ADIOLOGY l1.11 -­ NCOLOGY March 2002 Vol. 36 No. 1 Ljubljana ISSN 1318-2099 .TI. Editorial office Radiologij and OncologiJ Marc/z 2002 Tnstit11le of Oncology Vol. 36 No. 1 Zaloška 2 Pages 1-85 51-1000 Ljubljana ISSN 1318-2099 Slovenia UDC 616-006 Phone: + 386 1 4320 068 CODEN: RONCEM Plwne/Fnx: +386 1 4337 410 E-mail: gsersa.Amko-i.si Airns and scope Radiology mzd Oncology is a journal devoted to publication of original contrib11tions in diagnostic and interventional radiology, co111p11terized tomography, 11ltraso1111d, nzagnetic resonance, nuclear medicine, radiotherapy, c/inical and experimental oncology, radiobiology, radiophysics and radia/ion prolection. Editor-in-Chief Editor-in-Chief Erneritus Gregor Serša Tomaž Benulic Ljubljana, Slovenia Ljubljana, Slovenia Executive Editor Editor Viljem Kovac Uroš Smrdel Ljubljana, 5/ovenia Ljubljana, Slovenia Editorial board Maja Osmak Marija Auersperg Valentin Fidler Zagreb, Croatia Ljubljana, Slovenia Ljubljana, Slovenia Branko Palcic Nada Bešenski Be1a Fornet Vancouver, Canada Zagreb, Croatia Budapest, Hzmgary Jurica Papa Karl H. Bohuslavizki Tullio Giraldi Zagreb, Croatia Hamburg, Germany Trieste, Italy Dušan Pavcnik Haris Boko Andrija Hebrang Portland, USA Zagreb, Croatia Zagreb, Croatia Stojan Plesnicar Nataša V. Budihna Laszl6 Horvath Lj11bljana, Slovenia Ljubljana, Slove11ia Pecs, Hzmgary Ervin B. Podgoršak Marjan Budihna Berta Jereb Montreal, Canada Ljubljana, Slovenia Ljubljana, Slovenia Jan C. Roos Malte Clausen Vladimir Jevtic Amsterdam, Netherlands 1-Iamburg, Germany Ljubljana, Slovenia Slavko Šimunic Christoph Clemm H. Dieter Kogelnik Zagreb. Croatia Miine/zen, Germa11y Salzb11rg, Austria Lojze Smid Mario Corsi Jurij Lindtner Ljubljm.a,Slovenia Udine, Italy Ljubljana, Slovenia Borut Stabuc Ljubomir Diankov Ivan Lovasic Ljubljana, 5/ovenia Sofia, Bulgaria Rijeka, Croatia Andrea Veronesi Christian Dittrich Marijan Lovrencic .vimw, Italy Vienna, A11stria Zagreb, Croatia Ziva Zupancic Ivan Drinkovic LulcaMilas Ljubljana, Slovrnia Zagreb, Croatia Houston, USA Gillian Duchesne Metka Milcinski Melbourne, Australia Ljubljana, Slovenia Publisher Associatio11 of Radiology alld OHcology Affiliated with S/ove11ia11 Medica/ Associatio11 -S/ovellia11 Associatio11 of Radiology, Nuclear Medicine Society, Slove11ia11 Society for Radiotherapy a11d O11cology, m1d Slovenim1 Ca11cer Society Croafian Medica/ Associatio11 -Croatia11 Society of Radiology Socielas Radiologon1111 HuHgarorum Fri11/i-Ve11ezia Giu/ia regio110/ groups of S.I.R.M. (Jtalia11 Society of Medica/ Radiology) Copyright © Radiology 0111/ O11cology. All rig/1/s reserved. 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Ljubljana, Slovenia ISSN 1318-2099 March 2002 UDC 616-006 Vol. 36 No. 1 CODEN: RONCEM CONTENTS RADIOLOGY Primary non-Hodgkin lymphoma of the cecum: A case report Kropivnik M, Jamar B, Cernelc B 1 Carotid angioplasty with cerebral protection Miloševic Z, Žvan B, Zaletel M, Šurlan M 5 SONOGRAPHY Endosonographic appearance of the anal sphincters in patients following colostomy Sudof-Szopiliska I, Szczepkowski M, Panorska KA, Jakubowski W 13 Endosonography of the puborectalis muscle-interobserver comparison of the anal and vagina! ultrasonography Sudof-Szopi1iska I, Szczepkowski M, Pnnorska AK, Jakubowski W, Snrti D 23 ONCOLOGY Modulation of radiotherapy-and chemotherapy-induced normal tissue response as prophylaxis of their side effects PlevoV!i P Lymphangioleiomyomatosis Anderluh F Infantile myofibromathosis of the maxilla. A case report Ihan Hren N 47 A brief overview of the tumor vaccines through the last decade Novalcovic S, Jezeršek Nova/covic B 53 Environment and breast cancer -the role of xenooestrogens in breast cancer carcinogenesis Plesnicar A, Družina B, Kovac V, Kralj B 63 SLOVENIAN ABSTRACTS 73 NOTICES 80 Primary non-Hodgkin lymphoma of the cecum: A case report Mateja Kropivnik, Breda Jamar, Bojana Cernelc Clinical Institute of Radiology, University Medical Centre, Ljubljana, Slovenia Background. Primary lymphoma of the colon is rare, constituting 0.4 % of primary colonic malignancies and usually involves cecum or rectum. The aim of this paper is to present the role and the importance of do­uble contrast barium enema (DCBE) in the diagnostic process. Case report. A 77 years old male was admitted because of suspected inflammation in the area of total en-doprosthesis of the left hip, inserted ten years before. Listeria monocytogenes was isolated from the aspira­te and the patient treated with antibiotics. Twenty years ago the patient underwent nephrectomy because of hypernephroma of left kidney. At the time of admission he had sideropenic anaemia and he was febrile. Conclusion. The patient underwent many diagnostic procedures: ultrasound (US), computed tomography (CT), double contrast barium enema, which showed a tumour in the cecum, small bowel follow-through and scintigraphy. The diagnosis of primary non-Hodgkin lymphoma was established by histology after biopsy at colonoscopy. Key words: cecal neoplasms – radiography; contrast media; barium; lymphoma, non-hodgkin Introduction Malignant lymphomas involve the gastrointe­stinal tract either as primary neoplasms or as part of disseminated disease. Primary lympho­ma of the colon is rare, constituting 0.4 % of all colonic malignancies. Non-Hodgkin lympho­ma accounts for almost all colonic lympho- Received 28 February 2002 Accepted 6 March 2002 Correspondence to: Prim. Breda Jamar, M.D., Clinical Institute of Radiology, University Medical Centre, Lju­bljana, Slovenia; Phone: +386 1 522-34-14; e-mail: bre­da.jamar@kclj.si mas.1-3 The signs and symptoms of colonic lymphoma are non-specific. The lack of speci­fic symptoms can be the reason for delayed di­agnosis.4 The most common presentation is abdominal pain, with weight loss and chan­ging bowel habits in 60-90 % of patients.1,5 A palpable abdominal mass can someti­mes be noted on the initial physical examina­tion.6 Double-contrast barium enema (DCBE) shows the changes in the large bowel, caused by lymphoma, but there is a broad spectrum of radiological variations: lymphoma is a gre­at mimicker.7 Ultrasound (US) is often the first imaging modality used in patients with vague abdomi­nal symptoms and can detect several patterns of involvement in cases of lymphoma.8 Computerised tomography (CT) is invalua­ble for the staging of the disease and is an es­sential complementary study to barium exa­mination. It establishes the extent and shape of a lymphoma, demonstrates nodal involve­ment and possible infiltration of the liver or spleen.9 In our case, however, the location, the size and the appearance were determined by DCBE. Case report A 77 years old male was admitted to the hos­pital at the beginning of August 2001, becau­se of pain in the left hip and high body tem­perature. Ten years ago he had a total endoprosthesis of the left hip inserted and septic coxitis was suspected. He had had a hypernephroma of the left kidney, treated by nephrectomy, 20 year prior to admission. He was also complaining of vague lower abdomi­nal pain, weakness and a short episode of di­arrhoea. On the admission his body temperature was 38.3 °C, he had sideropenic anaemia (E 3.25, Hb 189, and Fe 4.7) and his SR was 131. There was no palpable peripheral lymph no­des enlargement, abdominal mass or enlarge­ment of liver or spleen. The patient was treated by antibiotics, a needle aspiration of left hip was done and an orthopaedic surgeon was consulted. Scinti­graphy showed a slightly higher activity in the area of left hip and in the right lower qu­adrant of the abdomen. Listeria monocytogenes was isolated from the aspirate, antibiotics therapy was changed and an underlying disease was suspected. US showed enlarged mesenterial and re-troperitoneal lymph nodes and a bizarre, hyperaemic formation at the lower pole of the right kidney (Figure 1). CT showed normal li- Figure 2. Computerised tomography: a slight mural thickening in the area of ileocecal valve. ver parenchyma, slightly enlarged spleen, en­larged mesenterial and retroperitoneal lym­phatic nodes, enlarged right kidney with pa-rapelvic cysts, but no mass in the abdomen was described (Figure 2). Repeated US on the same day suggested that the tumour was in the area of distal segments of ileum. At the beginning of September a double contrast barium enema was performed, which showed an approximately 4 ×4 cm lar­ge, lobulated, well defined tumour in the area of ileocecal valve (Figure 3). The tumour did not have characteristics of colon carcinoma. A small bowel follow- through was normal. At colonoscopy an ulcerated, cauliflower mass was found in the cecum and biopsy was performed. The histopathologic diagnosis was non-Hodgkin, B-cell lymphoma. Discussion Colon is a rare site of gastrointestinal non-Hodgkin lymphoma. Radiologic examination of large bowel and colonoscopy with biopsy are sufficient for definitive diagnosis, but US and/or CT are invaluable for the staging of the disease.10 Colonic lymphoma has a variety of diffe­rent presentations, which are best seen by the use of double contrast barium enema techni­que.11 The radiologic changes can be divided into five groups: mucosal nodularity, endo­exoenteric mass, intraluminal mass, mural in­filtration and mesenteric invasion.3 Intralu­minal mass is the predominant feature, often lobulated and ranging in size up to 20 cm, mostly situated in the cecum, causing irregu­lar enlargement of the ileocecal valve. In our case the tumour, as seen on double contrast barium enema, met the criteria of co-lonic lymphoma as described in literature and it clearly did not have radiological characteri­stics of colonic carcinoma. At US, enlarge­ment of lymph nodes was found and the tu­mour was seen, but its location and nature were not defined. CT is invaluable for the staging in cases of primary colonic lymphomas, for definition of tumour invasion and spread. CT findings of intestinal tumour can throw a suspicion of lymphoma. Cecal tumours which are fairly demarcated from the surrounding pericolonic fat and show no evidence of invasion or ob­struction of neighbouring viscera are sugge­stive of lymphoma.12 In our case lymphoma of cecum was not obvious on CT examination. Because of US findings, which suggested pa­thology of the right kidney, the colon was not cleansed and there were a lot of faecal residua in the lumen, which made the proper evalua­tion of colonic disease difficult. Also, the tu­mour was small, only 4 cm in diameter. Ne­vertheless, on retrograde evaluation, the area of ileocecal valve showed mural thickening. Conclusion In the era of many imaging modalities, double contrast barium enema remains one of very sensitive, if not specific, diagnostic tools. The exact location and size can be determined and differential diagnoses suggested, even before the definitive diagnosis with biopsy is established. References 1. Rubesin SE, Furth EE. Other tumors. In: Gore M E, Levine M S, Laufer I, editors. Textbook of gastrointe­stinal radiology. Philadelphia etc.: Saunders, 1994. p. 1200-7. 2. Cho MJ, Ha CS, Allen PK, Fuller LM, Cabanillas F, Cox JD. Primary non-Hodgkin lymphoma of the large bowel. Radiology 1997; 205: 535-9. 3. O’Connell DJ, Thompson AJ. Lymphoma of the colon: the spectrum of radiologic changes. Gastro­intest Radiol 1978; 2: 377-85. 4. Doolabh N, Anthony T, Simmang C, Bieligk S, Lee E, Huber P, et al. Primary colonic lymphoma. J Surg Oncol 2000; 4: 257-62. 5. Zinzani PL, Magagnoli M, Pagliani G, Bendandi M, Gherlinzoni F, Merla E, et al. Primary intestinal lymphoma: clinical and therapeutic features in 32 patients. Haematologica 1997; 3: 305-8. 6. Zighelboim J, Larson MV. Primary colonic lymphoma. Clinical presentation, histopathologic features, and outcome with combination chemo­therapy. J Clin Gastroenterol 1994; 4: 291-7. 7. Mendelson RM. The gastrointestinal tract. In: Pet-tersson H, editor. A global textbook of radiology. Lund: The Nicer Institute; 1995. p. 891-1025. 8. Goerg C, Schwerk WB, Goerg K. Gastrointestinal lymphoma: sonographic findings in 54 patients. Am J Roentgenol 1990; 4: 795-8. 9. Herlinger H, Maglinte DDT. Tumors of the small intestine. In: Herlinger H, Maglinte DDT, editors. Clinical radiology of the small intestine. Philadelphia etc.: Saunders; 1989. p. 399-451. 10. Montini F, Mascio DE, Fossaceca R, Frino F, Ange-lucci D, Errichi BM. Primary non-Hodgkin lymphomas of the colon: apropos of a case with double localisation. Chir Ital 1994; 46: 59-65. 11. Torres WT, Gedgaudas-McClees RK. Lymphoma. In: Gore RM, Levine MS, Laufer I, editors. Textbo­ok of gastrointestinal radiology. Philadelphia etc.: Sa­unders; 1994. p. 2570-82. 12. Wyatt SH, Fishman EK, Hruban RH, Siegelman SS. CT of primary colonic lymphoma. Clin Imaging 1994; 18: 131-41. Carotid angioplasty with cerebral protection Zoran Miloševic1, Bojana Žvan2, Marjan Zaletel2, Miloš Šurlan1 1Clinical Radiology Institute, University Medical Center, Ljubljana, Slovenia 2Neurology Clinic, University Medical Center, Ljubljana, Slovenia Background. Carotid endarterectomy (CEA) is widely used in the management of high-grade carotid steno-sis. It is a surgical procedure requiring general anaesthesia and is suitable only for lesions located at or clo­se to the carotid bifurcation. It may develop complications, such as stroke, death, cranial nerve palsies, wo­und haematoma and cardiac complications. The risk of complications is increased in patients with recurrent carotid artery stenosis following CEA, in subjects undergoing radiotherapy to the neck, and in patients with cardiopulmonary disease. The drawbacks of CEA have led physicians to search for alternative treatment op­tions. Carotid angioplasty and stenting (CAS) is less invasive than CEA. The method is particularly suita­ble for the treatment of recurrent stenosis after previous CEA and distal internal artery stenosis, which is inaccessible for CEA. CAS does not cause cranial nerve palsies. Moreover, it does not require general ana­esthesia and causes lower morbidity and mortality in patients with severe cardiopulmonary disease. The complications of CAS include stroke due to distal immobilisation of a plaque or thrombus dislodged during the procedure, abrupt vessel occlusion due to thrombosis, dissection or vasospasm, and restenosis due to in­timal hyperplasia. CAS is a relatively new procedure; therefore, it is essential to establish its efficacy and safety before it is introduced widely into clinical practice. Patients and methods. In Slovenia, we have also started with carotid angioplasty by the study: Slovenian Carotid Angioplasty Study (SCAS). We performed CAS in 17 patients (12 males and 5 females) aged from 69 to 82 years. All patients were symptomatic with stenosis greater than 70 %. 10 patients suffered transi­ent ischemic attacks, 4 patients minor strokes and 3 patients amaurosis fugax. Results. Technical success (< 30 % residual stenosis) was achieved in all cases. In 14 patients, no residual stenosis was found, in 2 patients a 15 % residual stenosis persisted and in 1 patient, a 30 % residual steno-sis was detected. In 15 patients, CAS was performed without complications, in one patient the hyperperfu­sion syndrome occurred and in one periprocedural stroke occurred. Conclusions. According to our initial experience on 17 patients CAS could gain more importance in stroke prevention with proper selection of patients with brain ischemia and improved cerebral protection during procedure. Key words: carotid stroke; angioplasty; stents; cerebral infraction – prevention and control Correspondence to: Zoran Miloševic, M.D., Clinical Radiology Institute, University Medical Centre Ljub­ljana, Zaloška 2, SI-1525 Ljubljana, Slovenia; Phone: +386 1 52 23 421; Fax: +386 1 43 31 044; E-mail: zo­ran.milosevic@guest.arnes.si Received 25 January 2002 Accepted 11 February 2002 Introduction Stroke is an important public health problem and the third most common cause of death, after heart diseases and cancer.1 In Slovenia, stroke incidence, measured as a first ever stro­ke per 100000 population, is 190.5 and morta­lity rate is 19.3 %.2 The proportion of ischemic stroke increases with age (33 % before 45 and 80 % after 50). Of all cases, 20 to 30 % are sup­posed to be due to carotid stenosis.3 The most common cause of carotid stenosis is athero­sclerosis. The mechanism of brain ischemia was thought to be either direct hemodynamic impact on the cerebral blood circulation or in­direct as a source of thromboembolic materi­al.4 Three possible treatment modality are ava­ilable to prevent stroke caused by carotid stenos is. The first is medical treatment, se­cond surgical treatment, and third the newest approach, endovascular treatment by carotid angioplasty and stenting (CAS). Platelet antiaggregants such as acetilsalicil acid or ticlopidine, reduce the risk of stro-ke.5,6 Recently, preventive treatment with clo­pidogrel in combination with acetilsalicil acid are recommended.7 Reducing the risk factors such as smoking, obesity, dyslipidemia, hypertension, diabetes is necessary. In surgical approach, the atheromatous plaque is extirpated, removed and the artery is sutured. The first operation on carotid ar­tery – carotid endarterectomy (CEA) was per­formed by DeBakey in 1953.8 The number of the procedures increased in the following ye­ars. In 1984, 120000 CEA operations were performed.9 After this year the number of CEA began to decrease because of its uncerta­in effectivness.10 In 1991, randomised pros­pective surgical trials, North American Symptomatic Carotid Endarterectomy Trial (NASCET)11 and European Carotid Surgery Trial (ECST)12 showed a significant stroke risk reduction by CEA compared with medi­cal treatment in symptomatic patients with carotid stenosis greater than 70 %. The reas­sessment of the results by the American He­art Association (AHA) Stroke Council indica­ted that CEA was three times as effective as medical treatment in reducing the frequency of stroke.13 However, CEA carried a risk of cancer complications.1 The benefit of CEA was dependent on maintaining a low compli­cation rate. Most important complications during the procedure were perioperative stro­ke and death. Combined stroke and death ra­tes exceeding 3 % for patients with asympto­matic stenosis and 6 % for patients with symptomatic stenosis would eliminate the be­nefit in stroke reduction.14 Post-CEA resteno-sis should also be mentioned, since they are not rare. The rate is estimated between 1.2 and 23.9 %, depending on the operative te­chnique.15 The risk of complications by a reo­peration was high.16 Injuries of cranial nerves was seen due to the neck incision in 7.6 to 27%.17 CEA is the “gold standard” so far, but it is not without risks and limits as regards high-risk patients (elderly patients, patients suffe­ring from coronary diseases, respiratory in­sufficiency...), supra-aortic lesions located in the upper section, and carotid lesions associ­ated with severe intracranial lesions. Therefo­re, less invasive CAS seems to have its place in the treatment of carotid stenoses. CAS has a history more than 20 years. Af­ter experiments on animal model Mathias in 1977 proposed the treatment of carotid steno-sis for the first time using angioplasty.18 The first carotid angioplasty was performed in 1980 by Kerber.19 Carotid angioplasty with or without stenting has been investigated du­ring last two decades. This procedure has not received wide acceptance because of the em-bolic stroke risk during the procedure. Till 1997 the perioperative stroke rate following CAS without cerebral protection ranged from 5.3 % – 8.2 %.20,21 Initial results were criticised because of high neurological complications rate.22 The main cause of perioperative com­plications are thought to be embolic particles released from the carotid plaque during angi­oplasty.23 In 1990, Theron, the father of cere­bral protection, developed and advocated the use of cerebral protection device during CAS.24 The risk of embolisation and the need for cerebral protection during CAS was con­firmed later.25 Comparing the safety and efficacy of CAS with cerebral protection versus CEA, a pros­pective randomised trial was being organised: Carotid Revascularization Endarterectomy versus Stent Trial (CREST), which was started in the beginning of the year 2001.26 In Slovenia, we have also started with CAS by setting up the study “Slovenian Carotid Angioplasty Study (SCAS)” in order to evalu­ate the safety and efficacy of the method. Patients and methods Study protocol The study has taken the form of a prospective clinical trial conducted over a period of 2 years on 60 patients enrolled according to well-defi­ned inclusion and exclusion criteria. The pati­ents were evaluated independently by a neu­rologist prior to and during the procedure and follow-up examination performed at 1, 6, 12 and 24 months. Evaluation of cerebral protec­tion devices was incorporated into the study. The safety of CAS was assessed on the ba­sis of acute procedural success and occurren­ce of major clinical events during or within 30 days after the procedure. The efficacy of CAS was determined with respect to minor ipsila­teral neurological events, major stroke and death occurring during or within 30 days of the procedure and recurrent stenosis establi­shed within 24 months of CAS. Oral and written information on the study was provided to all patients, and a written, witnessed informed consent was obtained from each of them. The study was been ap­proved by the National Medical Ethics Com­mittee. Patients We performed CAS in 17 patients (12 of them were males and 5 females) aged from 69 to 82 years. All patients were symptomatic with stenosis greater than 70 %. 