg type 60003 diamond detector, an Exradin A12 ion chamber, a PTW-Freiburg PinPoint ion chamber and a Varian aS500 EPID. Dose measurements were made in a clinical prostate intensity modulated beam. Due to difficulties encoun­tered when dosimetric measurements are made in high dose gradient regions, probe positioning within IM­RT fields was investigated and a method to establish better probe positions is proposed. Measured doses were compared with HELAX-TMS calculated doses to verify performance of the TPS used in this center. Results. The diamond detector dosimetry is extremely sensitive to positioning particularly in high dose gra­dient regions. The results indicate that improved agreement between doses measured with various dosime­ters can be obtained by appropriate selection of the probe position. Avoidance of high dose gradient regions improves agreement between measured doses particularly for the PinPoint chamber, the diamond detector and the EPID. Conclusions. The use of diamond detectors and EPIDs in dosimetry is an attractive option particularly for verification of IMRT treatments. Although 2D dose verification of IMRT treatments is a more desirable op­tion than point dose verification, an independent check of EPID or film verification is beneficial. Use of a di­amond detector is an excellent option for dose measurements in cases where portal imaging devices are not available such as the case of helical tomotherapy. Key words: radiotherapy dosage; radiotherapy; diamond detector, intensity modulated radiotherapy Received 4 August 2004 Accepted 14 August 2004 Correspondence to: Prof. B. Gino Fallone, PhD, FC­CPM, ABMP, Department of Physics and Oncology, University of Alberta, and Department of Medical Physics, Cross Cancer Institute, Edmonton, Alberta; Phone: +1 780 432-8750; Fax: +1 780 432-8615; E-mail: gfallone@phys.ualberta.ca Introduction The present day movement in radiation ther­apy is towards intensity modulated radiation therapy (IMRT). The aim of these conformal radiation treatments is to achieve a higher dose within the target volume(s) while mini­mizing the damage to the organs at risk. IM­RT improves upon the technique of 3D con­formal radiation therapy by not only improv­ing the conformation of the treated volume to the target volume, but by allowing for more homogeneous doses to be delivered to target volumes.1 IMRT is a particularly valuable technique when target volumes are concavely shaped and closely neighbored by sensitive volumes that can tolerate very little radiation damage.2 The fields required to deliver inten­sity modulated treatments in step and shoot IMRT consist of a number of beam segments that can be more complex in shape than fields previously encountered in radiation therapy. Not only are the segments making up individ­ual IMRT fields smaller than conventional ra­diotherapy beams, but higher dose gradients are also present in intensity modulated beams (IMB). Within high dose gradients volume av­eraging effects become more pronounced par­ticularly for large volume point dosimeters. Volume averaging of a signal is not a signifi­cant problem if the signal is constant or changes in a linear manner within the sensi­tive volume of the detector.3 In high dose gra­dients the response of a detector may differ substantially from the absorbed dose.4 A re­duction in the size of the sensitive volume yields a reduction in the magnitude of volume averaging effects and therefore leads to more accurate measurements in high dose gradient regions. Also within these dose gradients electronic equilibrium may not exist. The ef­fect of electronic disequilibrium on dosimet­ric measurements in narrow beams has been investigated by various groups, particularly in the field of stereotactic radiosurgery.6-8 According to Heydarian et al., ion chamber based dosimetry in steep dose gradients in the absence of lateral electronic equilibrium is not appropriate.8 The presence of ion cham­bers in a radiation field enhances the lateral electronic disequilibrium.9 Bjärngard et al. ex­amined the effect of incomplete lateral elec­tronic equilibrium on central axis dose meas­urements and made comparisons with Monte Carlo simulation. This group concluded that the detectorís sensitive volume must be sig­nificantly smaller than the radius of the stereotactic beam in which dosimetric meas­urements are to be made. Their simulations indicated that at a beam radius of 1.5 cm, lat­eral electronic equilibrium was reached for a 6 MV simulated beam.5 For higher beam qual­ities, a larger field size is required to ensure the existence of lateral electronic equilibrium. Diamond detectors are an attractive option for making dosimetric measurements in small fields due to the inherently small sensi­tive volume of these devices as well as energy and directional independence as documented by a number of groups.10-12 In a study con­ducted by Heydarian et al. it was found that lateral electronic disequilibrium can cause dose measurement errors particularly for large volume non-tissue equivalent detec­tors.8 Since diamond detectors are small vol­ume essentially tissue equivalent dosimeters, the presence of lateral electronic equilibrium is not a strict requirement for diamond detec­tor dosimetry. The objective of this investigation was to determine the feasibility of making point dose measurements in IMBs that may contain small segments and high dose gradients. Dose measurements in solid water phantom were conducted for 15 MV linear accelerator generated beam generated by a Varian 2100 EX linear accelerator [Varian Medical Systems, Palo Alto, CA]. Dose measurements were made using a PTW-Freiburg type 60003 diamond detector, Exradin A12 ion chamber, PTW-Freiburg PinPoint ion chamber and a Varian aS500 EPID. Materials and methods The diamond detector employed in this study is a type 60003 (S/N 9-032) [PTW-Freiburg, Germany]. The sensitive volume consists of a natural diamond crystal with a sensitive area of 6.8 mm2, a thickness of 0.25 mm giving a sensitive volume of 1.7 mm3. This volume is oriented in the probe housing such that the sensitive volume is positioned 1 mm from the front face of the cylindrical probe. Prior to all dosimetric measurements, the diamond de­tector was irradiated to a dose of at least 5 Gy to ensure the stability of the response. Diamond detectors are known to exhibit a dose rate dependence that is described by . i = R .