ADIOLOGY '11111 NCOLOGY September 2005 Vol. 39 No. 3 Ljubljana ISSN 1318-2099 · ADIOLOGY AND NCOLOGY Editorial office Radiologij and OncologtJ September 2005 Institute of Oncology Vol. 39 No. 3 Zaloška 2 Pages 171-235 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 Radiologi; and Oncology is a joumal devoted to publication oj original contributions in diagnostic and interventional radiology, computerized tomography, ultrasound, magnetic resonance, nuclear medicine, radiotherapy, clinical and experimental oncologi;, radiobiology, radiophysics and radiation protection. 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Indexed and abstracted by: BIOMEDICINA SLOVENICA CHEMICAL ABSTRACTS EMBASE / Excerpta Medica Sci Base Scopus This journal is printed on acid-free paper Radiology and Oncology is available on the internet at: http://www.onko-i.si/radioloncol ISSN 1581-3207 Ljubljana, Slovenia ISSN 1318-2099 September 2005 UDC 616-006 Vol. 39 No. 3 CODEN: RONCEM CONTENTS SONOGRAPHY AND COMPUTER TOMOGRAPHY Endosonography in the diagnosis of recurrent anal fistulas Sudol-Szopinska I, Jakubowski W, Kolodziejczak M, Szopinski T, Panorska AK 171 Diagnostics and operative treatment of retrorectal cysts -description of five cases Kolodziejczak M, Grochowicz M, Sudol-Szopifzska I, Kosim A, Stefafzski R 177 Communicating saccular pyloroduodenal duplication. Case report Sjekavica I, Batinica M, Lušic M, Senecic-Cala I, Oberman B, Štem-Padovan R 181 Coronary artery calcium scoring in myocardial infarction Bešlic š, Dalagija F 185 Small-bowel carcinoid presenting with acute bleeding detected upon wireless capsule endoscopy Mrevlje Ž, Sever M, Kocijancic B 193 ONCOLOGY Molecular biology of the lung cancer Panov SZ Setup error and its effect on safety margin in conformal radiotherapy of the prostate Kragelj B 211 RADIOPHYSICS Missing tissue compensation with wax filter compensators in radiotherapy of the head and neck region Grabec D, Strojan P SLOVENIAN ABSTRACTS 219 225 NOTICES 233 Radiol Oncol 2005; 39(1): 171-5. Endosonography in the diagnosis of recurrent anal fistulas Iwona Sudol-Szopinska1, Wieslaw Jakubowski1, Malgorzata Kolodziejczak2, Tomasz Szopinski3, Anna K. Panorska4 1Department of Diagnostic Imaging, Medical University Warsaw and Central Institute for Labour Protection – National Research Institute, Warsaw, Poland; 2Subdepartment of Proctology, Srodmiejski Hospital, Warsaw, Poland; 3Department of Urology, Central Railway Hospital, Warsaw-Miedzylesie 4, Department of Mathematics and Statistics, University of Nevada, Reno, USA, Background. The aim of this work was to compare non-contrast endosonography (NCE) and contrast-en­hanced endosonography (CEE) in the diagnostics of recurrent anal fistulas. Methods. In the years 1999-2002 we diagnosed 148 patients with anal fistulas. Fifty-one out of this group had recurrent anal fistulas, remaining had primary disease. For anal endosonography a Bruel&Kjaer scan­ner with 7.0 MHz transducer was used and 3% solution of hydrogen peroxide was used for CEE. In each case, NCE was followed by CEE, and results of both methods were compared. Results. The difference of percentages of correct diagnoses between NCE and CEE carried out 35.29% in a group of patients with recurrent anal fistulas (95% confidence interval 50.5% - 20.09%); while the differ­ence in a group of patients with primary anal fistulas was only 4.55% (95% confidence interval 11.09% ­2.00%). Conclusions. CEE significantly improves the efficiency of endosonography in diagnosing recurrent anal fistulas, whereas in primary fistulas the value of NCE and CEE is comparable. Key words: rectal fistula-diagnosis; endosonography; recurrence Introduction The accuracy of anal endosonography (AES) in diagnosing the type of anal fistula, accord- Received 1 September 2005 Accepted 15 September 2005 Address to correspondence: Assist. Prof. Iwona Sudol-Szopinska, MD, PhD, Zaklad Diagnostyki Obrazowej, Wojewodzki Szpital Brodnowski , ul Kondratowicza 8, 03-285 Warsaw; Fax +(48)22 326 5991; E-mail: iwsud@ciop.pl ing to different authors, is from 25% to 100% and in cases of recurrent fistulas is the low­est.1-4 In spite of underlined difficulties re­sulting first of all from impossibilities of the differentiation of fistula with scar, this prob­lem has still not been examined exactly. This study presents the own results of standard, non –contrast endosonography (NCE) and contrast-enhanced endosonography (CEE) in diagnosing the recurrent anal fistulas, and compares them with the ones obtained in the group of primary fistulas. Methods In years 1999-2002 AES was performed at 148 patients (86 male and 62 female, aged be­tween 15 to 73 years, average 46.3 years) with the clinical diagnosis of anal fistulas. In 51 from among 148 persons fistula had a recur­rent character. AES was performed by one ex­perienced radiologist, and patients were op­erated by surgeons from different centres, from which one drove a compact cooperation. In order to compare NCE with CEE only fis­tulas which on a day of executing research had a permeable external outlet were diag­nosed. For AES a Bruel&Kjaer scanner 3535 with a mechanical transducer of frequency 7.0 MHz with the plastic cone or water balloon was used.2 No preparation was necessary pri­or to AES. Patients were examined in the left-lateral position with knees pulled up to ab­domen. The study was performed in two-steps. The initial type of anal fistula using Park’s classification was defined,5 together with differentiation between simple and com­plex fistula, and the location of the internal opening of this fistula was defined. It was fol­lowed by CEE, given through the external opening, and with the use of silicone catheter (Nelaton 10-fr), 1-2 ml of contrast which was 3% solution of hydrogen peroxide.3,6,7 Again one estimated the type of fistula, including the presence of extensions, and location of in­ternal opening. And then results obtained in both, NCE and CEE, were compared. For test­ing statistical differences between propor­tions of correct diagnoses in NCE and CEE methods for comparisons of dependent pro­portion were used.1 Results of NCE and CEE were compared with surgery. The interval be­tween AES and the operation did not exceed 8 days (1-8 days, average 2.8 days). Results In a group of 51 persons with recurrent anal fistulas one ascertained: 37 transsphincteric fistulas, 10 intersphincteric, 3 suprasphinc­teric, and 1 extrasphincteric (Table 1). Initially in NCE 40.8% of fistulas were simple, and 59.2% had extensions. After a contrast in­jection CEE showed that 82.4% of fistulas Table 1. Comparison of non–contrast endosonography (NCE) and contrast-enhanced endosonography (CEE) in differentiation simple from complex fistulas in 51 patients with recurrent anal fistulas Type and number NCE CEE Surgery simple complex simple complex simple complex transsphincters 37 14 23 32 5 30 7 intersphincteric 10 5 5 8 2 8 2 suprasphincteric 3 1 0 1 2 1 2 extrasphincteric 1 0 1 1 0 1 0 were simple, and only 17.6% were complex. From among all of complicated fistulas shown in NCE, in CEE one did not confirm the presence of extensions in 68, 9% of fistu­las; changes described as extensions repre­sented scars after the treatment of fistula (Figures 1a, 1b). Surgery confirmed most of diagnoses of CEE and showed 78.4% of simple fistulas and 21.6% complex ones. A statistical analysis was performed in or­der to qualify whether CEE is significantly more exact in differentiation simple from complex recurrent anal fistulas than NCE. In NCE correct diagnoses were obtained in 56.86%, whereas in CEE 92.16%. The differ­ence of percentages of correct diagnoses be­tween NCE and CEE carried out 35.29% and a 95% confidence interval for this difference was from 50.5% to 20.09%. A significant dif­ference was showed between NCE and CEE in differentiating of simple and complex re­current fistulas (p<0.0006), which proved that CEE is significantly more exact in differenti­ating simple from complex recurrent anal fis­tulas. The divergence between CEE and sur­gery is ascertained only in two transsphinc­teric fistulas. The injection of contrast exten­sions were not confirmed, in spite of the fact that the former ones were visible in NCE and became confirmed during the surgery. However, the general efficiency of CEE was significantly greater than that of NCE which proved to be not reliable of differentiating scars with the active fistula. The percentage of falsely positive diagnoses of complex fistu­las in NCE carried out 36.7% (18 from 49 fis­tulas found in NCE), in CEE falsely positive results did not ascertain. To confirm the diagnostic value of the use of contrast in the investigation of recurrent fistulas, the above results were compared with the endosonographic image of primary fistulas (Table 2). To compare this analysis more accurately, only the types of primary fistulas which were found in a group of re­current fistulas (i.e. transsphincteric, inter-sphincteric, suprasphincteric, and extras-phincteric) were included. In NCE 89.9% of simple, and 10.1% of complex fistulas were found. After the contrast administration 97.1% appeared simple and 2.99% had exten­sions. By the surgery 97% were found simple, and 3% complex, similarly as in CEE. Identical as for recurrent fistulas a statisti­cal analysis was done for the primary fistulas. Table 2. Comparison of non–contrast endosonography (NCE) and contrast-enhanced endosonography (CEE) in differentiation simple from complex fistulas in 66 patients with primary anal fistulas Type and number NCE CEE Surgery simple complex simple complex simple complex transsphincteric 36 31 5 34 2 34 2 intersphincteric 13 12 1 13 0 13 0 suprasphincteric 7 10 0 8 0 7 0 extrasphincteric 10 9 1 10 0 10 0 In NCE 93.94% of correct diagnoses were ob­tained and in CEE 98.48%. The difference be­tween percentage of correct diagnoses in NCE and CEE was 4.55% and 95% confidence interval was from 11.09% to 2.00%. A statisti­cal difference between NCE and CEE in dif­ferentiating simple from complex primary fis­tulas was found at the level of significance p=0.09. The test was not characteristic on 5% but only on 10% level. Therefore it is ascer­tained that CEE only slightly improves the di­agnostic accuracy of endosonography for the primary anal fistulas. Discussion Cheong et al3 underlines that CEE is especial­ly precious in diagnosing recurrent and com­plex anal fistulas. Our statistical analysis con­firmed that for recurrent anal fistulas CEE is significantly more accurate than NCE (p<0.0006). In NCE 36.7% of falsely positive diagnoses of complex fistulas were found, in CEE such results were not observed. The effi­cient treatment of fistula depends on the eradication of all extensions. However, limi­tations of AES in patients with a history of surgery of anal fistula or abscess, resulting from difficulties in differentiating scars with the active fistula, and especially with its ex­tensions, were well known.3,4,8 Although Law et al9 describes that the scar has lower and more homogeneous echogenicity than the fis­tula and smooth outlines as well; the most of­ten image of these two is identical. Additi­onally narrow, irregular lumen of the recur­rent fistula and its extensions has often no content liquid or air, which have a character­istic image.6 Consequently not recognized and not removed extensions are the main reasons of the recurrence of fistula, and a wrong estimated type of fistula can lead to damages of anal sphincters.3,4,8 In spite of underlined difficulties with en-dosonographic diagnostics of recurrent fistu­las, one did not examine the scale of this problem. This study confirmed a large num­ber of false diagnoses of complex fistulas in NCE. A comparative analysis with primary fistulas showed that in a group of primary fis­tulas it had a place only in 7.2% of fistulas. In NCE scars following previous surgery were interpreted as extensions, and so the accura­cy in such differentiation was only 56.86%. The introduction of contrast raised to 92.16%. Also Cheong et al3 and Kruskal et al6 empha­sized that only CEE can be accurate. Using CEE Kruskal et al accurately differentiated scars with fistulas in 20 from 30 patients (67%), including 39 patients with a doubtfully initial, without contrast, image. Our results showed that in only in two cases (4%) exten­sions of transsphincteric fistulas were not recognized in CEE. One ran in the direction of the top of ischio-rectal fossa, the second crossed the levator ani muscle. The former was probably blocked by thick secretion, and the latter would become visible when AES was supplemented by the use of a water bal­loon. In this case, however, too hastily initial NCE became interpreted as scar and one did not extend the investigation of ampulla of the rectum. It seems that such an approach should be done in case of high fistulas, espe­cially the recurrent ones. The other thing is that, in spite of the proved significantly high­er accuracy of CEE, one should also taken in­to account the result of NCE. Results ob­tained in a group of primary fistulas (66 pa­tients) diametrically differed from those of the recurrent ones. The number of complex fistulas was not large, both in NCE and in CEE, and the per­centage of falsely diagnosed complex fistulas in NCE was only 7.24%. As in a case of recur­rent fistulas, the scars after the treatment of fistula were responsible for correct diag­noses; so, in the primary fistulas the only rea­son was the inability to differentiate exten­sions from the heterogeneous echotexture of perirectal tissues. A statistical analysis showed that NCE has comparable values to CEE. However, although it seems that it is more important not to miss the extension that gives a false diagnosis of extension (regarding the risk of surgical complications: recurrence, damage of sphincters), one must remember that too aggressive approach during the oper­ation, in order to find indicated in NCE ex­tensions, can also lead to complications - cre­ating of iatrogenic fistula. Conclusions 1. Standard, NCE is not reliable method in differentiation scars with active recurrent fis­tula and application of contrast significantly improves efficacy of AES. 2. In the case of primary anal fistulas, NCE and CEE have comparable efficiency. References 1. Agresti A. Categorical data analysis. 2nd edition. New Jersey: John Wiley & Sons; 2002. 2. Bartram CI, Frudinger A. Handbook of anal en-dosonography. Petersfield: Wrightson Biomedical Publishig LTD; 1997. 3. Cheong DMO, Nogueras JJ, Wexner SD, Jagelman DG. Anal endosonography for recurrent anal fis­tulas: image enhancement with hydrogen perox­ide. Dis Colon Rectum 1993; 36: 1158-60. 4. Choen S, Nicholls RJ. Anal fistula. Br J Surg 1992; 79: 197-205. 5. Parks AG, Gordon PH, Hardcastle JD. A classifi­cation of fistula-in-ano. Br J Surg 1976; 63: 1-12. 6. Kruskal JB, Kane RA, Morrin MM. Peroxide-en­hanced anal endosonography: technique, image interpretation, and clinical applications. Radio­graphic 2001; 21: 51-73. 7. Poen AC, Felt-Bersma RJF, Eijsbouts QAJ, Cuesta MA, Meuwissen SGM. Hydrogen peroxide-en­hanced transanal ultrasound in the assessment of fistula-in-ano. Dis Colon Rectum 1998; 41: 1147-52. 8. Halligan S. Review imaging fistula-in-ano. Clin Radiol 1998; 53: 85-95. 9. Law PJ, Talbot RW, Bartram CI, Cuesta MA, Meuwissen SGM. Anal endosonography in the evaluation of perianal sepsis and fistula in ano. Br J Surg 1989; 76: 752-5. Radiol Oncol 2005; 39(3): 177-80. Diagnostics and operative treatment of retrorectal cysts – description of five cases Malgorzata Kolodziejczak1, Maciej Grochowicz1, Iwona Sudol-Szopinska2, Anna Kosim1, Robert Stefanski1 1Proctology, Sub-Department of General Surgery, City Traumatic Hospital, Warsaw, Poland 2Central Institute for Labour Protection – National Research Institute, Warsaw and Department of Imaging Diagnostics, Second Faculty, Medical School, Warsaw, Poland Background. Retrorectal cysts (RC) are unusual lesions. Publications on RC are very rare and describe a few cases at most. Methods. Authors describe five patients with RC. The diagnostics of RC was based on the medical history of the patients and the basic diagnostic investigation was trans rectal ultrasonography. An operation to re­move the cysts from perineal access was the treatment administered in these cases. Results. In three cases the histopathological examination showed cystis epidermalis. In another case a cyst epithelialized with ciliated epithelium was found. In the last case bone tissue, fatty tissue and fibrous tissue were depicted, all in the state of chronic inflammation. Conclusions. Per rectum digital exam is the basic examination decisive in making the diagnosis. TRUS should be employed as the diagnostic investigation in order to estimate precisely the size of a cyst and its proportion to the rectum wall. Retrorectal cystectomy in perineal access is an effective method of treatment of this disease. This article, likewise other research works, describes a small group of patients, therefore, its conclusions should be treated as preliminary ones. Key words: rectal disease-ultrasonography-surgery; cysts Introduction Retrorectal cysts (RC) are unusual lesions. The majority of publications on this subject concerns a few cases at most or describe one Received 27 May 2005 Accepted 4 June 2005 Correspondence to: Iwona Sudol-Szopinska, MD PhD, CIOP-PIB, ul. Czerniakowska 16, 00-701 Warszawa, Poland; E-mail: iwsud@ciop.pl casuistic patient.1-5 In majority of cases (75%) the cysts are congenitally inborn.6 There are many classifications of retrorectal cysts and tumours. They are mostly based on a histopathological structure of the cysts which is connected with the embryonic development of these lesions. Levelady’s and Deckerty’s classi­fication is the most frequent one and covers the following changes: dermoidal cysts, chordo-mas, myelomenin-gocele hernias, cysts on retrorectal intestine and other tumours, among them leiomyomas, neuromas and sarcomas. Dermoidal cysts are lined with stratified squamous epithelium and contain skin ap­pendages. They are filled with liquid or greasy contents whereas chordomas are filled with thick jelly-like contents. Due to direct anastomosis with sacral and coccygeal bones chordomas cause deterioration of these os­seous structures and, when growing, they can exert pressure on nervous trunks. Cysts on retrorectal intestine are mainly teratomas. In majority of the cases they contain histologi­cally mature tissues i.e. elements of the skin and their appendages, teeth or osseous frag­ments. They occur more often in women. Cysts are mainly of a mild character. However, they can be hormonally active3,4 and can also undergo a malignant transfor­mation. Dermoidal cysts turn malignant in 10-15% of the cases. A malignant transforma­tion of chordomas occurs in 10% of the cases and a similar transformation of teratomas oc­curs in 10–20% of the cases. Retrorectal cysts can be positioned differ­ently and they can grow to different sizes. In a few cases of newborns with congenitally in­born cysts retrorectal tumours are placed be­hind pelvis minor7 but they relocate and exert pressure on rectum. In adults RC are mainly positioned between the rectum and the sacral bone. The cysts can cause anal pain and sen­sation of tenesmus. They can suppurate. It may occur that patients suffering from such ailments are diagnosed with coccygodynia and they undergo a long-term ambulatory treatment with analgesics, steroid and non-steroid anti-inflammatory drugs. Per rectum the examination plays the decisive role in di­agnosis of RC. It reveals tense tender resist­ance on the posterior wall of the rectum. It is sometimes difficult to differentiate between a cyst and a high extra levator abscess; the di­agnosis depends on clinical symptoms. In many patients, who are diagnosed with retrorectal cysts, rectoscopy is an effective so­lution. Transrectal ultrasonography (TRUS) is an investigation which confirms the diagno­sis and allows determining precisely the size of a cyst and its relation to the rectum wall.1 Endosonography determines - to a certain point - whether the lesion merely models the rectum wall or infiltrates it. Transperineal ul­trasound is an additional supplementing di­agnostic investigation which together with TRUS gives a full picture of the lesion. In the following article the authors present cases of five female patients who have been treated for retrorectal cysts and describe the diagnostics as well as the treatment of these patients. Methods Patients Five female patients from 36 to 55 years of age (the average 44 years) were operated on between 1 January 2001 and 30 June 2004 in Proctology Department of City Hospital at Solec (Table 1). Diagnostics The diagnostics of RC was based on the med­ical history of the patients. They all notified of severe pain and sensation of tenesmus which were growing in a sitting position. As the result of per rectum investigation elastic tender resistance of a different size was found and it was protruding from the posteri­or wall of rectum. The rectoscopic picture showed that the mucous membrane of rec­tum was unchanged. TRUS was the basic