10 patients suffe­red transient ischemic attacks, 4 patients mi­nor stroke and 3 patients amaurosis fugax. Seven patients had stenosis on right internal carotid artery, 8 on left internal carotid artery and 2 on right common carotid artery. Two patients had occlusion of the contralateral ca­rotid artery. In the first 6 patients, we did not use cerebral protection devices. In other 11 patients, cerebral protection filter devices we­re used. Procedure All patients were give aspirin, 325 mg/d and clopidogrel (75 mg/d) starting the 7th day be­fore the procedure. Heparin, given as an in-tra-arterial bolus, was titrated to maintain the activated clotting time between 200 and 250 seconds. The procedures were done with lo­cal anaesthesia. Neurologic status was moni­tored. Atropine (0.5-1 mg) was given as requ­ired during balloon inflation. Heart rate and blood pressure were monitored throughout the intervention. Percutaneous access was gained through the femoral artery. Selective catheterization of carotid arteries was performed with stan­dard techniques. The diagnostic angiography visualised the origins of the brachiocephalic arteries from the aortic arch, both carotid bi­furcations, both vertebral arteries, intracrani­al parts of both carotid arteries and the domi­nant vertebral artery. Once the diagnostic angiography was completed and the stenotic internal carotid artery was identified, the 5F catheter was advanced using the 0.035-inch glide wire (Terumo Radiofocus Guide Wire, Terumo, Inc.) into the ipsilateral external ca­rotid artery. The glide wire was withdrawn and replaced with an extra stiff 0.035-inch ex­change wire (Extra Stiff Amplatz Wire, 260 cm; Cook, Inc.). The 5F catheter was with­drawn, and the 8F 90-cm guiding sheath (Ca­rotid Vista Brite Tip; Cordis, Inc.) was advan­ced into the common carotid artery over the exchange Amplatz wire, which was anchored in the external carotid artery. Carotid angio­graphy was again performed to measure the vessel diameter to facilitate the sizing of bal­loons, stents and cerebral protection filter de­vices. In the patients without cerebral protec­tion, stenoses were then crossed with flexible coronary guidewires (V-18 Control Wire; Bo­ston Scientific Corp, Watertown, Mass). Ele­ven patients underwent CAS with cerebral protection filter device Angioguard (Cordis, Inc): a low-profile guidewire-based, filter-type device (4F) that was placed in the distal ICA after crossing the stenotic lesion. It captured embolic debris while maintaining distal per­fusion. After that we started with interventi­on on stenosis. The size of the initial angio­plasty balloon was dictated by the severity of the stenosis. Very severe lesions were predi-lated with low-profile coronary balloons (Bypass Speedy Monorail Catheter, Boston Scientific Corp); in the case of less severe le­sions, the initial dilatation may be performed with a definitive balloon sized to the distal normal artery. A Carotid Wallstent Monorail (Boston Scientific Corp) was deployed across the lesion. The stent was dilated at high pres­sure (14 to 16 atm) to firmly embed it into the vessel wall. After that filter with trapped em-boli was removed and the procedure was fini­shed. Completion angiography was perfor­med on the ipsilateral intracranial vessels. The patients were transferred to the intensive care unit. The sheaths were removed. The pa­tients were discharged on either the first or second day after the procedure. Clopidogrel was continued for 3 weeks, whereas aspirin was continued permanently. Results Procedural results are summarised in Table 1. Technical success (< 30 % residual stenosis) was achieved in all cases. In 14 patients, no residual stenosis was found, in 2 patients a 15 % residual stenosis persisted and in 1 pati­ent, a 30 % residual stenosis was detected. Figure 1. Digital subtraction angiography. Lateral views of the left carotid artery bifurcation. A. High grade circumferential, atherosclerotic stenosis of the internal carotid artery origin before CAS. B. No resid­ual stenosis after CAS. Table 1. Procedural results in 17 patients Stenosis % Pt Vessel Symptoms Age CLO Pre Post Procedural Severe Comments in years Stroke CAD 1 R ICA TIA 74 90 0 No Yes 2 L ICA Stroke 72 Yes 99 0 No No 3 R ICA TIA 63 70 0 No No 4 R CCA TIA 68 80 0 No Yes 5 L ICA Amaurosis 72 95 0 No No After five days, an episode of fugax seizure and transitory Tod’s hemi- paresis occurred. CT of the bran demonstrates small hemorrhage on the left frontal side. After a week, she recovered completely. 6 L ICA Stroke 67 Yes 87 0 Yes Yes Occlusion of right ICA. Cerebral embolism occurred during the filter removal. He became aphasic and had right hemiplegy. We dissolved the embolus on the bifurcation of MCA with intraarterial thrombolysis using rTPA, but some hemiparesis persisted. 7 R CCA TIA 66 80 0 No No The right iliac stenting followed same procedure. 8 L ICA Amaurosis 70 Yes 75 No No Yes fugax 9 R ICA Stroke 64 90 15 No No 10 L ICA TIA 68 76 0 No No 11 RICA TIA 82 80 0 No Yes 12 R ICA TIA 68 71 0 No No 13 L ICA TIA 82 75 0 No Yes 14 R ICA TIA 61 73 0 No No 15 L ICA Stroke 76 99 30 No Yes 16 R ICA Amaurosis 57 85 0 No No fugax 17 L ICA TIA 53 75 15 No No CAD = coronary artery disease; CCA = common carotid artery; CLO = contralateral carotid occlusion; ICA = inter­nal carotid artery; L = left; MCA = middle cerebral artery; Pt = patient; R = right; TIA = transient ischemic attacks. From patient 6 (Table 1), cerebral protecti­on filter device was used. In one patient (Patient 5, Table 1) hyperper-fusion syndrome occurred. It occurred in 72­year-old female with carotid stenosis more than 90 %, who suffered from earlier amauro-sis fugax. The stenting was performed succes­sfully without residual stenosis and immedia­te complications (Figure 1). The 5th day after CAS, a generalized seizure with Tod’s hemipa­resis on the right side occurred. After admissi­on, we performed brain CT that showed a small haemorrhage on the left front side (Figu­re 2). She recovered completely after a week. Periprocedural stroke occurred in one pati­ent (Patient 6, Table 1). This was 67 years old male with a previous minor stroke and 90 % stenosis of the left internal carotid artery due Figure 3. Digital subtraction angiography. Lateral views of the left carotid artery bifurcation. A. 90 % stenosis of left internal carotid artery before CAS. B. Cerebral protection filter device during CAS. C. No residual stenosis after CAS. to a lipid-laden plaque and the occluded right carotid artery. In this case we used a cerebral protective filter. CAS was successfully done (Figure 3). Cerebral embolism occurred during the filter removal. He became aphasic and had hemiplegy. We dissolved embolus on bifurca­tion of middle cerebral artery with intra-arteri­al thrombolisis using rTPA (Figure 4). In 15 patients, CAS was performed witho­ut complications. The follow-up in all patients (average follow-up period of 3 months) revea­led no transient ischemic attacks or new stro- Figure 4. Digital subtraction angiography. Antero-posterior views of the left intracranial internal carotid artery with branches. A. An acute oclusion of left mid­dle cerebral artery at the bifurcation. B. Recanalisation of the occlusion after intra-arterial thrombolysis. kes. All patients remained at their neurologic baseline. Long-term clinical or imaging fol­low-up is not yet available. Discussion In the last years, angioplasty has been succes­sfully used in coronary and peripheral disor- ders and has been also applied at the carotid level. Throughout the world, several teams are actively engaged in research in order to determine the indications, the suitable te­chniques, the adjunct treatments, and the fol­low-up conditions. The final aim of carotid angioplasty is to prevent cerebral vascular ne­urological events and not to overshadow sur­gery. It could be an alternative or a comple­ment to surgery if the results were comparable or better. Indications must be de­fined through randomised multi-centred stu­dies and are currently much debated. Some would like them to be limited to high risk pa­tients, restenosis, radiation-induced lesions, or lesions located in the upper internal caro­tid artery near the skull, while others would like them to be more extensive, including le­sions of the carotid bifurcation.27 In later time cerebral protection devices have the potential to enhance the safety of CAS.28 First report of larger series by Wholey29 shows that the peri-operative complication rate after CAS with the cerebral protection is 1.6 % which is signi­ficantly lower than with CEA and CAS witho­ut cerebral protection. We treat now all patients using cerebral protection filter device. In all filters we found embolic material. In two cases, filters were occluded due to a massive amount of embolic material. We suppose that, in such cases where a high risk of complications exists, it is very important to know the type of plaque, which can dislodge a large amount of embolic material. For the evaluation of plaque compo­sition we performed ultrasound. We did not performed CAS in patients with echolucent plaques (Tip 1) due to high embolic risk.30 Fi­brous plaques seem to carry a very low risk of rupture and embolisation. We expect to learn more about plaque composition using MRI. MRI additionally shows the thickness of fi­brous cap and pre-existent ruptures of the plaque.31 By demonstrating thick or thin fi­brous cap of the plaque and correlating data with the amount of emboli, trapped in the fil­ter, we could be able to analyse the risk of pe­riprocedural complications. This information would enable a better selection of patients for CAS. According to our initial experience on 17 patients CAS could gain more importance in stroke prevention with proper selection of patients and improved cerebral protection during procedure. References 1. Hurst RW. Carotid angioplasty. Radiology 1996; 201: 613-16. 2. Žvan B. Epidemiology of stroke in Republic of Slo­venia. Acta Clin Croat 1998; 37 (Suppl 1): 95-7. 3. De Bakey M. Carotid endarterectomy revisited. J Endovasc Surg 1996; 3: 1-4 4. Riles TS, Lieberman A, Kopelman, I, Imparato AM. Symptoms, stenosis, and bruit: interrelation­ships in carotid artery disease. Arch Surg 1981; 116: 218-20. 5. Sze PC, Reitman D, Pincus MM, Sacks HS, Chal­mers TC. Antiplatelet agents in the secondary pre­vention of stroke: Meta-analysis of the randomi­zed control trials. Stroke 1988; 19: 436-42. 6. Hass WK, Easton JD, Adams HP and the Ticlopi-dine Aspirin Stroke Study Group. A randomized trial comparing ticlopidine hydrochloride with as­pirin for the prevention of stroke in high-risk pati­ents. N Engl J Med 1989; 321: 501-7. 7. CAPRIE Steering Committee. A randomised, blin­ded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1329-39. 8. Eastcott HHG, Pickering GW, Rob CG. Recon­struction of internal carotid artery in a patient with intermittent attacks of hemiplegia. Lancet 1954; 2: 994-6. 9. Pokras R, Dyken ML. Dramatic changes in the per­formance of endarterectomy for diseases of the ex-tracranial arteries of the head. Stroke 1988; 19: 1289-90. 10. Barnett HJM, Plus F, Walton JN. Carotid endarte­rectomy: an expression of concern. Stroke 1984; 15: 941-3. 11. North American Symptomatic Carotid Endarterec­tomy Trial Collaborators. Beneficial effect of caro­tid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991; 325: 445-53. 12. European Carotid Surgery Trialists’ Collaborative Group. MRC European Carotid Surgery Trial: Inte­rim results for symptomatic patients with severe (70-99 %) or with mild (0-29 %) carotid stenosis. Lancet 1991; 337: 1235-43. 13. Albers GW, Hart RG, Lutsep HL, Newell DW, Sacco RL. Supplement to the guidelines for the management of transient ischemic attacks: from the Ad Hoc Committee on Guidelines for the Ma­nagement of Transient Ischemic Attacks of the Stroke Council of American Heart Association. AHA medical/scientific statement. Stroke 1999; 30: 2502-11. 14. Moore WS, Barnett HJ, Beebe HG, Bernstein EF, Brener BJ, Brott T, et al. Guidelines for carotid en-darterectomy: a multidisciplinary consensus state­ment from the Ad Hoc Committee, American He­art Association. Stroke 1995; 26: 188-201. 15. Raithel D. Recurrent carotid disease: optimum te­chnique for redo surgery. J Endovasc Surg 1996; 3: 69-75. 16. Bergeron P, Chambran P, Benichou H, Alessandri C. Recurrent carotid disease: will stents be an al­ternative to surgery? J Endovasc Surg 1996; 3: 76-9. 17. Brown MM. Balloon angioplasty for extracranial carotid disease. Advances in Vascular Surgery 1996; 4: 53-69. 18. Mathias K. Ein neues Katherersystem zur perkuta­nen transluminal Angioplastie von Karotidsteno-sen. Fortschr Med 1977; 95: 1007-11. 19. Kerber CW, Hornwell LD, Loehden OL. Catheter dilatation of proximal carotid stenosis during di­stal bifurcation endarterectomy. AJNR 1980; 1: 348-9. 20. Wholey MH, Eles G, Jarmolowski CR, Lim MC, Vozzi C, Londero H, et al. Percutaneous translu­minal angioplasty and stents in the treatment of extra-cranial circulation. J Invasive Cardiol 1996; 9: 225-31. 21. Henry M, Amor M, Masson I, Henry I, Tzvetanov K, Chati Z, et al. Endovascular treatment of athe­rosclerotic internal carotid artery stenosis. J Endo­vasc Surg 1997; 4(Suppl.1): 1-14. 22. Naylor AR, Bolia A, Abbott RJ, Pye IF, Smilth J, Len­nard N, et al. Randomized study of carotid angio­plasty and stenting versus carotid endarterectomy: a stopped trial. J Vasc Surg 1998; 28(2): 326-34. 23. DeMonte F, Peerless SJ, Rankin RN. Carotid tran­sluminal angioplasty with evidence of distal embo­lisation. J Neurosurg 1989; 70: 138-41. 24. Theron J, Courtheoux P, Alachkar F, Bouvard G, Maiza D. New triple coaxial catheter system for ca­rotid angioplasty with cerebral protection. AJNR 1990; 11: 869-74. 25. Ohki T, Marin M, Lyon R, Berdejo GL, Soundara­rajan K, Ohki M, et al. Ex vivo human carotid ar­tery bifurcation stenting: correlation of lesion cha­racteristics with embolic potential. J Vasc Surg 1998; 27: 463-71. 26. Roubin GS, Hobson RW 2nd, White R, Diethrich EB, Fogarty TJ, Wholey M, et al. CREST and CA­RESS to evaluate carotid stenting: time to get to work! J Endovasc Ther 2001; 8(2): 107-9. 27. Veith FJ, Amor M, Ohki T, Beebe HG, Bell PRF, Bolia A, et al. Current status of carotid bifurcation angioplasty and stenting based on a consensus of opinion leaders. J Vasc Surg 2001; 33(2 Suppl): S111-6. 28. Jiri J., Vitek A, Gary SR, Al-Mubareka N, Gishel N, Sriram SI. Carotid artery stenting: technical consi­derations. AJNR 2000; 21: 1736-43. 29. Wholey MH. Will protection devices set free caro­tid angioplasty? Carotid Angioplasty Conference 2001. CV Channel Internet. 30. de Bray JM, Baud JM, Delanoy P, Camuzat JP, De-hans V, Descamp-Le Chevoir J, et al. Reproducibi­lity in ultrasonic characterization of carotid pla­ques. Cerebrovasc Dis 1998; 8(5): 273-7. 31. Hatsukami TS, Ross R, Polissar NL, Chun Yuan C. Visualization of fibrous cap thickness and rupture in human atherosclerotic carotid plaque in vivo with high-resolution magnetic resonance imaging. Circulation 2000; 102: 959-64. Endosonographic appearance of the anal sphincters in patients following colostomy Iwona Sudol-Szopinska1, Marek Szczepkowski2, Anna Panorska3, Wieslaw Jakubowski1 1Department of Diagnostic Imaging, Second Faculty of Medicine, Warsaw, Poland 2Second Surgical Department, Bielany Hospital, Warsaw, Poland 3Desert Research Institute-DHS, Reno, NV, USA Background. The aim of the study was to visualize, by anal ultrasound (AUS), the suspected defects of the anal sphincters in the patients after colostomy and to analyze possible factors that could have led to such defects. Patients and methods. AUS, using a 7.0 MHz endorectal probe, was performed in a group of 25 patients with colostomy. The internal anal sphincter (IAS), external anal sphincter (EAS) and puborectalis muscle (PR) were visualized and the defects within them were qualified and quantified. For statistical analysis, the analysis of variance (ANOVA) was used. Results. The IAS was thin in all but three patients (22 patients; 88 %) with the mean thickness of 1.62 mm. A circular reduction of the thickness along the entire length of the IAS was seen in 20 patients (90.9 %). The echogenicity of the IAS was increased in 15 patients (60 %), and in 10 of them (66.6 %), this defect embra­ced the whole length and circumference of the IAS. The margins of the IAS were not well-defined in 10 pa­tients (40 %). A significant correlation was found between the length of the patient’s life with the stoma and the IAS echogenicity defect (p-value = 0.0001). No significant correlation was found between the dynamic examination, the IAS thickness and the IAS borders definition. Conclusion. The reduced thickness, increased echogenicity and borders definition defect of the IAS are se­en in the patients after colostomy. The only significant correlation was confirmed between the length of the patient’s life with the stoma and the IAS echogenicity defect. Key words: colostomy; anus – ultrasonography Received 11 November 2001 Accepted 26 November 2001 Correspondence to: Iwona Sudol-Szopinska, MD, PhD, Zaklad Diagnostyki Ultrasonograficznej, Wo­jewódzki Szpital Bródnowski, ul. Kondratowicza 8, 03-285 Warszawa; Phone/Fax +48 22 811 95 91; Mobi­le 0 501 716 407; E-mail: mdyvonne@wp.pl Introduction Anal ultrasonography (AUS) is well establi­shed as a method of the visualization of nor­mal and damaged sphincters. The defects of the internal anal sphincter (IAS) and external anal sphincter (EAS) are well represented. The structural abnormalities of either muscle as well as more subtle abnormalities of the in­ternal sphincter smooth-muscle texture and composition can be identified.1 AUS has now replaced electromyographic mapping in the demonstration of the defects of the sphinc­ters.2 This examination is safe, easy to per­form and causes little patient discomfort. Endosonographic assessment of the anal sphincters is very important before deciding whether or not to perform decolostomy or close a loop colostomy. In order to recognize the suspected defects of the anal sphincters in patients after colo­stomy, we evaluated a group of patients with colostomy, assessed the IAS, EAS and pubo-rectal muscle (PR), and analyzed possible fac­tors that could have led to such defects. Patients and methods Patients Twenty-five consecutive patients with colo­stomy were investigated by AUS between March 3, 2000 and June 30, 2000. The group comprised 17 women and 8 men with a me­dian age of 71 (47 to 82 years old). No peria­nal operation was performed before and af­ter colostomy. Two women had forceps deliveries (one gave birth to four children, with the largest baby weighing 3000 g and the second delivered twice with the babies weighing 3500 g each), two others had the se­cond-degree tear of the peritoneum and four gave birth to babies with the birth weight ex­ceeding 4000 g. Additional six with no com­plications at the delivery gave birth to one or two children with the birth weights below 4000 g and the last three women had not gi­ven birth. The patients were inquired about defecati­on problems before operation: constipation and anal incontinence for gas and feces. Six patients (all women) complained about con­stipation present longer than ten years. All but one patient incontinent for gas were sub­jectively satisfied with the level of conti­nence. In our analyzed group of patients with co­lostomies, there were six patients with loop-colostomies; the remaining nineteen had end-colostomies in the course of Hartmann’s operation. The most frequent indication for performing colostomy was adenocarcinoma of the sigma (fifteen patients). Others were as follows: rectal carcinoma (one patient), ade­nocarcinoma of the colon descendens (one), adenocarcinoma of the rectosigmoid (one), diverticulitis (two), complicated diverticulitis (one), colon ischemia (one), dehiscence ana­stomosis (two), tumor inflammatorious si­gmae and urinary bladder (one). The length of life with stoma ranged from eight weeks to sixteen years (median 38.17 months). Methods AUS was performed with the ultrasound scanner Bruel & Kjaer type 1846, Naerum, Denmark using a rotating 7.0 MHz transdu­cer (type 1850). The transducer was covered by a plastic cone with an external diameter of seventeen mm and filled with degassed wa­ter. All the examinations were performed and read by one independent radiologist who was blind to the length of the patients life with the stoma and to clinical information. No bowel preparation was indicated. The examinations were performed in the left lateral position. Serial images were assessed along the length of the anal canal. Image analysis The thickness of the IAS was measured from the screen of the machine using electronic ca­lipers in the distal and proximal part of the anal canal in each quadrant of the IAS. The echogenicity and margins of the IAS were as­sessed as increased or normal and not well-defined or well-defined, respectively. The EAS and the PR echogenicity were assessed as normal or not-homogenous/decreased. The dynamic activity of the EAS and PR was observed during rest and maximal contracti­on of these muscles and diagnosed subjecti­vely by examining physician as: normal, poor or lack of contraction. Results In all but 3 patients (88 %), the IAS was thin with the mean thickness of 1.62 mm. Twenty patients had a circular reduction of the thic­kness (90.90 %) and remaining 2 (9.09 %) par­tial, i.e. restricted to one or two walls of the anal canal. In 12 patients, the entire length of the IAS was equally thin over the complete circumference, in 5, a circular reduction was seen only in the proximal part, and in 3 pati­ents, only in the distal part of the anal canal (Figure 1). In one patient, the thinning of the IAS was not circular, but occurred on the po­sterior wall in a deep part, and in one patient, only on the posterior wall in a proximal part and on the lateral walls in the distal part of the anal canal. Three patients (12 %) had nor­mal thickness of the IAS – at least 3.0 mm. Their length of life with stoma was 1.5, 14 and 18 months (mean 11.17 months). For the remaining patients with thin IAS, the thic­kness of the IAS was the smallest (less than 1 mm in nine cases) in patients with the colo­stomy from 8 weeks to 10 years (mean 24.94 months); the thickness of at least one but be­low 2 mm was seen in 7 patients living with the stoma from 3 months to 16 years (mean 43.57 months). The thickest IAS (at least 2 but less than 3 mm, six cases) was observed in the patients who had the stoma from 5 months to 10 years (mean 42.67 months). Echogenicity of the IAS was increased in 15 patients (60 %) who lived with the stoma between 1.2 and 16 years (mean 7.71 years). Six of them (40 %) had colostomy for less than one year and remaining 9 (60 %) for a longer time. Ten patients out of 15 (66.6 %) had a cir­cular increase of echogenicity seen within the entire length of the IAS (71.42 %) and their length of life with the stoma was from 6 months to 10 years, (mean 34.35 months). In 4 cases, it was seen only in the proximal part and the length of life with the stoma ranged from 1.5 months to 10 years (mean 56 months). One patient with the increased echogenicity had colostomy for 16 years in the distal part of the IAS. The borders of the IAS were not well defi­ned in 10 patients (40 %), including 7 who had the stoma from 1.5 to 11 months (mean 5.28 months) and 3 with the length of life with the stoma of 4, 5 and 10 years (mean 6.33 years; i.e. 75.96 months). In 6 of these 10 patients, the margins of the IAS were not well defined only within a proximal part of the anal canal. All but one had stoma for less than one year. In 4 cases, the increased echogenicity was ob­served on the whole sphincter. These patients mostly had colostomy for a longer time. The dynamic assessment of the EAS and PR in AUS was good in 18 patients (72 %), po­or in 3 (12 %) and no contraction was seen in 4 patients (16 %). The length of life with the stoma in the patients with good contraction ranged from 1.5 months to 16 years (mean 40.72 months), in the