(D [1] ). + idark where i is the diamond current, R is a con­ . stant of proportionality, D is the dose rate, .is the sublinear response parameter of the diamond detector and idark is the dark current of the detector.13,14 The magnitude of the dark current of diamond detectors is suffi­ciently small that this additive term in this equation can be neglected. The .and R value of this detector are 0.995 ± 0.002 and 0.0254 ± 0.0003 nA/cGy/min, respectively. Correc­tions for the dose rate dependence were made according to equation 1. The PinPoint ion chamber used in this study is a PTW-Freiburg type 31006 (S/N 0290) [PTW-Freiburg, Germany]. This detec­tor has a 0.015 cm3 air filled sensitive volume. The wall material is 0.56 mm of PMMA and 0.15 mm of graphite. The sensitive volume is cylindrical in shape with a length of 5 mm and a radius of 1 mm. The pre-irradiation dose of 2 Gy as recommended in the instruc­tion manual was delivered prior to all dosi-metric measurements. The primary substandard ion chamber used by this centre is an Exradin A12 ion chamber (S/N 396) [Standard Imaging, Middleton, WI]. This dosimeter is a Farmer type chamber with a collecting volume of 0.651 cm3. The diameters of the sensitive vol­ume and the collector are 6.1 mm and 1.0 mm respectively. The wall, collector and guard material of this device are made with Shonka air-equivalent plastic C552 with a wall thick­ness of 0.5 mm. The Varian Portalvision aS500 EPID [Varian Medical Systems, Palo Alto, CA] con­sists of an amorphous silicon solid state flat-panel imaging device. Dosimetry measure­ments using a PortalVision aS500 EPID [Varian Medical Systems, Palo Alto, CA] were made with a technique involving convolu-tion-type calculations described by B. Warkentin et al. and S. Steciw et al.15,16 Dosimetry of clinical prostate intensity modulated beam The probes were positioned at isocenter of a Varian 2100 EX linear accelerator [Varian Medical Systems, Palo Alto, CA] at a depth of 10 cm in a solid water phantom [Gammex, Middleton, WI] with their axes of symmetry perpendicular to the beam central axis (CAX). The responses of the dosimeters to a step and shoot clinical prostate plan were monitored as a function of time using a Wellhöfer Dosimetrie System [Scanditronix-Wellhofer, Schwarzenbruck, Germany]. The Wellhöfer system outputs a signal in terms of percent dose. In order to relate this percent dose dur­ing the delivery of the irradiations at various field sizes, the percent dose response of the dosimeters in a 10 x 10 cm2 field was also ob­served for all point dosimeters. At the time of experimentation the output of the linac was measured with a PR-06C Farmer type cham­ber [CNMC Company, Nashville, TN] in a 10 x 10 cm2 field in a constancy device that en­sures the uniform probe positioning that is used for routine quality assurance. The per­cent dose output of the Wellhöfer system was converted to a dose rate by making use of the relationship between the Wellhöfer electrom­eter response to the 10 x 10 cm2 radiation field at a depth of 10 cm and the dosimetry measurements under the same conditions. In addition to monitoring the diamond response using the Wellhöfer system, the diamond cur­rent response to a 10 x 10 cm2 irradiation field at a depth of 10 cm was monitored using a Keithley 6514 electrometer [Keithley Instruments, Inc., Cleveland, OH]. This addi­tional step is required when conducting dosimetry using a diamond detector as the di­amond current is related to the dose rate by equation 1. The percent dose rate output of the Wellhöfer system was converted to a dia­mond current by means of this cross calibra­tion. The resulting diamond current was sub­sequently converted to a dose rate. To arrive at the total dose during the IMB delivery, the dose rates were integrated with time. EPID dose distributions for each field segment were measured according to the method de­scribed by B. Warkentin et al and S. Steciw et al The method described in these works re­sults in the dose distribution at a depth of 10 cm for an source surface distance of 90 cm.15,16 The central pixel values of the EPID dose distributions for each segment were ex­tracted and compared with doses measured with the point dosimeters. Dose calculations of this IMB delivered to a water phantom were made using HELAX­TMS [Nucletron, Veenendaal, The Nether­lands]. In addition to the IMB, a 5 x 5 cm2 field centered about a different isocenter was included in the calculation space to allow for the conversion of calculated percent doses to doses. This 5 x 5 cm2 field was positioned suf­ficiently far from the IMBs so that the scatter contribution from this field to the IMB was negligible.17 Comparison of the calculated point dose at isocenter was made to the dose measured with the various dosimeters. Dosimetry of clinical prostate intensity modulated beam at improved detector positions Due to the difficulties associated with con­ducting point dose measurements in high dose gradients, it is desirable to make point dose measurements in low dose gradient re­gions. In order to establish improved detec­tor positions, Matlab code [Mathworks, Natick, MA] was written that excluded probe positions based on their vicinity to segment edges. For a given segment, possible probe positions were deemed acceptable if the beam edges were distanced 1 cm from the probe position thereby avoiding measure­ment positions within the penumbral regions of that segment. A probe position map for the IMB was then generated based on the ac­ceptable probe positions for each of the seg­ments comprising the beam according to the respective segment weightings in the IMB. Although probe positions outside the treat­ment field are considered to be improved de­tector positions according to segment edge exclusion criteria, these positions were not considered to be improved positions. The dose within the treatment field is the quanti­ty of interest, not the dose delivered via scat­ter to the surrounding volume. Comparison between measured and calculated doses was made. Results Dosimetry of clinical prostate intensity modulated beam The beam segments that comprise the prostate step and shoot IMB are shown in Figure 1. The coordinates (0,0) of each seg­ment correspond to isocenter. The results of the dose measurements at isocenter of the clinical prostate IMRT treatment are summa­rized in Table 1. By viewing the segment shapes shown in Figure 1 it is apparent that the poorest agree­ment between the measured doses occurs in cases where segment edges abut the point of measurement. This poor agreement is attrib­uted to volume averaging effects within the sensitive volumes and errors introduced by this diamond detector is 0.25 mm, an uncer-probe positioning. Although the extremely tainty of ± 0.5 mm in probe positioning can small sensitive volume of the diamond detec-mean the difference between centering the tor is desirable for many applications, it sensitive volume in the open portion of the makes the positioning of the probe critical. beam or in the penumbral region of segments Since the thickness of the sensitive volume of that abut the point of measurement. Thus di- Table 1. Doses measured at isocenter during delivery of 8 segment clinical prostate intensity modulated beam Dose (cGy) Segment A12 PinPoint Diamond detector EPID HELAX-TMS 1 25.5 ±0.4 29.0 ±0.2 10.9 ±0.1 19 ±4 23.6 2 25.9 ±0.4 29.5 ±0.2 11.2 ±0.1 19 ±4 23.8 3 26.1 ±0.4 28.2 ±0.2 15.2 ±0.2 21 ±4 21.7 4 40.3 ±0.6 40.0 ±0.3 40.2 ±0.5 39.9 ±0.1 39.5 5 36.0 ±0.4 35.9 ±0.2 36.1 ±0.5 35.9 ±0.1 35.6 6 34.9 ±0.5 38.9 ±0.3 40.2 ±0.5 39.7 ±0.1 40.5 7 9.3 ±0.1 10.8 ±0.1 7.5 ±0.1 10 ±2 2.7 8 2.18 ±0.03 2.24 ±0.01 2.26 ±0.01 2.5 ±0.1 0.0 Total 200 ±1 214.5 ±0.5 164 ±1 186 ±7 187 Table 2. Doses measured at improved detector position 1 (-1.3 cm 1.7 cm) during delivery of 8 segment intensity modulated field Dose (cGy) Segment A12 PinPoint Diamond detector EPID HELAX-TMS 1 2.58 I 0.04 1.61 I 0.02 1.40 I 0.02 1.7 I 0.1 1.1 2 2.63 I 0.04 1.65 I 0.02 1.47 I 0.02 1.7 I 0.1 1.1 3 10.1 I 0.2 3.23 I 0.05 2.61 I 0.04 3.0 I 0.3 2.6 4 40.6 I 0.7 41.0 I 0.6 40.9 I 0.6 40.2 I 0.1 39.5 5 36.4 I 0.7 36.9 I 0.6 36.5 I 0.6 36.2 I 0.1 35.6 6 39.4 I 0.6 40.6 I 0.5 40.2 I 0.5 40.0 I 0.2 39.9 7 5.0 I 0.1 4.69 I 0.05 4.61 I 0.05 4.5 I 0.5 1.3 8 3.17 I 0.04 2.75 I 0.03 2.72 I 0.03 2.8 I 0.2 0.0 Total 140 I 1 132 I 1 130 I 1 130.1 I 0.7 121.2 Table 3. Doses measured at improved detector position 2 (0.7 cm, 3.0 cm) during delivery of 8 segment intensity modulated field Dose (cGy) Segment A12 PinPoint Diamond detector EPID HELAX-TMS 1 1.23 I 0.02 1.15 I 0.01 1.00 I 0.01 1.36 I 0.05 0.2 2 1.26 I 0.02 1.22 I 0.01 1.04 I 0.01 1.35 I 0.04 1.1 3 1.26 I 0.02 1.18 I 0.01 1.00 I 0.01 1.26 I 0.04 0.9 4 37.3 I 0.6 39.7 I 0.3 39.2 I 0.5 38.4 I 0.3 39.2 5 33.8 I 0.5 36.3 I 0.2 35.6 I 0.5 35.0 I 0.2 35.5 6 38.2 I 0.6 41.2 I 0.3 40.4 I 0.5 39.7 I 0.3 36.6 7 45.6 I 0.7 49.9 I 0.3 49.8 I 0.7 48.7 I 0.2 49.6 8 36.9 I 0.6 44.9 I 0.3 45.6 I 0.4 44.9 I 0.1 46.1 Total 196 I 1 216 I 1 214 I 1 210.8 I 0.5 209.1 amond detector dosimetry is extremely sensi­tive to positioning particularly in high dose gradient regions. The doses calculated by HELAX-TMS ap­pearing in Table II are included for compara­tive purposes only. It is not assumed that these values represent the most accurate de­termination of dose. Dosimetry of clinical prostate intensity modulated beam at improved detector positions The map used to establish improved detector positions for the clinical IMB is shown in Figure 2. The positions within the treatment Figure 1. Shape of eight segments that comprise single intensity modulated beam and »fluence map« resulting from delivery of eight step and shoot segments - thick lines illustrate segment geometry, thin lines illustrate main collimator settings. field with the highest value assigned to them are the most appropriate positions to make point measurements according to the criteria described in the preceding section. The ar­rows in Figure 2 indicate the positions that best avoid high dose gradients, (0.7 cm, 3.0 cm) and (-1.3 cm, 1.7 cm), the cross-plane and in-plane positions respectively relative to isocenter. The results of the dose measure­ments at the improved probe positions as es­tablished using the in house software of the clinical prostate IMRT treatment are summa­rized in Tables 2 and 3. The results summarized in Tables 2 and 3 indicate that improved agreement between doses measured with various dosimeters can be obtained by appropriate selection of the probe position. Avoidance of high dose gradi­ent regions improves agreement between measured doses particularly for the PinPoint chamber, the diamond detector and the EPID. By measuring the dose at the first improved detector position as determined by the tech­nique previously described, excellent results are obtained. The total doses measured by the PinPoint chamber, diamond detector and