di­agnostic investigation (Figures 1a, 1b). Therapy An operation to remove the cysts from per-ineal access was the treatment administered in these cases. The patients were placed on their side with legs pulled up. The incision was made between the anus and the coccygeal bone. In three cases it was necessary to per­form a resection of the coccygeal bone. The wound was drained using Redon’s method. Figures 1a, 1b. Retrorectal cyst presented with transperineal and transrectal ultrasonography. The material was sent for histopathological examination. In all these cases there were no complications in postoperative course. Results In three cases the histopathological examina­tion showed cystis epidermalis. Its wall was formed with fibrous tissue epithelialized with cornifying stratified squamous epithelium. In another case a cyst epithelialized with ciliated epithelium was found. In the last case the re­sult depicted bone tissue, fatty tissue and fi­brous tissue, all in the state of chronic in­flammation. The patients had regular check-ups at Proctologic Hospital Clinic. In four cases the ailments subsided completely. One patient still suffers from ailments of different inten­sification. She also has degenerative changes in lumbosacral segment of vertebral column. Discussion In the presented material of all cases full com­patibility between preoperative diagnostics Table 1. Characteristics of patients with retrorectal cysts and their treatment Age Under 30 years old 0 0 30 – 40 years old 2 40% over 40 years old 3 60% Sex Male 0 0 Female 5 100% Duration of symptoms < 3 months 1 20% 3 – 6 months 0 0 6 – 12 months 1 20% > 12 months 3 60% Type of surgical procedure Cystectomy 2 40% Cystectomy combined 3 60% with resection of the coccygeal bone Compatibility between Compatible 5 100% surgery and transrectal ultrasonography Non-compatible 0 0 Position in relation to Intramural 2 40% the rectum wall Adjacent to the rectum wall 3 60% and surgical evaluation of the lesion was found. In spite of an apparent easiness in the di­agnostics of this disease, it often happens that patients have been treated with an inef­fective method for many months before they finally receive professional help. The most probable reason for such a situation is the rarity of retrorectal cysts occurrence and physicians’ lack of experience in their diag­nostics. Singer et al describe seven patients who suffered from ailment caused by RC but who were wrongly diagnosed with, for example, anal fistula, pilonidal cyst, anorectal abscess, psychiatric disease, pain after an injury, post partum pain or proctalgia fugax. They con­clude that the best diagnostic investigation is an accurate per rectum examination supple­mented with the computer tomography.8 There are investigators who recommend the use of magnetic resonance in RC diagnos­tics.9 However, it is well known that this in­vestigation is expensive and less available than the ultrasound scan. Due to the risk of malignant transforma­tion, suppuration and pressure symptoms, RCs should be removed in an operation in perineal or abdominal access. Many investigators describe cystectomy combined with the resection of the coccygeal bone as a good operative method.2 If the cyst is closely bound to the caudal bone, it has to be removed together with the fragment of the bone as it is the point where the cyst grows from. Leaving it behind may cause the re­growth of the cyst (local malignancy). There are cases that laparatomy ensures more accu­rate evaluation and surgical access.1 The choice of surgical access depends on the size and location of the cyst, its anatomical posi­tion in relation to other organs and the expe­rience of a surgeon. In order to qualify a pa­tient for laparatopy it is advisable to supple­ment the preoperative diagnostics with CT of pelvis and abdominal cavity. Conclusions 1. Per rectum digital exam is the basic ex­amination decisive in making the diagnosis. 2. TRUS should be employed as the diag­nostic investigation in order to estimate pre­cisely the size of a cyst and its proportion to the rectum wall. 3. Retrorectal cystectomy in perineal ac­cess is an effective method of treatment of this disease. 4. This article, likewise other research works, describes a small group of patients, therefore its conclusions should be treated as preliminary ones. References 1. Sudol-Szopinska I, Bielecki K, Szenk P. Endosonografia w diagnostyce guza pozaodbyt­niczego – opis przypadku. Polski Przeglad Chirurgiczny 2002; 74: 823-30. 2. Kulaylat MN, Doerr RJ, Neuwirth M, Satchidanand SK. Anal duct/gland cyst: report of a case and a review of the literature. Dis Colon Rectum 1998; 41: 103-10. 3. Mourra N, Caplin S, Parc R, Flejou J-F. Presacral neuroendocrine carcinoma developed in a taulgut cyst: report of a case. Dis Colon Rectum 2003; 46: 411-3. 4. Gorski T, Khubchandani IT, Stasik JJ, Riether R. Retrorectal carcinoid tumor. South Med J 1999; 92: 417-20. 5. La Manna L, Ponchio L, Moro G, Parziale A, Ruggiero R, Baldi M, et al. Retrorectal tumors: a case report. Chir Ital 2002; 54: 545-8. 6. Góral R. Chirurgia odbytnicy i okreznicy. Warszawa: PZWL; 1993. p. 382-3. 7. Bielecki K, Dziki A. Proktologia. Warszawa: PZWL; 2000. p. 362-7. 8. Singer MA, Cintron JR, Martz JE, Schoetz DJ, Abcarian H. Retrorectal cyst: a rare tumor fre­quently misdiagnosed. J Am Coll Surg 2003; 196: 880-6. 9. Erden A, Ustuner E, Erden I, Kuzu MA, Heper AO. dRetrorectaldermoid cyst in male adult: case re­port. Abdom Imaging 2003; 28: 725-7. Radiol Oncol 2005; 39(3): 181-4. case report Communicating saccular pyloroduodenal duplication. Case report Ivica Sjekavica1, Marko Batinica1, Mario Lušic1, Irena Senecic-Cala2, Božidar Oberman1, Ranka Štern-Padovan1 1 Clinical Institute for Diagnostic and Interventional Radiology, School of Medicine, University Hospital Center Zagreb – Rebro; 2 Clinical Department of Pediatrics, School of Medicine, University Hospital Center Zagreb – Rebro, Zagreb, Croatia Background. Duplication anomalies of pyloroduodenal region are not common. Intestinal duplications should be considered if additional specific development malformations are present. Case report. We report a case of the pyloroduodenal duplication in 22-month-old girl by whom intermit­tent nausea and vomiting were the first symptoms. US revealed an anechoic cystic lesion between the stom­ach and the left liver lobe. The upper gastrointestinal contrast study revealed stenosis in the pylorobulbar region, as a result of the extrinsic compression. The diagnosis of the alimentary tract duplication cyst com­pressing the atypically formed head of pancreas was highly suspected by the contrast enhanced multi slice computerized tomography (MSCT). The intraoperative contrast application detected a communication be­tween both, duplication and pyloric region. The patohistological examination confirmed a duplication cyst containing gastric and duodenal mucosa with no ectopic pancreatic tissue. Conclusions. The ultrasound examination, as the initial diagnostic procedure of intestinal duplication, usu­ally reveals a cystic anechoic lesion. Additional barium study, contrast enhanced CT or MRI scan are use­ful in diagnosis of alimentary tract duplications, providing supplementary information. Key words: pylorus-abnormalities; duodenum-abnormalities Introduction Isolated duplications of the alimentary tract are rare congenital malformations with a re- Received 12 September 2005 Accepted 20 September2005 Correspondence to: Marko Batinica, M.D., Clinical Institute for Diagnostic and Interventional Radiology, University Hospital Center Zagreb – Rebro, Kišpaticeva 12, 10000 Zagreb, Croatia; Phone: +385 1 2388 455; Fax: +385 1 2388 250; E-mail: marko.batinica@zg.htnet.hr ported incidence of 1:5000.1,2 Duplication anomalies of the pyloroduodenal region are not common as well. Intestinal duplications should be considered if additional specific de­velopment malformations are present. The aetiology of duplication cysts may be multi­factorial.3 The usual symptoms in patients with alimentary duplication cysts are gas­trointestinal obstruction, vomiting, diffuse abdominal pain and sometimes melena. 2,4 Case report A 22-month-old girl with abdominal pain and recurrent vomiting was presented in the re­cent 15-month-period. Physical examination findings showed a small palpable mass in the left epigastrium. Early sonographic findings revealed an anechoic oval structure between the stomach and the left liver lobe suspected to be a duplication of the alimentary tract. There was no proof of any communication to intraperitoneal structures. No communica­tion with the gastrointestinal tract could be demonstrated as well (Figure 1). The radiological examination included the upper gastrointestinal contrast radiography which revealed stenosis in the pyloroduode­nal region, 4 cm in length. Stenosis was con­sidered as a sign of the extrinsic compression (Figure 2). The contrast enhanced multi slice comput­erized tomography (MSCT) was compatible with US findings and contrast radiography. It revealed a well-defined cystic fluid collection, 3.3 x 3.9 cm, located between the left liver lobe and pylorus, suggesting an enteric dupli­cation and extrinsic compression on the duo­denal region. A mesenteric cyst, however, could not be excluded. The head of pancreas was severely deformed due to the cyst forma­tion. There were no signs of acute pancreati-tis (Figures 3,4). The explorative surgery revealed a spheri­cal duplication anterior to the pyloric region. The intraoperative contrast application through the cystic structure suggested a nar­row communication between the duplication and alimentary tract. A partial resection was performed due to the common wall with py­lorus shared in small segment. Mucosa of the remnant cyst wall was excised. The histopa­tological examination of specimen confirmed a pyloroduodenal duplication cyst containing gastric and duodenal mucosa. Discussion Duplication cysts are spherical or elongated hollow structures, lined by epithelium which is usually identical to a part of the alimentary tract they are aligned to, usually sharing com­mon blood supply.1 Duplications occur due to a fault recanal­ization of the temporarily obliterated fetal in­testine or incomplete embryogenic budding. They tend to be associated with other congen­ital malformations, mostly vertebral anom­alies, intestinal atresia, double gallbladder or double uterus.2,5 A gastrointestinal duplica- Figures 3, 4. Contrast enhanced MSCT of the upper abdomen. Well-defined cystic fluid collection, 3,3x3,9 cm, between left liver lobe and pylorus, suggesting an enteric duplication. tion may develop at any level of the gastroin­testinal tract, often containing ectopic tissue. Gastric mucosa and pancreatic tissue are the only ones that have clinical significance. The usual localization of duplication development is enteromesenteric side of the alimentary tract. The majority of duplications are diag­nosed in the early childhood due to symptoms developing in the first years of life.3,6-7 Differential diagnoses of duplications in children include cystic neoplasm, congenital and parasitic cysts and pancreatic pseudocyst. Symptoms of intestinal duplications in children are mostly non-specific, depending on the localization. They may present as vom­iting, palpable abdominal mass, problems with feeding and pancreatitis. Lesions in dis­tal segments of intestine include flank ab­dominal pain, palpable tumour and melena.3 As a method of treatment, surgery should be attempted to remove the duplication radi­cally, even if together with adjacent gut seg­ment. If the cyst is closely related to vital structures, a total excision may not be possi­ble. In such cases, the partial excision remains as a possible solution. The diagnosis of a duplication cyst may be suspected on barium enhanced radiographs demonstrating the extrinsic pressure pro­duced by abdominal mass.8 US, CT and MR confirm a definitive diagnosis. On US, duplications appear as anechoic mass with a thin echogenic rim representing mucosa, covered by a hypoechoic muscular wall. These findings are characteristic for the non-communicating type of a duplication cyst.7,9 CT demonstrates the location and exten­sion of the duplication defining adjacent structures and excluding additional abnor­malities. Rarely, CT demonstrates cyst wall calcifications.7,10 MR cholangiography is helpful in detect­ing biliary and ductal anomalies.11,12 In addi­tion, radionuclide imaging with 99mTc can show the increased uptake if a cyst contains gastric mucosa.7 Conclusions Duodenal duplications constitute about 5% of all alimentary tract duplications. Pato-histological findings in duplications usually show ectopic tissue such as gastric and/or pancreatic mucosa.3 Complications as bleed­ing, perforation of ulceration may occur. A malignant alteration of duplication is ex­tremely rare.13 In our case, the diagnosis of the alimentary tract saccular duplication compressing the atypically formed head of pancreas was high­ly suspected by US and contrast enhanced CT. A contrast study of duplication during the surgical excision detected a communication between the duplication and pyloric region. The patohistological examination confirmed a duplication cyst containing gastric and duo­denal mucosa. The ultrasound examination, as an initial diagnostic procedure of the intestinal dupli­cation, usually reveals a cystic anechoic le­sion. Additional barium study, contrast en­hanced CT or MRI scan can be useful in the diagnosis of alimentary tract duplications, providing the supplementary information. References 1. Taft DA, Hairston JT. Duplication of the alimenta­ry tract. Am Surg 1976; 42: 455-62. 2. Schalamon J, Schleef J, Höllwarth ME. Experience with gastro-intestinal duplications in childhood. Langenbeck’s Arch Surg 2000; 385: 402–5. 3. Kim SK, Lim HK, Lee SJ, Park CK. Completely iso­lated enteric duplication cyst: case report. Abdom Imaging 2003; 28: 12–4. 4. Lad RJ, Fitzgerald P, Jacobson K. An unusual cause of recurrent pancreatitis: duodenal duplica­tion cyst. Can J Gastroenterol 2000; 14: 341-5. 5. Pinter AB, Schubert W, Szemledy F, Gobel P, Schafer J, Kustos G. Alimentary tract duplications in infants and children. Eur J Pediatr Surg 1992; 2: 8-12. 6. Savci G, Balkan E, Ozyaman T, Dogruyol H, Tuncel E. Thoracoabdominal duplication cyst: US, CT and MR findings. Eur Radiol 1997; 7: 382–4. 7. Macpherson RI. Gastrointestinal duplications: clinical, pathologic, etiologic, and radiologic con­siderations. Radiographics 1993; 13: 1063–80. 8. Magnano MM, Occhi M, Mattioli G, Pesce F, Jasonni V, Toma P. Pancreatitis caused by duode­nal duplication. Pediatr Radiol 1998; 28: 524–6. 9. Teele RL, Henshke CI, Tapper D. The radiograph­ic and ultrasonographic evaluation of enteric du­plication cysts. Pediatr Radiol 1980; 10: 9–12. 10. Bissler, JJ, Klein, RL. Alimentary tract duplications in children. Clin Pediatr 1988; 27: 152–7. 11. Rotondo A, Scialpi M, Pellegrino G, Salzano De Luna F, Coppola L, Angelelli G. Duodenal dupli­cation cyst: MR imaging appearance. Eur Radiol 1999; 9: 890-93. 12. Carbognin G, Guarise A, Biasiutti C, Pagnotta N, Procacci C. Duodenal duplication cyst identified with MRCP. Eur Radiol 2000; 10: 1277-9. 13. Grosfeld JL, O’Neill JA, Clatworthy HW. Enteric duplications in infancy and childhood. Ann Surg 1970; 172: 83–90. Radiol Oncol 2005; 39(3): 185-91. Coronary artery calcium scoring in myocardial infarction Šerif Bešlic, Faruk Dalagija Institute of Radiology, Clinical Center University of Sarajevo, Bolnicka 25, Sarajevo, Bosnia and Herzegovina Background. The aim of this study was to evaluate coronary artery calcium scoring and the assessment of the risk factors in patients with myocardial infarction (MI). Methods. During the period of three years, 27 patients with MI were analyzed. The average age of patients was 66.1 years (46 to 81). Coronary arteries calcium was evaluated by multi row detector computed tomog­raphy (MTDC) «Somatom Volume Zoom Siemens«, and, retrospectively by ECG gating data acquisition. Semi automated calcium quantification to calculate Agatston calcium score (CS) was performed with 4 x 2.5 mm collimation, using 130 ml of contrast medium, injected with an automatic injector, with the flow rate of 4 ml/sec. The delay time was determined empirically. At the same time several risk factors were evaluated. Results. Out of 27 patients with MI, 3 (11.1%) patients had low CS (10- 100), 5 (18.5%) moderate CS (101­499), and 19 (70.4%) patients high CS (>500). Of risk factors, smoking was confirmed in 17 (63.0%), high blood pressure (HTA) in 10 (57.0%), diabetes mellitus in 7 (25.9%), positive family history in 5 (18.5%), pathological lipids in 5 (18.5%), alcohol abuse in 4 (1.8%) patients. Six (22.2%) patients had symptoms of angina pectoris. Conclusions. The research showed high correlation of MI and high CS (>500). Smoking, HTA, diabetes mellitus, positive family history and hypercholesterolemia are significant risk factors. Symptoms are rela­tively poor in large number of patients. Key words: myocardial infarction; coronary vessels; calcinosis; tomography; X-ray computed Introduction Atherosclerosis is a systemic generalized dis­ease which usually occurs in different parts of Received 7 March 2005 Accepted 20 April 2005 Correspondence to: Assist. Prof. Šerif Bešlic; MD, PhD, Institute of Radiology, Clinical Center University of Sarajevo, Bolnicka 25, 71000 Sarajevo, Bosnia and Herzegovina; Phone/Fax: +387 33 444 553; E-mail: sbeslic@bih.net.ba arterial system, and affection of coronary ar­teries is of special interest.1,2 Coronary calcifications are almost always a sign of coronary atherosclerosis.3 That is the reason why the level of coronary calcification can be considered as a risk factor.4 Conse­quently, coronary artery calcium is taken as a predisposing marker of coronary atheroscle­rosis.5,6 Therefore, the risk of future cardiac disease can be higher in patients with coro­nary calcifications than in those without them. Coronary calcifications are presented on CT scans as more than two consecutive pixels over 130 HU.6 Coronary calcification has prognostic value in identification of asympto­matic patients who are at higher risk of coro­nary disease.7 Accurate and reproductive quantification of calcium is essential in the assessment of the progression of coronary calcification, as atherosclerosis markers, in a certain patient.6 Screening of coronary calcification started in 1990, primarily for the identification of pa­tients with the coronary artery disease.1 Agatston et al. have introduced this method for quantification of coronary artery calcium, by multiplication of calcified plaques zones based on plaque attenuation values.6 However, detection and quantification of coronary calcification is more adjusted for the risk evaluation of a sudden cardiac attack in asymptomatic patients than for the identifi­cation of symptomatic patients with the is-chemic heart disease.1 The fact is that patients with higher Agatston score may have an increased risk for the fu­ture cardiac attack. That gives the fundamen­tal motivation for the measurement of coro­nary calcium scoring, a better definition of patients who are at risk of myocardial infarc­tion and of a sudden coronary death.4 The current stand-point of the American Society of Heart is that coronary heart disease (CHD) and atherosclerosis are less likely if a CT shows no coronary calcification. The risk of unexpected cardiac attack, like myocardial infarction and sudden death, can be very low in the period of consecutive two to five years. Besides, patients without coronary calcifica­tion will most probably have a normal finding at coronary angiography.3 The coronary calcification test is consid­ered to be a strong indicator of cardiac mor­tality in elderly people, and it is independent of other cardiac risk factors.8 However, CHD cannot be confirmed, or ruled out only on the basis of coronary calci­fication.3 Initial examinations found noncal­cified plaques more often in patients with un­stable angina, while calcified lesions were found mostly in patients with stable angina. Early diagnosis is important for the plaque characterization, and the selection of treat­able patients before the appearance of an is-chemic attack. This helps a physician to dis­tinguish lesions which are reversible with the medical treatment, from these that will need a surgical or endovascular treatment. It is be­lieved, that the most promising techniques will be those which will be able to detect in­flammatory processes in the plaque.1 CHD have been the most common cause of hospitalization and mortality in industrial­ized countries for many years.9 It is usually caused by the rupture of an atherosclerotic plaque, which results with the total occlusion of the coronary artery. In developed world, 1/2 of a male and 1/3 of a female population will suffer from it after the age of 40 years.7 Currently, main available options for treat­ment are surgical revascularization with the coronary artery bypass graft (CABG), and in-terventional transluminal, catheter based procedures. Selection of treatment procedure depends on reliable diagnostic