patients with poor con­traction from 5 to 18 months (mean 8.17 months), and in the patients without contrac­tion of the muscles from 3 months to 3.5 ye­ars (mean 15.38 months). Scars inside the EAS were seen in 4 pati­ents and in one patient in both, the EAS and the PR. We have performed standard statistical analysis to assess if any significant correlati­on exists between the length of the patient’s life with the stoma and the IAS thickness, echogenicity, border and the results of the dynamic exam. Detailed results are given below. All signi­ficance tests were performed on 0.05 signifi­cance level and the results were reported ac­cordingly, unless otherwise noted.3 Statistical analysis of results The length of the patient’s life with the stoma versus IAS thickness We have started by computing the Pearson correlation coefficient between the length of the patient’s life with the stoma and the IAS thickness. It amounted to 0.025, which is not statistically significant, considering the 0.05 levels. The next step was to divide the obser­vations into the following 4 categories with respect to IAS thickness: IAS thickness less than 1 mm, IAS thickness at least 1 but less than 2 mm (between 1 and 2), IAS thickness at least 2 but less than 3 mm (between 2 and 3), and IAS thickness at least 3 mm. The sta­tistics for the length of the patient’s life with the stoma for each IAS thickness category are summarized in Table 1. With IAS thickness as a categorical variable we performed analysis of variance (ANOVA) to detect any significant relation between the IAS thickness and the length of the patient’s life with the stoma. ANOVA yielded no signi­ficant results. Therefore we believe that we do not have enough evidence to draw any signifi­cant conclusion regarding the length of the pa­tient’s life with the stoma and IAS thickness. The length of the patient’s life with the stoma versus IAS echogenicity The IAS echogenicity was recorded as a ca­tegorical variable with three categories: ”0” – Table 1. Summary statistics for the length of the patient’s life with the stoma versus IAS thickness category IAS thickness Mean length of 95 % Confidence Interval* for mean Number of patients (in mm) life with stoma length of life with stoma (in months) (in months) Below 1 24.94 (0, 55.6) 9 Between 1 and 2 43.57 (0, 110.3) 7 Between 2 and 3 42.67 (0, 86.17) 6 At least 3 11.17 NA (only 3 observations) 3 Overall 32.76 (12.8, 52.7) 25 *The confidence intervals were truncated from below at zero normal, not changed, “1” – increased echoge­nicity in the deep part of the anal canal, “2” – increased echogenicity in the superficial part of the anal canal, “3” increased echogenicity of the entire muscle. ANOVA confirmed a signi­ficant effect (p value = 0.0001) of the length of the patient’s life with the stoma on echogeni-city. That means that not all the mean lengths in different echogenicity categories were the same. Further analysis (pairwise comparisons) showed that the mean length of the patients’ life with the stoma in normal (“0”) echogeni-city category was significantly shorter (p value = 0.01) than that of the patients with an incre­ased echogenicty (categories “1”, “2” and “3” combined). Moreover, the mean length of the patients life with the stoma in the “0” echoge­nicity category was significantly shorter (p va­lue = 0.0059) than that of the patients in the “1” echogenicity category. All other pairwise comparisons of the mean lengths of the pati­ents’ life with the stoma in different IAS echo-genicity categories were not significant. The statistics for the length of the patient’s life with the stoma for each IAS echogenicity cate­gory are summarized in Table 2. The “box-and-whiskers” Figure 2 shows different distributions of the lengths of the patient’s life with the stoma (in months) for the three main echogenicity categories. The solid horizontal line in each box is located at the median of the length of the patient’s life with the stoma. The ends of the box show the lower and upper quartiles and “whiskers” ex- Levels of IAS echogenicity: 0-normal IAS echogeni-city; 1-increased echogenicity of the IAS in a deep part of the anal canal; 3-increased echogenicity of the who­le sphincter. Figure 2. The length of life with the stoma versus IAS echogenicity levels. tend to the maximum and minimum values of the length of the patient’s life with the stoma for each IAS echogenicity category. Note the visible increase of the average length of life with the stoma of the patients with increased echogenicity. The length of the patient’s life with the stoma versus IAS borders definition The IAS border/margin definition was re­corded as a categorical variable with three ca­tegories: “0” – normal, not changed, “1” – de­creased border definition in the deep part of the anal canal only, and “2” – decreased bor- Table 2. Summary statistics for the length of the patient’s life with the stoma versus IAS echogenicity IAS echogenicitys Mean length of 95 % Confidence Interval* for Number of patients category life with stoma length of life with stoma (in months) (in months) 0 5.95 (2.02, 9.88) 10 1 56 (0, 145.48) 4 2 NA (only one observation) NA 1 3 34.35 (8.68, 60.02) 10 *The confidence intervals were truncated below at zero Table 3. Summary statistics for stoma duration versus IAS border definition category IAS border Mean length of 95 % Confidence Interval* for mean Number of patients definition life with stoma length of life with stoma (in months) (in months) 0 31.93 (2.41, 61.45) 15 1 17.67 (0, 52.86) 6 2 58.5 (0, 133.42) 4 *The confidence intervals were truncated below at zero Table 4. Summary statistics for the mean length of life with stoma versus the results of the dynamic exam Dynamic exam Mean length of 95 % Confidence Interval* for mean Number of patients result life with stoma length of life with stoma (in months) (in months) 1 15.38 (0, 43.98) 4 2 8.17 (0, 29.76) 3 3 40.72 (13.54, 67.91) 18 *The confidence intervals were truncated below at zero der definition in the entire muscle. ANOVA detected no significant effect of the border definition on the mean length of the patient’s life with the stoma. The statistics of the length of the patient’s life with the stoma for each IAS border definition category are sum­marized in Table 3. The length of the patient’s life with the stoma versus the results of dynamic examination Dynamic exam results were recorded as a categorical variable with three categories: “1” – low, “2” – poor, and “3” – good contraction capabilities. ANOVA showed no significant effect of the mean length of the patient’s life with the stoma on the dynamic exam results. The statistics for the length of the patient’s li­fe with the stoma for each exam result cate­gory are summarized in Table 4. Discussion Endosonographic assessment of the anal sphincters is very important before deciding for decolostomy after Hartmann’s operations or closing a loop colostomy. We did not find any information on the anatomy of the anal sphincters after colo­stomy with defunctioning ileostomy in the li­terature. There is very little information abo­ut the anatomy of these muscles after IPAA where the thickness of the IAS is significantly smaller compared with normal subjects.4,5 This finding was also the most striking abnor­mality we found in the majority of the pati­ents after colostomy. Twenty two patients (88 %) had a thin IAS with the mean thickness 1.62 mm. Twenty of them (90.90 %) had a cir­cular reduction of the IAS thickness and the remaining two (9.09 %) partial, i.e. restricted to one or two walls. Within the group with a circular thinning of the IAS, twelve (60 %) had the entire muscle equally thin, in the remai­ning eight (40 %), the thinning was seen only within the posterior or lateral walls and in the distal or proximal part of the anal canal. The IAS thickness and proportion of fibro­us tissue increases with age.1 Several hypo­thetical reasons for the thinning of IAS are being proposed, such as denervation, ische-mia or changes caused by direct trauma to the IAS as in patients after the ileal pouch anal anastomosis (IPAA) due to transanal muco­sectomy.4-6 This thinning, however, was visi­ble in the patients with mucosectomy as well as after handsewn anastomosis. During the IPAA, the brunt of the injury is due to the dis­section and mobilization of the anorectum, which may damage the extrinsic autonomic nerve supply that is crucial for the IAS func­tion.7 The transection of the rectal wall at the level of the levator ani muscles may cut thro­ugh the layer of specialized circular muscle that forms the IAS. The damage so inflicted involves the intramural nerve plexus, blood supply and the muscle itself. Such direct da­mage to the IAS at this level is presumably inevitable.6 The transection at a higher level, as in the case of our patients, is unlikely to produce such defect. In a study which used anal manometry and endosonography, a strong correlation between the endosonogra­phic thickness of the IAS and the resting pressure was found.1,8 There are, of course, several reasons leading to abnormal image of the IAS in AUS, including the thinning of this muscle. Passive fecal incontinence is related to the degeneration of the IAS smooth mu­scle, where the muscle atrophies and is repla­ced by fibrous tissue.9 AUS reveals thin, hyperechoic sphincter with poor defined margins, without the usual increase in the thickness of the IAS with age. This condition affects predominantly older men and women. Mean age of our population with colostomy was 76 years and we cannot exclude this fact as accountable for the abnormalities in the IAS detected by the anal ultrasound, especi­ally since very few patients had evidence of structural defects of IAS or EAS and of an EAS weakness. Likewise, in neurogenic, idio­pathic incontinence, the denervation of the EAS and pelvic floor muscles is associated with the damage to the IAS.10 The muscle da­mage is probably the result of autonomic de­nervation. In our material, the scars of the EAS were seen in 4 patients: in 3 women, of whom 2 were without risk factors for the sphincter damage and one having a typical episiotomy scar, and a man who was inconti­nent for gas. He was the only patient suffe­ring from fecal incontinence before colo­stomy was performed. He was 76 years old with a colostomy for 16 years. Anal ultraso­und detected a thinning only in the proximal part of the IAS, the increased echogenicity only in the distal part of the anal canal, and the scars in the EAS not affecting its contrac­tion in the dynamic examination. Thirty-eight per cent of women with for­ceps deliveries experience symptoms of in­continence and up to 2 % of women delivering vaginally have a third -degree obstetric tear in­volving one or both of the anal sphincters.1 Al­though women constitute the main group suf­fering from fecal incontinence, none of our patients did have it. However, there were a few with the risk factors, including two with obstetric tears, two others after forceps delive­ries, and four having delivered babies with the birth weight exceeding 4000 g. In AUS, the thinning of the IAS was seen in all of them, the increased echogenicity of the whole mu­scle in six; and in the proximal part of the anal canal in the remaining two. In one case, a scar after episiotomy was seen. The dynamic exa­mination was normal. In this group, two wo­men who had babies with the birth weight ex­ceeding 4000 g and two with the second-de­gree tears of the peritoneum suffered from constipation for more than 10 years. AUS may be considered to be used also in the patients with obstructed defecation in or­der to identify those patients with internal sphincter hypertrophy or its degeneration af­ter permanent constipation with straining. In our group, 6 patients suffered from constipa­tion for more than 10 years before colostomy was done.11 AUS revealed thinning, increa­sed echogenicity and not well-defined mar­gins of the IAS in 4 of them; in another 2 on­ly the thinning of the IAS was seen. We regarded the length of the patient’s li­fe with the stoma as the main factor accoun­table for an abnormal image of the sphincters in AUS. Three patients had the normal thic­kness of the IAS (at least 3 mm) and their me­an time of life with the colostomy was 11.17 months. Nine patients with the IAS thickness below 1 mm (which was the smallest) had the colostomy for mean 24.94 months. Seven pa­tients with the IAS thickness at least one but below 2 mm had colostomy for 40.57 months on average. The thickest but still thin (at least 2 but below 3 mm) IAS was seen in 6 patients with colostomy for a mean time of 42.67 mo­nths. It is interesting that patients with the shortest life with the stoma (mean 11.17 months) had normal thickness of the IAS, whe­reas in the rest of the patients with longer life with the stoma the IAS was thinned. The re­sults of the statistical analysis however didn’t show any significant difference between the IAS thickness and the length of life with sto-ma. The IAS was the thinnest in the patients with the average life with the stoma of 24.94 months and it was the thickest in the patients with a longer period of colostomy. The analyses of the IAS echogenicity sho­wed that it was increased in 15 of the patients (60 %). Nine patients (60 %) had the colostomy for more than a year (mean 7.71 years) and 6 (40 %) less than a year. The length of time with the stoma appeared to correlate well with the echogenicity disturbances within the IAS. The most typical was the circular increa­se of echogenicity seen within the whole length of the IAS (10 patients – 66.62 %); ho­wever, there was no correlation, if not rever­se, between the length of the patient’s life with the stoma and the range of abnormal echogenicity. A circular defect was seen in the patients with the mean colostomy of 34.35 months. A partially increased IAS was seen in the deep part of the anal canal after an average of 56 months of life with colo­stomy and in the distal part of the anal canal in the patient with the longest life with the stoma (16 years). Our statistical analysis sho­wed that the mean life with the stoma stoma in the patients with normal echogenicity of the IAS was significantly shorter than that in the patients with increased echogenicity (p = 0.01). However we could not find any si­gnificant correlation between the subgroups of patients with the abnormal echogenicity of the IAS and their length of life with colo­stomy. The margins of the IAS were not well defi­ned in 10 patients (40 %) and in most of them (seven cases – 70%) already after a mean colo­stomy of 5.28 months. Although this abnor­mality was seen in less than half of the pati­ents, it appeared to have inflicted the IAS very early. Also, interestingly, 6 out of these 10 patients did not have well defined margins of the IAS only inside a deep part of the anal canal and all but one of them had the stomas for less than one year (mean 17.67 months). In 4 remaining cases, the whole sphincter had abnormal margins and these were all cases except one with a long life with the stoma (mean 58.5 months). ANOVA however, sho­wed no significant correlation between the length of the patient’s life with the stoma and the border definition defects. We have not performed manometry or electromyography (EMG); so, the only way we could assess the function of the striated muscle was the anal ultrasound during con­traction of the anal sphincter. This imaging technique applied during contraction of the anal sphincter is a useful adjunct to the stan­dard study at rest. It gives better definition of the EAS and PR and is helpful in defining whether or not a defect is present.2 The ultra­sound image of a defect correlates well with absent electromyographic activity, and the former is more accurate at picking up lesi­ons.1 Eventually, anal endosonography redu­ced the need for EMG to identify EAS de­fects. In our group of patients with no contraction (4 cases), AUS depicted scars in­side the EAS in one case only. There was no history of obstetric trauma, operations or any factors that could lead to such a defect. Poor contraction was seen in 3 patients, 2 of them women (one delivered a large baby with the birth weight exceeding 4000 g, the second had forceps delivery) and one man with no risk factors. The impaired contraction of the EAS and PR was also not related to the length of life with the colostomy. The mean length of life with the stoma in the majority of the pati­ents with good contraction (18 patients- 72 %) was 40.66 months. In the patients with poor contraction (3 patients- 12 %), that mean length was 8.16 months and in patients wi­thout contraction (4 patients; 16 %), the mean life with the stoma was 15.37 months. No si­gnificant effect of the length of the patient’s life with the stoma on the dynamic exam re­sult was found. This study confirmed the suspicion that the patients after colostomy have anal sphinc­ters, especially IAS defects. In an attempt to identify other factors predictive of the anal sphincter complications, we took into acco­unt the age, gender, obstetric history, history of constipations, fecal incontinency and the length of the patient’s life with the stoma. It appeared that only a few of analyzed factors had an effect on the sphincters defect. These findings were unexpected to us because we thought that constipation, obstetric trauma, as well as the length of the patient’s life with the stoma would have a significant effect on the sphincter outcome. In our study, we fo­und a correlation only between the length of the patient’s life with the stoma and the chan­ges in echogenicity of the IAS. However, the­re was no correlation between the length of li­fe with colostomy and the range of those defects. The thickness of the IAS was preser­ved in patients with the short life with the stoma, but there was no correlation between the patient’s length of life with the stoma and thinning of the IAS. Although our findings could implicate the dysfunction of the IAS, we would like to emphasize that their value is limited because manometry, electromyo­graphy or pudental nerve terminal motor la­tency (PNTML) were not performed in order to obtain a better assessment of the function deterioration of the IAS. The obstetric hi­story, tears, forceps and birth weight excee­ding 4000 g showed surprisingly little correla­tion with the IAS defects. All 8 women with the above risk factors had thin IAS, but only in 2 of them, the whole muscle was thin. In majority of cases, the increased echogenicity of the IAS was noted; in most of them, it in­volved the whole muscle, but 4 of them also experienced coexisting constipations. We ha­ve a few explanations for these findings. First, our population of patients was older (mean age 76 years) and presumably many other comorbid illnesses had influenced the image of the IAS, including degeneration mentioned above. Second, constipations la­sting for a long time with accompanying stra­ining can led to the degeneration manifested in AUS as thinning, increased echogenicity and poorly defined borders of the IAS. Six our patients with colostomy suffered from constipation and all of them had thin IAS, whereas increased echogenicity and not po­orly defined margins were seen in four of them. Third, presumably the most crucial de­fect of the presented group of patients is the degeneration of the anal sphincters as the re­sult of a lack of the intestinal passage in the rectum and of abnormal activity of the sphincter muscles during the defecation. Endosonographic assessment of the anal sphincters is very important before deciding for decolostomy after Hartmann’s operations or closing a loop colostomy. A reduction of thickness of the IAS and as circular reduction inside the whole muscle is the most typical disorder for this condition due to the stoma. No correlations were found between the ex­tent of the thinning and the length of the pa­tient’s life with the stoma, although the thic­kness was well preserved through the first year after colostomy was done. A discrepancy was also noticed among the length of life with the stoma and the range of increased echoge­nicity of the IAS. This defect occurred late af­ter colostomy. Although echogenicity was normal in patients with the shortest colo­stomy in comparison to those with a longer ones, between those with a longer colostomy with different range of the echogenicity de­fects no correlation was found. Our statistical analysis showed that the only characteristic of the IAS and EAS significantly associated with the length of the patient’s life with the stoma was the IAS echogenicity and that this variable was preserved only in the patients with the shortest colostomy. The margins defect occurred early after the colostomy had been performed and, with ti­me, the range of this defect increased. Howe­ver, the results of the statistical analysis sho­wed no significant correlation between those two: the length of life with colostomy and the borders defect. References 1. Kamm MA. Obstetric damage and faecal inconti­nence. Lancet 1994; 10: 730-3. 2. Rieger NA, Downey PR, Wattchow DA. Short com­munication: endoanal ultrasound during contracti­on of the anal sphincter-improved definition and di­agnostic accuracy. Br J Radiol 1996; 69: 665-7. 3. Johnson RA, Witchen DW. Applied multivariate sta­tistical analysis. London: Prentice Hall; 1992. 4. Silvis R, Eekelen JW, Delemarre JBVM, Gooszen HG. Endosonography of the anal sphincter after ileal pouch-anal anastomosis. Dis Colon Rectum 1995; 38: 383-8. 5. Tuckson W, Lavery I, Oakley J, Church J, Milsom J. Manometric and functional comparison of ileal pouch anal anastomosis with and without anal manipulation. Am J Surg 1991; 161: 90-6. 6. Lavery IC, Tuckson WB, Easley KA. Internal anal sphincter function after total abdominal colec­tomy and stapled ileal pouch-anal anastomosis wi­thout mucosal proctectomy. Dis Colon Rectum 1989; 32: 950-3. 7. Williams NS, Marzouk DEMM, Hallan RI, Wal­dron DJ. Function after ileal pouch and stapled po­uch-anal anastomosis for ulcerative colitis. Br J Surg 1989; 76: 1168-71. 8. Speakman CTM, Kamm MA. The internal anal sphincter-new insights into faecal incontinence. Gut 1991; 32: 345-6. 9. Vaizey CJ, Kamm MA, Bartram CI. Primary dege­neration of the internal anal sphincter as a cause of passive faecal incontinence. Lancet 1997; 349: 612-5. 10. Lubowski DZ, Nicholls RJ, Burleigh DE, Swash M. Internal anal sphincter in neurogenic fecal incon­tinence. Gastroenterology 1988; 95: 997-1002. 