EPID are very nearly in agreement within one standard error. Although the agreement be­tween the doses measured at the second im­proved detector position is not as good as at the first improved detector position, the PinPoint and EPID values differ by less than 1.5 % from the diamond detector measured value. Comparison of the results summarized in Tables 1 through 3 indicates that improve­ment in the agreement between doses meas­ured with various dosimeters can be obtained by choosing measurement points appropri­ately. Avoidance of high dose gradient re­gions is necessary to avoid volume averaging effects that greatly affect large volume cham­ber and to eliminate the high sensitivity of dosimeters to small errors in positioning. Discussion IMRT gives rise to smaller field sizes and higher dose gradients than were previously encountered in conventional radiation thera­py with the exception of stereotactic radio-surgery. Point dose measurement of IMBs can be complicated by the presence of high dose gradients within these fields. Dose measure­ment in the absence of these gradients is nec­essary to avoid volume averaging effects. The technique employed in this investigation to select better probe positions for the clinical IMB that avoid these high dose gradients gave rise to improved agreement between the dosimeters used in this study. Sub-optimal agreement was obtained between measured and HELAX-TMS calculated doses. This re­sult is attributed to the difficulties associated with penumbral modeling in the release of HELAX-TMS used in this center. The use of diamond detectors and EPIDs in dosimetry is an attractive option particu­larly for verification of IMRT treatments. Although 2D dose verification of IMRT treat­ments is a more desirable option than point dose verification, an independent check of EPID or film verification is beneficial. Use of a diamond detector is an excellent option for dose measurements in cases where portal im­aging devices are not available such as the case of helical tomotherapy. Also for acceler­ators that are equipped with multi-leaf colli­mators but lack a portal imager, diamond de­tector dosimetry is a viable technique. The EPID dosimetry technique employed in this study is applicable only to specific geometric conditions at the present time, while dia­mond detector dosimetry is not limited by these conditions allowing for point verifica­tion at different positions and depths within phantom. Acknowledgments E. Barnett would like to thank NSERC and AHFMR for their financial support as well as Dr. S. Steciw and B. Warkentin for use of software to convert EPID images to dose dis­tributions and H. Warkentin for assistance with HELAX-TMS. References 1. Martens C, Claeys I, De Wagter C, De Neve W. The value of radiographic film for the characteri­zation of intensity-modulated beams. Phys Med Biol 2002; 47: 2221-34. 2. Webb S. Intensity-Modulated Radiation Therapy. Bristol: Institute of Physics Publishing; 2001. 3. Mack A, Scheib SG, Major J, Gianolini S, Pazmandi G, Feist H, et al.. Precision dosimetry for narrow photon beams used in radiosurgery-de­termination of Gamma Knife output factors. Med Phys 2002; 29: 2080-9. 4. Martens C, De Wagter C, De Neve W. The value of the PinPoint ion chamber for characterization of small field segments used in intensity-modulated radiotherapy. Phys Med Biol 2000; 45: 2519-30. 5. Bjarngard BE, Tsai JS, Rice RK. Doses on the cen­tral axes of narrow 6-MV x-ray beams. Med Phys 1990; 17: 794-9. 6. Houdek PV, VanBuren JM, Fayos JV. Dosimetry of small radiation fields for 10-MV x rays. Med Phys 1983; 10: 333-6. 7. Arcovito G, Piermattei A, D'Abramo G, Bassi FA. Dose measurements and calculations of small ra­diation fields for 9-MV x rays. Med Phys 1985; 12: 779-84. 8. Heydarian M, Hoban PW, Beddoe AH. A compar­ison of dosimetry techniques in stereotactic radio-surgery. Phys Med Biol 1996; 41: 93-110. 9. Heydarian M, Hoban PW, Beddoe AH. Dose rate correction factors for diamond detectors for mega-voltage photon beams. Phys Med Biol 1997; 13: 55­60. 10. De Angelis C, Onori S, Pacilio M, Cirrone GA, Cuttone G, Raffaele L, et al. An investigation of the operating characteristics of two PTW diamond detectors in photon and electron beams. Med Phys 2002; 29: 248-54. 11. Laub WU, Kaulich TW, Nusslin F. A diamond de­tector in the dosimetry of high-energy electron and photon beams. Phys Med Biol 1999; 44: 2183­92. 12. Laub WU, Wong T. The volume effect of detectors in the dosimetry of small fields used in IMRT. Med Phys 2003; 30: 341-7. 13. Laub WU, Kaulich TW, Nusslin F. Energy and dose rate dependence of a diamond detector in the dosimetry of 4-25 MV photon beams. Med Phys 1997; 24: 535-6. 14. Fowler JF, Attix FH. Solid state electrical conduc­tivity doseimeters. In: Attix FH, Roesch WC, edi­tors. Radiation dosimetry. Vol. 1. New York: Academic; 1966. 15. Steciw S, Warkentin BM, Rathee S, Fallone BG. A Monte Carlo based method for accurate IMRT ver­ification using the aS500 EPID. Med Phys 2003; 30: 1331. 16. Warkentin B, Steciw S, Rathee S and Fallone B G. Dosimetric IMRT verification with a flat-panel EPID. Med Phys 2003; 30: 3143-55. 