assessment of coronary arteries.9 However, imaging of the coronary arteries is challenging. Their small dimension and position, together with breathing and heart pulsation artefacts, make visualization and detection of stenosis partic­ularly difficult.10 Cardiac catheterization is a method of choice for determining the morphological sta­tus of coronary arteries, and it was often com­bined with interventional treatment proce­dures, like balloon angioplasty and stent im­plantation.9 A selective catheterization of the heart primarily shows morphological changes combined with stenotic CHD, but also gives the parameters of myocardial function, and possibility for the measurement of haemody­namic parameters. The main limitations of the coronary an-giography are general contraindications, pro­jection, and stenosis of the left branch, my­ocardial bypasses, endoluminal summation effects, and impossibility of the coronary ar­tery wall visualization.7 Cardiac catheteriza­tion is an invasive method which is connect­ed with a certain risk and certain complica­tions. In recent years, many intensive researches have been undertaken with diagnostic proce­dures of low risk in order to replace and sup­plement, at least partially, current diagnostic cardiac procedures. Alternative imaging methods are: electron beam computed to­mography (EBCT), multirow detector CT (MDCT) and magnetic resonance imaging (MRI).9 EBCT was the first CT modality which made possible the imaging of coronary arter­ies without movement artefacts. Agatston and co-operators proved EBCTs superiority in the detection of coronary calcification over fluoroscopy. Besides, they set up the quantifi­cation algorithm for the identification of pa­tients with and without ischemic coronary ar­tery disease.3 EBCT has the best overall accuracy, and is considered to be even better than MRI on the adequate visualization of proximal and mid­dle segments of coronary artery, as well as on the detection of stenosis in these segments. Both modalities can be used, and they are complementary to each other. Being time-consuming, they cannot be alternative to the conventional coronary angiography for the time being.10 CT and MRI have a wide range of indica­tions in non-invasive diagnostics, and they are partially overlapping in their clinical ap­plication.9 Besides the visualization of the coronary artery lumen, the vessel wall can also be seen on CT transversal scans.3 Non-invasive CT coronary angiography (CTA) may have even higher potential in the presumption of cardiac risk than calcium scoring. So, not only the lumen of the coro­nary artery can be visualized, but also non-calcified and non-stenotic atherosclerotic plaques can be detected on axial CT scans.4 With contrast enhancement, both calcified and non-calcified lesions can be completely evaluated.3 A high negative predictive value of the coronary CTA can justify the examination of symptomatic patients with low or moderate pre-test probability of coronary artery dis­ease. This technique could be used for the ex­clusion of coronary microangiopathy, and to avoid unnecessary cardiac catheterizations. Past researches proved that the wall of the coronary artery and its lumen can be seen by MDCT.11 This method gives the possibility to follow-up the progression of coronary athero­sclerosis in a non-invasive way.5 MDCT coro­nary artery calcium scoring has been im­proved with retrospective ECG – gated data acquisition.12 CT and MRI have proved to be useful in the assessment of the changes in the vessel wall, and in the identification of highly risk patients who may benefit from treatment.1 MR angiography of the coronary arteries and MDCT angiography are the leading ways to supplement the diagnostic cardiac catheterization, whose role is mainly limited to the diagnosis of coronary atherosclerosis and measurement of the degree of stenosis.13 The aim of this study was to confirm coro­nary artery calcium scoring (CS), and risk fac­tors in patients with the history of the previ­ous myocardial infarction (MI). In this way, we wanted to indirectly confirm the relation of MI and the level of CS, as a risk factor. Methods During the three-year period, a large number of patients with various referral diagnoses were examined at our Institute of Radiology. Among them, 27 patients had the history of previous myocardial infarction. The average age of the patients was 66.1 years, the youngest was 46 and the oldest patient was 81 years old. Out of these patients, 23 (85.2%) were male and 4 (14.8%) female. In all pa­tients, CS was determined according to the Agatston. The patients were divided into three categories based on the CS results: pa­tients with the lowest CS (10-100), the inter­mediate CS (101-499), and the highest CS (>500) (Figure 1). All patients were examined on MDCT ma­chine with the four-row detectors, Siemens »Somatom Volume Zoom«. Calcium quantifi­cation Agatston calcium score program was used for examinations, native and contrast series were done, with non-ionic contrast medium applied by the automatic injector in the cubital vein. We used the collimation 4 x 2.5 mm, rotation time 500 msec, pitch 1.5 and FOV 200. 130 ml of contrast medium was in­jected, followed by 20 ml of saline, and a flow rate of 4ml/sec applied. The delay time was empirically determined, and it was in the range from 25 to 30 sec. The retrospective ECG gating was used during the examina­tions as well. The following risk factors were taken from the patient’s histories as relevant: smoking, arterial hypertension, diabetes mellitus, fami­ly history, increased lipids, alcohol abuse, and symptoms of angina pectoris. Results In the period from 2001 to 2003, we examined 27 patients with the history of myocardial in­farction. The ratio of men to women was 5.7 to 1. In average, women were older than men for 3.9 years (Table 1). In 27 patients with the history of myocar­dial infarction by whom we measured Agatston calcium score, 3 (11.1%) patients had low CS (10-100), 5 (18.5%) moderate CS (101-499), and 19 (70.4%) patients high CS (>500). Of risk factors, smoking was con­firmed in 17 (63.0%) patients, high blood pressure (HTA) in 10 (37.0%), diabetes melli­tus in 7 (25.9%), positive family history of car­diac disease in 5 (18.5%), pathological lipids in 5 (18.5%), and alcohol abuse in 4 (14.8%) patients. Six (22.2%) patients had symptoms of angina pectoris. Discussion As it has been shown by this study, coronary artery disease is predominantly a male dis­ease because 85.2% of our patients were male, while only 14.8% were female. Therefore, male were 5.7 times more often victims of myocardial infarction. Besides, female who had myocardial infarction were in average older than male (69.7 to 65.8 years). This proves that age and male sex are significant risk factors, which is in accordance with the results from the literature. Out of other risk factors related to the in­creased CS and development of myocardial infarction, smoking is at the first place, then hypertension, diabetes mellitus and hyperc­holesterolemia. It is also proved that only 1/4 of the patients with the history of the my- Table 1. Frequency of the risk factors in relation to age, sex and CS in patients with myocardial infarction N Age Sex Smoking HTA F. History Diabetes HHL MI Alcoholism AP CS 1 70 M++ -+++ + -75 2 68 M+----+ -+>500 3 44 M++ -+++ -->500 4 71 F++ ---+ -+>500 5 72 F++ + + -+ -->500 6 62 M+----+ -->500 7 62 M++ -+ -+ + ->500 8 66 M+----+ -+>500 9 70 M+-+ -++ -+>500 1080M+-+ -++ --187 1171M+----+ -->500 1261M-----+ --222 1346M-----+ --257 1468M++ + --+ -+ 232 1581M+----++-->500 1663M+----+ -->500 1761M-----+ -->500 1878F-----+ --323 1977M---+-+ -->500 2078M---+-+ -+>500 21 72M++ ---+ -->500 2266M-----+ --97 23 58F++ ---+ -->500 2464M-----+ -->500 2561M-----+ -->500 26 75M++ ---+ -->500 2748M-+ + +++ + -10 Total 1710 5 7527 4 6 % 63.0 37.0 18.5 25.9 18.5 100 14.8 22.2 N = number; HTA = high blood pressure; F. History = positive family history; HHL = Hypercholesterolemia; MI = myocardial infarction; AP = angina pectoris; CS = calcium score; M = male: F = female ocardial infarction had symptoms of angina pectoris. That points out the importance of CS and the necessity of precaution in patients with high CS and those who are without any symptoms. Data from the literature show the correla­tion between the high coronary artery calci­um scores and the increased risk of the coro­nary artery disease and death.8 The same data show that the persons with the score over 500 had 2.7 times higher risk of death caused by heart attack than those with the score 101 or lower. Therefore we can con­clude that 23.7 more deaths per 1000 peo-ple/per year are among patients with the highest score sets. Persons with scores from 101 to 500 have shown two-times higher risk of cardiac death in comparison to persons with scores lower than 101.8 In this study, CS score was measured in patients with the history of previous myocar­dial infarction, and, as it is showed in the Table 1, 19 (70.4%) patients had calcium score >500, while only 3 (11.1%) patients had a low Figure 2a. Calcification of left coronary artery. CS, and 5 (18.5%) patients had an intermedi­ate CS. Therefore, among the patients with myocardial infarction, there were 6.3 times more those with the high CS than those with the low CS, and 3.8 times more than those with the intermediate CS. During the study, it was noticed that the most of coronary calcification was in the prox­imal 2/3 segments of the coronary arteries, while the distal parts were less affected. Distal segments are also more difficult to analyze on the four-row detector MDCT machine. These findings are in accordance with the data from the literature (Figures 2a and 2b). In autopsy studies, which included over 14.000 corpses with CHD, only 16% of steno-sis was found in distal parts of coronary ar­tery, while 66% of all haemodynamically rele­vant stenosis was located in a proximal third and 40% in a medial third of one or more coronary arteries.9 It can be visualized 68% of all segments of coronary artery by a four-row detector CT an­giography (CTA). In these segments available for the analysis, sensitivity and specificity in detection of significant luminal stenosis, in comparation with conventional angiography, is 91% and 84%, respectively. This is in accor­dance with the previous reports.14 As shown in the literature, and proved by this study as well, the measurement of CS is Figure 2b. Calcification of left coronary artery (arrow) important in patients suspect of CHD, it is predictive for coronary accident and corre­lates with the severity of it. The next step is going to be the analysis of the soft plaque, and the technical development of MDCT (64 row detectors); with its transversal plains it should make it possible. According to the literature, soft plaque can be even more dangerous than the calcified atherosclerotic plaque, although the latest contains soft parts too. Previous data show that, besides the meas­urement of CS in CHD, CTA has a significant role as well. In comparison to cardiac catheterization, coronary CTA has positive and negative predictive value in coronary ar­terial stenosis 59-85% and 96-98%, respective­ly. In other words, coronary CTA can exclude CHD with highly negative predictive value. Patients with low to moderate pre-test values are particularly good candidates for the coro­nary CT examination.3 Some previous studies show that MDCT’s negative predictive value of 96-98% for coro­nary artery stenosis, is sufficient for the iden­tification of patients who do not need cardiac catheterization. Its positive predictive value, with the range from 60 to 85%, suggests that some improvements have to be made before it replaces catheterization.13 Other studies on MDCT angiography (MDCTA) show mean sensitivity, specificity, accuracy, and positive and negative predictive values for detecting significant coronary artery stenosis as 86%, 90%, 76% and 97%, respectively. This indi­cates that high negative predictive value of MDCTA can really exclude coronary artery disease.11 When talking about CS in patients with the history of previous myocardial infarction, a question arises - what was the condition before the infarction, and in what extent the coronary calcification, or high CS, is the result of repara­tory mechanisms after the infarction? Therefore, this problem needs further re­searches, to give the insight into the other fac­tors significant for development of CHD, as well as for the position of CS and soft plaque in this context. Some of these solutions are al­ready coming in sight with the further devel­opment of MDCT and MRI. Conclusions This study shows the high correlation be­tween the level of coronary artery calcium scoring, calculated by Agatston method, and myocardial infarction, or that 70.4% patients with the previous myocardial infarction had CS > 500. The low CS was rarely found in pa­tients who had a myocardial infarction, which presumes that the same is less com­monly connected with the coronary artery disease. It leads to the conclusion that coro­nary CS is the significant screening method in predicting a potential coronary attack in asymptomatic patients, and in those with the symptoms of angina. Thanks to this method, it is often possible to avoid coronary angiog­raphy in certain number of patients. The main risk factors include: age, sex, smoking, hypertension, diabetes, heredity and hyperc­holesterolemia. MDCT has shown to be an efficient method for the examination of coronary cal­cifications in proximal 2/3 segments of coro­nary arteries. References 1. Ward Ph, Sandrick K. Multislice CT challenges MR in plaque detection. Diagnostic Imaging Europe 2004; 20: 5-7. 2. Carrington C. CT gets to grips with vascular dis­ease. Diagnostic Imaging Europe 2002; 18: 34-9. 3. Becker CR. Coronary artery stenosis and athero­sclerosis: assessment by contrast-enhanced 16 de­tector row CT. Medical Imaging International 2002; 12: 17-8. 4. Becker CR, Schoepf UJ, Reiser MF. Coronary ar­tery calcium scoring: medicine and politics. Eur Radiol 2003; 13: 445-7. 5. Shemesh J, Koren-Morag N, Apter S, Rozenman J, Kirwan BA, Itzchak Y, et al. Accelerated progres­sion of coronary calcification: four-year follow-up in patients with stable coronary artery disease. Radiology 2004; 233: 201-9. 6. Schlosser T, Hunold P, Schmermund A, Kuhl H, Waltering KU, Debatin JF, et al. Coronary artery calcium score: influence of reconstruction interval at 16-detector row CT with retrospective electro-cardiographic gating. Radiology 2004; 233: 586-9. 7. Ward P. MDCT challenges EBCT in coronary im­aging. Diagnostic Imaging Com 2004; 20: 15-7. 8. Brice J. Calcium test predicts heart attack risk, mortality. Diagnostic Imaging Com 2003; 25: 62-4 9. Rodenwaldt J. Multislice computed tomography of the coronary arteries. Eur Radiol 2003; 13: 748-57. 10. Abella H. EBCT, MRI spot coronary artery stenosis with accuracy. Diagnostic Imaging Europe 2002; 18: 9-10. 11. Becker CR. MDCT assists evaluation of cardiac function. Diagnostic Imaging Europe 2003; 19: 25-9. 12. Kaiser CP. Calcium protocols focus on radiation dose. Diagnostic Imaging Com 2003; 25: 61-3. 13. Brice J. Cardiac imagers assess clinical value of MR, CT. Diagnostic Imaging Com 2003; 25: 57-9. 14. Schoenhagen P, Halliburton SS, Stillman AE, Kuzmiak SA, Nissen SE, Tuzcu EM, et al. Noninvasive imaging of coronary arteries: current and future role of multi-detector row CT. Radiology 2004; 232: 7-17. Radiol Oncol 2005; 39(3): 193-6. case report Small-bowel carcinoid presenting with acute bleeding detected upon wireless capsule endoscopy Živa Mrevlje1, Marko Sever2, Borut Kocijancic1 1Clinical Department of Gastroenterology, University Medical Center Ljubljana, Slovenia 2Clinical Department of Abdominal Surgery, University Medical Ljubljana, Slovenia Background. Intestine carcinoid usually presents with clinical symptoms and signs deriving from its en-docrinological influences and rarely bleeds profusely. Case report. We present a patient with intestinal bleeding of unknown origin. After conventional diagnos­tic procedures only wireless capsule endosopy was able to discover a tumour of small bowel, which was the reason of bleeding. On patohistological examination after the surgical resection it proved to be a small bow­el carcinoid. Conclusions. There are indications that WCE, besides being the first small bowel imaging technique, is a very important diagnostic tool, deserving consideration in the early phases of diagnosing small-bowel dis­ease, especially in less intensive or occult bleeding. Key words: intestinal neoplasms-dignosis; carcinoid tumor; endoscopy Introduction The small intestine has to-date been a prob­lematic section of the gastrointestinal (GI) tract for exploration. In patients with obscure or manifest GI bleeding the major part of the small bowel was unreachable by means of esophagogastroduodenoscopy (EGDS), push enteroscopy (PE) and coloileoscopy (CIS), the Received 19 July 2005 Accepted 1 August 2005 Correspondence to: Živa Mrevlje, MD, Department of Gastroenterology, Clinical Center Ljubljana, Japljeva 2, 1000 Ljubljana, Slovenia; E-mail: ziva@mrevlje.org Abbreviations: GI – gastrointestinal, EGDS – esopha­gogastroduodenoscopy, PE – push enteroscopy, WCE – wireless capsule endoscopy, RBC – red blood-cell count, MCV – medium red blood-cell volume major limitations being its remoteness from GI tract openings and its length (3.4-7.9m ap­prox.). Other conventional diagnostic proce­dures in small bowel bleeding are blood pool scintigraphy, angiography and barium small bowel series. Virtual endoscopy, employed lately, is an interesting alternative to conven­tional diagnostic techniques.1 In recent years a novel endoscopic tool, the wireless capsule endoscopy (WCE) has been developed.2 It allows to endoscopically ex­plore the small intestine in its entirety using a system composed by a peristalsis propelled video capsule with a radio transmitter, a sen-sor-array attached to the patients abdominal wall and a data recorder worn at the patient’s belt. The data collected can then be retrieved and analyzed using a workstation. We present a case of manifest GI bleeding in which WCE facilitated identification of the bleeding site, its localization and treatment. Case report A 58-year-old man with maelena lasting for 3 days prior to the admission was referred to our hospital. On admission the patient was complaining of minor fatigue during the past few days. He had been on antihypertensive and statin therapy for several years. He was otherwise in good health, somewhat pale; on rectal examination black semi-fluid stools were found. The only pathological laboratory finding was normocytic anaemia (red blood-cell count - RBC 3.75 109/L, Hb 11.4 g/dL, medium red blood-cell volume - MCV 89.5 fL). He underwent oesophagogastroscopy with no positive finding. On colonoileoscopy, two polyps in the sigmoid without any sign of recent haemorrhage were found and frank maelena was seen to be flowing from the ileum into the caecum. Blood pool scintigra­phy showed some active bleeding in a region projecting into the right upper abdominal quadrant, most probably a part of the small bowel. On angiography of the superior mesenteric artery and celiac trunk no ex-travasate was found in their course. On WCE performed with an M2A plus capsule and an­alyzed using the RAPID software (both Given Imaging Inc., Yoqneam, Israel) small bowel mucosa showed few small angiodisplasia-like mucosal changes in the proximal jejunal re­gion. Following 3.5 hours of small bowel tran­sit time we visualized a bleeding site in the vicinity of the tumour of 7 mm in diameter. The tumour was projected into the right low­er quadrant of the abdomen (Figure 1). On explorative laparotomy, a small umbil­ication of jejunal serosa lying 50 cm distally to the ligament of Treitz was found. At this site a 10 mm fixed tumour was palpable. Distally from it the lumen was filled with blood, which was even more evident on tran­sillumination. A jejunal segmental resection of 5cm (Figure 2), followed by a one-layer ter­minoterminal anastomosis, was performed. The surgeon found no pathology on palpato­ry examination of the liver. On patohistological examination the re-sected formation was found to be a well dif­ferentiated malignant (more than 10 mm in diameter) carcinoid of the small intestine, ini­tial stage T2 N0. The tumour cells expressed serotonin, some of them somatostatin. There Figure 1. Capsule endoscopy view of the tumour. Figure 2. Tumour after excision. was no need for the additional therapy, only the follow-up was recommended. Discussion When haemorrhage from the GI tract is sus­pected, we usually choose from, or combine, upper GI tract endoscopy and colonoscopy, which gain visual access to both end-sides of the GI tract and only to a small part of the small bowel, proximal jejunum and distal ileum. We performed both in this case, but didn’t visualize any actively bleeding sites, and consequently deduced that bleeding de­rived from the small intestine. PE has a diagnostic yield ranging between 13 and 38%; in a randomized trial its sensitiv­ity was 37% compared to 