11. Nielsen MB, Rasmussen OO, Pedersen JF, Christi­ansen J. Anal endosonographic findings in pati­ents with obstructed defecation. Acta Radiol 1993; 34: 35-8. Endosonography of the puborectalis muscle- interobserver com­ parison of the anal and vaginal ultrasonography Iwona Sudol-Szopinska1, Marek Szczepkowski2, Anna Panorska3, Wieslaw Jakubowski1, Dariusz Sarti4 1Department of Diagnostic Imaging, Second Faculty of Medicine, Warsaw, Poland, 2Second Surgical Department, Bielany Hospital, Warsaw, Poland, 3Desert Research Institute-DHS, Reno, NV, USA, 4Department of Proctology, Warsaw County Hospital, Poland Background. The aim of this study was to compare the anal ultrasonography (AUS) and transvaginal ul­trasonography (TVUS) and also the interobserver variability assessment in the above comparison of visua­lization and dynamic activity assessment of the puborectalis muscle (PR). Patients and methods. AUS and TVUS were performed in 25 women aged 20-72 years (median age 42). All examinations were performed by Bruel and Kjaer system, using a 7.0-MHz rotating endoprobe covered with a water-filled hard cone. All women were examined by two operators and AUS and TVUS were per­formed in each case. Results. In 15 out of 25 women (60 %), a better definition of the PR was achieved in TVUS than in AUS. Both observers agreed with these findings. In the assessment of the PR function a discrepancy between the two methods and the two observers was found: in 4 women by both observers (16%) and in an additional 3 women by observer 1 (28 %). In all these cases, the PR function appeared to be better in TVUS than in AUS. Conclusions. AUS and TVUS enable assessment of the morphology and dynamic activity of the PR. In the majority of cases (60 %), the PR was better visualized by means of TVUS than in AUS. In the assessment of the PR function, both methods were inconsistent in 7 cases (28 %) by the operator 1 and in 4 cases (16 %) by the operator 2. In all these cases, TVUS showed a better PR function than AUS. In 3 cases (12 %), we found the interobserver disagreement in the PR function assessment. Key words: anal ultrasonography; vagina – ultrasonography; puborectal muscle Correspondence to: Iwona Sudol-Szopinska, MD, PhD, Zaklad Diagnostyki Ultrasonograficznej, Wo­jewódzki Szpital Bródnowski, ul. Kondratowicza 8, 03 285 Warszawa: Phone/Fax +48 22 811 95 91, Mobile 0 501 716 407; E-mail: mdyvonne@wp.pl or uro@waw.pl Received: 11 November 2001 Accepted: 4 January 2002 Introduction Anal ultrasound (AUS) enables accurate as­sessment of the anal sphincters and is a use­ful method in the diagnostics of patients with different pathologies of the anal canal, inclu­ding fecal incontinence. In addition to the vi­sualization of the internal anal sphincter, the anal ultrasound allows the assessment of the morphology and contraction activity of the striated muscles of the anal canal, including the puborectalis muscle (PR).1,2 AUS also supplements other traditional tests for the as­sessment of muscle contractions such as: electromyography (EMG), manometry and pudendal nerve terminal motor latency (PNTML).3-5 The visualization of the anal ca­nal is also possible after introduction of the endoanal probe into the lumen of the vagi­na.6-8 The assessment of the deep part of the anal canal, representing the PR location, is then possible. The PR muscle loops around the posterior wall of the anal canal and, du­ring contraction, creates a sharp angle betwe­en the rectum and the anal canal. It is this an­gle, together with the annulus anorectalis, that is considered to be among the most im­portant factors responsible for gas and feces continence.9 The aim of this study was twofold: 1. a comparison of the transvaginal ultraso­und (TVUS) and AUS with the use of the same anal endoprobe, and 2. an assessment of the interobserver variabi­lity in the above comparison of visualizati­on and dynamic activity assessment of the puborectalis muscle. Material and method Ultrasonography was performed on a group of 25 women aged 20-72 years (median age 42). Eighteen women were multiparous and 7 nulliparous. Four women had Crohn’s Disea­se (CD), 3 suffered from ulcerative colitis (UC), 2 had ileostomies because of UC, 1 had ileostomy because of CD and fecal inconti­nence after the delivery complicated by a third degree tear and recto-vaginal fistula, 1 had colostomy because of rectal adenocarci­noma, 2 suffered from constipations, 1 had a third degree tear after delivering a 4000 mg baby. The 11 remaining women did not suffer from any disturbances nor had a history of obstetric trauma or any surgery. Eight of the 25 women were incontinent: 1 nulliparous with UC for gas and 7 for gas and feces, including both women with the history of the perineal tear, 2 with UC and 3 other who were multiparous. To analyze the interobserver variability in the assessment of the PR contraction in TVUS and AUS, a study was designed with two doctors (observers). Each patient was examined by both of them. Before the study, they agreed on the examination procedure. All examinations were performed in the left lateral position. No bowel preparation was made. A Bruel and Kjaer ultrasound scanner type 1846 (Naerum, Denmark) was used. It was equipped with the 7.0 MHz rotating en-doprobe with the focal range of 2-5cm and co­vered with a hard sonolucent plastic cone (ex­ternal diameter 1.7 cm) and filled with degassed water. First, the probe was introduced into the lu­men of the vagina. Second, AUS was perfor­med. Each time, the PR echotexture, outlines and dynamic activity were assessed. The defect within the PR was defined on the basis of visualization of the hypoechoic area within the normal striated PR architectu­re and comparison with the opposite branch of this muscle. The muscle’s outlines were as­sessed as distinct or not well visible. The dynamic activity of the muscle was assessed according to a subjective scale as lack of, po­or or good (well visible) contraction. It was as­sessed on the basis of the comparison betwe­en the images of the PR taken at rest and during the maximal contraction. The results of the TVUS and AUS perfor­med by the two doctors were analyzed and compared retrospectively. The degree of agree­ment between the radiologists separately for AUS and TVUS was quantified. The percenta­ge of the patients in the study on whose results the radiologists were in agreement were pre­sented within the 95 % confidence intervals. The results of the two examination methods by the two radiologists were also compared. Results In 15 out of 25 women (60 %), a better defini­tion of the PR outlines together with its poste­rior loop was obtained by TVUS than by AUS. Both observers agreed with this assessment. In 2 women (8 %), a hypoechoic scar was visible in the right branch of PR. It was seen Table 1. Results of the study by observer and diagno­stic method Number TVUS 1 AUS 1 TVUS 2 AUS 2 of patients 1 0 0 0 0 2 1 1 1 1 3 1 1 1 1 4 2 1 2 1 5 2 0 2 0 6 2 2 2 2 7 2 2 2 2 8 2 2 2 2 9 1 1 1 1 10 2 2 2 2 11 2 1 2 1 12 1 0 1 0 13 0 0 0 0 14 1 1 1 1 15 2 2 2 2 16 2 2 2 2 17 1 0 1 1 18 1 1 1 1 19 2 1 1 1 20 0 0 0 0 21 2 2 2 2 22 2 1 1 1 23 1 1 1 1 24 2 2 2 2 25 0 0 0 0 TVUS1 = transvaginal ultrasonography made by radi­ologist 1; AUS1 = anal ultrasonography made by radi­ologist 1; TVUS2 = transvaginal ultrasonography ma­de by radiologist 2; AUS2 = anal ultrasonography made by radiologist 2 0 = lack of contraction of the puborectalis muscle; 1 = poor contraction; 2 = good contraction of the puborec­talis muscle in both TVUS and AUS by both observers. Both women had episiotomies. In the PR function assessment, a discre­pancy between two methods and two obser­vers was noted (Table 1). Discrepancies bet­ween TVUS and AUS results were found by both observers in 4 women (16 %) and in an additional 3 only by observer 1 (7 women, 28 %). These discrepancies between the dia­gnoses of both radiologists in the 4 women were as follows: PR good contraction in TVUS and poor in AUS – 2 cases; PR poor contraction in TVUS and lack of it in AUS – 1 case; PR good contraction in TVUS and lack of it in AUS – 1 case. Additionally, only observer 1 found the following differences in diagnoses for 3 more women: a) PR good contraction in TVUS and poor in AUS – 2 cases; b) PR poor contraction in TVUS and lack of it in AUS – 1 case. In each of these 3 cases, the observer 2 consistently diagnosed poor PR contraction using both techniques. In the remaining 18 cases (72 %), the diagnoses of both observers for both methods were unanimous as follows: a) PR good contraction – 8 cases; b) PR poor contraction – 6 cases; c) PR lack of contraction – 4 cases. Discussion Anal ultrasound is a reliable method for the visualization of the layered structure of the anal canal and it is a useful method for the di­agnostics of the anal canal diseases and con­sequences of injuries to the anorectal area. The visualization of the anal canal is also pos­sible using the transvaginal approach which has several advantages.7 First, the anus is not disturbed, not compressed by the insertion of the probe into the lumen of the anal canal, so the inner diameter of the IAS, its thickness and anal cushions may be measured in their true resting state.7 Although this characteri­stics are of little diagnostic value with regard to the anal incontinence, this approach may allow the assessment of the anal canal if pain or stenosis are present. In the study by Poen et al.8, TVUS added important information to that obtained by AUS in 25 % of the patients with fecal incontinence and perianal sepsis. In spite of a limited visualization range being considered as drawback of TVUS, the same study8 concluded that it was not possible to image the anal sphincters in only 10 % of the patients. In the remaining 90 % the IAS, EAS and PR were visible and the defects such as sepsis possible to diagnose. The PR passes di­rectly backward from the back of the pubis with its inner surface in contact with the late­ral walls of the vagina or prostate and the anorectal junction.9 Two legs of the PR meet at the posterior of the anorectal junction to form a sling with the angle to the anorectal junction of 92 ° during rest and 137 ° during straining.9 The main function of the PR is to contribute to the maintenance of the anorec­tal angle, thereby producing a flap valve ef­fect when the intra-abdominal pressure ri­ses.9 This effect can not be visualized by defecography and only EMG is available to determine the contribution of the EAS and the PR to the continence and defecatory me­chanisms.9 The denervation of the PR in ca­ses of idiopathic fecal incontinence can also be demonstrated using transrectal PNTML measurements.9 Although the results of ma-nometry correlate well, but not always with EMG potentials for the EAS,9 the assessment of only the PR is not possible with the use of manometry. The loop of the PR is well visible in AUS and appoint the deep part of the anal canal. Transvaginal PR assessment is a useful ad­junct technique to the standard anal ultraso­nography. In spite of being limited to the de­ep canal level, TVUS, in many cases, allows a better visualization of the PR than AUS. In our study, such a situation was observed in 15 women (60 %) where both observers noted better visualization of the PR by TVUS than by AUS. We felt that an effect of perspective created by the distance between the vagina and the anal canal was the most probable re­ason for this finding. This perspective provi­ded a better visualization of the whole loop of the PR and its external outlines as well as the muscle contraction. We therefore believe that the difficulties in the visualization of the po­sterior side of the EAS using TVUS, mentio­ned by Poen et al.8 referred to the subcutane­ous and superficial parts of the anal canal not its deep part and the level of PR, which is very well visible by TVUS.7 Another finding of Poen et al.8 was a poor correlation between TVUS and AUS in diagnosing the defects of the EAS which were seen in AUS but could not be reproduced by TVUS. The authors sug­gested that AUS might have overestimated the EAS defects and suspected that the arti­facts from the air in vagina or fibres from the deep transverse perineal muscle or stretching the anal canal by a probe might have been responsible for that result. Again, this study referred only to the EAS and not the PR and we could not find any data in the literature concerning solely the PR and diagnosing its defects. In 8 % of our patients (two women), the hypoechoic defects were seen in the right branches of the PR. Both women had a hi­story of episiotomies and both defects were seen by the two observers in TVUS and AUS. We do not have any reason to suspect any overaging of one method over another in de­fining the defects of the PR. Generally, beca­use the definition of this muscle in TVUS as well as in AUS is very good and much less, if not at all, controversial to the EAS image, we believe that our diagnoses were correct. Apart from the morphology of the anal ca­nal muscles, endosonography enables the as­sessment of the contraction activity of the striated muscles of the anal canal, including PR.1 The imaging technique during the con­traction of the anal sphincter is already known as a useful adjunct to the standard study at rest.1 Given a better definition of the EAS, it is helpful in defining the defects in 62 % of the patients. Because continence depends on the functi­on of these muscles, their accurate diagnosis requires, first of all, an assessment of the ne­uromuscular axis of the anorectum. The eva­luation usually begins with the palpation fol­lowed by manometric measurement of pres­sures within the anal canal at rest and during squeezing or by means of EMG. PNTML is al­so assessed.6 Although manometry is the most widely used examination of the anal sphincter function, the assessment of the PR only cannot be achieved by this method. Ad­ditionally, in the patients with a deep defect of the EAS, the manometry does not always correlate with AUS findings and usually shows a normal function of the EAS. The rea­son can be a pull-through technique of mano­metry which may show a short anal canal or suggest a proximal defect, whereas a sleeve technique will not give this information.10 Si­milarly, EMG, although correlating highly with AUS in mapping of the EAS defects, is suitable only for the assessment of a superfi­cial and subcutaneous parts of the EAS.11 The deep parts of the EAS and PR are beyond the reach of the standard 3 cm concentric nee­dles.10,11 In short, it is difficult to assess the function of the PR. First, apart from the limi­tations of the most common methods presen­ted above, the majority of these methods can­not differentiate between the striated mu­scles, the EAS and PR. Second, interpretation of the findings of these tests frequently dif­fers from one radiologist to another. Finally, they do not provide the surgeon with the ana­tomic information needed to plan an anato­mic repair.2,6 AUS enables a clear imaging of the IAS, the EAS and the PR. The accuracy of clinical examination in diagnosing these mu­scles’ defects is 50 %, whereas that of EMG and of anal manometry is 75 % each.2 AUS is more accurate than clinical and conventional physiological methods.2 We did not find any data in the literature referring to the possibi­lities of endosonography in the assessment of the function of either the PR or EAS. This is not surprising since this examination is focu­sed on the imaging of the morphology rather than physiology of the anal muscles. In this study, we found such a possibility for both AUS and TVUS which, especially in the light of the above difficulties in assessing the func­tion of the PR, could have a considerable dia­gnostic value. In the majority of women (18 women; 72 %), the assessment of the PR contraction (i.e. lack/poor/good) was identical in TVUS and AUS. The 95 % confidence interval for the overall percentage of identical diagnoses using TVUS and AUS was then 50.4 % and 87.1 %, respectively. We also analyzed the percentage of identical diagnoses for each ra­diologist. The 95 % confidence intervals for these individual percentages were 50.4 % and 87.1 % for radiologist 1 and 63.1 %, 94.7 % for radiologist. In order to find out whether the two diagnostic methods yielded significantly different results, we needed to decide on a threshold percentage of identical diagnoses. The threshold would be used as an evaluation tool. If the confidence interval for the percen­tage of identical diagnoses reaches the thre­shold, we may infer that the two diagnostic methods do not differ significantly. We deci­ded to use a subjective, yet reasonable thre­shold of 85 %. Since all above confidence in­tervals reach the threshold of 85 %, we may conclude that with reference to 95 % confi­dence level the two diagnostic methods do not differ significantly. The details about the differences in diagnoses using TVUS and AUS are presented below. Discrepancies were noted in 7 women by operator 1 and, in 4 of them, also by operator 2. In all these cases, the result of TVUS was better than that of AUS, i.e. the lack of or po-or PR contraction in AUS appeared poor or go­od in TVUS. In one case, confirmed by the two operators, the discrepancy was most pronoun­ced. A good contraction of the PR, detected by TVUS could not be confirmed by AUS, which showed a lack of contraction. None of these seven women with inconsistent diagnoses of the PR function suffered from fecal inconti­nence. All women with the symptoms of fecal incontinence were in the group of 18 women for whom both operators on the basis of two approaches consistently diagnosed the lack of contraction of the PR (4 women) and poor con­traction (3 women). The eighth woman incon­tinent only for gas had good contraction of the PR. It is known that the damage to the PR may be inflicted during parturition.10 All (10) wo­men with impaired (poor or lack of) PR con­traction diagnosed by both radiologists by TVUS and AUS were multiparous. Two of them had additional history of the third de­gree perineal tear and two suffered from UC. Two women suffering from constipations had normal function of the PR seen by the two operators by both methods, TVUS and AUS. It is known that, in idiopathic anorectal inconti­nence and rectal prolapse, with or without in­continence, often associated with a long hi­story of excessive straining during defecation in the constipated patients, the PR is not at all or only sligthly damaged.10,12 The innervation of the PR is most probably responsible for its preserved function in constipated patients. Li­kewise the anterior part of the EAS, the PR and levator ani muscle receive innervation from the perineal nerve.13 The main nerve supply to PR arises from the direct branches of S3 and S4 reaching the muscle from above the pelvic floor.10 We assume that two reasons could be res­ponsible for the discrepancies in the diagno­sis of the PR contraction by TVUS and AUS (7 cases by operator 1 and 4 cases by operator 2). First, similar to a better visualization of the PR in TVUS, a better assessment of its acti­vity by TVUS could be due to a different pers­pective that we achieved from the lumen of the vagina. Second, the discrepancies could be due to a kind of mental sensation in some patients who were unable to contract PR na­turally having the probe introduced into the anal canal. Thus, the PR function visualized by TVUS was better. In our study, we did not observe any reverse reaction, namely worse (i.e. lack or poor) PR contraction by TVUS and better (i.e. good or poor) by AUS. This finding is in accordance with the second sug­gestion above. Moreover, it was supported by clinical data. Except multiple deliveries in 6 out of 7 women with worse diagnosis of the PR contraction by AUS than by TVUS, all had a history of peritoneal tear or constipation, therefore, we did not have any reasons to sus­pect that TVUS was incorrect. In the assessment of the PR morphology in all 25 examined cases, the diagnoses of the two observers agreed. Knowing the endoso­nographic appearance of the PR, it is not dif­ficult to recognize its defects. Such finding se­ems to be objective. The interpretation of the dynamic activity of the PR varied between the two operators and caused some diagnostic differences in our study. In 3 cases (12 %), we found the interobserver variability in the esti­mation of the PR contraction. This variability could have been due to a subjective scale we have used to assess the PR function. An objective scale, like the flow measurements, B-mode and Doppler ultrasound measure­ments, does not eliminate all the interobser­ver variability.14 In an ideal situation, the da­ta variance due to observers should be non-significant and the effect of the operator can be eliminated entirely by cooperative tra­ining and surely by using the same operator in both examinations.14 In this study, we chose 85 % as a threshold of agreement between the radiologists as ade­quate to define insignificant interobserver va­riability at a 95 % confidence level. We quantified the degree of agreement between the radiologists separately for TVUS and AUS. For TVUS, a 95 % confidence inter­val for the percentage of agreement was 72.5 % and 98.6 %, respectively. For AUS, the corresponding confidence interval was 77.7 % and 99.8%, respectively. The overall percenta­ge of agreement between the two radiologists and for both methods was 72 % (18 patients out of 25) with a 95 % confidence interval (50.4 %, 87.1 %). Since our threshold of 85% was attained by all confidence intervals, we may conclude that the interobserver variabi­lity, although present, was not significant. Conclusions AUS is currently a method of choice for obta­ining detailed images of the IAS, EAS and PR. It is unable to detect denervation of the EAS and PR, although the identification of the sphincters with no scars, a thickened IAS and a decreased anal sonography index (which means thin EAS and thick IAS) seem to be the indicators of a denervation pathogene­sis.15 Because it is painless, available, inex­pensive and rapid, AUS is recommended as the examination suitable for screening.3,4 Our study showed that AUS and TVUS of the anal canal can be useful adjuncts to physiologic studies of anorectal function. Of course, as imaging techniques they are not the methods of choice for the assessment of the anorectal functions. For this purpose, anal manometry, EMG and PNTML are suggested because they offer full and objective estimation of the func­tional disorders of the anal sphincters. The anal ultrasound supported by transvaginal ul­trasonography seem to be valuable methods in assessing the PR morphology. They are al­so very promising in initial diagnosis of the PR function indicating an eventual necessity to perform more precise, more objective but less available method as e.g. manometry or EMG. References 1. Rieger NA, Downey PR, Watchow DA. Short com­munication: endoanal ultrasound during contracti­on of the anal sphincter – improved definition and diagnostic accuracy. Br J Radiol 1996; 69: 665-7. 2. Sultan AH, Kamm MA, Talbot IC, Nicholls RJ, Bar­tram CI. Anal endosonography for identification external sphincter defects confirmed histologi­cally. Br J Surg 1994; 81: 463-5. 