17. MacKenzie MA, Lachaine M, Murray B, Fallone BG, Robinson D and Field G C. Dosimetric verifi­cation of inverse planned step and shoot multileaf collimator fields from a commercial treatment planning system. J Appl Clin Med Phys 2002; 3: 97­109. Radio/ Oncol 2005; 39(1): 1-4. Simptomatska neperforirana Cowperjeva siringokela pri S-letnem decku Roic' G, Boric I, Posaric V, Basti<: M, Župancic B Izhodišca. Cowperjeva siringokela je redka anomalija Cowperjeve žleze pri otrocih. Nastane zaradi obstrukcije žleznega izvodila. Simptomatske oblike zdravimo glede na velikost siringokele in starost bolnika. Odlocamo se za endoskopsko ali odprto perinealno operacijo. Prikaz primera. Porocamo o simptomatski neperforirani siringokeli pri S-letnem decku. Ceprav obicajno siringokelo najlepše prikažemo z izpraznitveno cistouretrografijo, s to preiskavo nismo zaznali nobene utesnitve ali polnitvenega defekta v bulbarnem delu secnice. Seringokelo smo dokazali z ultrazvocno vodeno perinealno punkcijo, med katero smo injicirali kontrast v cisticno spremembo. Zakljucki. Pri neperforirani siringokeli je ultrazvocna preiskava koristna metoda, zlasti pri mladih bolnikih in nam pomaga pri odlocitvi za perinealni operativni poseg. Radio/ Oncol 2005; 39(1): 5-8. Ultrazvocni pregled plevralnega prostora pri zdravih nosecnicah -preliminarni rezultati Kocijancic I Izhodišca. Namen naše študije je bil ugotoviti pogostnost ultrazvocnega prikaza fiziološke plevralne tekocine pri zdravih nosecnicah. Bolnice in metode. Pri 47 zdravih nosecnicah smo naredeli ultrazvocno preiskavo plevralnega prostora, najprej v položaju na komolcu in potem še sede, obakrat z 9-12 MHz linearno sondo. Ce smo na ta nacin našli anehogen plašc plevralne tekocine širok vsaj 2 mm, smo preiskavo ponovili še z 3-6 MHz konveksno abdominalno sondo. Rezultati. Anehogen plašc plevralne tekocine tipicne klinaste oblike je bil viden pri 28/47 (59·5%) nosecih prostovoljkah, od tega na obeh straneh pri 18/47 (38·3%) in le na eni strani pri 10/47 (21 ·2%). Povprecna širina plašca tekocine (povprecje rezultatov v obeh položajih) je bila 2,79 mm (SD 0,91 mm, razpon od 1,8 mm do 6,4 mm). Število nosecnic z vidno plevralno tekoci­no, ki so nosile ženske in moške plodove je bilo enako, toda razlika v povprecni širini plašca tekocine enih in drugih je bila statisticno pomembna (t-test: p=0,041). Vec kot 3 mm plevralne tekocine smo z lahkoto prikazali s 3-6 MHz abdominalno konveksno sondo pri 7 /47 (15%) vseh preiskovank. Zakljucki. Pri ultrazvocnem pregledu plevralnega prostora, pa tudi zgornjega dela trebušne vot­line lahko vcasih najdemo manjšo kolicino plevralne tekocine pri sicer zdravih nosecnicah. Take izolirane slucajne najdbe ne smemo smatrati kot bolezenski znak. Radio! Oncol 2005; 39(1): 9-13. Poškodba aksilarne arterije. Diagnosticiranje pooperativne arterijske okluzije in kolateralnega pretoka z dvojnim ultrazvokom Krnic A, Sucic Z, Vucic N, Bilic A Izhodišca. Poškodba aksilarne arterije je življenjsko nevarna. Zahteva takojšnjo pomoc s kom­presijo žile in pri mnogih bolnikih moramo narediti eksplorativno operacijo. Zaradi ugotavljan­ja prehodnosti žile je po posegu cesto potrebno narediti tudi angiografijo. Prikaz primera. Porocamo o poškodbi aksilarne arterije pri 28-letni bolnici. Ceprav smo z dvo­jnim ultrazvokom natancno opredelili postoperativne prestenoticne in poststenoticne spre­membe, smo jih potrdili še z angiografijo. Preiskava je pokazala obsežen kolateralen pretok v ak­sili in motnje perfuzije z aksilarno arterijo. Bolnico smo ponovno operirali, narejena je bila trombektomija v aksilarni arteriji in prišlo je do znatnega izboljšanja prekrvavitve zgornjega uda. Zakljucki. V opisanem primeru smo z dvojnim ultrazvokom natancno opredelili spremembe v aksili in bi lahko celo opustili preiskavo z angiografijo. Radio/ Oncol 2005; 39(1): 15-21. Ultrazvocne znacilnosti akutnega vnetja slepica pri otrocih Vegar-Zubovic S, Lincender L, Dizdarevic S, Sefic I, Dalagija F Izhodišca. Najpogostejši vzrok bolecin v trebuhu pri otrocih, ki zahteva kirurško obravnavo, je akutno vnetje slepica. Nobeden od klinicnih znakov nima absolutne diagnosticne in napovedne vrednosti. Namen naše raziskave je bil opredeliti ultrazvocne znacilnosti akutnega vnetja slepica ter jih povezati s patomorfološkimi izvidi in intenzivnostjo vnetja. Metode. V prospektivni raziskavi smo ultrazvocno pregledali 50 otrok z znaki akutnega abdom­na. Pri vseh bolnikih smo ultrazvocno diagnozo potrdili kirurško in patohistološko. Zanimalo nas je ali se trajanje simptomov do bolnišnicne obravnave razlikuje glede na patohis­tološki izvid. Pri raziskavi smo uporabljali Toshiba Sonolayer ultrazvok s 3,75 MHz konveksno in 8 MHz linearno sondo. Rezultati. Od 8 ultrazvocnih znakov akutnega vnetja slepica so se zanesljivi pokazali le anteri­orno-posteriorna debelina slepica, debelina periapendikularnega mašcobnega tkiva in odsotnost peristaltike. Najpogostejši patohistološki izvid je bilo flegmonozno vnetje slepica (44%). Pri vec kot polovici bolnikov smo odkrili perforirano gangrenozno vnetje slepica (30%) ali samo gan­grenozno vnetje (22%), kar kaže na dolg casovni interval trajanja simptomov pred bolnišnicno obravnavo. Statisticna analiza je pokazala možnost ocenjevanja stopnje vnetja z anteriorno-pos­teriorno debelino slepica in debelino periapendikularnega mašcobnega tkiva kot znakoma zade­belitve stene crevesa. Zakljucki. Ultrazvocna preiskava je metoda izbire, kadar ob klinicni preiskavi dvomimo, ali ima otrok akutno vnetje slepica. Z anteriorno-posteriorno debelino slepica, debelino stene in debeli­no periapendikularnega mašcobnega tkiva lahko zanesljivo ultrazvocno ocenimo stopnjo inten­zivnosti vnetja slepica. Radio/ Oncol 2005; 39(1): 23-35. Odkrivanje ledvicnih tumorjev in dolocevanje razširjenosti bolezni z magnetnoresonacno preiskavo Kirova K Izhodišca. Magnetnoresonancna preiskava je ena najbolj ustreznih preiskovalnih metod, saj bol­nik ni izpostavljen ionizirajocemu sevanju in ne zahteva injiciranja jodovih kontrastnih sred­stev. Visoka zmogljivost, dobra racunalniška podpora in tehnologija hitrih pulznih frekvenc so tiste lastnosti, ki omogocajo dobro celostno oceno ledvicnih bolezni. Zakljucki. Pri magnetnoresonacnih preiskavah predstavljajo posebno težavo razlicni protokoli preiskav, zato je pomembno, da tehnike preiskav cimbolj standardiziramo. Na ta nacin omogoci­mo ponovljivost in primerljivost