64% for WCE.3,4 It has the advantage of allowing treatment and specimen cropping and has higher specificity in its range.5 Because of the proximity of the bleeding lesion to the ligament of Treitz (50cm) in our patient’s case PE would have probably led to the diagnosis without any need to perform WCE, but we didn’t perform it. In regard to its lower diagnostic yield and the possibility of performing WCE, we didn’t perform barium small bowel series. Besides involving patient radiation, trial barium small bowel series were in different studies shown to be less diagnostic than WCE (27% vs. 45% of cases).6,7 The explorative surgery unaccompanied by additional techniques has a yield of ap­proximately 10%.8 The recognition of vascular lesions cannot be achieved without the aid of transillumination or intraoperative en­doscopy. The latter is invasive and associated with many complications, i.e. postoperative paralytic ileus and perforation. We refrained from performing explorative surgery with in-traoperative endoscopy, as the bleeding wasn’t haemodinamically or otherwise threatening to the patient in the immediate time, not ad­vocating for such an invasive technique. Other morphologic and functional tech­niques, such as angiography of the superior mesenteric artery and blood pool scintigra­phy with marked erythrocytes promised to bring some insight into the diagnostic prob­lem. Blood pool scintigraphy gives a positive scan with at least 5 ml of intraluminal blood. It may confirm small intestinal bleeding, it confers no information about the nature of the bleeding lesion and accurate localization is impossible. With sequential scanning it al­lows the detection of intermittent bleeding. Angiography of mesenteric arteries can demonstrate active bleeding and well vascu­larized nonbleeding lesions. Its diagnostic yield is 50-70%, but falls to 25-50% when the bleeding slows or stops; a positive find can only be gained with bleeding rates exceeding 0.5 or 1 ml/min.9 In our case blood pool scintigraphy pinpointed to a bleeding site in the small intestine, whereas with angiogra­phy no bleeding site was identified. It might be that the bleeding site in our patient was smaller than required for identification, the more probable explanation is that at the time of angiographical examination there was no bleeding from the site. Following angiography and blood pool scintigraphy we performed WCE. We visual­ized a bleeding site just before the tumorous formation and concluded it could be an an-giodisplasia. When surgery was performed, besides the tumour, no angiodisplastic lesion was found. During WCE we probably wrong­ly interpreted blood in the lumen as deriving from a »lesion« of the intestinal mucosa, which, revising the WCE images, we conclud­ed could well be an adherent coagulum or just superimposed blood. As we know of, our diagnostic mistake had no repercussions on the patients’ well being. Aftermath, we reconsidered the diagnostic path we took in view of the diagnostic yield of single diagnostic techniques and their cost. EGDS and colonoscopy were well employed in our case as they helped eliminate the re­gions inspected as possible sites of bleeding and gave ground to suspicion of ongoing bleeding in the small intestine. From here we proceeded to angiography and blood pool scintigraphy, costly techniques, which drew us no nearer to the diagnosis. The cost of WCE is approximately that of angiography alone and in our case it gave the only defini­tive information, which in consequence led to the cessation of bleeding by removal of the tumour. Therefore, it would have been more cost-effective, if we had performed WCE be­fore employing other techniques. It has been demonstrated that WCE has many advantages over conventional proce­dures; it produces visual images and has a greater sensitivity in uncovering small bowel disease. It is also safe, easy for the patient, can be repeated many times, it has limited contraindications and a low complication rate. Its limitations are almost as obvious as its advantages; it confers diagnostic potential, but lacks possibilities of tissue sampling and treatment,10 the exact site of the abnormality is not readily determined and it is demanding in view of the time needed to view the pro­duced images. More experience will be needed in this field, but there are indications that WCE, be­sides being the first small bowel imaging technique, is a very important diagnostic tool, deserving consideration in the early phases of diagnosing small-bowel disease, especially in less intensive, or occult bleeding. Reference 1. Kuwayama H, Iimuro M, Kitazumi Y, Luk G. Virtual endoscopy: current perspectives. J Gastroenterol 2002; 37(Suppl 13): 100-5. 2. Iddan G, Meron G, Glukhovsky A, Swain P. Wireless capsule endoscopy. Nature 2000; 405: 417. 3. Eli C, Remke S, May A, Helou L, Henrich R, Mayer G. The first prospective controlled trial comparing wireless capsule endoscopy with push en-teroscopy in chronic gastrointestinal bleeding. Endoscopy 2002; 34: 685-9. 4. Appleyard M, Fireman Z, Glukhovsky A, Jacob H, Shreiver R, Kadirkamanathan S, et al. A random­ized trial comparing wireless capsule endoscopy with push enteroscopy for the detection of small bowel lesions. Gastroenterology 2000; 119: 1431-8. 5. Berner J, Mauer K, Lewis B. Push and sonde en-teroscopy for the diagnosis of obscure gastrointesti­nal bleeding. Am J Gastroenterol 1981; 19: 113-5. 6. Costamagna G, Shah SK, Riccioni ME, Foschia F, Nutignani M, Perri V, et al. A prospective trial comparing small bowel radiographs and video capsule endoscopy for suspected small bowel dis­ease. Gastroenterology 2002; 123: 999-1005 7. Maglinte DD, Kelvin FM, O’Connor K, Lapps JC, Chernish SM. Current status of small bowel radi­ography. Abdom Imaging 1996; 21: 247-57. 8. Lewis BS. Small intestinal bleeding. Gastroenterol Clin North Am 2000; 1: 67-95. 9. Browder W, Cerise E, Litwin M. Impact of emer­gency angiography in massive lower gastrointesti­nal bleeding. Ann Surg 1986; 204: 530-6. 10. Scapa E, Jacob H, Lewkowicz S, Migdal M, Gat D, Gluckhovski A, et al. Initial experience of wireless capsule endoscopy for evaluating occult gastroin­testinal bleeding and suspected small bowel pathology. Am J Gastroenter 2002; 97: 2776-9. Radiol Oncol 2005; 39(3): 197-210. review Molecular biology of the lung cancer Sasho Z. Panov Laboratory for Molecular Biology, Institute of Biology, Faculty of Natural Sciences and Mathematics, “Ss. Cyril and Methodius” University, Skopje, Republic of Macedonia Background. Lung cancer is one of the most common malignant diseases and leading cause of cancer death worldwide. The advances in molecular biology and genetics, including the modern microarray technology and rapid sequencing techniques, have enabled a remarkable progress into elucidating the lung cancer ethiopathogenesis. Numerous studies suggest that more than 20 different genetic and epigenetic alterations are accumulating during the pathogenesis of clinically evident pulmonary cancers as a clonal, multistep process. Thus far, the most investigated alterations are the inactivational mutations and losses of tumour suppressor genes and the overexpression of growth-promoting oncogenes. More recently, the acquired epigenetic inactivation of tu­mour suppressor genes by promoter hypermethylation has been recognized. The early clonal genetic abnor­malities that occur in preneoplastic bronchial epithelium damaged by smoking or other carcinogenes are be­ing identified. The molecular distinctions between small cell lung cancer (SCLC) and non-small cell lung can­cer (NSCLC), as well as between tumors with different clinical outcomes have been described. These inves­tigations lead to the “hallmarks of lung cancer”. Conclusions. It is realistic to expect that the molecular and cell culture-based investigations will lead to discov­eries of new clinical applications with the potential to provide new avenues for early diagnosis, risk assessment, prevention, and most important, new more effective treatment approaches for the lung cancer patients. Key words: lung neoplasms-genetics; genes, tumor suppressor Introduction Lung cancer is one of the most common ma­lignant diseases and leading cause of cancer Received 24 August 2005 Accepted 11 September 2005 Correspondence to: Sasho Z. Panov, PhD, Teaching and Research Assistant of Molecular Biology and Molecular Genetics, Institute of Biology, Faculty of Natural Sciences and Mathematics, “Ss. Cyril and Methodius” University, Arhimedova bb., MK-1000, Skopje, Republic of Macedonia; Phone: 389 70 248 790; Fax: 389 2 3228 141; E-mail: sasho@mt.net.mk death worldwide with estimated more than 1.3 million new cases each year.1 The lung cancer incidence and mortality have risen into epi­demic proportions in Western world during the 20th century.2 The majority of lung cancer patients is inoperable or has disseminated dis­ease at the time of diagnosis and displays a re­markable insensitiveness to chemotherapeu­tics and radiation therapy.3 Over 85% of these patients eventually die from disseminated dis­ease during the first 5 years and this extreme mortality has not changed significantly during the last three decades. Despite diagnostic and therapeutic improvements, the 5-year survival rate has barely increased from 7 to 14% since 1970-thies to the present. Moreover, the lung carcinoma is accounting for nearly 29% of all cancer-related deaths in both genders, that ex­ceeds the sum of the next three leading causes of death due to breast, colon, and prostate can­cer.4 It is believed that smoking is the primary eti­ologic agent in more than 80% of lung cancer patients.5 The other risk factors include, but are not limited to, passive smoking, exposure to environmental pollutants, occupational expo­sure to chemicals (arsenic, asbestos, chromi­um, nickel and vinyl chloride) and to the natu­ral radioactive gas radon.2 Genetic predisposi­tion, especially polymorphisms of the tumor suppressor genes and the allelic variants of the genes involved in detoxification, are implicated into the susceptibility to the disease.6 Based on the histopathological classifica­tion (WHO, 1977), lung cancer is divided into two main types: non–small cell (NSCLC) and small cell lung cancer (SCLC), which are delin­eated by their biological and clinical features. Furthermore, NSCLC consists of several sub­types, predominantly adenocarcinoma, squa-mous-cell carcinoma, and large-cell carcinoma. SCLC is a distinct clinicopathological entity with neuroendocrine pathophysiologic fea­tures and characteristic microscopic morphol­ogy.7 SCLC represents roughly 20% of all pul­monary cancers. The histologic distinction be­tween NSCLC and SCLC is clinically extreme­ly important. There are considerable differ­ences between those two groups in both, ther­apeutic approach and prognosis of the disease. Recently, molecular classification of lung car­cinomas has been made using mRNA expres­sion profiling by microarray technology.8-10 Molecular biology of lung cancer It is generally accepted that the pathogenesis of human cancer involves the accumulation of multiple molecular abnormalities over time. Those alterations lead to acquired cellu­lar capabilities that can be classified in the following six functional sets: a) self-sufficien­cy in growth signals due to mutations in pro-to-oncogenes, b) insensitivity to antiprolifera­tive signals as a result of mutations affecting the tumour suppressor genes, c) evading of apoptosis by up-regulation of antiapoptotic or down-regulation of proapoptotic molecules, d) limitless replicative potential due to the ac­tivation of telomerase, e) sustained angiogen­esis and f) capability for tissue invasion and capability for dissemination into distant sites (metastasis).11 Those molecular alterations can occur at the level of gene up-regulation or down-regulation, DNA sequence changes (point mutations), loss of heterozygosity (i.e., deletion of one copy of allelic DNA se­quences), DNA segment amplification or whole chromosome gains or losses with the simultaneous genomic instability and alter­ations in microsatellite DNA.12,13 The advances in molecular biology and ge­netics, including the modern microarray tech­nology and rapid sequencing techniques, have enabled a remarkable progress into elu­cidating the lung cancer ethiopathogenesis. Numerous studies suggest that more than 20 different genetic and epigenetic alterations are accumulating during the pathogenesis of clinically evident pulmonary cancers as a clonal, multistep process.14-16 Thus far, the most investigated alterations are the inactiva­tional mutations and losses of tumor sup­pressor genes and overexpression of growth-promoting oncogenes. More recently, the ac­quired epigenetic inactivation of tumor sup­pressor genes by promoter hypermethylation has been recognized. The early clonal genetic abnormalities that occur in preneoplastic bronchial epithelium damaged by smoking or other carcinogenes are being identified. The molecular distinctions between SCLC and NSCLC, as well as between tumors with dif­ferent clinical outcomes have been described. These investigations lead to the “hallmarks of lung cancer”.3 It is realistic to expect that the molecular and cell culture-based investiga­tions will lead to discoveries of new clinical applications with the potential to provide new avenues for early diagnosis, risk assess­ment, prevention, and most important, new more effective treatment approaches for the lung cancer patients. Growth stimulation by oncogenes Protein-tyrosine kinases (PTKs) are vital reg­ulators of intracellular signal-transduction pathways that mediate development and cell-to-cell communication. Their activity is nor­mally firmly controlled and regulated. Disturbances in the PTK signaling resulting from mutations and other genetic alterations contribute to the malignant transformation. A number of growth factors and their recep­tors are expressed by lung cancer cells or their neighboring stromal cells, thus produc­ing autocrine or paracrine growth stimulation loops. Several are encoded for by proto-onco­genes which become activated in the course of the lung cancer development.3 The overex­pression of cell cycle regulatory proteins such as cyclin D1,17 cyclin E,18 and cyclin B1,19 en­hance the cell proliferation, decrease the cel­lular apoptotic potential and are commonly found in NSCLC tumor specimen. Epidermal growth factor receptor (EGFR), also called ErbB-1, is the member of a sub­family of closely related proteins. After lig­and-binding, the intracellular tyrosine kinase domain of the EGFR receptor is activated and undertakes autophosphorylation, which initi­ates a cascade of intracellular events. A downstream signaling pathway involves the activation of p21-Ras and mitogen-activated protein kinases (MAPKs). EGFR signaling is critical for the normal cell proliferation, but its deregulation is crucial for cancer patho­genesis, neoangiogenesis, metastasis, and apoptosis inhibition.20 EGFR is overex-pressed in the advanced NSCLC, and is asso­ciated with the poor survival and resistance to chemotherapeutic agents, including cis­platin. The results of different studies investi­gating the prognostic value of EGFR expres­sion in lung cancer are contradictory.3 However, since EGFR expression is clearly in­volved in the lung cancer pathogenesis, this molecule is an attractive target of different therapeutic approaches.21 Few EGFR in­hibitors (CP358774, ZD1839-Iressa and OSI774) are under intensive clinical trials in lung cancer patients.3 HER-2/neu (ErbB-2) gene is located on chromosome 17p21 and encodes for a 185­kDa transmembrane glycoprotein (p185HER­2/neu) that has high homology with EGFR. HER-2/neu is overexpressed in about 30% of NSCLCs, particularly in adenocarcinomas and is associated with multiple drug resist­ance phenotype and high prevalence of metastases.3 A point mutation resulting in the substitution of the amino acid residue 664 from valine to glutamic acid is commonly found, and this mutation contributes to the malignant transform of affected cells. Alterations and amplifications of HER-2/neu gene have been reported in NSCLC.20 Chemotherapy combined with trastuzumab (Herceptin), a monoclonal antibody against the HER2/neu receptor is now under clinical trials.3 MYC proto-oncogene belongs to a family of related genes (c-MYC, N-MYC, L-MYC) which encode transcription factors that acti­vate genes involved in the growth control and apoptosis. The MYC phosphoproteins are lo­calized in the nucleus.22 The transcriptional regulation by MYC proteins is mediated by heterodimerizing with partner proteins such as MAX, MAD or MX11.23 MYC-MAX het­erodimer binds to specific DNA sequences named E-box elements in the neighborhood of promoters of downstream target genes and activate their transcription. Histone acetylase is activated and leads to alterations in chro­matin structure, which, in turn, modulate the gene transcription. On the other hand, the MYC-MAX complex represses a transcrip­tional activation. MAX can bind MAD and MX11 proteins to repress transcription, an­tagonize MYC, and promote cellular differen­tiation.20 The molecular abnormalities involv­ing the MYC genes or their transcriptional deregulation were found to be an important molecular mechanism in the pathogenesis of human lung cancers.23 The most frequent ab­normality involving MYC members in lung cancer is gene amplification or gene overex­pression without amplification. The overex­pression of a MYC gene, with or without am­plification, occurs in 80 to 90% of SCLCs.22 In contrast to SCLC, the amplification of the MYC gene occurs only in approximately 10% of NSCLC samples. However, MYC overex­pression without MYC gene amplification oc­curs in over 50% of NSCLC investigated spec­imens.22 MYC gene overexpression has been identified to be a late event in lung cancer pathogenesis in the vast majority of SCLCs.20 Lung tumor cell lines established from metastatic tumors have a high frequency of MYC amplification, and this probably ex­plains the correlation of MYC amplification with a poor clinical prognosis.24 The anti-sense oligonucleotides therapy models direct­ed at downregulating MYC expression show encouraging results in cell culture.3 The dominant RAS proto-oncogene is ex­tremely important for the transduction of the growth-promoting signals from the mem­brane to the nucleus and consequently for the cellular proliferation. The RAS family of genes includes: the HRAS gene (homologous to the oncogene of the Harvey rat sarcoma virus), the KRAS2 gene (homologous to the oncogene of the Kirsten rat sarcoma virus) and the NRAS gene (initially cloned from hu­man neuroblastoma cells). The RAS genes code for four highly homologous 21 kDa pro­teins called p21 anchored to the inner side of the plasma membrane, where they can effec­tively interact with their upstream activators and downstream targets. In active state RAS proteins binds to guanosine triphosphate (GTP) and through the intrinsic GTPase ac­tivity and conformational change of RAS, the GTP hydrolyze to guanine diphosphate (GDP) and after interacting with its substrate Raf1, RAS returns to the inactive state. The cell proliferation signal is subsequently trans­mitted by a cascade of RAS-dependent kinas-es, activating the MAPK, which translocate to the nucleus and initiate transcription factors.20 This signal transduction pathway is sometimes called SOS-Ras-Raf-MAPK mito­genic cascade.11 In malignant cells, the point mutation in the RAS gene can make the RAS protein defective in the intrinsic GTPase ac­tivity that becomes locked into the growth stimulatory GTP-bound form, constantly sending the signal stimulating cell prolifera­tion signals to the nucleus.25 RAS mutations are very rare or absent in SCLC, but can be identified in 15-20% of NSCLC. Up to 50% of the lung adenocarcinomas carry RAS muta­tions,26 usually affecting codon 12 of KRAS (85% of cases), and rarely codon 13 of HRAS, or codon 61 of NRAS gene.23 The majority (up to 70%) of these mutations are G.T trans-versions that are induced by benzopyrene di­ethyloxide (BPDE), nitrosamines and other DNA adducts-forming agents that are present in the tobacco smoke. It is believed that this is the reason for the correlation between smoking history and the frequency of KRAS mutations in NSCLC samples which are asso­ciated with poor prognosis.27 Few clinical tri­als are conducted: using vaccination with mu­tant KRAS peptides, by suppression of the mutant RAS gene using antisense oligonu­cleotides, or by inhibition of the farnesylation of the RAS protein that is necessary for its ac­tivation.3 The distinguishing feature of SCLC tumors is the production and release of a broad range of neuropeptides from the neoplastic cells. Angiotensin, bombesin, insulin-like growth factor 1, vasopressin, serotonin, and sub­stance P are among the best studied signal molecules released by SCLC cells.28 These peptides act as ligands for high-affinity re­ceptors on the tumor cell surface, and their binding consequently activate the G-protein coupled receptors enabling a further intracel­lular transmission of the proliferative signal. By this, SCLC