3. Law PJ, Kamm MA, Bartram CI. A comparison bet­ween electromyography and anal endosonography in mapping external anal sphincter defects. Dis Colon Rectum 1990; 33(5): 370-3. 4. Tjandra JJ, Milsom JW, Schroeder T, Fazio VW. Endoluminal ultrasound is preferable to electrom­yography in mapping anal sphincteric defects. Dis Colon Rectum 1993; 36(7): 689-92. 5. Hill MC, Rifkin MD, Tessler FN. Ultrasound eva­luation of the anal sphincter in fecal incontinence. Ultrasound Quarterly 1998; 14(4): 209-17. 6. Alexander AA, Liu JB, Merton DA, Nagle DA. Fe­cal incontinence: transvaginal US evaluation of anatomic causes. Radiology 1996; 199: 529-32. 7. Frudinger A, Bartram CI, Kamm MA. Transvaginal versus anal endosonography for detecting damage to the anal sphincter. AJR 1997; 168: 1435-8. 8. Poen AC, Felt-Bersma RJ, Cuesta MA, Meuwissen GM. Vaginal endosonography of the anal sphinc­ter complex is important in the assessment of fae-cal incontinence and perianal sepsis. Br J Surg 1998; 85: 359-63. 9. Rasmussen O. Anorectal function. Dis Colon Rec­tum 1994; 37: 386-403. 10. Bartolo DC, Jarratt JA, Read MG, Donnelly TC, Re­ad NW. The role of partial denervation of the pu­borectalis in idiopathic faecal incontinence. Br J Surg 1983; 70: 664-7. 11. Rieger NA, Sweeney JL, Hoffmann DC, Young JF, Hunter A. Investigation of fecal incontinence with endoanal ultrasound. Dis Colon Rectum 1996; 39(8): 860-4. 12. Burnett SJ, Speakman CT, Kamm MA, Bartram CI. Confirmation of endosonographic detection of ex­ternal anal sphincter defects by simultaneous elec­tromyographic mapping. Br J Surg 1991; 78: 448-50. 13. Parks AG, Swash M, Urich H. Sphincter denerva­tion in anorectal incontinence and rectal prolapse. Gut 1997; 18: 656-65. 14. Paivansalo MJ, Suramo I, Merikanto J, Lindholm EL. Interobserver, interequipement and intersu­bject variability of echo-Doppler examination of the common carotid and vertebral arteries. Eur J Ultrasound 1998; 7: 145-51. 15. Emblem R, Dhaenens G, Stien R, Morkrid L, Aa-sen AO, Bergan A. The importance of anal endoso­nography in the evaluation of idiopathic fecal in­continence. Dis Colon Rectum 1994; 37(1): 42-8. Modulation of radiotherapy- and chemotherapy-induced normal tissue response as prophylaxis of their side effects Pavlína Plevová Department of Radiotherapy, University Hospital, Ostrava, Czech Republic Background. Ionising radiation and cytostatic agents used in cancer therapy induce an immune response in normal tissues mediated by cytokines and adhesion molecules. Strategies modulating this response may downregulate cancer therapy side effects. The data published on the given topic have been reviewed. Conclusions. The strategies influencing the tissue immune response with the aim to reduce the side effects of chemotherapy and radiotherapy are conflicting. Some of them inhibit this response supposing that an exaggerated reaction may have a damaging effect (e.g. corticosteroids, nonsteroidal anti-inflammatory drugs (NSAID), lisofylline, anti-cytokine antibodies, anti-sense oligonucleotides, sialyl Lewis X analogues), others promote this reaction by inducing endogenous production of cytokines (AS101) or use recombinant forms of appropriate cytokines involved in this response in order to intensify the physiologic tissue response. In clinical practice, corticosteroids and NSAID are widely used to modulate this response, while other agents are still experimental. Key words: radiotherapy – adverse effects; antineoplastic agents; antineoplastic agents – adverse effects; adjuvant, immunologic Introduction Ionising radiation and cytostatic agents used in cancer therapy exert damaging effects on normal tissues and induce there a complex response at the cellular and molecular levels. Cytokines and adhesion molecules are relea- Received 25 February 2002 Accepted 11 March 2002 Correspondence to: Pavlína Plevová, M.D., Fr. Lyska 8, Ostrava-Belsky les, 700 30 Czech Republic, Phone: +420 69 6717841 or +420 69 6984370; Fax: +420 69 6919010; E-mail: pavlina.plevova@volny.cz sed during this response and mediate inter-cellular interactions among the effectors of immune and other systems.1,2 Medical strate­gies that modulate this response in order to reduce chemotherapy- and radiotherapy-in­duced side effects are contradictory. Some of them inhibit this reaction, and their use is ba­sed on the hypothesis that exaggerated or persisting inflammatory response enhances the tissue damage; others stimulate this res­ponse in order to enhance physiological pro­tective processes. Acknowledgements: The author is indebted to Pavel Vodvárka for his helpful comments and Lenka Zivcáková for technical assistance. a) Inhibition of the tissue response Glucocorticoids exert strong anti-inflamma­tory effects including inhibition of pro-in­flammatory cytokine production.1-5 The mole­cular mechanism of their effects is not com­pletely understood, but they inhibit the acti­vity of some transcription factors.3 In clinical practice, corticosteroids are used to prevent or treat chemotherapy-induced nausea and vomitus6 and to prevent radiation- and che-motherapy-induced pneumonitis and fibro­sis.7,8 Although corticosteroids suppressed radiation pneumonitis in an experimental model they were not able to reduce pulmo­nary fibrosis development.9 In another study, short-term use of dexamethasone suppressed temporarily radiation-induced pro-inflamma­tory cytokine gene expression in the mouse lung, but a rebound was observed after the drug withdrawal and the drug did little to change the essence and course of the pneu­monitic process.10 Dexamethasone is widely used in the prophylaxis of radiation-induced brain oedema and inflammation; this effect was demonstrated on an experimental mo­del.7,11 Dexamethasone significantly reduces the incidence of the somnolence syndrome after prophylactic cranial irradiation in chil­dren with leukemia.12 Betamethasone was be­neficial in radiation-induced oral mucositis in a few patients.13 Dexamethasone delays the development of experimental radiation ne­phropathy; it does not stop the progression of injury.14,15 Captopril, an angiotensin conver­tase enzyme inhibitor, enhanced the benefici­al effect of dexamethasone in radiation ne­phropathy.15 Corticosteroids suppress cytoki­ne secretion in irradiated animal skin.16 They reduce hematotoxic effects of 5-fluorouracil and methotrexate, but not of other cytostatic agents in an experimental model.17 Nonsteroidal anti-inflammatory drugs (NSAID) inhibit the prostaglandin synthesis through cyclooxygenase blockade,18 activati­on of the transcription factor of nuclear factor .B (NF-.B)19 and adhesion of neutrophils as a result of a decreased expression of L-selecti­ne.18 In clinical practice, they are used in the treatment of fever, pain, and fatigue associa­ted with chemotherapy and radiotherapy. Mesalazine has been studied in the preventi­on of oral mucositis;20 however, the result of this non-randomised study lacks clinical rele­vance. Indomethacine did not influence the survival of lethally irradiated mice.21 Lisofylline is a xanthine derivative able to inhibit the release of various cytokines, such as TNF-a, TGF-ß, MIP-1a, IFN-., Il-1ß, IL-6, IL-10.22,23 Its mechanism of action is thought to involve inhibition of acyl-substituted unsa­turated phosphatidic acid, a second messen­ger lipid implicated in pro-inflammatory cyto-kine cellular activation.24,25 It also decreases white cell adhesiveness.26 Lisofylline inhibi­ted 5-fluorouracil-induced release of TGF-ß and maybe also other hematopoiesis inhibi­ting cytokines and thus enhanced trilineage hematopoietic recovery after 5-fluorouracil treatment in mice.27 Pentoxifylline is a xanthine derivative with profound immunomodulatory properties in vitro, including inhibition of TNF-a, Il-1ßand IL-10 release.23,28 Elevated levels of TNF-aha­ve been shown to correlate with both the de­velopment and severity of transplantation-re­lated complications.29 Although pentoxifylli­ne reduced these complications in a study,30 these results were not reproduced in others including the one focused on 5-fluorouracil-induced oral mucositis.31-33 The results of a study with a TNF-aneutra­lising monoclonal antibody in transplant pa­tients lack clinical significance.34 Intravenous immunoglobulin, especially in high doses, has profound immunomodula­tory effects, including the inhibition of anti-inflammatory cytokine release;35,36 in additi­on, high TGF-ß concentrations have been detected in intravenous immunoglobulin pre­parations.37 Intravenous or intramuscular im­munoglobulin has been studied sporadically in the prophylaxis or therapy of irradiation or chemotherapy-induced oral mucositis and ra­diation pneumonitis. It is not possible to ma­ke a definite conclusion of its effects from these results.38-41 As TGF-ßplays an important role in the pa­thogenesis of fibrosis development, its inhibi­tion might reduce the risk of this complicati­on. Neutralising antibodies to both TGF-ß1 and TGF-ß2 significantly reduced the bleomy­cin-induced increase in the accumulation of lung collagen in an experimental model;42 However, fibrosis was ameliorated only parti­ally.43 TGF-ß antisense oligonucleotides, short synthetic deoxyribonucleotide oligo­mers complementary to DNA, prevent prote­in production.44 They have been investigated in the prevention of experimental peritoneal fibrous adhesions.45 There are no reports on their use in association with chemotherapy or radiotherapy. IL-4 has been shown to be able to downre­gulate radiation-induced production of medi­ators of inflammation, including IL1ß in the lung, suggesting its anti-inflammatory poten­tial in regulating the radiation-induced res­ponse.46 Interferon ., taurine, and niacin reduced bleomycin-induced pulmonary fibrosis in an animal model via TGF-ßinhibition and subse­quent procollagen expression downregula­ tion.47-49 The endothelial selectins (E-selectin and P-selectin) bind to sialylated tetrasaccharide si­ alyl Lewis X and A counter receptors on neu­trophils, monocytes and lymphocytes, media­ting their emigration into the tissue.50,51 The analogues of sialyl Lewis X such as glycyrrhi­zin and carminic acid bind to E-selectin on ir­radiated endothelial cells and thereby inhibit adhesion of leukocytes and inflammatory res­ponse in vitro.52 b) Stimulation of the tissue response It has been known for more than forty years that immunomodulators stimulating the cells of the reticulo-endothelial system can protect against deleterious effects of radiation.53 AS 101 (ammonium trichloro (dioxyethyle-ne-0,0’) tellurate) stimulates some subpopula­tions of white cells and increases the release of various cytokines, including IL-1, IL-2, IL­6, TNF-a, GM-CSF, stem cell factor (SCF), and IFN-..54-57 AS 101 reduces hematotoxic effects of cyclophosphamide, 5-fluorouracil, doxorubicine, lomustine, carboplatin and eto-poside,56-59 and alopecia after carboplatin and etoposide.57 It also has been shown to exert radioprotective effects.60 The physiological role of cytokines in the immune response and tissue regeneration has led to experiments studying the effective­ness of recombinant forms of cytokines in the protection of normal tissues from damaging effects of chemotherapy and radiotherapy. The results of these experimental studies we­re successful, depending on the schedule and the dose of the cytokine used.61,62 Recombinant IL-1a, TNF-a, INF-. admini­stered before treatment reduced hematotoxic effects of both irradiation and chemotherapy with various agents.21,62-70 G-CSF, GM-CSF, SCF act as radioprotectors both in vitro and in vivo;71-75 on the contrary, their concomitant administration with chemotherapy increases the sensitivity of hematopoietic cells to its cytotoxic effects.76 MIP-1a exerts chemopro­tective effects on bone marrow cells.77 IL-1a also reduced small gut and lung toxicity of ra­dio- or chemotherapy.78-80 The combination of IL-1 and TNF-a had synergistic effects.66 Both cytokines are relati­vely toxic due to their physiological roles in inflammation, especially after systemic appli­cation.81 G-CSF and GM-CSF are well tolera­ted and potentiate radioprotective effects of IL-1.66 Local application of TGF-ß3 on oral muco­sa significantly reduced the 5-fluorouracil-in­duced oral mucositis in hamsters.82,83 IL-1, EGF, FGF have been shown to protect mice against ARA-C-induced alopecia.84,85 The mechanism of the protective effects of cytokines might be explained by the following hypothesis: 1) Exogenous cytokines activate the physiological pathways of immune res­ponse through their receptors, thus activating and amplifying the defence of the organism. The induction of enzymes with antioxidant ef­fects86,87 could be a part of this response. 2) Some cytokines, such as IL-1 or SCF, may di­rectly or indirectly, through release of other cytokines, stimulate hematopoietic progenitor cells.61,62,74 3) Cytokines might inhibit the cell proliferation, thus reducing the sensitivity to proliferation-inhibiting agents or inducing the cell-cycling so that the cells enter into the rela­tively radio- or chemoresistent phases of the cell cycle, the S and G1 ones.61,77 4) Certain cytokines, such as IL-6, IFN-., GM-CSF, inhi­bit cell apoptosis including its cytotoxic agents- and irradiation-induced activation.88-91 Conclusions The modulation of the tissue response to the damaging effects of radiotherapy and chemo­therapy may reduce toxic effects of these trea­tment modalities. Only corticosteroids and NSAID are used in clinical practice to reduce acute toxicity of cancer therapy. The agents that could affect late sequels are studied expe­rimentally; AS101 is being tested at the clinical level. The response-modifying use of recombi­nant cytokines to reduce toxicity of radiothe­rapy or chemotherapy did not progress into cli­nical usage. The local use of TGF-ß in association with chemotherapy-induced oral mucositis is promising. The suppression of the inflammatory res­ponse must be used with caution in the clini­cal practice, however. Although corticostero­ids are beneficial in the modulation of acute side effects, this effect results from inhibition of the protective response that is of pivotal importance in the maintenance of organism integrity and whose suppression might have detrimental end-effects as has been demon­strated by reduced survival of mice that were administered dexamethasone after irradiati­ on.92,93 References 1. Thalmeier K, Meissner P, Reisbach G, Hültner L, Mortensen BT, Brechtel A, et al. 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The in vivo effects of interleukin 1: I. Bo­ne marrow cells are induced to cycle after admini­stration of interleukin 1. J Immunol 1987; 139: 1861-6. 65. Castelli MP, Black PL, Schneider M, Pennington R, Abe F, Talmadge JE. Protective, restorative and therapeutic properties of recombinant human IL-1 in rodent models. J Immunol 1988; 140: 3830-7. 66. Neta R, Oppenheim JJ, Douches SD. Interdepen­dence of the radioprotective effects of human re­combinant interleukin 1, tumor necrosis factor, granulocyte colony-stimulating factor, and murine recombinant granulocyte-macrophage colony-sti­mulating factor. J Immunol 1988; 140: 108-11. 67. Futami H, Jansen R, MacPhee MJ, Keller JR, McCormick K, Longo DL, et al. Chemoprotective effects of recombinant human IL-1a in normal and tumor-bearing mice. Protection from acute to­xicity, hematologic effects, development of late mortality and enhanced therapeutic efficacy. J Im­munol 1990; 145: 4121-30. 68. Slordal L, Warren DJ, Moore MAS. 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Comparative analysis of the in vivo radioprotecti­ve effects of recombinant granulocyte colony-sti­mulating factor (G-CSF), recombinant granuloc-yte-macrophage CSF, and their combination. Blood 1991; 77: 2364-71. 74. Zsebo KM, Smith KA, Hartley CA, Greenblatt M, Cooke K, Rich W, et al. Radioprotection of mice by recombinant rat stem cell factor. Proc Natl Acad Sci USA 1992; 89: 9464-8. 75. Liebmann J, DeLuca AM, Epstein A, Steinberg SM, Morstyn G, Mitchtell JB. Protection from le­thal irradiation by the combination of stem cell factor and tempol. Radiat Res 1994; 137: 400-4. 76. Meropol NJ, Miller LL, Korn EL, Braitman LE, MacDermott ML, Schuchter LM. Severe myelo-suppression resulting from concurrent admini­stration of granulocyte colony-stimulating factor and cytotoxic chemotherapy. J Natl Cancer Inst 1992; 84: 1201-3. 77. Dalmau SR, Freitas CS, Savino W. Radio- and che­moprotection of bone marrow cells by opposite cell cycle-acting cytokines. Leuk Res 1997; 21: 93-9. 78. Neta R, Douches S, Oppenheim JJ. Interleukin 1 is a radioprotector. J Immunol 1986; 136: 2483-5. 79. Dorie MJ. Protection by interleukin 1 against lung toxicity caused by cyclophosphamide and irradia­tion. Radiat Res 1991; 128: 316-9. 80. Damia G, Komschlies KL, Futami H, Back T, Gruys ME, Longo DL, et al. Prevention of acute chemotherapy-induced death in mice by recombi­nant human interleukin 1: protection from hema­tological and nonhematological toxicities. Cancer Res 1992; 52: 4082-9. 81. Maisin JR. Bacq and Alexander Award Lecture. Chemical radioprotection: past, present and futu­re prospects. Int J Radiat Biol 1998; 73: 443-50. 82. Sonis ST, Lindquist L, van Vugt V, Stewart AA, Stam K, Qu GY, et al: Prevention of chemothe- rapy-induced ulcerative mucositis by transforming growth factor ß3. Cancer Res 1994; 54: 1135-8. 83. Sonis ST, van Vugt AG, Brien JP, Muska AD, Bru-skin AM, Rose A, et al. Transforming growth fac­tor-ß3 mediated modulation of cell cycling and at­tenuation of 5-fluorouracil induced oral mucositis. Oral Oncol 1997; 33: 47-54. 84. Jimenez JJ, Wong GH, Yunis AA. Interleukin 1 protects from cytosine arabinoside-induced alope­cia in the rat model. FASEB J 1991; 5: 2456-8. 85. Jimenez JJ, Yunis AA. Protection from 1-beta-D­arabinofuranosylcytosine-induced alopecia by epi­dermal growth factor and fibroblast growth factor in the rat model. Cancer Res 1992; 52: 413-5. 86. Masuda A, Longo DL, Kobayashi Y, Appella E, Oppenheim JJ, Matsushima K. Induction of mito­chondrial manganese superoxide dismutase by in­terleukin 1. FASEB J 1988; 2: 3087-91. 87. Wong GHW, Goeddel DV. Induction of mangano-us superoxide dismutase by tumor necrosis factor: possible protective mechanism. Science 1988; 242: 941-4. 88. Lotem J, Sachs L. Differential suppression by pro­tease inhibitors and cytokines of apoptosis indu­ced by wild-type p53 and cytotoxic agents. Proc Natl Acad Sci USA 1996; 93: 12507-12. 89. Lotem J, Sachs L. Control of apoptosis in hemato­poiesis and leukemia by cytokines, tumor sup­pressor and oncogenes. Leukemia 1996; 10: 925-31. 90. Lotem J, Sachs L. Cytokine suppression of protea­se activation in wild-type p53-dependent and p53­independent apoptosis. Proc Natl Acad Sci USA 1997; 94: 9349-53. 91. Mor F, Cohen IR. IL-2 rescues antigen-specific T cells from radiation or dexamethasone-induced apoptosis. Correlation with induction of Bcl-2. J Immunol 1996; 156: 515-22. 92. Nam SY, Cho CK, Kim SG. Correlation of increa­sed mortality with the suppression of radiation-in­ducible microsomal epoxide hydrolase and gluta­thione D-transferase gene expression by dexamethasone: effects on vitamin C and E-indu­ced radioprotection. Biochem Pharmacol 1998; 56: 1295-34. 93. Rudat V, Kupper JH, Weber KJ. Trans-dominant inhibition of poly(ADP-ribosyl)ation leads to de­creased recovery from ionizing radiation-induced cell killing. Int J Radiat Biol 1998; 73: 325-30. review Lymphangioleiomyomatosis Franc Anderluh Department of Radiotherapy, Institute of Oncology, Ljubljana, Slovenia Background. Lymphangioleiomyomatosis is a rare disease of unknown origin, which affects women in the­ir reproductive period. It is characterised by non-neoplastic proliferation of atypical smooth muscle cells in the lung parenchyma, lymphatic vessels and mediastinal and abdominal lymph nodes. The most common presenting symptoms are spontaneous pneumothorax, dyspnea, hemoptysis and chylothorax. Conclusions. High-resolution computed tomography (HRCT) and open lung biopsy followed by the immu­nohistologic studies are two diagnostic procedures with which diagnosis can be confirmed. Various trea­tment modalities are applied, particularly hormonal therapy, though their efficacy remain unknown. The prognosis of patients is bad. Key words: lymphangiomyomatosis – diagnosis – therapy Introduction Lymphangioleiomyomatosis (LAM) is a rare disease of unknown origin which occurs ex­clusively in women. It is characterised by non-neoplastic proliferation of atypical smo­oth muscle cells in the lung parenchyma and thoracic and abdominal lymph nodes and lymphatic vessels. This leads to progressive loss of lung function and, ultimately, death. The disease was first mentioned in medical li­terature in 1937, and until today, not much has been known about its aetiology and trea­tment efficacy. The incidence varies from co­untry to country and it seems to be increasing Received: 22 January 2002 Accepted 5 February 2002 Correspondence to: Franc Anderluh, MD, Department of Radiotherapy, Institute of Oncology, Zaloška 2, 1000 Ljubljana, Slovenia; Fax +386 1 43 14 180. in recent years, which is probably due to a more extensive use of, and easier accessibility to the high-resolution computed tomography (HRCT) that is essential in LAM diagnosing.1 According to some estimates, there are aro­und 300 cases of LAM in the USA, whereas exact data for Slovenia are not available. In the last 20 years, 2 cases have been diagnosed at the Clinical Department of Pulmonary Di­seases and Allergology at Golnik, Slovenia.2 The first study in which the data on a gre­ater number of patients was gathered, was the study by Cornog and Enterline which was published in 1966. They examined 20 pati­ents with the disease that is today known as LAM and was earlier referred to as lymphan­gioma, lymphangiomyoma, lymphangioperic­ytoma, leiomyomatosys, lymphangious mal­formation and intrathoracic angiomatous hyperplasia. In these first reports arguments were made in favour of the malignant charac­ter of the disease because of the diffuse and extensive infiltration of smooth muscle cells into the soft tissue, lymphatic vessels and lymph nodes in the thorax and abdomen. Cornog and Enterline supported the view that the disease could not be regarded as mali­gnant because of a well organised structure of lung lesions and absence of mitotic overacti­vity, cell atypia and distant metastases.3 Several authors also suggest that LAM may be a form of tuberous sclerosis complex (TSC). TSC is an autosomally inherited form of conge­nital hamartomatosis, which usually affects the skin and central nervous system. It is cha­racterised by mental retardation, epileptic at­tacks and angiofibromas on the face. The inci­dence of the disease is similar in both sexes. In contrast to epileptic attacks, the TSC pulmo­nary lesions develop only