rezultatov preiskav. Radio/ Oncol 2005; 39(1): 37-47. Primerjava kvadrantne in razširjene biopsije prostate kot prvo vzorcenje pri bolnikih z napredovalo obliko raka prostate Zoran Brnic Z, Anic P, Garyarov S, Radovic N, Kucan D, Vidas ž, Zeljko Z, Lozo P, Ramljak V Izhodišca. Pri bolnikih z zgodnjim rakom prostate omogoca razširjena biopsija prostate (BP) boljšo senzitivnost in natancnejšo zamejitev tumorja, pri bolnikih z razširjenim rakom prostate pa je potrebna samo potrditev raka z BP. Z raziskavo smo želeli ugotoviti, ali je kvadrantna BP primerna za patološko oceno pri bolnikih, ki imajo verjetno napredovali rak prostate. Prav tako smo želeli ugotoviti, ali zmanjšanje števila vzorcev poslabša zanesljivost BP zaradi manjkajocih kvantitativnih histoloških podatkov. Bolniki in metode. Pregledali smo podatke 84 moških, pri katerih je bila opravljena BP in so bili razdeljeni v skupini »H« (verjeten) in »L« (malo verjeten) napredovali rak prostate. Patohistološke izvide 5-12 vzorcev BP in simuliranih kvadrantnih BP smo retrospektivno primer­jali med seboj, posebej glede na prisotnost raka prostate, volumen tumorja, Gleasonovo tocko­vanje in prisotnost prostaticne intraepitelne neoplazme visokega gradusa (HGPIN). Rezultati. V skupini H je bila stopnja detekcije raka prostate primerljiva, signifikantno pa je padla v skupini L pri simuliranih kvadrantnih BP. Tako se je število pozitivnih vzorcev v skupi­ni H samo neznacilno spremenilo (p = 0,39) in se je znacilno zmanjšalo v skupini L (p = 0,04) zaradi zmanjšanja vzorcenja. Prav tako v skupini H nismo spregledali nobene HGPIN, medtem ko smo v kupini L spregledali dve. Kot posledica zmanjšanja števila vzorcev se je Gleasonovo tockovanje v obeh skupinah neznacilno spremenilo. Zakljucki. Pri bolnikih z napredovalim rakom prostate je kvadrantna BP primeren prvi diag­nosticni postopek, saj z njo dobimo dovolj pomembnih podatkov. Zmanjšanje števila vzorcev praviloma ne vpliva na odlocitev o vrsti zdravljenja napredovalega raka prostate. Radio/ Oncol 2005; 39(1): 49-53. Multipli primarni malignomi pri bolnikih s pljucnim rakom Kurishima K, Satoh H, Homma S, Kagohashi K, Ishikawa H, Ohtsuka M, Sekizawa K Izhodišca. Da bi ugotovili incidenco in vrsto multiplih primarnih malignomov pri bolnikih s pljucnim rakom, smo naredili retrospektivno raziskavo. Metode. Analizirali smo podatke o 1194 bolnikih s pljucnim rakom, ki smo jih na našem odd­elku obravnavali v 29-letnem obdobju do avgusta 2004. Rezultati. Ugotovili smo, da je 98 (8,2%) od 1194 bolnikov s pljucnim rakom imelo multipli pri­marni malignom. Metahrono so bili odkriti v 77,6% , sinhrono pa v 21,4%. Bolj pogosto so nas­tajali pri napredovalih oblikah pljucnega raka (v stadijih IIIA do IV 67,3%) kot pa v zgodnji ob­likah (v stadijih IA do IIB 32,7%). Najpogostejši je bil skvamoznocelicni karcinom (pri 40 bol­nikih oz. pri 40,8%). Najpogostejši prvi primarni tumor smo našli v gastrointestinalnem traktu, nato v pljucih in maternici. 57 (85,1 %) od 67 bolnikov, ki je imelo malignom v prebavilih, dihal­ih ter glavi in vratu, je bilo kadilcev. Od 98 bolnikov, ki so imeli multipli primarni malignom, jih je bilo kirurško zdravljenih le 26 (26,5%), ceprav jih je 40 (40,8%) imelo omejeno obliko pljucne­ga raka s stadijem IA-IIIA. Zakljucki. Ugotovili smo, da pri bolnikih z nedrobnocelicnim pljucnim rakom predstavlja metahroni multipli primarni malignom statisticno znacilen napovedni dejavnik (p=0,0480), kar pa nismo uspeli potrditi pri bolnikih z drobnocelicnim pljucnim rakom in pri sinhronih malig­nomih. Radio/ Oncol 2005; 39(1): 55-9. Prikaz primera karcinoma znojnih žlez, ki je razjedal lobanjske kosti Arslan M, Karadeniz AN, Aksu G, Giiveli M Izhodišca. Karcinomi znojnih žlez so redki tumorji. Prav tako so redki tisti karcinomi znojnih žlez, ki so žlezno aktivni. Do sedaj je v literaturi opisanih le okoli 200 primerov in samo eden je razjedal lobanjske kosti. Zaradi njihove redkosti tudi ne poznamo najprimernejšega in na­jucinkovitejšega zdravljenja. Prikaz primera. Opisujemo 47-letno bolnico, ki so jo po zacetni operaciji leta 1989 še šestkrat operirali zaradi ponavljajocega se tumorja v predelu kože kraniuma. Patomorfološki pregled je po vsaki operaciji pokazal benigni tumor (adenom znojne žleze, cilindrom), razen po zadnji, ko smo ugotovili maligni cilindrom. Pred zadnjo operacijo smo ugotovili, da je recidivni tumor, ki je ležal v levi parietalni regiji velik 10 x 6 cm. Z racunalniško tomografijo pa smo videli, da je 11 x 5 cm velik tumor poškodoval lobanjske kosti, vrašcal v duro ter povzrocal periostalno reakcijo. Zaradi maligne transformacije in velike nevarnosti ponovitve bolezni smo se odlocili za postop­erativno radioterapijo. Zakljucki. Do sedaj je ob naši bolnici opisan samo še en primer, kjer je tumor znojnih žlez vrašcal v lobanjske kosti. Radio/ Onco/ 2005; 39(1): 61-70. Z dimetilhidrazinom inducirani tumorji debelega crevesa in danke pri podgani Perše M, Cerar A Živalski modeli so pri raziskavah raka na debelem crevesju in danki nepogrešljivi, saj omogoca­jo raziskovanje in testiranje številnih dejavnikov, ki jih ni mogoce neposredno ugotavljati pri ljudeh. Edinega izmed živalskih modelov raka na debelem crevesju in danki predstavljajo z dimetil­hidrazinom (DMH) inducirane podgane, ki razvijejo tumorje debelega crevesa in danke zelo podobne humanim. S clankom želimo predstaviti morfološke in genetske spremembe tega mod­ela, ki je veliko prispeval k današnjemu poznavanju etioloških in drugih dejavnikov, ki vplivajo na nastanek in razvoj raka. Danes pa je nepogrešljiv pri raziskavah crevesnih karcinogenov in kemopreventivnih substanc. Radio/ Oncol 2005; 39(1): 71-8. Uporaba diamantnega detektorja pri meritvah absorbirane doze pri IMRT Barnett E, MacKenzie M, Fallone BG Izhodišca. Pri