cells are self-stimulating the growth by autocrine and paracrine manner. Insensitivity to anti-growth signals: tumor suppressor genes Tumor suppressor genes (TSG) play a critical role in cell’s antiproliferative circuitry and are also involved in the cellular response to DNA damage and consequent reparation process­es. There is a frequent loss of tumor suppres­sor genes during the pathogenesis and pro­gression of lung cancers, as in many epithe­lial cancers. The inactivation of the tumor suppressor genes occurs by loss of one allele from the chromosomal locus, termed loss of heterozygosity (LOH) and damage to the oth­er allele by gene mutation or the epigenetic hypermethylation of its promoter. The chro­mosomal regions that where found to be most frequently affected by LOH in lung carcino­mas are 1p, 3p, 4p, 4q, 5q, 8p, 9p (p16 TSG lo­cus), 9q, 10p, 10q, 13q (RB-retinoblastoma lo­cus), 15q, 17p (p53 locus), 18q, 19p, Xp, and Xq.3 The allelic loss at several loci on the chromosome arm 3p is one of the most fre­quent and earliest genetic events in lung can­cer pathogenesis found in up to 96% of carci­nomas and 78% of preneoplastic bronchoep­ithelial lesions.29 The high frequencies of LOH and frequent homozygous deletions found in many lung cancer cell lines and tu­mor samples suggest that few potential tumor suppressor genes reside at this chromosome region.23 Moreover, the frequency and size of the allelic loss of 3p correlate with the severi­ty of histopathological preneoplastic/preinva­sive grades. There are a number of other can­didate tumor suppressor genes located at 3p and their allelic loss may probably be the ear­liest acquired genetic abnormality in the lung cancer pathogenesis.3,30 FHIT is a tumor-suppressor gene located at 3p14.2, coding for a dinucleoside 5’, 5’’’-P1­P3-triphosphate hydrolase protein product (often denoted as pFHIT). The loss of the gene results in the accumulation of diadeno-sine tetraphosphate, thus stimulating DNA synthesis and cell proliferation. A decreased expression of FHIT has been found in 49% of NSCLC specimen by immunochemistry. pFHIT expression is significantly reduced in a large number of early-stage NSCLC and pre-neoplastic lesions in chronic smokers. The as­sociation between cigarette smoking and pFHIT expression suggests a role for FHIT in the initiation of smoking-related lung car­cinogenesis.20 It was demonstrated that the reintroduction of wild-type FHIT inhibits lung cancer in vitro growth and in vivo tumori­genicity in nude (athymic) mice.23 The RARß. (retinoic acid receptor beta) gene, located at 3p24 is a strong TSG candi­date. Low or absent RARß. expression was detected with high frequency in lung cancer cell lines and primary lung tumours.23 It ap­pears to result from the aberrant promoter methylation of the RARß and was observed in approximately 40% of primary SCLCs. The TP53 tumor-suppressor gene (p53) is located at chromosome arm 17p13.1 and en­codes a 53 kDa nuclear protein that acts as a DNA-binding, sequence-specific transcrip­tion factor that activates the expression of genes engaged in promoting growth arrest in the G1 phase or cell death in response to the genotoxic stress.31 Thus, p53 has a role of “guardian of the genome”, maintaining the genome integrity during the cellular stress from DNA damage, hypoxia, and activated oncogenes. Also, p53 prevents cells with damaged DNA from undergoing mitosis when they enter the G2 phase. p53 blocks cells at the G2 checkpoint, at least partially, by inhibition of cdc2, the cyclin-dependent kinase required to enter mitosis. The ability of p53 to inhibit cellular proliferation or to in­duce apoptosis is suppressed by HDM2 pro­tein product, the human homologue of the murine double minute 2 (MDM2). This pro­tein blocks p53 regulation of target genes and enhances its proteasome dependent degrada­tion.31 On the other hand, p53 upregulates the expression of HDM2 by directly binding and activating the HDM2 promoter and thus p53 is downregulating its own expression. This autoregulatory loop keeps p53 at virtual­ly undetectable levels in normal cells.3 Missense mutations (mainly G.T transver­sions) clustered in the middle of the gene at codons 157, 245, 248, and 273 abolishes its tumor suppressing activity and extend the p53 mutant protein half-life that can be easi­ly detected by immunohistochemistry. The p53 gene mutations in lung cancer have been extensively investigated and were found that p53 is inactivated in 75% of SCLCs and about 50% of NSCLCs and the frequency of muta­tions correlate with cigarette smoking.20 It is intriguing that the mutations at codon 157 ap­pear to be unique to pulmonary carcinomas, while codon 248 and 273 hot spots mutations occur in other cancers, e.g., colon, liver, and prostate.22 Nonsmokers who develop lung cancer have a completely different, almost random grouping of p53 mutations.22 Although the prognostic role of p53 muta­tions in NSCLC p53 is still under debate, their presence influences the clinical re­sponse to cisplatin-based chemotherapy and radiotherapy.3 The RB tumor-suppressor gene is located on chromosome 13q14 and its protein prod­uct is a nuclear phosphoprotein initially iden­tified in childhood retinoblastomas. RB pro­tein cooperates with p53 in the regulation and control of cell cycle progression, the tran­scriptional level, and the equilibrium be­tween the cell differentiation and prolifera­tion. The phosphorylation status of the RB protein and its interaction with transcription factor E2F is most important for the regula­tion of G0/G1 cell cycle transition. When RB is dephosphorylated, it suppresses the G1 to S phase transition.32 During G1 phase, cyclin D1 is associated with cyclin-dependent–ki­nases CDK2 and CDK4 that results in phos­phorylation and activation of RB. Hypo-phosphorylated RB binds the E2F transcrip­tion factor, thus blocking the transcription of genes regulating the cell cycle. On the con­trary, when RB is phosphorylated, E2F disso­ciates and activates the transcription, thus fa­cilitating S phase entry.23 Abnormalities of the RB gene in lung cancer include deletions, nonsense mutations, pathogenic splicing variations and chromosomal deletions. The disruption of the pRb pathway releases E2Fs allowing cell proliferation to proceed and making the cell insensitive to antigrowth fac­tors that normally function to control a tran­sition through the G1 phase of the cell cy­cle.11 More than 90% of the SCLC and 15-30% of the NSCLC neoplasms have abnormal or no RB expression.22 Although RB plays an im­portant role in pulmonary cancer pathogene­sis, pRB status has no prognostic significance in NSCLC patients.20 PTEN (Phosphatase Tensin Homolog Deleted on Chromosome Ten) gene is located at chromosome 10q23 encodes a lipid phos­phatase which dephosphorylates PIP3 and posses tumor suppressor activity in vitro and in vivo. Mutations or deletions of the PTEN gene have been found in a few lung cancer cell lines and tumor samples.23 Transforming growth factor-ß (TGF-ß) is multifunctional protein that inhibits the pro­liferation of many epithelial cells through binding with a set of cell receptors. It is a checkpoint inhibitor involved in the cell cy­cle regulation, causing cells to cease prolifer­ation and arrest in G1.22 The reduced levels of TGF-ß expression was found in NSCLC samples by immunocytochemical staining studies. Another candidate TSG on chromosome 10q25-26 is DMBT1. It is frequently down regulated and occasionally homozygously deleted in lung cancer.23 The overexpression or activation of insulin-like growth factor I receptor (IGF-IR) has been observed in many human cancers including pulmonary carcino­mas. The p16INK4 (also termed CDKN2A) is a tumor-suppressor gene located on chromo­some 9p21 and codes for two proteins trans­lated by alternative mRNA splicing: a-tran­script that is translated into p16 (p16INK4) and ß-transcript that is translated into p14ARF protein. p16 protein that is part of the p16-cy­clin D1-Cdk4-RB pathway.32 p16 regulates cell-cycle progression through a G1/S restric­tion point by inhibiting CDK4 and CDK6/cy­clin D-mediated phosphorylation of pRB.20 The disruption of p16 function results in in­appropriate hyperphosphorylation and, therefore, inactivation of pRB. The overex­pression of the E2F transcription factor up-regulates p16 expression and inhibits cyclin D-dependent kinase activity, suggesting the presence of a feedback loop. p14ARF protein binds to and stabilizes HDM2 (MDM2 homo­logue), increasing its availability of wild-type p53. The loss of p14ARF or p53, which are common genetic lesions in lung cancer, per­mits an amplified MYC free opportunity for the cell proliferation and transformation. p14ARF appears to bridge a gap between onco­genic signals and p53 whereby p14ARF-in­duced activation would be critical to move the compromised cell toward apoptosis.22, 31 The expression of p16INK4 gene in NSCLCs is frequently altered by abnormal promoter methylation (25% of cases) and homozygous deletions or point mutations (10%-40%).23 It was found that the disturbances in both, the p16/pRb and p53 pathways are essential for the enhanced proliferation of NSCLC cell lines. There is an inverse relation between p16 and Rb in pulmonary carcinomas: Rb is mutated and p16 is intact in SCLC, while p16 expression is disrupted and Rb is usually in­tact in NSCLC.22 p19ARF binds to the MDM2­p53 and prevents p53 degradation. The loss of p19ARF is more frequent in lung tumours with neuroendocrine features.23, 31 Evading apoptosis Apoptosis or programmed cell death is a ge­netically controlled process that is essential for tissue remodeling during embryogenesis and for the maintenance of the homeostatic balance of cell numbers during adult life. A deregulation of cell death pathways is impli­cated in tumor initiation, progression, and drug resistance in many human cancers and is one of the hallmarks of cancer.11, 33 Two major intracellular apoptosis signaling pathways can lead to programmed cell death, the mitochon­drial pathway (intrinsic) and the death recep­tor (extrinsic) pathway. Mediated by a cascade of caspase activations and other mediator pro­teins, both pathways finally lead to the prote­olytic cleavage of a variety of cellular proteins, induces DNA fragmentation and numerous morphological changes that are characteristic of cells undergoing apoptosis. Key genes that regulate apoptosis include the p53 tumour suppressor gene and the Bcl-2 gene family. Simplified, the BCL-2 family members are ma­jor regulators of the apoptotic process, where­as caspases are the major executioners. Bcl-2 (B-cell lymphoma-2) gene was the first oncogene found to function through the production of an inhibitor of apoptosis. The bcl-2 gene family consists of more than 15 members, which either promote or inhibit the apoptosis.34,35,36 The bcl-2 gene is located on chromosome arm 18q21 and the BCL-2 pro­tein product is localized within the outer mi-tochondrial membrane, endoplasmic reticu­lum and the nuclear envelope, where it exerts anti-apoptotic effect within many cell types.34 Following the apoptotic stimulation, pro-apoptotic proteins are activated through post-transcriptional modifications or changes in their conformation. BCL-2 protein forms het­erodimers with proapoptotic BCL-2 family members, leading to their inactivation. In ad­dition, BCL-2 proteins may interfere with crit­ical steps during the integration of proapop­totic signals at the level of mitochondria, thereby abrogating cytochrome-C release. BAX is a BCL-2-related protein which pro­motes apoptosis and is a downstream tran­scription target of p53. BCL-2 protein het­erodimerizes with BAX consequently inhibits apoptosis. Tumor cells often escape apoptosis as the normal physiological response when challenged by cellular and DNA damage. BCL-2 overexpression, detected by immuno-histochemistry, was found in 75%-95% of SCLC tumors, 25%-30% of the squamous cell carcinomas and in 10% of adenocarcinomas.37 The significantly higher incidence of bcl-2 overexpression in SCLC is unexpected as these tumors are more sensitive to chemother­apeutic agents that induce an apoptotic re­sponse.3 Interestingly, the expression of BAX and BCL-2 proteins is inversely related in neu­roendocrine cancers. Namely, high BCL-2 and low BAX expression occurs in most SCLC tu­mors which are also mostly p53 deficient.3 The significance of the bcl-2 expression in lung cancer for the overall survival is controversial, but bcl-2 expression was found to be associat­ed with a better prognosis in NSCLC patients that may be associated with the lower tumor vascularization.20,38 Limitless replicative potential - telomeres and telomerases Telomeres are specialized heterochromatin structures at the end of each chromosome that serves as protective caps and plays a role in the maintaining chromosome integrity, re­versibly represses the transcription of neigh­boring genes and prevents the end-to-end fu­sion or degradation of the chromosomes.39 Due to the inability of the conventional DNA polymerases to replicate the 5’-end of linear DNA, telomeres shorten during each cell divi­sion in the normal human somatic cells. This phenomenon is known as an end-replication problem. This shortening does not produce the loss of the essential genes in which each of the 46 human chromosomes is capped with long repeats of non-coding DNA sequences named telomeres. The human telomeres con­sists of highly repetitive DNA of tandem se­quences TTAGGG)n.40,41 It has been calculat­ed that roughly 50–100 bp are lost with each round of cell division.42 Human cells are esti­mated to have the potential to undergo on av­erage 50–70 divisions. At this point the cell growth arrests and enters senescence. A dozen of telomeric proteins are needed to hide the telomeres from the cellular machinery that would normally treat the end of a linear DNA molecule as a broken strand needing repair.43 The key telomeric DNA binding proteins are the telomeric repeat binding factors, Tankyrase, heterogeneous nuclear ribonucleo-proteins and few other functionally related proteins. The physiologic maintenance of the telomere requires complex interactions among these proteins, telomeric DNA, and other cellular factors. Telomere integrity is al­so essential for the chromosome numerical and positional stability and the telomere shortening facilitates the evolution of cancer cells by promoting chromosome end-to-end fusions and the development of aneuploidy. The inhibition of telomerase in immortal can-cer-cell lines by genetic or pharmacological methods results in telomere shortening and eventually halts cell proliferation.44 Telomerase is a specific ribonucleoprotein enzyme complex that elongates and maintains the preexisting telomeres of eukaryotic chro­mosomes, using an intrinsic RNA molecule as a template and thus is extending the number of divisions the cell may undertake.45 Telomerase holoenzyme contains two main components that are essential for the activity: hTERT subunit (RNA-directed DNA poly­merase, i.e. reverse transcriptase, EC 2.7.7.), and hTR, 451-nt RNA chain that serves as a template. The enzyme complex also contains many proteins necessary for the full enzymat­ic activity that are collectively named as telomerase-associated proteins. The gene for the telomerase catalytic subunit hTERT is more than 37 kb in length and consists of 16 exons.46 The telomerase activity is absent in the majority of normal cells in adult organ­isms, but is increased during the development and neoplasia.47 Since over 90% of human neoplastic cells have increased telomerase ac­tivity, it is now generally accepted that this is a one of the cancer hallmarks and extremely frequent and consistent cancer-associated molecular abnormality. Generally, the telom-erase expression in malignant tumors is deter­mining the capacity for the unlimited prolifer­ation and thus immortality. A high telomerase activity was detected in almost 100% of SCLC and 80% of NSCLC samples using a PCR-based telomeric repeat amplification protocol (TRAP assay). A high telomerase activity in primary NSCLC was found to be associated with the increased cell proliferation rates and advanced pathologic stage.48 Recently, the telomere shortening was found to be an early molecular abnormality in bronchioepithelial carcinogenesis, preceding telomerase expres­sion and p53/Rb inactivation that occurs in most high-grade preinvasive lesions.49 Since the telomerase activity is associated with ma­lignant growth, it is a marker for lung cancer detection, and a important target for novel therapeutic approaches.23 Tumor angiogenesis New blood vessel growth (neovascularization or neoangiogenesis) is required for tumors to sustain and grow beyond 3 mm in diameter and for metastasis. Different inducers and in­hibitors regulating endothelial cell prolifera­tion and migration are involved in the process of angiogenesis. Growth factors that have been shown to stimulate angiogenesis in­clude vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived endothelial cell growth factor (PD-EGF) and platelet-derived growth factor (PDGF).3,23 The productions of angiogenesis factors apparently influence the clinical outcome of lung cancer patients. Namely, the VEGF levels in plasma are corre­lated with the degree of angiogenesis in NSCLC and the VEGF expression was found to be associated with the decreased overall and disease-free survival in NSCLC pa­tients.50 Immunochemical studies demon­strated that bFGF is a prognostic indicator in lung adenocarcinoma, since the 5-year sur­vival rate was significantly lower for bFGF positive patients and the more aggressive clinical behavior was associated with up-reg­ulation of PDGF.23 In a few clinical trials, im­pressive results were achieved by targeting VEGF with a “humanized” monoclonal anti-VEGF antibody. Unfortunately, unexpected bleeding from large necrotic lung neoplastic masses occurred in the initial trials, but this should be approachable by a more careful pa­tient selection.3 Tissue invasion and metastasis Molecular mechanisms that lead to the com­plex ability of the primary lung cancer cells to invade the adjacent tissue and to disseminate to the distant organs of the patient’s body are mainly unknown.3 This process involves degradation of the basement membrane, in­vasion of the surrounding stroma and the blood or lymphatic vessel, ability to growth without adhesion, angiogenesis, cell prolifer­ation, and migration.11 Few different genes and their protein products are identified to be important for the process of tissue invasion and metastatic capability of the neoplastic cells. E-cadherin is a cell adhesion molecule that is universally expressed on epithelial cells. During the pathogenesis of most epithelial cancers, E-cadherin function is lost by the mutational inactivation of the E-cadherin or ß-catenin genes, as well as by the transcrip­tional repression, or enhanced proteolysis. This results in reduced E-cadherin-mediated cell-cell adhesion and enables the malignant cells to invade the tissues and to enter the blood or lymphatic vessels.51 Therefore, E-cadherin gene is sometimes referred to as the “suppressor of invasion” gene.52 It was demonstrated that E-cadherin loss in lung cancer is associated with the increased metas­tasis capability.53 A degradation of the basal membrane and of the extracellular tissue ma­trix by proteases is very important for the lo­cal invasiveness and blood or lymphatic metastasis. Matrix metalloproteinases (MMPs) are members of the family of zinc-containing pro­teolytic enzymes that facilitate the tumor in­vasion, the metastatic capabilities, and the tu-mor-related angiogenesis. Conversely, matrix metalloproteinase inhibitors (MMPIs) have been shown to inhibit tumour growth and dissemination in preclinical models. It is therefore not clear why not all lung cancers express the MMPs and there are conflicting reports about the prognostic importance of MMPs expression in lung cancer.54 It was found that CRMP-1, a protein that mediates the effect of collapsins, has reduced the expression in more aggressive and metastatic lung cancer samples.55 This down-regulation is believed to enhance the cell mi­gration ability, which is important for the process of metastasis. CRMP and other mem­bers of the collapsin/semaphorin protein families might control the cell’s movement.56 Laminins and integrins are proteins in­volved in the adjacent tissue invasion through the basement membrane and further spread of the lung cancer cells. The reduced expression of laminin a chains (a3 and a5) in lung neoplastic tissue might result in the basal membrane fragmentation necessary for the cancer cell invasion.57 Changes in the in-tegrin expression are found in metastatic cells in many human neoplasms, including the lung cancer.11 Recently, a study conduct­ed by Manda and collaborators, identified that the LAMB3 gene (coding for the laminin ß3 chain, a component of laminin-5) was ex­pressed only in NSCLC cells and not in SCLC tumor cells.58 In the same study, the a6ß4 in-tegrin, the specific laminin-5 binding recep­tor, was expressed only in NSCLC cells but not in SCLC cells. This suggests that laminin­5 might be a critical microenvironmental fac­tor for the growth of NSCLC tumours.58 Overview of the molecular abnormalities in lung cancer pathogenesis The model of lung cancer pathogenesis is de­picted on the Figure 1 and was developed based on the previous studies.59 The carcino­gens from the tobacco or other environmental pollutants lead to the loss of the 3p21.3 allele in thousands of cells on different sites of the respiratory epithelium. Later, the tumor sup­pressor genes located in the 3p21.3 chromo­some arm become haplo-insufficient. The next hit occurs in genes that are critical for the cell proliferation, such as RB, p53, p16 or oth­er genes either by the mutational inactivation or by the promoter hypermethylation. That permits a clonal outgrowth of the initially transformed cells. Some authors suggest that the molecular pathogenesis differs significant­ly between SCLC and NSCLC main tumor types.30 It is proposed that during the patho­genesis of the SCLC neoplastic cells arise di­rectly either from normal or hyperplastic ep­ithelial cells without passing through charac­teristic preneoplastic intermediate pathologi­cal stages (parallel theory of lung cancer Figure 1. Main molecular abnormalities occurring during lung cancer pathogenesis (according to References 59 and 22). pathogenesis). On the contrary, the NSCLC pathogenesis is accompanied with sequential morphological changes (sequential theory). Conclusions Recent progress into the elucidation of the mo­lecular genetic abnormalities involved in the lung cancer has been achieved using modern technologies for the mutation detection as well as for the gene expression quantitation using microarray techniques. 