in adults and are de­tected in only 0,1-2-3 % of all patients, of whom 84 % are women. Histologically, TSC pulmo­nary lesions are similar to that of LAM lesi­ons.4 Nevertheless, the relation between TSC and LAM has not been definitely confirmed.5 Clinical features LAM usually affects women aged 30 to 40 ye­ars although several patients have been dia­gnosed as having LAM after menopause. The initial and typical signs and symptoms are advancing dyspnea on exertion, cough, he-moptysis and recurrent pneumothorax. Other signs and symptoms that develop later in the course of the disease are persistent dry co­ugh, chest pain, chylous pleural effusion and chylous ascites. The interrupted lymphatic flow may result in the chylous ascites, chylop­tysis, chyluria, chylous pericardial effusion and oedema of the lower extremities. The physical examination may reveal crackles and wheezing, clubbing and signs and symptoms of pneumothorax, pleural effusion and asci­tes.6 The rate of the disease progress varies from case to case and the survival usually ranges from 10 to 20 years from the diagno­sis.2 LAM may develop or progress conside­rably during pregnancy. Yet, so far, it has not been made clear whether the symptoms and signs of LAM are only detected earlier due to hemodynamic and ventilatory changes asso­ciated with pregnancy. The application of exogenous estrogens is another cause that can induce the disease or worsen the clinical picture.7 Renal angiomyolipoma is a rare hamarto­matous tumour, composed of smooth muscle cells, blood vessels and adipose tissue. It ra­rely occurs autonomously, but may develop in relation to TSC and is also frequent in the patients with LAM. Usually these tumours are asymptomatic, though they may be cha­racterised by palpable mass and pain in the lumbar region or hematuria.8 Histopathology Histopathologic characteristics of LAM are diffuse cystic changes in the lung related to the proliferation of the atypical smooth mu­scle cells, also termed as LAM cells. The pro­liferation can occur in all structures of the lung. The proliferation of LAM cells in the wall of bronchioles may result in the obstruc­tion of small airways and formation of the air-filled parenchymal cysts. The rupture of the cysts located on the surface of the lung can le­ad to pneumothorax. Involvement of the ve­nules and arterioles may result in partial or total occlusion of these vessels and subsequ­ent pulmonary venous hypertension. Hemop­tysis may be due to ruptures of the small blo­od vessels and minor bloodshedings into alveolar spaces. Obstruction of lymphatic channels may disrupt normal lymph flow and cause chylous pleural effusions or chylop­tysis. Sometimes pleura is also involved.9 Pulmonary emphysema additionally impa­irs the pulmonary function. So far, it has not been clarified how the emphysema develops. Some authors believe that it is a result of the respiratory tract obstruction whereas others support the theory that it may be due to disin­tegration of the elastic tissue caused by degra­nulation of the elastase- filled granules which were found in the cytoplasm of LAM cells.10 The thoracic duct may be considerably en­larged and divided into multiple microscopic channels with poor passage by the network of smooth muscle fibbers. Pathologic changes may be observed in the intra- and extrathora­cic lymph nodes. Involved nodes appear grossly spongy and resilient. Microscopic examination shows progressive replacement of the lymphatic tissue with atypical LAM cells.11 Other associated abnormalities include re­nal angiomyolipomas and abdominal or pel­vic masses, which may be cystical and histo-logically appear as cords of smooth muscle cells and a network of lymphatic channels.12 Many authors have reported the presence of oestrogen and progesterone receptors in the cytosol of LAM cells. In healthy subjects these receptors were found in the myometri-um, but not in the smooth muscle cells in the colon, bladder and lung. As the normal lung tissue does not display any of these receptors, most probably the hormones affect LAM tis­sue. However, the mechanism of this process remains unclear.13 Monoclonal antibody HMB-45, that reco­gnises antigens in the cytoplasm of melano­ma cell lines, specifically binds to the LAM cells, too. As in the normal lung parenchyma or in the case of interstitial lung disease this type of binding does not occur, immunohisto-chemical staining with HMB-45 may be a very effective diagnostic method, particularly when only a transbronchial biopsy specimen is available. HMB-45 reactivity has also been documented in retroperitoneal LAM and in renal angiomyolipomas.14,15 Multifocal micronodular pneumocyte hyperplasia, clear-cell tumours of the lung and non-caseating granulomas have also been noted in patients with LAM.16 Diagnosis Due to the rarity of LAM and because of the frequent non-specific nature of the clinical symptoms and signs and findings on the chest radiograph, many cases of LAM are ini­tially misdiagnosed as more common disea­ses, such as asthma or chronic obstructive pulmonary disease. In most cases, patients are seeing the doctor and complaining about non-specific chest pain or dyspnea on exerti­on as a complication of spontaneous pneu­mothorax. Such clinical picture is present in number of other lung diseases, so it is not a surprise that the first diagnosis is usually in­correct in almost all cases. LAM should be in­cluded in differential diagnosis, when a yo­ung female patient presents with dyspnea, recurrent pneumothorax or chylothorax.17 Diagnostic imaging methods In the initial stages of the disease, the changes in the lung are so discrete that they are seen only on CT image. At this stage chest X-ray (CXR) is usually misleading. In later stages of the disease, the CXR shows a generalised, symmetric reticular or reticulonodular inter­stitial infiltrate in the lung parenchyma as a consequence of the smooth muscle cell proli­feration in the walls of lymphatic and small blood vessels. At the beginning the infiltration is limited to the base of the lung, in later sta­ges it is found throughout the lung parench­yma. However, these findings are non-specific and may be detected in patients with other in­terstitial lung diseases, as well. The lung volu­me in LAM is usually not changed, but due to the pulmonary emphysema, the CXR may al­so show evidence of hyperinflation.18-20 The obstruction of lymphatic vessels is se­en as septal or Kerley’s B lines and a rough re-ticular pattern. In the terminal stage of the di­sease honeycombing, pneumothorax or pleu­ral effusion may be seen.20 HRCT is a highly sensitive method for the detection of the disease in its early stages as the changes in the lung parenchyma are pres­ent long before they are seen on CXR. HRCT scans reveal the diffuse cystic changes that account for the reticulation seen on CXR. The cysts are air-filled, have thin walls and are scattered all over the lung parenchyma. Their size ranges from 2 to 60 mm and are usually round, but may be polygonal or bizarrely sha­ped. The surrounding parenchyma is usually normal. With the progress of the disease, the cysts are growing in size and number. Tho­ugh cysts are typical for LAM, they are not pathognomic, since they may be detected al­so in histiocytosis X.18-20 In order to detect or confirm renal angiom­yolipomas and enlarged retroperitoneal, para-aortic and pelvic lymph nodes it is advisable to perform ultrasonography or computed to­mography of the entire abdomen.12 Lym­phangiography may detect abnormal filling and cystic changes in the involved lymph no­des.21 Abnormal pulmonary blood flow may be detected on nuclear perfusion scan.22 Lung function tests The pulmonary physiologic features of pati­ents with LAM are variable and depend on the severity of the disease. They include ob­structive, restrictive or mixed patterns. The diffusing capacity for carbon monoxide (DL­CO) is reduced in most patients, resulting in some degree of blood hypoxia. Total lung ca­pacity and residual volume are usually incre­ased.6 Lung biopsy A definitive diagnosis of LAM usually requi­res an open lung biopsy and the judgement of the experienced pathologist. Occasionally, transbronchial lung biopsy or even cytologi-cal analysis of pleural fluid is sufficient. In ca­se of the extrapulmonary tissues involve­ment, many authors recommend biopsy of the involved structures. Whenever lung bi­opsy cannot be performed, the diagnosis can be established with a fair degree of certainty when characteristic HRCT findings are seen along with renal angiomyolipoma.23,24 Therapy Because of the rarity of the disease and the variable clinical course little data is available on different therapeutic strategies and their success. Given the occurrence of the disease in women in child-bearing years, reports of worsening of the clinical picture following administration of exogenous estrogens, and the presence of oestrogen and progesterone receptors in the proliferating LAM cells, hor­monal manipulation would seem to be appro­priate for therapy. Several techniques of hor­monal blockage have been proposed: ovariec­tomy, progesterone, tamoxifen or other antie­strogen agents, luteinizing hormone releasing hormone (LHRH) agonists or radioablation of the ovaries. In some cases various combinati­ons of these treatments have been attempted. Responses to such treatments have been vari­able, and no deffinitive conclusions should be drawn from these reports.25-28 In addition to hormonal medications in­tended to interrupt the proliferation of LAM cells, various interventions aimed at preven­ting or treating the complications of LAM, such as pneumotorax and pleural or peritone­al fluid collections, have been advised, too. The repetitive drainage of chylous pleural flu­id collections may be hazardous due to the loss of proteins. Chemical or surgical pleuro­desis has been performed with variable suc­cess in preventing recurrent pneumothorax or pleural effusion. The ligation or irradiation of the thoracic duct may prevent the depositi-on of chylous pleural effusion. Recently, the option of the lung transplantation is conside­red in the patients with heavily impaired lung functions in the end-stage lung disease rela­ted to LAM.29,30 A few cases of recurrence were reported in the patients who have un­dergone the lung transplantation. Intere­stingly, in some of these cases, the donor lungs were also from males, which raises the possibility of some kind of so far unknown circulating mitogen in the pathogenesis of the disease.31 Conclusion Because LAM is the disease with low inciden­ce and because little is known about its aeti­ology, it should be included in the differenti­al diagnosis in women in child-bearing years presenting with clinical signs and symptoms of dyspnea, hemoptysis and recurrent spon­taneous pneumothorax. HRCT and open lung biopsy followed by the immunohistolo­gic studies are two diagnostic procedures with which diagnosis can be confirmed. Mo­re studies have to be performed, to under­stand the mechanisms of the disease better, for up to date, the treatment of the disease has been rather ineffective and its prognosis is bad. References 1. Baum GL, Crapo JD, Celli BR. Textbook of pulmo­nary diseases. 6th ed. Vol. 1. London: Little Brown; 1998. p. 467-71. 2. Mušic E, Vencelj B, Bajrovic N, Kern I, Debeljak A, Gabrijelcic J. Limfangioleiomiomatoza kot vzrok spontanih pnevmotoraksov. Zdrav Vestn 2000; 69: 15-8. 3. Cornog JL, Enterline HT. Lymphangiomyoma, a benign lesion of chyliferous lymphatics synon­ymous with lymphangiopericytoma. Cancer 1966; 19: 1909-30. 4. Uzzo RG, Libby DM, Vaughan ED Jr, Levey SH. Coexisting lymphangioleiomyomatosis and bilate­ral angiomyolipomas in a patient with tuberous sclerosis. J Urol 1994; 151: 1612-5. 5. Bonetti F, Chiodera P. Lymphangioleiomyomato-sis and tuberous sclerosis: where is the border? Eur Respir J 1996; 9: 399-401. 6. Kitaichi M, Nishimura K, Itoh H, Izumi T. Pulmo­nary lymphangioleiomyomatosis: a report of 46 patients including a clinicopathologic study of prognostic factors. Am J Respir Crit Care Med 1995; 151: 527-33. 7. Shen A, Iseman MD, Waldron JA, King TE. Exa­cerbation of pulmonary lymphangioleiomyomato-sis by exogenous estrogens. Chest 1987; 91: 782-5. 8. Kerr LA, Blute ML, Ryu JH, Swensen SJ, Malek RS. Renal angiomyolipoma in association with pulmonary lymphangioleiomyomatosis; forme fruste of tuberous sclerosis? Urology 1993; 41: 440­4. 9. Carrington CB, Cugell DW, Gaensler EA, Marks A, Redding RA, Schaaf JT, et al. Lymphangiolei­omyomatosis: physiologic pathologic radiologic correlations. Am Rev Resp Dis 1977; 116: 977-95. 10. Hayashi T, Fleming MV, Stetler-Stevenson WG, Liotta LA, Moss J, Ferrans VJ, et al. Immunohisto-chemical study of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in pul­monary lymphangioleiomyomatosis (LAM). Hum Pathol 1997; 28: 1071-8. 11. Graham ML, Spelsberg TC, Dines DE, Payne WS, Bjornsson J, Lie JT. Pulmonary lymphangioleiom­yomatosis with particular reference to steroid-re­ceptor assay studies and pathologic correlation. Mayo Clin Proc 1984; 59: 3-11. 12. Bernstein SM, Newell JD Jr, Adamczyk D, Morten-son RL, King TE Jr, Lynch DA. How common are renal angiomyolipomas in patients with pulmo­nary lymphangioleiomyomatosis. Am J Respir Crit Care Med 1995; 152: 2138-43. 13. Berger U, Khaghani A, Pomerance A. Pulmonary lymphangioleiomyomatosis and steroid receptors: an imunnocytochemical study. Am J Clin Pathol 1990; 93: 609-14. 14. Chan JKC, Tsang WY, Pau MY, Tang MC, Pang SW, Fletcher CD. Lymphangioleiomyomatosis and angiomyolipoma: closely related entities cha­racterized by hamartomatous proliferation of HMB-45-positive smooth muscle. Histopathology 1993; 22(5): 445-55. 15. Chan JK, Tsang WY, Pau MY, Tang MC, Pang SW, Fletcher CD. Lymphangioleiomyomatosis and an-giomyolipoma: closely related entities characteri­zed by hamartomatous proliferation of HMB-45 positive smooth muscle. Histopathology 1993; 22: 445-55. 16. Flieder DB, Travis WD. Clear cell “sugar tumor” of the lung: association with lymphangioleiomyoma­tosis and multifocal micronodular pneumocyte hi-perplasia in a patient with tuberous sclerosis. Am J Surg Pathol 1997; 21: 1242-47. 17. Sullivan EJ. Lymphangioleiomyomatosis. Chest 1998; 114: 1689-703. 18. Schiaffino E, Tavani E, Dellafiore L, Schmid C. Pulmonary lymphangioleiomyomatosis: report of a case with immunohistochemical and ultrastruc­tural findings. Appl Pathol 1989; 7: 265-72. 19. Lenoir S, Grenier P, Brauner MW, Frija J, Remy-Jardin M, Revel D, et al. Pulmonary lymphangiole­iomyomatosis and tuberous sclerosis: comparison of radiographic and thin-section CT findings. Radi­ology 1990; 175: 329-34. 20. Templeton PA, McLoud TC, Muller NL, Shepard JA, Moore EH. Pulmonary lymphangioleiomyoma­tosis: CT and pathologic findings. J Comput Assist Tomogr 1989; 13: 54-7. 21. Sherrier RH, Chiles C, Roggli V. Pulmonary lymphangioleiomyomatosis: CT findings. AJR Am J Roentgenol 1989; 153: 937-40. 22. Kawahara Y, Taniguchi T, Kadou T, Fujitani K, Yo-koyama M, Fukuzaki H, et al. Elevated pulmonary arterial pressure in pulmonary lymphangioleiom­yomatosis. Jpn J Med 1989; 28: 520-2. 23. Guinee DG Jr, Feuerstein I, Koss MN, Travis WD. Pulmonary lymphangioleiomyomatosis: diagnosis based on results of transbronchial biopsy and im­munohistochemical studies and correlation with high-resolution computed tomography findings. Arch Pathol Lab Med 1994; 118: 846-9. 24. Itami M, Teshima S, Asakuma Y, Chino H, Aoya-ma K, Fukushima N. Pulmonary lymphangiolei­omyomatosis diagnosed by effusion cytology: a ca­se report. Acta Cytol 1997; 41: 522-8. 25. de la Fuente J, Paramo C, Roman F, Perez R, Masa C, de Letona JM. Lymphangioleiomyomatosis: un­successful treatment with luteinizing-hormone-re­leasing hormone analogues. Eur J Med 1993; 2: 377-8. 26. Klein M, Krieger O, Ruckser R, Rosen A, Waldner R, Preis P, et al. Treatment of lymphangioleiomyo­matosis by ovariectomy, interferon alpha 2b and tamoxifen – a case report. Arch Gynecol Obstet 1992; 252: 99-102. 27. Eysvogel MMM, Page PS. Lymphangioleiomyoma­tosis . Chest 1990; 98: 1045-6. 28. Desurmont S, Bauters C, Copin MC, Dewailly D, Tonnel AB, Wallaert B. [Treatment of pulmonary lymphangioleiomyomatosis using a GnRH ago­nist]. [French]. Rev Mal Respir 1996; 13: 300-4. 29. Fuleihan GE. Tissue-specific estrogens – the pro­mise for the future. N Engl J Med 1997; 337: 1641­7. 30. Boehler A, Speich R, Russi EW, Weder W. Lung transplantation for lymphangioleiomyomatosis. N Engl J Med 1996; 335: 1275-80. 31. Nine JS, Yousem SA, Paradis IL, Keenan R, Grif­fith BP. Lymphangioleiomyomatosis: recurrence after lung transplantation. J Heart Lung Transplant 1994; 13: 714-9. Infantile myofibromathosis of the maxilla. A case report Nataša Ihan Hren Clinical Department of Maxillofacial and Oral Surgery, University Medical Centre, Ljubljana, Slovenia Background. Infantile myofibromatosis is a rare benign tumour in children. Its characteristic symptoms are firm masses in soft tissues, bones and visceral organs, and its common locations are head and neck. Three forms are well known: solitary, multicentric and visceral myofibromatosis. All have excellent prognosis, ex­cept the last one that may be lethal. Spontaneous regression can occur. Case report. We present an unusual case of infantile myofibromatosis of the maxilla in an adolescent. Conclusions. The infantile myofibromatosis should be managed with special caution because of the diffe-rential-diagnostic similarity with fibrosarcoma, leomyosarcoma, and histiocytosis. Key words: myofibromatosis; maxillary neoplasms; infant Introduction Infantile myofibromatosis (IM) is a rare be­nign tumor in children. It was first described as congenital fibrosarcoma. Later, sporadic cases were discussed, and in 1981, 61 cases were examined and named as IM. Three diffe­rent forms were described: solitary, multicen­tric and visceral IM.1 Three quarters of soft tissue tumours in children and adolescents are benign, 95 % of them are fibromatosis, 80 % of fibromatosis Received 14 January 2002 Accepted 21 January 2002 Correspondence to: Assist. Prof. Nataša Ihan Hren, MD, PhD, Clinical Department of Maxillofacial and Oral Surgery, University Medical Centre, Zaloška 2, 1000 Ljubljana, Slovenia. are IM and 19 % aggressive desmoid fibroma­tosis.2 The most frequent type is solitary IM. One third of these occur are in the head and neck. Its aetiology is not known. First, it was be­lieved that original cells are fibroblasts; but with the presence of desmins receptors in IM, this belief proved to be false. In fact, the ori­ginal cells of IM growth are smooth muscular cells.3 Genetic predisposition is likely since solitary form is twice as frequent in males than in females. Clinically, IM is expressed by slowly gro­wing painless firm solitary or multicentric nodes in the soft tissue, bones or visceral or­gans. Half of the cases develop in the dermis or subdermally.4 Their size is few millime­tres to few centimetres. Half of the cases are congenital, 90 % of all cases develop in first two years of life.1 The symptoms are rare ex­cept when IM obstructs the visceral organs or nerves. Spontaneous ulcerations can also occur. Pathohistological characteristics of IM are bundles of pinal cells – myofibroblasts, round and less differentiated cells may be found. In the centre, necrotic processes and calcinati-ons are also seen. Mitotic activity is most di­versified. On the X-ray of the skeleton, the IM is se­en as well differentiated osteolitic lesions with sclerotic margins. The IM may well be seen also by other diagnostic imaging techni­ques, such as CT and MR. Before final dia­gnosis, pathohistology of bioptic material should be performed. Differential diagnosis discovered some resemblances with fibro-sarcoma, histiocytosis, and leiomyosarcoma; therefore, the misinterpretations are pos­sible. The visceral type is lethal in 75 % of cases in neonatal period because of an acute cardi­opulmonary failure, haemorrhage or gastroin­testinal obstruction,1 whereas nonvisceral forms have excellent prognosis. The conservative tumour excision is curati­ve. Spontaneous regression may occur in the third of cases4 1 to 2 years;5 therefore, the ob­servation is a method of choice if IM is defini­tely pathohistologically conformed. The re­ported recurrence rates ranged from 7-10 % (1) to 31 % (4).1,4 Case report A fifteen-year-old boy came to our outpati­ents department because of a massive, firm oedema on the left cheek, which had been slowly progressing for 1 year. (Figures 1a, 1b) He as well as his parents connected it with the impacted upper canine tooth on the left that was operatively released by an oral sur­geon one year ago. The X-ray of the teeth ma­de at that period showed a tumour with a di-ameter of 2 cm in the alveoli of the maxilla. Medical history detected no genetic predispo­sition. Clinical investigations confirmed a large tumour mass, which vaulted over the hard palate, alveolar and buccal tissues. The boy’s face was strongly disfigured. The dermal and mucosal coating was intact. There were no other pathological changes in the oral cavity and head, except the lacking permanent pre­molar and first permanent molar teeth in the left maxilla. From the medical history it is evi­dent that they never existed. X-ray showed significant changes in the bone of the maxilla, partly osteolytic partly calcinated. They spread over the alveoli from the canine tooth to maxillary tuber and inva­de the maxillary sinus too orbital floor (Figu­re 2). CT scan showed no invasion into the or­bit, nasal cavity and pterigoids (Figures 3a, 3b). The serum alkaline phosphatase value was very high, the serum phosphate rate was also increased, whereas the values of the se­rum calcium and hormones were normal. From the clinical viewpoint, it could be possible that the boy had a sarcoma or a rare odontogenic tumour because of the lacking teeth. We took the biotic material samples from three different parts. Pathohistologic re­sults confirmed IM without mitotic activity and necrosis. The boy was operated on; the tumour was extirpated by conservative surgi­cal approach. It size was minimally 7 ×4 ×4 centimetres. After partial maxillectomy, the reconstruction was performed with local tis­sues. The final pathohistological findings we­re the same as those of previous biopsy. Mo­reover, the examination of IM tissue confir­med the presence of the ortotopic bone tis­sue. No postoperative complications occurred. The disfigurement was restored, whereas the lacking the lacking alveolar bone and the te­eth were replaced by obturator prosthesis. A year and a half after surgery, the boy is without the local recurrence or recurrence el­sewhere in the body (Figure 4a, 4b). The bone defect became smaller after the reparation of the marginal bone. After the boy’s growth is completed, a reconstruction by autologous bone and dental implants is planned. Discussion IM is a rare, but important tumour in children and, because of its common localisation, it should be known to all the surgeons of the head and neck. The spontaneous regression of IM is indu­ced by programmed cell death – apoptosis.6 This is probably the most significant example of this massively enhanced physiological me­chanism. However, it does not occur in all ca­ses, or it may be so slow that, in most cases, the conservative surgery is necessary. If its re­sults are very mutilating, adjuvant chemothe­rapy may be applied.4 From the revised references, the maxilla, as in our case, is a rare localisation. The most frequent localisations are the dermis or sub­cutis.4 Among the head bones, the calvarian bone is most frequently affected, whereas the temporal bone,7 the orbita with the zygomatic bone8 and the nasal cavity with the inferior turbinate are less frequent localisations.9 What is also unusual in our case is the boy’s age, which was relatively high for deve­loping IM in spite of late diagnostic trea­tment. The teeth germs destruction is also most unclear. If the obstruction and necrosis had been the causes, it should have develo­ped at the age of 4 to 6 years, well before the mineralization of the teeth germs occurred. In such circumstances it is unlikely that the tumour would grow so slow until the boy’s age of 14 years and speeded-up so much in the last year. In our case, the differential dia­gnosis suspected of rare odontogenic tumo­urs, which was exceptionality also in our case. As with other fibrous tumours, IM is frequ­ently misdiagnosed as malignancy, most com­monly as fibrosarcoma.10 It is also possible to mistake it for with leiomyosarcoma.11 In case of the malignant fibrous tumour, surgery sho­uld be very radical and, if it was but a misdia­gnosed IM, the morbidity unnecessary. The recurrence and new growth of IM is possible also on localizations other than pri­mary;5 therefore, a long-term follow-up of these patients is recommended. References 1. Chung EB, Enzinger FM. Infantile myofibromato-sis. Cancer 1981; 48: 1807-18. 