velikih obsevalnih poljih lahko s sistemi za nacrtovanje obsevanja natancno izracunamo prostorsko porazdelitev absorbirane doze, pri manjših poljih, ki jih uporabljamo v intenzitetno modulirani radioterapiji (IMRT), pa utegnemo biti manj natancni. Za zagotovitev kvalitete obsevanja so tako nujno potrebne dodatne meritve absorbirane doze pri uporabi IMRT polj. V manjših poljih ni lateralnega elektronskega ravnovesja, zaradi cesar ionizacijska celica, ki povpreci dozo po vsej svoji prostornini -pri meritvah doze v tocki -ni zanesljiva. V majhnih poljih z visokimi gradienti doze so primernejši dozimetri z manjšimi obcutljivimi prostorninami, kakršen je diamantni detektor. Material in metode. V študiji primerjamo dozimetricne meritve, opravljene z diamantnim de­tektorjem PTW-Freiburg (tip 60003), z ionizacijsko celico Extradin A12, s tockovno ionizacijsko celico PTW-Freiburg PinPoint in z Varianovim elektronskim sistemom za verifikacijo obseval­nega polja (ESVOP) aS500 EPID. Meritve so bile opravljene v intenzitetno moduliranem žarku nacrtovanem za obsevanje prostate. Zaradi težav z namešcanjem dozimetra, ki nastopijo pri meritvah v tocki v obmocju visokih doznih gradientov, smo razvili metodo iskanja naj­primernejše lege dozimetra. Izmerjene doze so primerjane z dozami, izracunanimi s sistemom za nacrtovanje obsevanja HELAX-TMS. Rezultati. Diamantni detektor je izredno obcutljiv na premike znotraj obmocij z visokim gradi­entom doze. Skladnost rezultatov meritev z razlicnimi dozimetri se poveca s primerno izbiro lege dozimetrov. Z izogibanjem obmocjem z visokimi doznimi gradienti izboljšamo ujemanje rezul­tatov meritev predvsem med tockovno ionizacijsko celico PinPoint, diamantnim detektorjem in Varianovim sistemom ESVOP. Zakljucki. Diamantni detektorji predstavljajo uporabno rešitev za dozimetricno preverjanje ob­sevanj z IMRT, še posebej v primerih, kjer sistem ESVOP ni primeren (npr. pri vijacni tomoter­apiji). Notices Natices submitted far publicatian shauld cantain a mailing address, phane and/ ar fax number and/ ar e-mail af a Contact persan ar department. Radiation oncology March, 2005 The ISRO international teaching course on »Palliative Care in Cancer Treatment« will take place in Dar es Salaam, Tanzania. See http://www.isro.be Brach ytherapy May 5-7, 2005 The Annual Brachytherapy Meeting GEC-ESTRO and pre-meeting workshop on breast cancer will take place in Budapest, Hungary. Contact ESTRO office, Avenue E. Mounier, 83/12, B-1200 Brussels, Belgium; or call +32 775 93 40; or fax +32 2 779 54 94; or e-mail info@estro.be; or see http://www.estro.be Clinical oncology May 13-17, 2005 The ASCO Meeting will be offered in Orlando, USA. E mail enews@asco.org; or see http://www/asco.org Lung cancer July 3-6, 2005 The » 11 th W orld Conference on Lung Cancer« will be offered in Barcelona, Spain. Contact Heather Drew, Imedex, Inc., 70 Technology Drive, Alpharetta, GA 30005 USA; or call +1 770 751 7332, or fax +1 770 751 7334; or e-mail h.drew@ imedex.com, or see www.imedex.com/calenders/on­cology/htm Radiation oncology September -October, 2005 The ISRO international teaching course on »Rational Developments from developing to devel­oped Countries« will take place in Lombok, Indonesia. See http://www.isro.be Lungcancer October 17-19, 2005 The IASLC workshop »Biology and Prevention of Lung Cancer« will be offered in Woodstock, Vermont, USA. Contact Taryn Klocke at Envision Communications; call +1 770 763 5690; or see www.lungcancerpreven­tion.net Oncology October 30 -November 3, 2005 The ESTRO 24 / ECCO 13 Conference will take place in Paris, France. Contact FECS office, Av. E. Mounier, 83/4, B-1200 Brussels, Belgium; or call +32 7759340; or fax +32 2 7795494; or e-mail info@estro.be; or see http:// www.fecs.be As a service to our readers, notices oj meetings ar courses wil/ be inserted free o f charge. Please send information to the Editorial office, Radiologij and OncologtJ, Zaloška 2, SI-1000 Ljubljana, Slovenia. 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 1000 LJUBLJANA TEL 0 1 51 9 1 2 77 FAKS 01 251 81 13 ŽR: 50100-620-133-05-1 0331 15-214779 Activity of »Dr. J. Cholewa« Foundation for Cancer Research and Education -A Report for the First Quarter of 2005 The Dr. J. Cholewa Foundation for Cancer Research and Education continues to support activities associated with cancer research and education in Slovenia through­out the first quarter of 2005. Several initiatives are in the course of examination and evaluation by the members of the Foundation and any problems, associated with the public calls for Foundationis grant applications are being dealt with immediately and thoroughly. Several problems and successful endeavours of the Foundation were thoroughly discussed during the course of 2004 and already during the first quarter of 2005. It is worth mentioning that many study and research grants have been already bestowed to researchers from various scientific fields associated with oncology in Slovenia and that many of them were also given grants and means to attend scientif­ic meetings, congresses, conferences and symposia dealing with oncology worldwide. Needless to say, the Dr. J. Cholewa Foundation for Cancer Research and Education is also determined to continue to support the regular publication of »Radiology and Oncology« international scientific journal, which is edited, published and printed in Ljubljana, Slovenia, as it has done over the last couple of years. As an ongoing concern of the Supervisory and Executive Boards of the Foundation, it has to be acknowledged that various public and privately owned enterprises find it ever more difficult to contribute financially to help running day to day operations of the Foundation and its numerous scopes of activity. Several new