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Shackelford RE, Kaufmann WK, Paules RS. Cell cycle control, checkpoint mechanisms, and geno-toxic stress. Environ Health Perspect 1999; 107: 5-24. 33. Schulze-Bergkamen H, Krammer PH. Apoptosis in cancer - implications for therapy. Semin Oncol 2004; 31(1): 90-119. 34. Reed J. Double identity for proteins of the Bcl-2 family. Nature 1997; 387(6635): 773-6. 35. Adams JM, Cory S. The Bcl-2 protein family: ar­biters of cell survival. Science 1998; 281(5381): 1322-6. 36. Belka C, Budach W. Anti-apoptotic Bcl-2 proteins: structure, function and relevance for radiation bi­ology. Int J Radiat Biol 2002; 78 (8): 643-58. 37. Kaiser U, Schilli M, Haag U. Expression of bcl-2— protein in small cell lung cancer. Lung Cancer 1996; 15(1): 31-40. 38. Martin B, Paesmans M, Berghmans T, Branle F, Ghisdal L, Mascaux C, et al. Role of Bcl-2 as a prognostic factor for survival in lung cancer: a sys­tematic review of the literature with meta-analysis. Br J Cancer 2003; 89(1): 55-64. 39. Zakian V. Telomeres: beginning to understand the end. Science 1995; 270(5242): 1601-7. 40. Moyzis RK, Buckingham JM, Cram LS, Dani M, Deaven LL, Jones MD, et al. A highly conserved repetitive DNA sequence (TTAGGG)n, present at the telomeres of human chromosomes. Proc Natl Acad Sci USA 1988; 85(18): 6622-6. 41. Wright WE, Tesmer VM, Huffman KE, Levene SD, Shay JW. Normal human chromosomes have long G-rich telomeric overhangs at one end. Genes Dev 1997; L 2801-9. 42. Harley C, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature 1990; 345(6274): 866–8. 43. Hahn WC. Role of telomeres and telomerase in the pathogenesis of human cancer. J Clin Oncol 2003; 21(10): 2034-43. 44. sEvans SK, Lundblad V. Positive and negative reg­ulation of telomerase access to the telomere. J Cell Sci 2000; 113 Pt 19: 3357-64. 45. Holt SE, Shay JW. Role of telomerase in cellular proliferation and cancer. J Cell Physiol 1999; 180(1): 10-8. 46. Cong YS, Wen J, Bacchetti S. The human telom-erase catalytic subunit hTERT: organization of the gene and characterization of the promoter. Hum Mol Genet 1999; 8(1): 137-42. 47. Shay JW, Zou Y, Hiyama E, Wright WE. Telomerase and cancer. Hum Mol Genet 2001; 10(7): 677-85. 48. Albanell J, Lonardo F, Rusch V, Engelhardt M, Langenfeld J, Han W, et al. High telomerase activ­ity in primary lung cancers: association with in­creased cell proliferation rates and advanced pathologic stage. J Natl Cancer Inst 1997; 89(21): 1609-15. 49. Lantuejoul S, Soria JC, Morat L, Lorimier P, Moro-Sibilot D, Sabatier L, et al. Telomere shortening and telomerase reverse transcriptase expression in preinvasive bronchial lesions. Clin Cancer Res 2005; 11(5): 2074-82. 50. Fontanini G, Vignati S, Boldrini L. Vascular Endothelial Growth Factor Is Associated with Neovascularization and Influences Progression of Non-Small Cell Lung Carcinoma. Clin Cancer Res 1997; 3: 861-5. 51. Christofori G, Semb H. The role of the cell-adhe­sion molecule E-cadherin as a tumour-suppressor gene. Trends Biochem Sci 1999; 24(2): 73-6. 52. Pecina-Slaus N. Tumor suppressor gene E-cad­herin and its role in normal and malignant cells. Cancer Cell Int 2003; 3(1): 17. 53. Ohira T, Gemmill RM, Ferguson K, Kusy S, Roche J, Brambilla E, et al. WNT7a induces E-cadherin in lung cancer cells. Proc Natl Acad Sci USA 2003; 100(18): 10429-34. 54. Bonomi P. Matrix metalloproteinases and matrix metalloproteinase inhibitors in lung cancer. Semin Oncol 2002; (1 Suppl 4): 78-86. 55. Shih JY, Yang SC, Hong TM, Yuan A, Chen JJ, Yu CJ, et al. Collapsin response mediator protein-1 and the invasion and metastasis of cancer cells. J Natl Cancer Inst 2001; 93(18): 1392-400. 56. Raper JA. Semaphorins and their receptors in ver­tebrates and invertebrates. Curr Opin Neurobiol 2000; 10(1): 88-94. 57. Akashi T, Ito E, Eishi Y, Koike M, Nakamura K, Burgeson RE. Reduced expression of laminin al­pha 3 and alpha 5 chains in non-small cell lung cancers. Jpn J Cancer Res 2001; 92(3): 293-301. 58. Manda R, Kohno T, Niki T, Yamada T, Takenoshita S, Kuwano H, et al. Differential ex­pression of the LAMB3 and LAMC2 genes be­tween small cell and non-small cell lung carcino­mas. Biochem Biophys Res Commun 2000; 275(2): 440-5. 59. Hirsch FR, Franklin WA, Gazdar AF, Bunn PA Jr. Early detection of lung cancer: clinical perspec­tives of recent advances in biology and radiology. Clin Cancer Res 2001; 7(1): 5-22. Radiol Oncol 2005; 39(3): 211-7. Setup error and its effect on safety margin in conformal radiotherapy of the prostate Borut Kragelj Department of Radiation Oncology, Institute of Oncology, Ljubljana, Slovenia Background. In radiotherapy, setup errors in positioning the patients influence the size of safety margin and thereby also the size of irradiation field and toxicity of radiotherapy. Methods. The setup errors were calculated by evaluating the deviations from the measured distance be­tween the irradiation field margin and the bony pelvis. Results. The research was performed on 23 patients. With respect to lateral, craniocaudal and anteropos­terior axis, the observed systemic error ranged from -5 to + 9 mm, -4 to +5 mm, and from -4 to +4 mm, re­spectively, whereas the observed random error ranged from 0 to 7.5 mm, 0 to 3.6 mm, and from 0 to 4.2 mm, respectively. The safety margin, with the 90% probability to cover clinical target volume (CTV) and al­lowing for the prostate position variability, measured 9 mm, 9.5 mm, 7 mm, and 10 mm in the respective lateral, craniocaudal, anterior and dorsal direction. Conclusions. Irradiation of the prostate with a 7 mm dorsal safety margin, allowing for 90% coverage prob­ability of CTV, was feasible in 22/23 patients on condition that the gross systemic error (>3mm) was elim­inated. Key words: prostatic neoplasms; radiotherapy, conformal Introduction Due to acute and particularly chronic postir-radiation complications in radiotherapy of the prostate, the dose application, and conse­quently also the irradiation effect, are re- Received 15 August Accepted 31 August Correspondence to: Borut Kragelj, MD, PhD, Department of Radiation Oncology, Institute of Oncology, Zaloška 2, SI-1000 Ljubljana, Slovenia; Phone: +386 1 587 9489; Fax: +386 1 587 9400; E-mail: bkragelj@onko-i.si stricted. The incidence and grade of acute and chronic complications depend upon the dose and volume of the surrounding organs involved in the irradiation area.1-4 As the restrictions on dose application should in no way be disregarded, the irradia­tion of the prostate can be performed on con­dition that the beam is aimed as accurately at the target volume as possible. The size of the irradiation field is dependent on the width of safety margin around the target volume that ensures that the area to be irradiated is actu­ally or most probably irradiated. However, the more the safety margin is extended, the greater is the exposure of the surrounding or­gans to irradiation and consequently also the risk of therapy-related complications. In the radiotherapy of prostate cancer, the safety margin width is dependent upon the prostate motion and patient positioning er­rors. The aim of our research was therefore to estimate the setup errors, and from the ob­tained results, determine an optimal safety margin. Methods Patients The patients who were irradiated at our Institute in the period from September 2004 to March 2005 were included into the study. These patients were given radiotherapy as a unique treatment or as adjuvant treatment af­ter primary prostatectomy. Irradiation technique Irradiation was performed by a 15-MeV linear accelerator (Varian, Clinac 2100 C/D), using the four-field technique, at the angles of 0, 90, 180, and 270 degrees in the sense of 3D con­formal radiotherapy. Irradiation simulation was carried out on Philips CT MX 8000 multi-slice simulator. Target volumes were mapped using the program CMS Focal, whereas the program CMS Xio 4.2.0 was used for irradia­tion planning that was carried out by beam-eye-view technique. The fields were framed by multileaf collimator. The patients were irradiated in supine po­sition with the feet resting on a support cush­ion (Sinmed Feetfix support cushion) and the knees provisionally supported. The isocenter was defined by three spots – one on the ab­dominal wall and two lateral spots. The posi­tion of each patient was additionally marked on the isocenter plane by four lines (with re­spect to the patient’s axis, three longitudinal lines and one transversal line). Irradiation area Clinical target volume (CTV) included the prostate, seminal vesicles, and in the patients at high risk, also regional lymph nodes. The safety margin determining the planned target volume (PTV) was 1.5 cm wide; in the closing phase of radiotherapy, in which only the prostate was exposed to irradiation, the safe­ty margin was reduced to 1 cm, and on the dorsal side, to 0.7 cm. Irradiation precision Irradiation precision was tested by amor­phous silicon-based portal imaging system (EPI). The image was additionally processed by Varian’s vision software, version 6.1 that allows a precise computerized reconstruction of irradiation field borders. The setup error in patient positioning was calculated by comparing the distance be­tween the field margin and selected bony pelvic structures of the digitally reconstruct­ed radiographs (DRRs) obtained from the planning CT data and EPI. The display and comparison of images as well as measure­ments were made by computer program Multiaccess, version 8,00J0, Impac Medical Systems. Methods The setup error in patient positioning was de­fined by the deviations along the craniocau­dal, anteroposterior and lateral axis. All devi­ations in the cranial direction, to the right and anterior were marked as positive and the de­viations in the caudal direction, to the right and dorsum were marked as negative. In or­der to eliminate errors in deviation measure­ments, more measurements were performed yielding a higher mean value. Therefore, in fi­nal evaluations of safety margins, the inaccu­racy of measurements was neglected. From the above measurements, a systemic (SE) and a random setup error (RE) with re-spect to each of the three axes was calculated for each individual patient. Systemic error was defined as a mean deviation of a patient positioning from the isocenter and random error as a deviation of each individual meas­urement from the mean value. The size of random error was marked as 1SD. The sys­temic and random setup errors were then cal­culated for the entire group of patients. The systemic error for the entire group (SEeg) was defined as arithmetic mean of all individual systemic errors. In calculating the random error for the en­tire group (REeg), random deviations of indi­vidual SE from SEeg were also taken into ac­count. The size of the random component of SE was estimated by 1 SD (SDse) and derived from an even distribution of individual SE around SEeg. The size of RE was also consid­ered and was derived from an even distribu­tion of individual RE around arithmetic mean of individual RE (AM RE). The size of indi­vidual RE deviations from AM RE was also defined as 1 SD (SDam). Adding AM RE and 1.63 SDam, SDre was obtained with 95% probability that all RE were comprised in SDre. In the calculation of REeg, SDse and SDre were considered as independent param­eters. REeg, expressed as 1 SD, was obtained by the square root of SDse2+ SDre2.5 From the obtained systemic (SEeg) and random (REeg) setup errors, the size of safety margin was calculated in order to compen­sate for the errors in positioning the patient along each of the axis. Because of relatively high prevalence and severity of late rectal ra­diation toxicity, the anterior and posterior safety margins along the anteroposterior axis were calculated separately. The safety margin calculation by adding SEeg and 1.5 SD REeg was based on Goitein’s estimation6 that 1.5 SD is a sensible compro­mise between the risk of underdosing the tar­get volume and of excessive overdosing of the surrounding healthy tissue. This complies well with 90% confidence interval of random deviation in any of the directions. In further calculations of safety margin, the prostate po­sition variability was taken into account in addition to the setup error. For the assess­ment of the position variability of the prostate, Zelefsky’s data were used.8 The safety margin was calculated by adding the arithmetic mean of the prostate movements and SEeg and 1.5 SD of the combined ran­dom error, calculated according to Rudat’s recommendations, taking into account the random setup error as well as the random prostate movement error. The calculations of safety margins were made for each axis and separately for anterior and posterior direc­tions. Results The research was performed on 23 patients in whom altogether 95 measurements were made for evaluating the position of a patient during irradiation. In each patient, three to maximum five positioning measurements were carried out. The deviations along the lateral axis ranged from -10 to +12 mm, along the cranio-caudal axis from -7 to 6 mm, and along the anteroposterior axis from -11 to +5 mm. The systemic error along the lateral axis was with­in the range of -5 to 9 mm, along the cranio- Table 1. The range of the set up errors and the systemic and random components of the setup errors with respect to the direction of the positioning deviation Deviation - direction Lateral Craniocaudal Anteroposterior Setup error-range (mm) -10 do +12 -7 do +6 -11 do +5 Systemic error (mm) -5.0 do +9.0 -4.2 do +4.8 -4.4 do +4.2 Random error (1SD in mm) 0 do 7.5 0 do 3.6 0-4.2 Table 2. Systemic (SEeg) and random (REeg) setup errors with respect to the entire group of patients (23) and the direction of pisitioning deviation by presenting SEeg, AMRE, SDam, SDre Deviation - direction Lateral (mm) Craniocaudal (mm) Anteroposterior (mm) Systemic error (SE eg) +0.53 +0.17 -0.87 SDse (1SD ) 2.9 2.3 2.5 Random error (REeg) 5.1 4.1 4.9 AMRE 2.6 1.9 2.3 SDam 1.6 1.0 1.2 SDre 4.3 3.5 4.2 caudal axis -4.2 to +4.8 mm, and along the an-teroposterior axis -4.4. to +4.2 mm. The ran­dom error with the size of 1SD varied along the lateral axis from 0 to 7.5 mm, along the craniocaudal axis from 0 to 3.6 mm, and along the anteroposterior axis from 0 to 4.2 mm (Table 1). The calculated systemic error for the entire group along the lateral, craniocaudal, and an-teroposterior axis was +0.57 mm, +0.17 mm, and -0.87 mm, respectively. The random error for the entire group in the lateral, craniocau­dal, and anteroposterior axis was 5.1 mm, 4.1 mm and 4.9 mm, respectively. The two errors (SEeg and REeg) as well as SDse, AM RE, SDam, and SDre are presented in Table 2. The safety margin (SM) that would, with a 90% probability, cover an inaccurate positioning of a patient with respect to the lateral and cran­iocaudal axis is 8.2 mm and 6.3 mm, respec­tively, and with respect to the anteroposterior axis, 6.5 mm towards the anterior and 8.3 mm posteriorily. The safety margin that would, in addition to the setup errors, compensate also for the prostate position variability (SM total) along the lateral and craniocaudal axis with the same confidence interval is 9.2 mm and 9.5 mm, respectively, and along the antero-posterior axis, 6.7 mm towards the anterior and 10.3 mm posteriorily (Table 3). Discussion The aim of this study was to determine an ad­equate safety margin that would allow an ac­ceptable exposure of a target area to irradia­tion. The difficulties of the prostate cancer patient radiotherapy that make this therapy unreliable are the prostate position variability as well as inaccuracy in all subsequent repo­sitionings of the patient in the initial pose. Monitoring the variability of prostate posi­tion is an exacting task, and so far, it has not been performed at our Institute. So, the size of safety margin, and thereby also the precision of irradiation, is dependent merely on the pre­cision in repositioning the patient in the initial irradiation position. In comparing our data on the patient repositioning precision to the pub­lished data, it may be concluded that our pre­cision was tolerably satisfactory. As reported by Rudat,5 the random error along the lateral, craniocaudal, and anteroposterior axis was 3.1 mm, 5.4 mm, and 4.9 mm, respectively. In our patients, the random error calculated by using a similar method, was 3.9 mm, 2.9 mm, and 3.5 mm, respectively. In the study by Song, the data on the deviations greater than 5 mm in 40% of repositionings of his patients9 also speak in favor of the satisfactory preci­sion in repositioning of our patients. Table 3. Safety margin depending on the setup error (SM) in conjunction with the prostate position variability (SMtotal) Direction Lateral Craniocaudalni Anterior Posterior SM (mm) 8.2 6.3 6.5 8.3 SM total (mm) 9.2 9.5 6.7 10.3 The safety margin was calculated from the measurements of setup errors (in positioning of our patients) and from the data published on the prostate position variability. Our cal­culated safety margin – approximately 1 cm in all directions – is similar to the margins re­ported by various authors of the studies on prostate irradiation, except for the margin on the dorsal side, which was allowed to be smaller than 1 cm.10 However, if the safety margin of less than 1 cm is not coordinated with the prostate position variability and set­up error, the coverage of CTV may not be suf­ficient - according to Zelefsky, in the patient in prone position and at a safety margins of 1 cm in the anterior lateral and craniocaudal directions and of 0.6 cm at the dorsal side, the coverage of CTV at the dorsal side is 85 % before and 96% after the corrections for set­up error and prostate displacement.8 In our patients, the coverage of CTV can be evaluat­ed only indirectly, by assessing the involve­ment of CTV dependent exclusively on the setup errors. The results are shown in Figures 1-3. The 90% probability of CTV coverage of the irradiation field at the safety margin of 1 cm along the lateral axis is achieved in 91% of patients, and in cranial and caudal directions in 91 % and 87% of patients, respectively, and on the anterior and posterior side in 96 % and 78 % of patients, respectively on side. By re­ducing the dorsal margin to 0.7 cm, the 90% probability of CTV involvement in the irradi­ation field would be obtained only in 74% of patients. The irradiation precision may not be im­proved either by changing the patient posi­tion or by additional support using various positioning aids. The prone position during irradiation may helps to reduce the exposure of the rectum to irradiation;8,11 however, there is no data proving that this position can improve the positioning precision, given that it somehow deprives the patient of comfort during irradiation. Additional disadvantage of the prone position is that, in this position, Table 4. Systemic and random setup errors in patients with less than 90 % probability of CTV cover­age and the direction of the setup errors Direction Patient’s no. Systemic Random error mm error mm Right 16 9 2 19 0.3 7.5 Left 15 5.0 5.8 19 0.3 7.5 Cranial 8 4.8 1.5 20 3.0 2.9 Caudal 6 3.8 2.9 14 1.8 3.3 23 3.7 2.3 Anterior 1 3.2 2.4 Posterior 5 6.4 3.5 15 3.5 4.2 20 4.4 4.2 Posterior 3 3.7 2.3 (0.7cm) 8 4.2 2.9 18 1.2 3.9 urethrography is hard to perform and, hence, the apex of the prostate cannot be reliably lo­cated. Considering the precision of the pa­tient positioning, even the use of support cushions may be questionable. Comparing different support systems, Song reported that a similar percentage of most evident errors, approx. 