2. Coffin CM, Dehner LP. Fibroblastic-myofibrobla­stic tumors in children and adolescent: a clinico-pathologic study of 108 examples in 103 patients. Pediatr Pathol 1991; 11: 559-88. 3. Fletcher CDM, Acho P, VanNoorden S, McKee PH. Infantile myofibromatosis: a light microsco­pic, histological and ammunohistochemical study suggesting true smooth muscle differentiation. Hi-stopathology 1987; 11: 245-58. 4. Beck JC, Devaney KO, Weatherly RA, Koopmann CF, Lesperance MM. Pediatric myofibromatosis of the head and neck. Arch Otolaryngol Head Neck Surg 1999; 125: 39-44. 5. Schrodt BJ, Callen JP. A case of congenital multi­ple myofibromatosis developing in an infant. Pedi­atrics 1999; 104: 113-5. 6. Fukasawa Y, Ishikura H, Takada A, Yokoyama S, Imamura M, Yoshiki T, et al. Massive apoptosis in infantile myofibromatosis. A putative mechanism of tumor regression. Am J Pathol 1994; 144: 480-5. 7. Behar PM, Albritton FD, Muller S, Todd NW. Mul­ticentric infantile myofibromatosis. Int J Pediatr Otorhinolaryngol 1998; 45: 249-54. 8. Duffy MT, Harris M, Hornblass A. Infantile miofi­bromatosis of orbital bone. A case report with computered tomography, magnetic resonance imaging, and histologic findings. Ophthalmology 1997; 104: 1471-4. 9. Walsh RM, Leen EJ, Gleeson MJ. Solitary infantile and adult myofibromatosis of the nasal cavity: a report of two cases. J Laryngol Otology 1996; 110: 574-7. 10. Hartig G, Koopman C, Esclamado R. Infantile myofibromatosis: A commonly misdiagnosed en­tity. Otolaryngol Head Neck Surg 1993; 109(4): 753­7. 11. De Saint Aubain Somerhausen N, Fletcher CDM. Leiomyosarcoma of soft tissue in children. Clini­copathologic analysis of 20 cases. Am J Surg Pathol 1999; 23(7): 755-63. review A brief overview of the tumor vaccines through the last decade Srdjan Novakovic1, Barbara Jezeršek Novakovic2 1Dept. of Tumor Biology, 2Dept. of Internal Medicine, Institute of Oncology Ljubljana, Slovenia How to destroy cancer cells without damaging the normal cells? How to make conventional methods of systemic cancer treatment that predominantly comprise cytotoxic drugs more selective and prevent the de­velopment of drug resistance? There is an abundance of such questions that do not have simple answers. If, a few years ago, unselective cytotoxic drugs were the method of choice for the treatment of cancer, in the last 25 years we are witnessing the rapid transition of immunotherapy from the laboratories to the clinics. Among the most attractive and promising immunotherapies for cancer, a special place is reserved for tumor vaccines. Exploiting the latest knowledge in immunology, tumor physiology, as well as in molecular biology, many outstanding approaches for the creation of tumor vaccines have been developed. With no intention to be comprehensive, in the present article some of those approaches are reviewed. Key words: neoplasms; gene therapy; cancer vaccines Introduction In the last few years, we have witnessed a gre­at progress in the fields of immunology, tu­mor physiology and molecular biology. Na­mely, the basic facts about the recognition of various structures by the immune system through the cooperation of MHC have been explained. The structures of MHC class I, and MHC class II have been studied and their function analyzed quite thoroughly. The com­plex mechanisms of antigen presentation and Received 14 January 2002 Accepted 6 March 2002 Correspondence to: Assoc. Prof. Srdjan Novakovic, Department of Tumor Biology, Institute of Oncology, Zaloška 2, 1000 Ljubljana, Slovenia. Tel. + 386 1 522 5118; Fax: +386 1 433 74 10; E-mail: snovako­vic@onko-i.si the role of presenting cells have been investi­gated in details.1,2 Various cell receptors (es­pecially T cell receptors) have been discove­red, and the methods of signal transduction and the activation of T lymphocytes (the ma­jor performers of the cellular immunity) have been elucidated.3,4 The production of mono­clonal antibodies towards different well-defi­ned structures has become a routine procedu­re, which facilitates the transition of such antibodies into clinical praxis.5 Today, we are also familiar with the structure of and are equipped to produce various immunomodu­latory cytokines, which in turn, assists their application in the treatment of some mali­gnant diseases (hairy-cell leukemia, mali­gnant melanoma, renal cell carcinoma).6-8 On the other hand, also the methods for precise determination of different genes and their transduction into mammalian cells have been extensively studied. Thus, the researchers created various vector systems that can be di­vided into two large groups: (1) viral vectors (retroviral, adenoviral, adeno-associated viral vectors, herpesviral vectors)9,10 and (2) nonvi­ral vectors (calcium-phosphate precipitation, liposomes, microinjections, electroporation, poly-lysine conjugates, receptor-mediated en-docytosis, gene gun).9,11-16 These discoveries have become the groundwork for the rene­wed and new biological approaches towards the treatment of malignant diseases. Tumor vaccines The first tumor vaccines were created on the principles of classical immunology and com­prised irradiated tumor cells and nonspecific immunomodulators. Further approaches to­wards the creation of tumor vaccines base on the principles of molecular immunology and quite often it is hard to distinguish them from the classical gene therapy approaches. The newer vaccines also include autologous or allogeneic cells, with the difference that various genes coding for proteins involved in the stimulation of immune response (e.g. ge­nes coding for growth factors and cytokines, as well as genes coding for co-stimulatory molecules) are introduced into these cells.17,18 Instead of whole cells, also certain specific structures that are responsible for the antitumor immune response can be used.19,20 Classical tumor vaccines It was not until recently that we gained some information about the specific antigens that are present on the surface of the tumor cells, and about the co-stimulatory molecules that are necessary for the activation of the immu­ne system, so the first true tumor vaccines were composed of (1) autologous or allogene­ic irradiated tumor cells, (2) tumor cell lysates with viral antigens or (3) tumor cells with nonspecific immunomodulators (Corynebacte­rium parvum, Bacillus Calmette-Guerin).21-27 These first-generation vaccines that base on the principles of classical immunology were termed classical tumor vaccines. The classical tumor vaccines were applied predominantly for the treatment of malignant melanoma and in the following text this tu­mor type will be used as an example of the advances in the last years. The most extensi­vely studied vaccine was the CancerVax that was prepared using three viable allogeneic malignant melanoma cell lines (MHC haplot­ype matches with 95 % of melanoma patients) chosen for their high immunogenicity.28 As the non-specific immunostimulatory agent the BCG was given with the first two doses. When patients with malignant melanoma sta­ge IV were treated with CancerVax in a clini­cal study, the five-years survival was as high as 25 %, which can be regarded as quite suc­cessful because the surviving fraction in the control group was only 6 %.29 In a different clinical trial, the melanoma patients received a classical tumor vaccine composed of autologous tumor cells and BCG. This therapy resulted in a complete res­ponse in four out of 40 malignant melanoma patients, and in a partial response in one pa­tient.30,31 Worth mentioning are also the studies of Mitchell et al. In the first study the authors ap­plied the tumor vaccine composed of the allo­geneic cell lysate and Detox (i.e. the detoxifi­ed endotoxin from Salmonella minesota, cell wall skeletons of Mycobacterium phlei, squala­ne oil and emulsifier), while in the second they applied the Melacin (i.e. the lyophilized version of melanoma lysate vaccine and De­tox). The first trial resulted in a partial or complete remission in 20 out of 106 melano­ma patients, with the median duration of res­ponse of 21 months. The survival of the mela­noma patients treated with Melacin in the second study equaled the survival of patients treated with chemotherapy. As expected, the response rate was lower in the vaccinated group but the toxic side effects were much more pronounced in the chemotherapy gro­ up.32,33 Additionally, the results of our pre-clinical study with a syngeneic melanoma vaccine proved the high efficacy of the prepared vac­cine. In the case of the aggressive intraperito­neal malignant melanoma tumor model we successfully protected more than 40 % ani­mals from tumor development with just a sin­gle application of sublethally irradiated tu­mor cells admixed with MVE-2 (nonspecific immunomodulator). When such a vaccine was applied twice, the number of the protec­ted animals rose to as much as 90 %. Conco­mitantly, we confirmed that our vaccine indu­ced the long lasting protective immunity, since over 60 % of the former survivors that were rechallenged with the tumor cells survi­ved again without any further treatment.34,35 Genetically modified and recombinant tumor vaccines The group of second-generation vaccines that base on the principles of molecular immuno­logy comprises genetically modified and recom­binant tumor vaccines. Just like the first-generation vaccines also the second-generation vaccines can be divi­ded into the ones that utilize whole autologo-us or allogeneic cells, and ones that utilize on­ly certain specific structures. Yet, unlike the first-generation vaccines that are prepared strictly with autologous or allogeneic tumor cells, the second-generation vaccines employ either tumor cells or non-tumor cells (mostly autologous) as fibroblasts and dendritic cells. Regarding the approach towards a better re­cognition of the tumor cells by the immune system, the second-generation vaccines can be subdivided into the (1) vaccines prepared with genetically modified tumor cells, (2) vac­cines prepared with genetically modified non-tumor cells (most frequently dendritic cells and fibroblasts), and (3) recombinant vaccines. The approach towards the creation of tu­mor vaccines on the base of genetically modi­fied tumor cells includes different modes of preparation. The more promising modes of preparation are the transfection of tumor cells with genes coding for antigens that are being presented through MHC class I and II, with genes coding for co-stimulatory molecu­les, and with genes coding for various cytoki­nes. With the transfer of genes coding for the structures that are being presented through MHC class I into the tumor cells we expect to accomplish an enhancement of the presenta­tion of specific antigens for the activation of CTL, while the transfer of genes coding for the structures that are being presented thro­ugh MHC class II should augment the activa­tion of helper T cells. Such studies were enco­uraged by the discovery of different specific tumor antigens that are quite often underex-pressed in tumor cells. The transfer of genes coding for the above mentioned structures in different studies resulted in an augmented ac­tivation of autologous CTL.36,37 Similarly to the transfer of genes into the antigen presen­ting cells (described below), the genes coding for tumor specific antigens from the group of MAGE, MART, MUC-1 and CEA were trans­ferred in these studies.38 The transfection of tumor cells with genes coding for B7 ligand should enable a direct activation of CTL, thus bypassing the role of antigen presenting cells. Namely, sole tumor antigens on the surface of tumor cells are in­sufficient for the activation of the effector cells and can even trigger the development of a complete immune tolerance. Therefore, an additional signal is needed for the activation of the cytotoxic T cells and is mediated thro­ugh the co-stimulatory molecules (B7.1 – CD80 and B7.2 – CD86) that bind to CD28 and CTLA-4. In humans, the B7 is expressed only on antigen presenting cells – it is expres­sed constitutively on dendritic cells but can be induced also on activated B, T and NK cells, as well as on macrophages. The studies that applied the transfer of gene for B7 into tumor cells demonstrated the transition of non-immunogenic tumor cells into highly im­munogenic tumor cells which resulted in tu­mor rejection in vivo.39,40 Quite similar was the effect of the transfection of tumor cells with genes coding for other co-stimulatory molecules as ICAM-1 and LFA-3. For that re­ason, it can be concluded that the presence of co-stimulatory molecules is obligatory for the activation of T lymphocytes while these mo­lecules are not needed for the function of al­ready activated CTL, since the achieved im­munity against the transfected cells was pre­served also in the case of non-transfected cells. The cytokines are expected to induce such a vigorous antitumor response that bystander native tumor cells would also succumb to it. Therefore, genes for various cytokines are be­ing transferred into tumor cells in order to achieve a higher level of production of the cytokines that are involved in the complex immune reactions including stimulation of CTL activation, acceleration of the multiplica­tion of activated cells (the cytokines act as growth factors), triggering of the expression of various cell receptors, cytokine cascades and antibody production and in some cases attaining of a direct cytostatic/cytotoxic effect on tumor cells. In contrast to the activities of exogenous cytokines, the cytokines produced in genetically changed tumor cells mimic the activities of natural endogenous cytokines (underlie to some extent control mechanisms of the organism), which on one hand impro­ves their effectiveness and on the other hand minimizes their toxic side effects. When pre­paring tumor vaccines, different researchers introduced genes for numerous cytokines or growth factors (IL-1, IL-2, IL-3, IL-4, IL-6, IL­7, IL-10, IFN-., TNF-a, GM-CSF and G-CSF), respectively, into tumor cells.41-45 Preclinical results in various tumor models in vivo prima­rily confirmed the expectations concerning the action of this kind of vaccines on the im­mune system. It was shown clearly that vacci­nes containing an imunomodulatory cytokine are indeed capable of CD4+ and CD8+ T lymphocyte activation46-49, activation of ma­crophages and neutrophils50,51, as well as sti­mulation of differentiation of precursor blood cells and dendritic cells (important antigen-presenting cells for T lymphocytes).52,53 Con­sidering all mentioned facts, a slightly diffe­rent effect was achieved on tumors than was expected. Even though the cytokine vaccines showed the potential to protect the animals from challenge with wild type tumor cells, none of these vaccines was efficient enough to cure the established tumors in a convin­cing proportion of experimental animals. The best protection, as well as the most pronoun­ced antitumor activity against formed tu­mors, has been ascribed to vaccines created of tumor cells bearing gene for GM-CSF, whi­le the most effective combination of genes for preparation of tumor vaccines comprised ge­nes for IL-2 and GM-CSF.52,53 The results of clinical trials are variable: there are reports about complete or partial tumor remissions after the treatment with cytokine vaccines, but also about an inadequate or missing clini­cal response.20,27 Regarding the mechanisms of action of these vaccines in humans it is li­kely that they are pretty similar to those in animal tumor model: the vaccines should at­tack the tumor cells by activating the CD8 T cells, NK cell response, dendritic cells and macrophages. The most impressive antitumor (antimelanoma) immune reaction was displa­yed by the patient who received the GM-CSF vaccine.54 The purpose of the vaccination with gene­tically modified non-tumor cells is also the transfer and the mediation of immune active structures/substances to the effector cells in the organism. This mode of preparation beca-me especially attractive after the discovery of specific tumor antigens and after the elucida­tion of the role of antigen presenting cells for the activation of naive T cells. The dendritic cells – DC (i.e. the most potent antigen pre­senting cells in the organism) that express the co-stimulatory and adhesion molecules (e.g. CD58, CD54, CD50, CD80 – B7.1, CD86 – B7.2) and MHC class I and II are employed in these reactions. The surface structures of DC bind to adequate structures on T cells (e.g. CD28) and through them mediate the signals for triggering of the primary immune respon­se. This approach is thus opposite to the ones where the tumor cells were transfected with the genes encoding costimulatory molecules: if, with the transfection of tumor cells with B7 ligand the intention was to bypass the functi­on of the antigen presenting cells, with this very approach it was intended to achieve the activation of specific CTL in the absence of tumor cells. The first approaches using DC were based on in vitro activation of these cells with speci­fic proteins as for example the OVA peptide, gp100, and MelaA/MART.55,56 The DC prepa­red in this way were capable of triggering the CTL response leading to lysis of target cells that contained the corresponding antigen structures. Later on, the researchers in order to achieve the presentation of these structu­res by the DC, rather transfected the DC with the genes for tumor (more or less) specific an­tigens (instead of growing the DC in vitro to­gether with certain antigen structures). Using various transfection techniques they succee­ded to transfect the DC with MART-1, MUC­1, 2-galactosidaze gene57-60, and demonstra­ted that the transfection of DC with genes coding for certain structures is a method that is superior in achieving the expression of the­se structures on the surface of antigen pre­senting cells to the in vitro activation of these cells with the very structures.60 The latest ap­proach in the field of DC application is the preparation of hybridomas, that is the fusion of DC with tumor cells. The resulting cells in­clude all of the tumor antigens as well as all of the co-stimulatory molecules. In one study, where the researchers fused MC38 tumor cell line with DC from the bone marrow of the ex­perimental animals, the vaccination with such vaccine prevented the development of lung metastases in 90 % of the treated ani­mals.61 In another research, 17 patients with renal carcinoma were treated with hybrido-mas created of autologous tumor cells and al­logeneic DC. Thirteen months after the vacci­nation four patients were in complete remission, one in partial remission, and in two patients there was a less than 50 % reduc­tion of the tumor burden.62 The group of recombinant vaccines com­prises predominantly the peptides, fusion proteins and immunoglobulins. In this con­text, a question arises, if it is more rational to transfer the genes coding for tumor associa­ted antigens into the antigen presenting cells and then apply these cells as tumor vaccines, or to apply such tumor antigens directly in the form of proteins and peptides as tumor vaccines. The immune response can be trig­gered by two main groups of peptides. Pepti­des with 8 to 11 amino acid residues that are bound in the MHC class I of the antigen pre­senting cells trigger through binding to the cell receptors of T lymphocytes (CD8+) the activation of CTL (cells responsible for the antitumor immunity).63,64 The second group of peptides with 11 to 15 amino acid residu­es is expressed through MHC class II of the antigen presenting cells. These peptides are responsible for the activation of CD4+ lymphocytes that, in turn, produce cytokines involved in the activation of CD8+ cells.65 The effectiveness of such vaccines depends upon if the treated organism carries the same MHC allele that will code for the recogniza­ble paratopes on lymphocyte receptors. Also oligopeptides that include both epitopes (the MHC class I epitope and the MHC class II epitope) can be used as tumor vaccines. Most of the specific oligopeptides represent mali­gnant melanoma specific antigens (MAGE-1, MAGE-3, MART-1, gp100, tyrosinase, gp75), colorectal carcinoma specific antigens (CEA), breast cancer specific antigens (MUC-1). Sin­ce there are many different epitopes on these oligopeptides, some studies demonstrated that these antigens trigger the immune res­ponse (activate CTL) regardless of the type of the MHC present (MHC-unrestricted man­ner).66,67 So far, only some of the above men­tioned antigens were tested in clinical studi­es. In one of these studies, Rosenberg et al. achieved the development of immunity in 90 % of the patients vaccinated with the vac­cine that included one of the peptides deri­ved from gp100 (i.e. one of the epitopes). In 13 out of 31 patients with metastatic melano­ma, that