initiatives and sug­gestions were discussed and evaluated during the recent meetings of the Foundation to address this problem. It is important to note that many public companies and pri­vate individuals remain committed to support the Foundationis activities. Andrej Plesnicar, MD Borut Štabuc, MD, PhD Tomaž Benulic, MD «•=-i 111 1 1• fii 1 temozol.mid kapsule • ¦ v ¦ resn1cno upanJe Izboljša kvaliteto življenja bolnikov. Zmanjšuje potrebe po kortikosteroidih. Omogoca varno in enostavno zdravljenje. Schering-Plough CE AG [bolnišnicna enota] Dunajska 22, 1000 Ljubljana, t: 01 3001070, f: 01 3001080 , • • Temodal 100 mg, 20 mg, 250 mg. Vsaka kapsula zdravila Temodal vsebuje 20 mg, 100 mg ali 250 mg temozolomida. KapsuleTemodal so indicirane za zdravljenje bolnikov z malignimi gliomi. kakor sta npr. multiformni glioblastom ali anaplasticni astrocitom, ki se po standardnem zdravlje ponovijo ali napredujejo. • , , • , · Odrasli bolniki in pediatricni bolniki, stari 3 leta ali starejši: Posamezen ciklus zdravljenja traja 28 dni. Bolniki, ki še niso zdravljeni s kemoterapijo, naj jemljejo Temodal peroralno v odmerku 200 mg/m' enkrat na dan prvih 5 dni, potem pa naj sledi 23-70 let) tveganje za nevlrope ali trombocitopenijo vecje kot pri mlajših, zato svetujemo posebno previdnost pri uporabi zdravila Temodal pri starejših bolnikih. Moški bolniki: Temozolomid lahko del genotoksicno. • Socasna uporaba zdravila Temodal in ranitidina ni povzrocila spremembe obsega absorpcije temozolomida. Jemanje zdravila Temodal s hran povzrocilo 33 % zmanjšanje Cmax in 9 % zmanjšanje AUC. Ker ne moremo izkljuciti moinosti, da bi bila sprememba Cmax lahko klinicno pomembna, priporocamo je zdravila Temodal brez hrane. Analiza populacijske farmakokinetike temozolomida v raziskavah druge faze je pokazala, da socasna uporaba deksametazona, proklorperazi fenitoina, karbamazepina. ondansetrona, antagonistov receptorjev H2 ali fenobarbitala ne spremeni ocistka temozolomida. Socasno jemanje z valproinsko kislino je bilo pove z majhnim, a statisticno znacilnim zmanjšanjem ocistka temozolomida. Uporaba zdravila Temodal v kombinaciji z drugimi mielosupresivi lahko poveca verjetnost mielosupre V klinicnih raziskavah so bili najpogostnejši neželeni ucinki. povezani z zdravljenjem, prebavne motnje, natancneje slabost (43 %) in bruhanje (36 %).Pogostn hude slabosti in bruhanja je bila 4 %. Drugi pogostejši neželeni ucinki so: utrujenost (22 %), zaprtje (17 %) in glavobol (14 %). Porocali so tudi o anoreksiji (11 %), driski (8 %) izpušcaju. zvišani telesni temperaturi in zaspanosti.Laboratorijski izvidi: trombocitopenija oz. nevlropenija 3. oz. 4. stopnje sta se pojavili pri 19 % oz. 17 % bolnikov, zdravlje zaradi glioma. Mielosupresija je bila predvidljiva {ponavadi se je pojavila v prvih nekaj ciklusih in je bila najizrazitejša med 21. in 28. dnem), okrevanje pa je bilo hitro, ponava 1-2 tednih. Znakov kumulativne mielosu resiJe niso ugotaviiaii. lmltilli1131!ml!!!l!JillllDl'lmiEiiml fJi!m'l:11.'l!lmD Schering-Ptough Central East AG, Luzern, Švica, Predstavni Sloveniji, Dunajska 22, 1000 Ljubljana Zdravilo se iz ·a samo na recept, u119rablja pa se pgd P9S0bnim nadzorom zdravnika specialista ali od nj d ika. •. Januar 2005. • , , kapsule raztopina za intravensko infundiranje Sestava 1 kapsula vsebuje 50 mg, 100 mg ali 150 mg flukonazola. 1 vlala vsebuje 200 mg flukonazola. Indikacije Sistemske kandldoze, mukozne kandldoza, preprecevanje kandldoza, kr1ptokokoze, vaginalna kandldoza In dennatomlkoze. Odmerjanje In nai!ln uporabe Velikost odmerka je odvisna od Indikacije. Odrasllm dajemo obli!ajno 50 do 800 mg flukonazola 1-kral na dan, otrokom pa 3 do 12 mg/kg telesne mase 1-kral na dan. Najvei!jl dnevni odmerek je 12 mg/kg telesne mase, za otroke, stare 5 do 13 let, pa 400 mg. Prvi dan zdRM]enJa priporocamo dvojni dnevni odmerek, ki Ja sicer predpisan za posamezno Indikacijo. TraJanJe zdravljena Je odvisno od kllnli!ne stike In mlkološkaga odziva. Bolniki z zman/§snlm delovanjem lefMc: Pri zdravfJenlu z wckratnlml odmerki flukonazola dnevna odmerke prilagodimo vrednostim kreatinlnakega oclatka. Kontraindikacije f>reob6utljlvos za zdravllo, pcilno1ne aeafalllne zdnMla In za druge azole. Sooaano Jemm1Je fluklonazDla:a terfetllllllnom ali claaprldom. Posebna opozorita In previdnostni ukrepi Pri bolnlklh z motnjami v dalovar1lu Jeter je treba redno apremljall akllvnoat Jabnfh encimov In bolnikovo stanje. Ob l)0IIIIC8lll akllvnoall Jalmlh encimov naj zdllMilk preaodl o korlatnoall nadaljeilanja zdnivlJel1a In tveganju hujia jetrne okvare. Noae&loat In dojenje Noaei!nlca zdravlki lahko jamlje la, i!e je ki>rfat zdravljenja za inalar vacJa od twganja za plod. Ker 80 koncentracfJe flukonazola v malallnem n\lakli podobne plazemskim koncentracijam, naj doJei!e matere med zdravljenjem s flukonazolom ne dojijo. Medsebojno delovanje z drugimi zdravlll Pri enkratnem odmerku flukonazola za zdRM]enje vaginalne kandldoza kllnli!no pomembnih Interakcij ni. Pri aooasnem zdravljenju z wckratnlml In wcjlml odmerki flukonazola so možne Interakcije s terfenadlnom, claaprldom, aaternfzolom, varfarlnom, derivati aulfonllureJe, hldrokloroUazldom, fanllolnom, rffamplclnom, clklosporinom, teoflllnom, lndlnavlrom, mldazolamom In zldowdk1om. Na!elenl ui!lnkl Lahko se pojavijo slabost, nepenjanja, bru., bolai!lne v trebuhu, driska. Motni 80 glavobol, krci In alopeclJa. Zelo redke 80 preobi!ulljM)stne reakcije. Pri bolnikih s hudimi glN!i!nlml obolenj lahko pride do ltlvkopenlja, trombocltopeillje, l)Oliiicai,e akllvnoall jetrnih encimov tar hujše motnje v delovanju Jeter. Oprema In nai!ln Izdajanja zdravita 7 kapsul po 50 mg, 28 kapsul po 100 mg, 1 liapauJa po 150 mg -na zdravniški recept; 1 wlfa a 100 ml raztopine za liltraveneko lilfuriclrarie (200 mg/100 ml) -Uf)