40%, was made in positioning the pa­tients by using any type of support as in posi­tioning them with no support at all.9 On the other hand, a better irradiation pre­cision may be achieved by eliminating most apparent systemic errors (Table 4). By deter­mining the systemic and random positioning errors, it is possible to asses an appropriate safety margin and, by eliminating the sys­temic error, the probability of CTV involve­ment into the irradiation field may increase. By correcting the systemic error, due to which the probability of involving CTV along one of the axes during the positioning was lower than 90%, an adequate CTV coverage may be obtained along the lateral axis in 96% of pa­tients, in the cranial and caudal directions, in 100% and 96%, respectively, and along the an-teroposterior axis, in 100% of patients. In cas­es when the dorsal safety margin is reduced to 0.7 cm, the correction of the most evident systemic error may help to achieve an ade­quate exposure of CTV to irradiation in as much as 96% of patients. In that case, the cor­rection of isocenter would be required in 10/23 patients. From the estimates of systemic and ran­dom error, it is possible to identify the pa­tients in whom CTV would have been includ­ed in the irradiation field with 90% probabili­ty provided that the systemic error had been eliminated and the patients in which the esti­mated exposure of CTV to irradiation would have been obtained only by increasing the safety margin. By redefining the isocenter, which would be required in almost half of our patients, an optimal exposure of the most critical part of the prostate to irradiation, i.e. of the dorsal part, would be obtained in 22/23 patients, even though the safety margin was reduced to 0.7 cm. References 1. Fiorino C, Sanguineti G, Cozzarini C, Fellin G, Foppiano F, Menegotti L, et al. Rectal dose-volume constraints in high-dose radiotherapy of localized prostate cancer. Int J Radiat Biol Phys 2003; 57: 953­62. 2. Bauman G, Rodrigues G. In regard to Fiorino et al. Rectal dose-volume constraints in high-dose radio­therapy of localized prostate cancer. Int J Radiat Biol Phys 2004; 59: 912-4. 3. Harsolia AR, Vargas CE, Kestin LL, Yan D, Brabbins DS, Lockman DM, et al. Predictors of chronic urinary toxicity following treatment of prostate cancer with 3D conformal radiotherapy: Dose volume analysis of a phase II dose escalation study. [abstract]. Int J Radiat Biol Phys 2004; 60(Suppl 1): S437-8 4. Wallner KE, Merrick GS, Benson ML, Butler WM, Maki J, Tollenaar BG. Penile bulb imaging. Int J Radiat Biol Phys 2002; 53: 928-33. 5. Rudat V, Schraube P, Oetzel D, Zierhut D, Flentje M, Wannenmacher M. Combined error of patient positioning variability and prostate motion uncer­tainty in 3D conformal radiotherapy of localized prostate cancer. Int J Radiat Biol Phys 1996; 35: 1027-34. 6. Goitein M. Nonstandard deviations. Med Phys 1983; 10: 709-11. 7. Zelefsky MJ, Happersett L, Leibel SA, Burman CM, Schwartz L, Dicker AP, et al. The effect of treatment positioning on normal tissue dose in pa­tients with prostate cancer treated with three-di­mensional conformal radiotherapy. Int J Radiat Biol Phys 1997; 37: 13-9. 8. Zelefsky MJ, Crean D, Mageras GS, Lyass O, Happersett L, Ling CC, et al. Quantification and predictors of prostate position variability in 50 pa­tients with multiple CT scans during conformal ra­diotherapy. Radiother Oncol 1999; 50: 225-34. 9. Song PJ, Washigton M, Vaida F, Lyass O, Happersett, Ling CC, et al. A comparison of four patient immobilization devices in the treatment of prostate cancer patients with three dimensional conformal radiotherapy. Radiother Oncol 1999; 50: 225-34. 10. Zelefsky MJ, Valicenti RK, Goodman K, Perez CA. Prostate cancer. Perez CA, Brady LW, Halperin EC, Schmidt-Ullrich RK, editors. Principles and 4th practice of radiation oncology. edition. Philadephia: Lippincot, Williams and Wilkins; 2004. p. 1692-762. 11. Bayley AJ, Catton CN, Haycocks T, Kelly V, Alasti H, Bristow R, et al. A randomized trial of supine vs. Prone positioning in patients undergoing esca­lated dose conformal radiotherapy for prostate cancer. Radiother Oncol 2007; 70: 37-44. Radiol Oncol 2005; 39(3): 219-24. case report Missing tissue compensation with wax filter compensators in radiotherapy of the head and neck region Daša Grabec, Primož Strojan Institute of Oncology Ljubljana, Ljubljana, Slovenia Background. In the conventional radiotherapy of the head and neck region, the inhomogeneity of the ab­sorbed dose in certain clinical situations can exceed ? 5% of the nominal dose. Depending on the pattern of dose inhomogeneity, treatment related toxicity is more pronounced and disease control reduced. The aim of our report is to present the wax filter compensation technique used in our department. Case report. A 46-year-old male with inoperable carcinoma of the oropharynx of clinical stage T3N2c was irradiated with 5 MV linear accelerator photon beams and conventional 3-field technique. In order to obtain more homogenous dose distribution in treated volume, the opposed lateral fields were modified using 2D­wax filter compensators. Results. Using conventional wedge filter compensation, the planed absorbed dose deviations in the treated volume were in the range of 94% to 113% of the prescribed dose. By modification of the opposed lateral fields with 2D wax filter compensators, the variations of the absorbed dose were reduced to the range from 93% to 105% of the prescribed dose. In the article, the planning and manufacturing as well as dosimetric checking of wax filter compensators are described. Conclusions. With the use of 2D wax filter compensators, the inhomogeneity of absorbed dose distribution was significantly reduced, and the quality of treatment considerably improved. Key words: head and neck neoplasms-radiotherapy; radiotherapy dosage Received 8 January 2005 Accepted 10 March 2005 Correspondence to: Daša Grabec, PhD, Radiophysics Unit, Department of Radiotherapy, Institute of Oncology Ljubljana, Zaloška 2, SI-1000 Ljubljana, Slovenia; Phone: +386 1 5225238; Fax: +386 1 4319108; E-mail: dgrabec@onko-i.si Acknowledgement This work was supported by the Ministry of Science and Technology of Republic Slovenia, Grant No. Z3­6144-0302-04/3.04. Introduction The conventional teleradiotherapy technique for head and neck tumors consists of two op­posing lateral fields, encompassing primary tumor and upper neck lymphatics, and one anterior field to cover the lower neck and supraclavicular regions. To provide a homog­enous dose distribution, the most elementary compensation technique is the wedge com­pensation of lateral fields. Even though, the precalculated variations of the delivered dose inside of the target volume can, in certain cas­es, highly exceed ± 5 % of the nominal dose as recommended by ICRU.1,2 The following two factors contribute to the inhomogeneity: (1) the difference in the amount of tissue be­tween different levels inside of the head and neck region that is more pronounced in thin patients and after extensive neck surgery (“geese neck”); (2) the difference in the tissue structure, i.e. different electronic tissue den­sity of various structures in the head and neck region (bones, soft tissue, air cavities). Both, the volume and the position of the low/high dose regions, together with the lev­el of variations from the nominal (reference) dose, can significantly compromise the quali­ty of treatment. »Hot spots« result in more pronounced acute side effects of irradiation, which could influence the scheduled radio­therapy course, and consequent late toxicity could importantly decrease the patient’s qual­ity of life during post-treatment period. In ad­dition, »cold spots« reduce the probability for controlling the disease and, therefore, the pa­tient’s chance for cure. When absorbed dose inhomogeneities in the treated region are considered to be unac­ceptable, the need for more sophisticated compensational technique emerges.3 The compensation technique should be chosen according to the individual clinical situation and technical and logistic possibilities in par­ticular radiotherapy department. When the full skin-sparing effect of megavoltage treat­ment beam is desirable, the use of filter com-pensators is indicated.4 The filter compensator material is chosen according to the electron density of the mate­rial and according to the quality of irradiating beam.5 The filter compensator material should also not significantly change the beam quality.6 Several studies showed that wax can be successfully used as a material for filter compensators.5 The required dose reductions for compensating purposes are usually up to 20 %. For 5 MV photon beam that is achieved using approximately around 5 cm of wax. The aim of our report is to present the wax filter compensation technique used in our de­partment. Case report A 46-year-old male with inoperable carcino­ma of the oropharynx of clinical stage T3N2c was referred to the Department of Radiotherapy at the Institute of Oncology Ljubljana, Slovenia, for curative treatment with radiotherapy. The patient was simulated on conventional simulator with CT option (Philips SLS-CT). Irradiation technique con­sisted of two opposed lateral fields (270° and 90°: 11.5 cm × 13.5 cm) to cower the region of primary tumor and upper neck lymphatic basins, and one anterior field (0°: 21 cm × 9 cm) to cower lower neck and supraclavicular regions. The parts of the fields to be spared of Figure 1. The simulator film of the right lateral field (270i). The positions of the CT images are indicated (central slice, through the isocenter; upper slice, 1.5 cm above the isocenter; lower slice, 4 cm below the isocenter). The blocked regions and the high dose re­gion that should be compensated are delineated. The three phases of the photon treatment are indicated: the whole treatment volume up to 46 Gy, avoiding medulla from 46 to 60 Gy and boost to gross disease from 60 to 70 Gy. Figure 2. The optimized dose distribution was calcu­lated using three CT slices (see Fig. 1). Applying only wedge filter compensators, the calculated inhomoge­nieties inside the treated volume were significant. The regions of different absorbed doses, expressed in the percentage of prescribed dose, are colored: 95 % = green <100 %; 100 % = red <105 %, 105 % = blue <110 %, 110 % = purple < 115 %. On the central slice (through isocenter), the dose varied from 95% to 100% of prescribed dose. On the lower slice (4 cm below isocenter), the ab­sorbed dose exceeded 110% of the prescribed dose. On the upper slice (1.5 cm above isocenter), the ab­sorbed dose hardly reached 95 % of the prescribed dose. The planed overall inhomogeniety range apply­ing only wedge filter compensators was 19 % of the prescribed dose. Figure 3. Applying the 2D paraffin wax filter compen­sator, the optimized dose distribution was calculated. In the high-dose region, the filter compensator was in­troduced as a block of 85% transmission. Dose distri­bution is presented on the same slice levels as on Fig.1 (central slice, +1.5 cm, - 4 cm). As the result, the dose distribution is much more homogenous as it was ap­plying only wedge filter compensators (Fig.2). At the central slice, the absorbed dose is almost homogenous (100% of the prescribed dose), at the lower slice, the maximum dose hardly reaches the 105%, and it ranges from 93% to 100% of the prescribed dose on the upper slice. irradiation were delineated on simulator film. The three CT slices were taken at three dif­ferent levels: central slice (through isocenter); upper slice, 1.5 cm above the isocenter; lower slice, 4 cm below the isocenter (Figure 1). The treatment was carried out in three phases. Phase 1: using 5 MV linear accelera­tor photon beams and 2 Gy daily fractions up to 46 Gy. Phase 2: from 46 Gy to 60 Gy; the lateral fields were shielded in the region of spinal cord which was boosted with 9 MeV electron beams. Phase 3: boost to gross dis­ease to cumulative dose of 70 Gy The optimal use of wedge filters and the ir­radiation times for each individual field were calculated with 2D planning algorithm with correction for tissue electron density (Multi-Data DSS, Multidata System International Corp., St. Louis, Missouri, USA). Applying wedge filters only, the planed inhomo­geneities inside the treated volume covered with the opposed lateral fields ranged from 94% to 113% of the prescribed dose. In this particular clinical situation, the de­gree of dose inhomogeneity (19%) indicated the use of compensator. The bolus type com­pensator was not suitable because we wished to preserve the skin sparing effect of mega-voltage photon beams. Therefore, the use of 2D wax filter compensator was indicated. The region of dose compensation (the »high dose« area) was indicated on the film as shown on Figure 2. The optimal dose compensation of the high dose region was calculated using the MultiData DSS planning system. The com­pensated region was introduced into the planning system as a block of a certain trans­mission T. The optimized transmission of the compensated region was found to be 85%, as shown on Figure 3. With the compensation of high-dose region, we could prolong the irradi­ation time of each individual opposed lateral field by 5%, thereby also increasing the deliv­ered dose to previously low-dose regions. Figure 4. The foam blocks with blocking filters made of Wood alloy and filter compensators made of paraf­fin wax, were manufactured for each of the lateral op­posed fields (gantries 270i and 90i). The central hole was drilled in each of the foam block in order to see the center of the optical fields. The positioning holes were drilled in the corners of the blocks. The 30 × 30 × 8 cm3 foam blocks had to be cut to the suitable di­mension for Philips SL 75/5 linear accelerator, i.e. to 21 × 30× 8 cm3. The foam blocks were fixed on the po­sitioning trays, ready to use. The paraffin wax compensator filter assembling technique The negative cut of the individual blocking filter and the negative cut of the compensator filter were milled in the previously calibrated 8 cm thick foam blocks (block dimensions: 30 cm × 30cm × 8cm) by the computer-guided milling machine (ACD – 5, Par Scientific, Denmark). For the selected field, both negatives, that of the blocking filter and that of the compen­sator block, were cut in the same foam block. For the blocking filters, the Wood alloy is used because of its high electronic density. For the same reason, Wood alloy is not suit­able as the compensator material. To increase compensating precision, the paraffin wax was used as the compensator material. The negative cuts of the compensated and blocked regions were separated from each other with thin paper wall. First, the blocking region was filled up with the Wood alloy, and consequently, as soon as the Wood alloy so-lidified, the region of compensating filter was filled with the liquid paraffin wax. In order to irradiate at gantry 270° and 90° (opposed lateral fields), the foam blocks with shieldings and compensators were fixed on the holding trays as can be seen on Figure 4. As the largest dimension of the foam blocks fixed on the holding trays, used in irradiation, is 21 × 30 × 9 cm3, the foam blocks of original dimensions 30 × 30 × 8 cm3, had to be cut off (the original dimensions just at the end of the positioning holes = 21 cm). The central hole was drilled in the center of the foam, allowing for the center of the irradiating field and the position of the blocks and compensator to be verified. Dosimetry Prior to the irradiation of the patient, the fil­ter compensators were checked by dosimetry of filtered beam. The delivered dose was also measured in vivo during the irradiation.7 For dosimetry checks, the micro-rod thermolumi­nescence dosimeters LiF:Mg:Ti (TLD 100) were used.8 Preheated TLD micro-rods were calibrated with 5 MV photon beam. Two TLDs were placed in the centre of the plastic water block (which simulated the patient’s head) and were irradiated with two opposed lateral fields. The beams set-up conditions were the same as planned for the treatment without compensators. The response for the delivered dose of 197 cGy in the center of plastic block was measured. Next, prior to patient treatment, the plastic water block with calibrated TLDs was irradi­ated according to the treatment plan, using shields and compensators. With applying compensators, we could increase the overall irradiation time and simultaneously the dose delivered at isocenter. The dose measured at the center of the plastic water block was 200 cGy. As it was the same as planned dose, we Figure 5. In vivo dosimetry is performed with the pre­heated and calibrated LiF:Mg:Ti micro-rod thermo-lu­minescence dosimeters (TLD - 100). TLD were placed in the tubes, covered with the 1.5 cm thick jelly and fixed on the patient. The delivered dose measured in the centers of the lateral opposed fields were 208 cGy on the left patient side and 197 cGy on the right pa­tient side (104% and 98.5% of the planned dose, re­spectively). The delivered dose in the center of the compensated region on the left patient side was 189 cGy, 94.5% of the prescribed dose. Without the com­pensation, the dose absorbed in this region would be in the range from 210 cGy to 220 cGy (from 105% to 110% of the prescribed dose 200 cGy). agreed that the filter compensator was appro­priate for clinical use. In vivo TL dosimetry was preformed twice during the irradiation. The first in vivo meas­urement was preformed on day 1 of the radio­therapy course. The two TL dosimeters were placed under the 1.5 cm thick jelly bolus in the center axis of each of the two opposed lateral fields. The delivered doses in the center of the irradiation fields were 208 cGy on the left and 197 cGy on the right patient’s side (i.e. 104% and 98.5% of the planned dose, respectively). The second measurement was done in the region of the compensated dose. On the left patient’s side, the measured dose in the cen­ter of the compensated region was 189 cGy, 94.5% of the prescribed dose. Without the compensation, the dose absorbed in this re­gion would be in the range from 210 cGy to 220 cGy (from 105% to 110% of the prescribed dose 200 cGy). On the right patient’s side, the dosimeter was placed too close to the blocked region and revealed the dose in the penumbra region. The in vivo dosimetry of the compen­sated region is presented on Figure 5. The dose reduction was measured also with film dosimetry. The portal image condi­tions (5 monitor units [MU], open field; 3 MU, shielded field) were simulated with the plan­ning system. The portal image was calibrated and used for the dose measurements. The overall delivered dose was in the range of 3% of the planned dose, whereas in the region of the dose lowered by the filter compensator the measured dose did not differ for more than 2 % from the planned dose. Conclusions Our method of missing tissue compensation using wax filter compensators proved to be precise enough to meet the expectations in clinical setting. Even though the manufactur­ing process of wax filter compensators is driv­en by computer-guided machinery, it is time consuming and should be properly scheduled and planned in advance. Anyhow, the quality of treatment was considerably improved. References 1. ICRU report 50. Prescribing, recording and report­ing photon beam therapy. Bethesda: International Commision on Radiation Units and Measu­rements; 1993. 2. ICRU report 62. Prescribing, recording and report­ing photon beam therapy (supplement to ICRU 50). Bethesda: International Commision on Radiation Units and Measurements; 1999. 3. Redpath AT, McNee SG. Treatment planning for external beam therapy: advanced techniques. In: Williams JR, Thawaites DI, editors. Radiotherapy physics in practice. Oxford: Oxford University Press; 2000. p. 180-204. 4. PurdyJA, Klein EE. External photon beam dosime­try and treatment planning. In: Perez CA, Brady LW, editors. Radiation oncology. Philadelphia: Lippincott-Raven Publishers; 1997. p. 281-320. 5. Lim MLF. Principles and Practice of Clinical Physics & Dosimetry. Madison: Advanced Medical Publishing; 2005. 6. Spezi E, Lewis DG, Smith CW. Monte Carlo simu­lation and dosimetric verification of radiotherapy beam modifiers. Phys Med Biol 2001; 46: 3007-2.9 7. Mayles WPM, Heisig S, Mayles HMO. Treatment verification and in vivo dosimetry. In: Williams JR, Thawaites DI, editors. Radiotherapy physics in prac­tice. Oxford: Oxford University Press; 2000. p. 220­46. 8. McKinlay AF. Thermo-luminescence dosimetry. Bristol: Adam Hilger Ltd; 1981. Radio/ Oncol 2005; 39(3): 171-5. Endoluminalni ultrazvok pri ugotavljanju ponavljajocih analnih fistul Sudol-Szopinska I, Jakubowski W, Kolodziejczak M, Szopinski T, Panorska AK Izhodišca. Namen raziskave je bil primerjati endoluminalno ultrazvocno preiskavo brez kon­trastnega sredstva in s kontrastnim sredstvom pri ugotavljanju ponavljajocih in primarnih anal­ nih fistul. Metode. V letih 1999-2002 smo pri 148 bolnikih ugotovili analno fistulo. Med njimi je bilo 51 bol­nikov, ki so imeli ponavljajoco fistulo, 97 pa jih je imelo primarno. Endoluminalne ultrazvocne preiskave smo opravljali z Brnel & Kjaer skenerjem in 7,0 MHz sondo. Preiskavi brez kontrast­nega sredstva je sledila preiskava s kontrastnim sredstvom, kjer smo uporabili 3% raztopino hidrogenega peroksida. Nato smo primerjali izsledke obeh preiskav. Rezultati. Pri ugotavljanju ponavljajocih fistul je bila ultrazvocna preiskava, kjer smo uporabili kontrastno sredstvo, 35,3% bolj natancna kot preiskava brez kontrastnega sredstva (95% inter­val zaupanja 50,5% -20,19%). Pri ugotavljanju primarnih fistul je bila razlika le 4,5% (95% inter­val zaupanja 11,1 % -2,0%). Zakljucki. Endoluminalna ultrazvocna preiskava s kontrastnim sredstvom statisticno znacilno izboljša natancnost glede na preiskavo brez kontrastnega sredstva pri ugotavljanju ponavlja­jocih analnih fistul. Pri ugotavljanju primarnih analnih fistul pa so rezultati obeh preiskav primerljivi in nismo našli znacilne razlike. Radio/ Oncol 2005; 39(3): 177-80. Diagnosticiranje in kirurško zdravljenje retrorektalnih cist -opis petih primerov Kolodziejczak M, Grochowicz M, Sudol-Szopiriska I, Kosim A, Stefariski R Izhodišca. Retrorektalne ciste so redka bolezen, pravtako so redke objave, ki opisujejo to bolezen. Obicajno porocajo le o nekaj primerih. Metode. Avtorji opisujejo 5 bolnikov, ki so jim diagnosticirali retrorektalne ciste. Bolezen so ugo­tovilili s pomocjo anamneze, klinicnega pregleda in transrektalnega ultrazvoka. Ciste so opera­tivno perinealno odstranili. Rezultati. Pri treh bolnikih je bila histološka diagnoza epidermalna cista. Pri cetrtem bolniku so ugotovili, da je bila cista epitelizirana z migetalcnim epitelijem, pri zadnjem pa so odkrili kost­no, mašcobno in vezivno tkivo kot del vnetnega stanja. Zakljucki. Digitalni rektalni klinicni pregled je osnovni pregled pri diagnosticiranju retrorek­talne ciste. Transrektalni ultrazvok je potreben za bolj natacno opredelitev velikosti ciste in lege glede na steno rektuma. Perinealna retrorektalna cistektomija je ucinkovita metoda pri zdravl­jenju te bolezni. Dosedanji objavljeni primeri bolezni pa so maloštevilni, zato so lahko zakljuc­ki le preliminarni. Radio/ Onco/ 2005; 39(3): 181-4. Komunikacijska sakularna piloroduodenalna podvojitev -prikaz primera Sjekavica I, Batinica M, Lušic M, Senecic-Cala I, Oberman B, Štern-Padovan R Izhodišca. Podvojitvene anomalije piloroduodenalne regije so redke. Ob crevesnih podvojitvah obicajno ugotovimo še dodatne malformacije. Prikaz primera. Opisujemo primer piloroduodenalne podvojitve pri 22-mesecni deklici, kjer so bili prvi bolezenski znaki intermitentne slabosti in bruhanje. Ultrazvocna preiskava je pokazala anehogeno cisticno spremembo med želodcem in levim jeternim režnjem. Preiskava zgornjega crevesa s kontrastom je pokazala stenozo v pilorobulbarni regiji kot posledico zunanjega pri­tiska. Na cisticno podvojitev v prebavnem traktu s pritiskom na glavo pankreasa smo posumili ob preiskavi z veclistnim CT-jem s kontrastom. Med opracijo pa smo s kontarstom ugotovili ko­munikacijo med podvojitvijo in pilorno regijo. Patohistološka preiskava je potrdila podvojitveno cisto, ki je vseboval želodcno in duodenalno mukozo brez ektopicnega pankreaticnega tkiva. Zakljucki. Ultrazvocna preiskava je prva slikovna preiskava pri ugotavljanju crevesnih podvo­jitev in obicajno pokaže cisticno anehogeno spremembo. Dodatne preiskave: rentgenska preiskava z barijem, kontrastna preiskava s CT-jem ali MRI-jem nam lahko pomagajo bolj natancno diagnosticirati podvojitve v prebavnem traktu. Radio/ Oncol 2005; 39(3): 185-91. Ugotavljanje koronarne kalcifikacije pri miokardnem infarktu Bešlic š, Dalagija F Izhodišca. Namen raziskave je bil ocenitev pomembnosti ugotavljanja koronarne kalcifikacije kot dejavnika tveganja pri bolnikih z miokardnim infarktom. Metode. V obdobju treh let smo pri 27 bolnikih z miokardnim infarktom ugotavljali stopnjo ko­ronarne kalcifikacije. Povprecna starost bolnikov je bila 66,1 let (46-81). Za merjenje kalcija v ko­ronarnih arterijah smo uporabljali vecrezno racunalniško tomografijo (MTDC) »Somatom Volume Zoom Siemens« in retrospektivno obdelali podatke glede na z EKG-jem merjen srcni ritem. Polavtomatsko smo izracunali kolicino kalcija po Agatstonu (CS). Uporabljali smo 4 x 2,5 mm veliki kolimator in 130 ml kontrastnega sredstava, ki smo ga vbrizgali z avtomatskim in­jektorjem s hitrostjo 4 ml/s. Empiricno smo dolocili zakasnitveni cas. Ocenili smo tudi razlicne dejavnike tveganja za miokardni infarkt. Rezultati. Med 27 bolniki z miokardnim infarktom so 3 (11,1 %) imeli nizek CS (10-100), 5 (18,5%) sreden CS (101-499), 19 (70,4%) bolnikov pa je imelo visok CS (>500). Ko smo ugotavl­jali druge dejavnike tveganja za miokardni infarkt, smo ugotovili, da je bilo 17 (63,0%) bolnikov kadilcev, 10 (57,0%) bolnikov je imelo povišan arterijski krvni tlak, 7 (25,9%) sladkorno bolezen, 5 (18,5%) srcno bolezen v družini, 5 (18,5%) zvišane lipide v krvi, 4 (1,8%) pa so bili alkoholiki. Le šest (22,2%) bolnikov je navajalo simptome angine pektoris. Zakljucki. Raziskava je pokazala veliko soodvisnost miokardnega infarkta in stopnje kalci­fikacije koronarnih arterij (CS>500). Tudi v naši skupini preiskovanih bolnikov smo ugotovili vecjo prisotnost preostalih dejavnikov tveganja za miokardni infarkt, kot so kajenje, zvišanje ar­terijskega krvnega tlaka, sladkorna bolezen, miokarni infarkt v družini in povišan holesterol v krvi. Pri vecini bolnikov pa nismo ugotovili izrazitih simptomov. Radio/ Oncol 2005; 39(3): 193-6. Karcinoid tankega crevesa z akutno krvavitvijo, ki smo ga diagnosticirali s kapsulno endoskopijo Mrevlje Ž, Sever M, Kocijancic B Izhodišca. Karcinoid tankega crevesa obicajno diagnosticiramo zaradi njegovih endokrinoloških simptomov, saj redko mocneje krvavi. Prikaz primera. Predstavljamo primer bolnika z nepojasnjeno krvavitvijo iz prebavil. S stan­dardnimi diagnosticnimi preiskavami nismo ugotoviti mesta krvavitve. S kapsulno endoskopijo smo ugotovili manjši tumor tankega crevesa, ki je bil vzrok krvavitve. Patohistološki pregled po kirurški resekciji je pokazal karcinoid tankega crevesa. Zakljucki. Kapsulna endoskopija je pomembna preiskava tankega crevesa in jo moramo upoštevati kot eno prvih preiskav pri ugotavljanju zacetnih oblik bolezni, še zlasti pri neizrazi­tih in okultnih krvavitvah. Radio/ Onco/ 2005; 39(3): 197-210. Molekularna biologija pljucnega raka Panov SZ Izhodišca. Pljucni rak je najpogostejše maligno obolenje in tudi glavni vzrok smrti rakavih bol­nikov. Neverjeten napredek pri poznavanju etiopatogeneze pri raku pljuc sta doprinesli moleku­larna biologija in genetika z moderno tehnologijo mikromrež in sekveniranja. Številne raziskave so ugotovile, da je kljub klonalnemu nastanku pljucnega raka potreben vecstopenjski proces z vec kot 20 razlicnimi genetskimi ali epigenetskimi spremembami. Do sedaj najpogosteje raziskovana podrocja so mutacije in druge genetske spremembe na onko­genih in na tumor supresorskih genih. V zadnjem casu je vse vec raziskav usmerjenih v ugo­tavljanje pridobljenih okvar na tumor supresorskih genih s hipermetilacijo promotorske regije. Poleg tega sedaj odkrivajo tudi zgodnje klonalne spremembe, ki nastajajo na preneoplasticnem bronhialnem epiteliju kot posledica kajenja ali drugih karcinogenov. Poznanih je že tudi veliko razlik na molekularni ravni med drobnocelicnimi in nedrobnocelicnimi karcinomi, ugotavljajo pa tudi razlike med tumorji z razlicnim biološkim potekom bolezni. Te raziskave vodijo v temeljitejše poznavanje biologije pljucnega raka. Zakljucki. Pricakujemo lahko, da bodo take raziskave doprinesle k boljši diagnostiki pljucnega raka, kot tudi boljšemu ocenjevanju tveganja, zgodnji prevenciji in novim prostopkom ucinkovitega zdravljenja bolnikov s pljucnim rakom. Radio/ Onco/ 2005; 39(3): 211-7. Napaka nastavitve bolnika in njen vpliv na varnostni rob pri konformnem obsevanju prostate Kragelj B Izhodišca. Napake pri nastavitvi položaja bolnikov med obsevanjem dolocajo velikost varnost­nega roba in s tem tudi velikost obsevalnih polj. Metode. Napako pri nastavitvi bolnikov smo ugotavljali z merjenjem odmikov robov obsevalne­ga polja od kosti medenicnega obroca. Rezultati. V raziskavo je bilo vkljucenih 23 bolnikov, pri katerih je bila glede na lateralno, kran­iokaudalno in anteroposteriorno os ugotovljena sistematska napaka od -5 do +9 mm, -4 do +5 mm in -4 do +4 mm ter nakljucna napaka od O do7,5 mm, 0-3,6 mm ter 0-4,2 mm. Varnostni rob za 90% verjetnost zajetja klinicnega tarcnega volumna (CTV) z upoštevanjem tudi gibanje prostate je bil 9 mm v lateralni, 9,5 mm v kraniokaudalni, 7 mm v anteriorni in 10 mm v dorzal­ni smeri. Zakljucek. Obsevanje prostate s 7 mm dorzalnim varnostnim robom je možno z odpravo izrazite sistematske napake(>3 mm), pri cemer je dosežena 90% verjetnost zajetja CTV pri 22/23 bol­nikov. Radio/ Oncol 2005; 39(3): 219-24. Vošceni filterski kompenzatorji pri obsevanju tumorjev glave in vratu Grabec D, Strojan P Izhodišca. Ob uporabi konvencionalne radioterapije podrocja glave in vratu lahko odstopanja absorbirane doze od predpisane presežejo ± 5%. Vzorec dozne nehomogenosti lahko vpliva na stopnjo izraženosti obsevalnih poškodb in uspeh zdravljenja. V clanku želimo predstaviti uporabo vošcenih filterskih kompenzatorjev na Onkološkem inštitutu v Ljubljani. Prikaz primera. 46-letni bolnik z neoperabilnim karcinomom ustnega žrela klinicnega stadija T3N2cM0, je bil obsevan na linearnem pospeševalniku s fotonskim snopom energije 5MV in konvencionalno tehniko treh polj. Za dosego vecje stopnje homogenosti razporeditve doze v ob­sevanem volumnu, sta bili nasprotno ležeci lateralni polji modificirani z vošcenima 2D-filtrski­ma kompenzatorjema. Rezultati. Ob uporabi konvencionalne kompenzacije s klinastimi filtri je znašalo predvideno odstopanje absorbirane doze znotraj obsevalnega volumna med 94% in 113% predpisane doze. Z modifikacijo nasprotno ležecih lateralnih polj z vošcenima 2D filtrskima kompenzatorjema se je zmanjšalo nihanje absorbirane doze na vrednosti od 93% do 105% predpisane doze. V clanku predstavljamo nacrtovanje obsevanja z vošcenimi filtrskimi kompenzatorji, njihovo izdelavo, ter rezultate dozimetricnega preverjanja pred in med obsevanjem. Zakljucki. Z uporabo 2D-vošcenih filtrskih kompenzatorjev smo uspeli znatno zmanjšati neho­mogenost v porazdelitvi absorbirane doze, s tem pa obcutno izboljšali kakovost zdravljenja. Notices Notices submitted far publication should contain a mailing address, phone and/ or fax number and/ or e-mail of a Contact person or department. Radiobiology October 2-6, 2005 The ESTRO course »Basic Clinical Radiobiology« will take place in Izmir, Turkey. Contact ESTRO office, Avenue E. Mounierlaan 83/12, B-1200 Brussels, Belgium; or call +32 2 775 93 40; or fax +32 2 779 54 94; or e-mail info@estro.be; or see http://www.estro.be Oncology October 7, 2005 The EORTC (European Organisation for Research and Treatment of Cancer) annual course »One-Day Introduction to EORTC Trials« will take place in Brussels, Belgium. Contact Danielle Zimmermann, EORTC Education Office, Avenue E. Mounier 83, bte 11, B-1200 Brussels, Belgium; or call +32 2 774 16 02; or fax +32 2 772 62 33; or e-mail dzi@eortc.be; or see http://www.eortco.be /Seminar/Educationpgrn/Programs/prog2005.htm Lung cancer October 16-20, 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 Clinical oncology October 19, 2005 The advanced cancer course »Molecular Oncology« will be offered in Rio de Janeiro, Brazil. Contact: ASCO International Affairs Department, 1900 Duke Street, Suite 200, Alexandria, VA 22314, USA; or cal +1 703 519 1448; or fax +1 703 299 1044; or e-mail: international@asco.org; or see http://www/asco.org 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 Thoracic oncology November 12, 2005 The 7th Annual UCSF/UC Davis Thoracic Oncology Conference will be held in San Francisco, California, USA Contact University of California, San Francisco, Office of Continuing Medica! Education, Box 0742, 3333 California St., San Francisco, CA 94143; or e-mail CME@ocme.ucsf.edu;or http://www.ucsfcme.com Radiation oncology November 13-18, 2005 The ESTRO course »Evidence-Based Radiation Oncology: Methodological Basis and Clinical Application« will take place in Dubrovnik, Croatia. Contact ESTRO office, Avenue E. Mounierlaan 83/12, B-1200 Brussels, Belgium; or call +32 2 775 93 40; or fax +32 2 779 54 94; or e-mail info@estro.be; or see http://www.estro.be Clinical oncology November 14-15, 2005 The advanced cancer course »Doctor-Patient Communication« will be offered in Bris bane, Australia. Contact: ASCO International Affairs Department, 1900 Duke Street, Suite 200, Alexandria, VA 22314, USA; or cal +1 703 519 1448; or fax +1 703 299 1044; or e-mail: international@asco.org; or see http://www/ asco.org 234 Notices Neurops ychiatr y November 16-18, 2005 The European Federation of Neuropsychiatry Annual Congress will be offered in Munich, Germany Contact: EFNP Secretariat, RPA Congress, Nottingham; or cal +44 (0)115 969 2016; or e-mail: in­fo@efnp.org; or see http:// www.efnp.org Oncology November 21-25, 2005 The EORTC (European Organisation for Research and Treatment of Cancer) course »Organization and Implementation of Cancer Clinical Trials« will take place in Leuven, Belgium. Contact Danielle Zimmermann, EORTC Education Office, Avenue E. Mounier 83, bte 11, B-1200 Brussels, Belgium; or call +32 2 774 16 02; or fax +32 2 772 62 33; or e-mail dzi@eortc.be; or see http://www.eortco.be /Seminar/Educationpgm/Programs/prog2005.htm Mesothelioma November 22-27, 2005 The »International Mesothelioma Symposium« will take place in Antalya, Turkey. Contact: Taryn Klocke; call +1 770-984-5113; fax: +90 232 278 33 73. Lung cancer December 9-1 O, 2005 The 6th European conference »Perspectives in Lung Cancer« will be offered in Amsterdam, The Netherlands. Contact Imedex, Alpharetta, Georgia, 30005-3969 USA; or call +1 770 751 7332; or fax +1 770 751 7334; or e-mail meetings@imedex.com; or see www.imedex.com Thoracic oncology January 13-15, 2006 The »5th Annual UCSF Clinical Cancer Update» will be held in Lake Tahoe, California, USA. Contact University of California, San Francisco, Office of Continuing Medica! Education, Box 0742, 3333 California St., San Francisco, CA 94143; or e­mail CME@ocme.ucsf.edu; or http://www.ucsfcme. com Radio/ Oncol 2005; 39(3): 233-5. Oncology March 9-12, 2006 The ESO advanced course »Modifying Cancer Response to Therapy: From Molecular signalling to Cancer Care« will be offered in Lugano, Switzerland. Contact: Chatrina Melcher, European School of Oncology, ESO Bellinzona Office, IOSI, Ospedale Regionale Bellinzona e Valli, CH-6500 Bellinzona, Switzerland; or cal +41 91 8111 8050; or fax +41 91 811 8051; or e-mail: eso2@esoncology.org Oncology March 12-15, 2006 ICTR 2006, the »3rd International Conference on Translation Research and Pre-Clinical Strategies in Radiation Oncology« will be offered in Lugano, Switzerland. Contact: ICTR 2006 Secretariat, Department of Radio-Oncology, Oncology Institute of Southern Switzerland, CH-6504 Bellinzona, Switzerland; or fax +41 91 811 8678; or http://www.iosi.ch/ictr2006.html Lungcancer April 19-26, 2006 The »2nd Latin American Conference on Lung Cancer« will be offered in Cancun, Mexico. Contact E-mail: LungCancerLA@meet-ics.com: or see http:// www.LCLA2006.com Clinical oncology May, 2006 The 42nd ASCO Meeting will be offered in Atlanta, USA. Contact E mail: enews@asco.org; or see http:// www/asco.org Lungcancer June 18-21, 2006 The »10th Central European Lung Cancer Conference« will be offered in Prague, Czech Republic. Contact: +420-608-408-708; or e-mail celcc@confer­ence.cz; or see http://www.conference.cz/celcc2006 Notices 235 Bronchology June 25-28, 2006 The 14th Word Congress of Bronchology and the 14th Word Congress of Bronchoesophagology will take place in Buenos Aires, Republica Argentina. Contact: General Secretariat, Ms. MarDa Graziani & Asociados with phone +4394 7726 4393 3437; or Fax: +541 439 33436; or E-mail: mg@mariagraziani.com Lungcancer September 28-30, 2006 The »2nd International Workshop Early Invasive Lung Cancer: New Diagnostic Tools & Treatment Strategies« will be held in Turin, Italy. Contact E-mail: a.crippa@congressiefiere.com or see http://www.congressifiere.com Lung and head & neck October 26-28, 2006 The »4th Lung & Head and Neck Conference« will be offered in Sheraton Hotel, Chicago, Illinois. Contact: Taryn Klocke; call +1 770-984-5113; or e­mail evokes@medicine.bsd.uchicago.edu Lungcancer November 8-12, 2006 The »3rd IASLC/ ASCO/ESMO International Confe­rence on Targeted Therapies in Lung Cancer« will be held in Taormina, Sicily. Italy. Contact E-mail: fred.hirsch@UCHSC.edu Lung cancer September 2-6, 2007 The »12th World Conference on Lung Cancer« will be offered in Seoul, Korea. Contact Conference Secretariat; e-mail WCLC2007 @ncc.re.kr; or see http://www.iaslc.orgiumages/ 12worldconfannounce. pdf As a service to our readers, notices of meetings ar courses will be inserted free oj charge. Please send infonnation to the Editorial office, Radiology and Oncologij, Zaloška 2, SI-1000 Ljubljana, Slovenia. Radio/ Oncol 2005; 39(3): 233-5. 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: 501 00-620-1 33-05-1 0331 1 5-214 779 Activity of »dr. J. Cholewa« foundation for cancer research and education -a report for the third 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 with dif­ferent grant applications and other applications for various types of financial support were being dealt by the responsible bodies formed by Foundation members with clin­ical and cancer research experience and members with important experience in fi­nance. The Dr. J. Cholewa Foundation for Cancer Research and Education also continues 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 and is considering it one of its permanent commit­ments. The Foundation bestowed various grants and other forms of financial support to in­terested individuals with projects dealing with problems in oncology affecting gener­al population and patients with cancer in Slovenia. Among the recipients were also some reputed non-government organisations, such as Slovenian Cancer Association and others. With this in mind and as already noted before, the Foundation acknowl­edges the importance of the commitment of various public companies and private in­dividuals to its cause. Borut Štabuc, MD, PhD Tomaž Benulic, MD; MSc Andrej Plesnicar, MD, MSc temozolomid 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. psuleTemodal so indicirane za zdravljenje bolnikov z malignimi gliomi, kakor sta npr. multiformnl glioblastom ali anaplasticni astrocitom, ki se po standardnem zdravljeni novijo ali napredujejo. • • • • • • • • • · Odrasti bolniki in pediatricni bolniki, stari 3 leta ali starejši: Posamezen ciklus zdravljenja traja 28 dni. Bolniki, ki še niso bi dravljeni 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 nevtropenij Ji trombocitopenijo vecje kot pri mlajših, zato svetujemo posebno previdnost pri uporabi zdravila Temodal pri starejših bolnikih. Moški bolniki: Temozolomid lahko deluj enotoksicno. · Socasna uporaba zdravila Temodal in ranilidina ni povzrocila spremembe obsega absorpcije temozolomida. Jemanje zdravila Temodal s hrano j vzrocilo 33 % zmanjšanje Cmax in 9 % zmanjšanje AUC. Ker ne moremo izkljuciti možnosti, da bi bila sprememba Cmax lahko klinicno pomembna, priporocamo jemanj dravila Temodal brez hrane. Analiza populacijske farmakokinetike temozolomida v raziskavah druge faze je pokazala, da socasna uporaba deksametazona, proklorperazin nitoina, karbamazepina, ondansetrona, antagonistov receptorjev H2 ali fenobarbitala ne spremeni ocistka temozolomida. Socasno jemanje z valproinsko kislino je bilo povezan majhnim, a statisticno znacilnim zmanjšanjem ocistka temozolomida. Uporaba zdravila Temodal v kombinaciji z drugimi mielosupresivi lahko poveca verjetnost mielosupresije V klinicnih raziskavah so bili najpogostnejši neželeni ucinki, povezani z zdravljenjem, prebavne motnje, natancneje slabost (43 %) in bruhanje (36 %).Pogostno ude 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 %) te pušcaju, zvišani telesni temperaturi in zaspanosti.Laboratorijski izvidi: trombocitopenija oz. nevtropenija 3. oz. 4. stopnje sta se pojavili pri 19 % oz. 17 % bolnikov, zdravljeni radi glioma. Mlelosupresija 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, ponavadi -2 tednih. Znakov kumulativne mielosu resije niso ugotavljali. • , • • · . . , , • , . • Schering-Plough Central East AG, Luzern, Švica, Predstavništvo loveniji, Dunajska 22, 1000 Ljubljana •. • Zdravilo se izda·a samo na recept, uporablja pa se pod posebnim nadzorom zdravnika specialista ali od njeg blašcenega zdravnika. •. -Januar 2005. • • • • • ---, , , , , kapsule raztopina za intravensko infundiranje Sestava 1 kapsula vsebuje 50 mg, 100 mg ali 150 mg flukonazola. 1 viala kandidoze, preprecevanje kandidoze, kriptokokoze, vaginalna kandidoza in dermatomlkoze. Odmerjanje in nacin uporabe Velikost odmerka je odvisna od indikacije. Odraslim dajemo obicajno 50 do 800 mg flukonaz.ola 1-krat na dan, otrokom pa 3 do 12 mg/kg telesne mase 1-l