received IL-2 beside the vaccine, they observed an objective clinical response to treatment.68 The preparation of fusion proteins and immunoglobulins is based on the use of monoclonal antibodies. Through the binding of the prepared monoclonal anti­bodies onto specific cell receptors the resear­chers aim to selectively influence the CTL and the antigen presenting cells. An example of such application is the preparation of mo­noclonal antibodies to CTLA-4 in order to re­duce the weakened activation of CTL. Ano­ther example, already employed in the clinical practice, is the production of antibo­dies (Herceptin) to HER-2 (receptor for the growth factor in various types of carcinoma). These antibodies block the binding sites for the growth factor needed by the tumor cells and thus prevent the growth of the tumor.69 The second mode of antibody application is the production of fusion proteins with cyto-kines. The most promising model is the em­ployment of monoclonal antibodies bound to the IL-2 molecule. In both preclinical and cli­nical studies this fusion protein successfully activated the tumor infiltrating lymphoc­ytes.69 Prospectus and conclusion I intend to start the conclusion like I began the abstract with one of the general questions related to the cancer: Do we know enough about the tumor cells and their relations to the host? The answer is not simply YES or NO. Yes, we do know a lot about the tumor cells: their physiology, morphology, signal transduction, about gene susceptibility....We also do know a lot about the relations to the other – normal cells in the organism. Yet, I fell like we have all parts for the simple clock and some additional for an extremely sophi­sticated one. All the time we are discovering more and more additional parts belonging to the sophisticated clock, but unfortunately, there are still some missing parts that unable us to complete the clock. So instead of put­ting together the parts of the simple clock and constructing the usable device, we are trying to construct a complicated apparatus with many functions that are less important for da­ily determination of time. Something similar is happening to us when we are trying to develop a systemic drug or therapy against cancer: we are targe­ting a single ultra-specific process offering the tumor cells plenty of time to rebuild the damaged functions. The researchers are di­scovering more and more details concerning the tumor cell but no one is open-minded enough to orchestrate all these pieces of in­formation into a global prospect of surviving and proliferation of tumor cells in the host or­ganism. Carcinogenesis as a process occurs in the living organisms much more often that could be concluded on the basis of real tumor incidence. Fortunately, only few of these ma­lignantly transformed cells succeed to deve­lop into tumor cell colonies and tumors. Ma­jority of them are being recognized by the immune system and are destroyed before the tumor mass becomes clinically detectable. Considering the diverse origin of the transfor­med tumor cells (tumors of epithelial, me-senchymal and other origins) that are reco­gnized by the one immune system in the or­ganism, it is clear that the immune system has the potency to distinguish between diffe­rent types of tumor cells and control their proliferation. Once when we recognize the tiny borderline in the relation between the host immune system and the tumors the ba­lance would be tilted in favor of the host. So speaking about the novel systemic cancer tre­atments, I am convinced that, rather than ap­proaches where the therapeutics are acting directly against tumor cells, the approaches that propose the mobilization of protective mechanisms in the host will turn out to be more effective. That implies the development of the tumor vaccines that would be capable of triggering an antitumor immune response and preparing the host for a long lasting con­trol of tumor growth and metastasis. At the moment, it is difficult to predict what kind of vaccine is going to be the most successful. It seams that the most effective one is going to be the vaccine that includes the tumor pre­senting cells armed with some genes enco­ding tumor antigens and immunostimulatory cytokines. On the other hand, the advantage will be given to the vaccine that comprises the elements of adjuvant and standard the­rapy allowing the application as a single adju­vant therapy after the surgical removal of the tumor, or in combination with the therapies that aggressively act directly against the tu­mor cells. In conclusion, I should emphasize that classical tumor vaccines (first generation vac­cines) are many times more potent than mo­dern tumor vaccines (genetically modified se­cond generation vaccines). The reason probably lies in the concepts used for the pre­paration of genetically modified vaccines (they are too specific in their activity). For that very reason the future of modern tumor vaccines is the preparation of vaccines that would be constituted of different major struc­tures necessary for the triggering of the im­mune system or in combining of the currently available vaccines. References 1. Townsend AR, Rothbard J, Gotch FM, Bahadur G, Wraith D, McMichael AJ. The epitopes of influen­za nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides. Cell 1986; 44: 959-68. 2. Lechler R, Aichinger G, Lightstone L. The endoge­nous pathway of MHC class II antigen presentati­on. Immunol Rev 1996; 151: 51-79. 3. Viola A, Lanzavecchia A. T cell activation determi­ned by T cell receptor number and tunable thre­sholds. Science 1996; 273: 104-6. 4. Schoenberger SP, Toes RE, van der Voort EI, Of-fringa R, Melief CJ. 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Relationship between immune response to melanoma vaccine immunization and clinical out­come in stage II malignant melanoma. Cancer 1992; 69:1157-64. 23. Hanna MG Jr., Brandhorst JS, Peters LC. Active specific immunotherapy of residual micrometasta-sis: an evaluation of sources, doses and ratios of BCG to tumor cells. Cancer Immunol Immunother 1979; 7: 65-73. 24. Hoover HC Jr, Surdyke M, Dangel RB, Peters LC, Hanna MG Jr. Delayed cutaneous hypersensitivity to autologous tumor cells in colorectal cancer pati­ents immunized with an autologous tumor cell: Bacillus Calmette-Guerin vaccine. Cancer Res 1984; 44: 1671-6. 25. Schirrmacher V, Hoegan P, Schlag P, Liebrich W. Active specific immunotherapy with autologous tumor cell vaccines modified by Newcastle disea­se virus: Experimental and clinical studies. In: Schirrmacher V, Schwartz-Abiez R, eds. Cancer Metastasis. Berlin: Springer-Verlag, 1989: 157-70. 26. Hersey P, Edwards A, Coates A, Shaw H, McCarthy W, Milton G. Evidence that treatment with vaccinia melanoma cell lysates (VMCL) may improve survival of patients with stage II melano­ma. Treatment of stage II melanoma with viral lysates. Cancer Immunol Immunother 1987; 25: 257­65. 27. Sinkovics JG: Viral oncolysates as human tumor vaccines. Int Rev Immunol 1991; 7: 259-87. 28. Conforti AM, Ollila DW, Kelley MC, Gammon G, Morton DL. Update on active specific immunothe­rapy with melanoma vaccines. J Surg Oncol 1997; 66: 55-64. 29. Chan AD, Morton DL. Active immunotherapy with allogeneic tumor cell vaccines: present sta­tus. Semin Oncol 1998; 25: 611-622. 30. Berd D, Maguire HC, Jr., Mastrangelo MJ. Inducti­on of cell-mediated immunity to autologous mela­noma cells and regression of metastases after tre­atment with a melanoma cell vaccine preceded by cyclophosphamide. Cancer Res 1986; 46: 2572-77. 31. Berd D, Maguire HC, Jr., McCue P, Mastrangelo MJ. Treatment of metastatic melanoma with an au­tologous tumor-cell vaccine: clinical and immuno­logic results in 64 patients. J Clin Oncol 1990; 8: 1858-67. 32. Mitchell MS, Harel W, Kempf RA, Hu E, Kan-Mit­chell J, Boswell WD, et al. Active-specific immuno-therapy for melanoma. J Clin Oncol 1990; 8: 856­69. 33. Mitchell MS, Harel W, Kan-Mitchell J, LeMay LG, Goedegebuure P, Huang XQ, et al. Active specific immunotherapy of melanoma with allogeneic cell lysates. Rationale, results, and possible mecha­nisms of action. Ann N Y Acad Sci 1993; 690: 153­66. 34. Novakovic S, Ihan A, Wraber B, Jezeršek B. An ef­fective tumor vaccine against malignant melano­ma: irradiated autologous tumor cells admixed with MVE-2. Int J Mol Med 1999; 3: 95-102. 35. Novakovic S, Ihan A, Jezeršek B. Effectiveness of a simply designed tumor vaccine in prevention of malignant melanoma development. Jpn J Cancer Res 1999; 90: 1130-8. 36. Boon T. Toward a genetic analysis of tumor rejec­tion antigens. Adv Cancer Res 1992; 58: 177-210. 37. Deres K, Beck W, Faath S, Jung G, Rammensee HG MHC/peptide binding studies indicate hie­rarchy of anchor residues. Cell Immunol 1993; 151: 158-67 38. Sobol ER, Shawler D, Dorigo O, Gold D, Royston I, Fakhrai H. Immunogene therapy of cancer. In: Sobol ER, Scanlon JK, eds. The internet book of gene therapy/Cancer therapeutics. Stamford: Appleton & Lange, 1995: 175-180. 39. Townsend SE, Allison JP. Tumor rejection after di­rect costimulation of CD8+ T cells by B7-transfec-ted melanoma cells. Science 1993; 259: 368-70. 40. Baskar S, Ostrand-Rosenberg S, Nabavi N, Nadler LM, Freeman GJ, Glimcher LH. Constitutive ex­pression of B7 restore immunogenicity of tumor cells expressing truncated major histocompatibi­lity complex class II molecules. Proc Natl Acad Sci USA 1993; 90: 5687-90. 41. Colombo MP, Ferrari G, Stoppacciaro A, Parenza M, Rodolfo M, Mavilio F, Parmiani G. Granulocyte colony- stimulating factor gene transfer suppres­ses tumorigenicity of a murine adenocarcinoma in vivo. J Exp Med 1991; 173: 889-97. 42. Colombo MP, Lombardi L, Stoppacciaro A, Mela-ni C, Parenza M, Bottazzi B, et al. Granulocyte-co­lony stimulating factor (G-CSF) gene transduction in murine adenocarcinoma drives neutrophil-me­diated tumor inhibition in vivo. J Immunol 1992; 149: 113-9. 43. Dranoff G, Jaffee E, Lazenby A, Golumbek P, Le-vitsky H, Brose K, et al. Vaccination with irradia­ted tumor cells engineered to secrete murine GM­CSF stimulates potent, specific and long lasting anti-tumor immunity. Proc Natl Acad Sci USA 1993; 90: 3539-43. 44. Asher AL, Mule JJ, Kasid A, Restifo NP, Salo JC, Reichert CM, et al. Murine cells transduced with the gene for tumor necrosis factor a. Evidence for paracrine immune effects of tumor necrosis factor against tumors. J Immunol 1991; 146: 3227-34. 45. Hock H, Dorsch M, Kunzendorf Uquin Z, Diaman-stein T, Blankenstein T. Mechanisms of rejection induced by tumor cell-targeted gene transfer of in­terleukin 2, interleukin 4, interleukin 7, tumor ne­crosis factor, or interferon 3. Proc Natl Acad Sci USA 1993; 90: 2774-8. 46. Fearon ER, Pardoll DM, Itaya T, Golumbek P, Le-vitsky HI, Simons JW, et al. Interleukin-2 produc­tion by tumor cells bypasses T helper function in the generation of an antitumor response. Cell 1990; 60: 397-403. 47. Gansbacher B, Zier K, Daniels B, Cronin K, Ban-nerji R, and Gilboa E. Interleukin-2 gene transfe­rinto tumor cells abrogates tumorigenicity and in­duces protective immunity. J Exp Med 1990; 172: 1217-24. 48. Gansbacher B, Zier K, Cronin K, Hantzopoulos PA, Bouchard B, Houghton A, Gilboa E, et al. Re-troviral gene transfer induced constitutive expres­sion of interleukin-2 or interferon gamma in irra­diated human melanoma cells. Blood 1992; 80: 2817-25. 49. Russell SJ, Eccles SA, Flemming CL, Johnson CA, Collins MK. Decreased tumorigenicity of a trans-pantable rat sarcoma following transfer and ex­pression of an IL-2 cDNA. Int J Cancer 1991; 47: 244-51. 50. Cavallo F, Giovarelli M, Gulino A, Vacca A, Stop-pacciaro A, Modesti A, Forni G. Role of neutro­phils and CD4+ T lymphocytes in the primary and memory response to nonimmunogenic murine mammary adenocarcinoma made imunogenic by IL-2 gene. J Immunol 1992; 149: 3627-35. 51. Blankenstein T. Observations with tumor necrosis factor gene-transfected tumours. Folia Biol – Prague 1994; 40: 19-28. 52. Mulligan R. The basic science of gene therapy. Sci­ence 1993; 260: 926-32. 53. Golumbek PT, Azhari R, Jaffee EM, Levitsky HI, Lazenby A, Leong K, et al. Controlled release, bio­degradable cytokine depots: a new approach in cancer vaccine design. Cancer Res 1993; 53: 5841­4. 54. Ellem KAO, O’Rourke MGE, Johnson GR, Parry G, Misko IS, Schmidt CW, et al: Acase report: im­mune responses and clinical course of the first hu­man use of granulocyte/mactophage-colony-sti­mulating factor-transduced autologous melanoma cells for immunotherapy. Cancer Immunol Immuno­ther 1997; 44: 10 20. 55. Celluzzi CM, Mayordomo JI, Storkus WJ, Lotze MT, Falo LD, Jr. Peptide-pulsed dendritic cells in­duce antigen-specific CTL-mediated protective tu­mor immunity. J Exp Med 1996; 183: 283-7. 56. Bakker AB, Marland G, de Boer AJ, Huijbens RJ, Danen EH, Adema GJ, et al. Generation of antime­lanoma cytotoxic T lymphocytes from healthy do­nors after presentation of melanoma-associated antigen-derived epitopes by dendritic cells in vi­tro. Cancer Res 1995; 55: 5330-4. 57. Ribas A, Butterfield LH, McBride WH, Jilani SM, Bui LA, Vollmer CM, et al. Genetic immunization for the melanoma antigen MART-1/Melan-A using recombinant adenovirus-transduced murine den-dritic cells. Cancer Res 1997; 57: 2865-9. 58. Song W, Kong HL, Carpenter H, Torii H, Granste-in R, Rafii S, et al. Dendritic cells genetically modi­fied with an adenovirus vector encoding the cDNA for a model antigen induce protective and therapeutic antitumor immunity. J Exp Med 1997; 186: 1247-56. 59. Henderson RA, Nimgaonkar MT, Watkins SC, Robbins PD, Ball ED, Finn OJ. Human dendritic cells genetically engineered to express high levels of the human epithelial tumor antigen mucin (MUC-1). Cancer Res 1996; 56: 3763-70. 60. Specht JM, Wang G, Do MT, Lam JS, Royal RE, Re­eves ME, et al. Dendritic cells retrovirally transdu­ced with a model antigen gene are therapeutically effective against established pulmonary metasta­ses. J Exp Med 1997; 186: 1213-21. 61. Gong J, Chen L, Chen D, Kashiwaba M, Manome Y, Tanaka T, et al. Induction of antigen specific an-titumor immunity with adenoviral transduced dendritic cells. Gene Therapy 1997; 4: 1023. 62. Kugler A, Stuhler G, Walden P, Zoller G, Zobywal-ski A, Brossart P, et al. Regression of human meta­static renal cell carcinoma after vaccination with tumorcell-dendritic cell hybrids. Nat Med 2000; 6: 332-6. 63. Henkart PA. Lymphocyte-mediated cytotoxicity: two pathways and multiple effector molecules. Im­munity 1994; 1: 343-6. 64. Kagi D, Vignaux F, Ledermann B, Burki K, Depra­etere V, Nagata S, et al. Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxi-city. Science 1994; 265: 528-30. 65. Stuhler G, Schlossman SF. Antigen organization regulates cluster formation and induction of cyto­toxic T lymphocytes by helper T cell subsets. Proc Natl Acad Sci USA 1997; 94: 622-7. 66. Finn OJ, Jerome KR, Henderson RA, Pecher G, Domenech N, Magarian-Blander J, et al. MUC-1 epithelial tumor mucin-based immunity and can­cer vaccines. Immunol Rev 1995; 145: 61-89. 67. Kirii Y, Magarian-Blander J, Alter MD, Kotera Y, Finn OJ. Functional and molecular analysis of T cell receptors used by pancreatic- and breast-(mu­cin-) specific cytotoxic T cells. J Immunother 1998; 21: 188-97. 68. Rosenberg S, Yang J, Schwartzentruber D. Immu­nologic and therapeutic evaluation of a synthetic peptide vaccine for the treament of patients with metastatic melanoma. Nat Med 1998; 4: 321-7. 69. Schlom J, Abrams IS. Tumor immunology. In: Bast CR, Kufe WD, Pollock ER, Weichselbaum RR, Holland FJ, Frei E, eds. Cancer medicine. London: B.C. Decker Inc. 2000: 153-67. review Environment and breast cancer – the role of xenooestrogens in breast cancer carcinogenesis Andrej Plesnicar1, Branko Družina2, Viljem Kovac3, Božo Kralj1 1University College of Health Care, 2Institute of Public Health, 3Institute of Oncology, Ljubljana, Slovenia Background. The survival rate of breast cancer patients has not changed much in the last few decades in developed countries. In order to improve the efficacy of breast cancer prevention and treatment, the role of xenooestrogens in the mechanisms of its development has been evaluated. These industrial chemicals bear little structural resemblance to each other and bind to the oestrogen receptors of exposed cells and/or trig­ger oestrogenic responses in laboratory test systems. Exposure to xenooestrogens has been regarded as a risk factor for carcinogenesis and a preventable cause of breast carcinoma. Several epidemiological and experi­mental studies in in vivo and in in vitro conditions of the influence of xenooestrogens on the occurrence of breast cancer have been conducted in the last decades and have shown ambiguous results. Conclusions. No increase in breast carcinoma incidence could be found in women who were exposed to re­latively high concentrations of xenooestrogens for extended periods and small quantities of these compounds that are present in the environment probably cannot act as etiological agents for the occurrence of this dise­ase. A multi step approach is suggested regarding the sequence of studies and measures that should be taken to further assess the importance of xenooestrogens on breast cancer carcinogenesis. Key words: breast cancer; xenooestrogens; carcinogenesis Received 16 November 2001 Accepted 4 December 2001 Correspondence to: Andrej Plesnicar, MD, MSc, Uni­versity College of Health Care, Poljanska c. 26a, SI 1000 Ljubljana, Slovenia; Phone: +386 1 300 11 67; E­mail: andrej.plesnicar@vsz.uni-lj.si Introduction The word cancer is used to describe several diseases that are caused by multiple genetic changes in the cells of different tissues. The­se changes may only manifest themselves af­ter several years, causing the proliferation and immortalisation of affected cells. The cli­nical consequences of these changes are spe­cific clinical states which lead to the prematu­re death of 25-30 % of the population.1 The improvement of survival in cancer, particu­larly breast cancer, the survival rate of which has not changed significantly in the last few decades in the developed countries, is thus among the declared goals that were set to im­prove the health of the whole population by the year 2000.2 The relative five-year survival rate of breast cancer patients in the United States (US) was practically constant at slight­ly less than 80 % for the 1974-1987 period.1 The relative five-year survival rate for the pa­tients with this disease who were diagnosed in the 1977-1985 period in Southern Australia was 72.8 %; however, patients who had breast cancer diagnosed there in the consequent 1986-1994 period had only slightly improved survival rate of 78 %.3 In order to further im­prove the efficacy of breast cancer prevention and treatment, conditions and mechanisms that lead to its development must be known. An especially critical assessment of the signi­ficance of and role played by environmental risk factors is therefore necessary. According to some sources, xenooestrogens, industrial chemicals that bear little structural resem­blance to each other and that bind to the oe­strogen receptors (ER) of exposed cells and/or trigger oestrogenic responses in labo­ratory test systems, are among these factors.4 Xenooestrogens and breast cancer Breast cancer: some characteristics By definition, breast cancer is a disease in the course of which malignant proliferation of the epithelial cells in lobules and ducts of the breast tissue takes place.5 However, this defi­nition could be regarded as too limited since breast cancer is a field researched by experts that are not necessarily specialised in cell and tissue pathology. Breast cancer is the second most frequent form of cancer affecting wo­men, non-melanocytic skin cancer being the most frequent.6 It is also the most common cause of death for female cancer patients,7 the incidence of which is up to five times hig­her in first-world countries than in some less developed Asian and African countries.8 Mo­reover, the incidence of breast cancer in first-world countries still seems to be rising slow­ ly.1,9 Histologically, breast cancer is usually a carcinoma that develops in the terminal duc­tal-lobular units. In most cases, a breast carci­noma develops from ductal cells and less fre­quently from lobular cells, whereas tumour formations that can be histologically classifi­ed as primary sarcoma, lymphoma or unclas­sified tumours are relatively rare, as are meta­static breast tumours that originate from other organs.5,10-12 The occurrence and rapid development of breast carcinoma and the as­sociated incidence of this disease in women is connected to the presence of certain risk fac­tors. They include a relatively low age at first menstruation and a relatively high age at me­nopause, a high age at first birth, obesity and a fat-rich diet, excessive alcohol consumpti­on, and benign breast disease and breast car­cinoma in the family’s medical history. The importance of oral contraception and post-menopausal hormone therapy for the occur­rence and development of this disease is not yet completely clear.1,5,11 Unfortunately, al- Table 1. Characteristics of patients with symptomatic breast carcinoma at the time of diagnosis 1. The most common symptom among diagnosed breast carcinoma patients is a lump (present in 90 % of cases that exhibit symptoms at time of diagnosis), discovered by the patient during self examination, showering or bathing. 2. Pain is present in 10 % of breast carcinoma pati­ents. 3. Skin-colour change on the skin of the affected breast, nodules or oedema (peau d’orange) are present in 5-10 % of breast carcinoma patients. 4. Changes on nipples are apparent in 5 % of pati­ents, half of which have also exhibited discharge from the breast; with the other half, retraction or eczematoid changes can be observed. most 80% of breast carcinoma patients only visit a doctor for the necessary diagnostic procedures after the symptoms and signs of the disease become apparent (Table 1).5,9,11 Xenooestrogens and breast carcinoma carcinogenesis According to several experts in this field, the increase in breast cancer incidence in recent decades appears to be caused by prolonged exposure to oestrogens. It is a well-known fact that the incidence of breast carcinoma in developed countries has risen the most in the population of post-menopausal women.4,13,14 Moreover, prolonged exposure to environ­mental oestrogens is probably a significant risk factor that contributes to the higher inci­dence of breast cancer in the US compared with the countries of East Asia. The impor­tance of prolonged exposure to oestrogens in connection with cancer can be shown by the fact that, in the US, first menstruation occurs at the average age of 12.8 years whereas in China it occurs at the average age of 17 ye­ars.4 Also noteworthy is the fact that the inci­dence of breast cancer in immigrants from East Asia and their descendants is practically the same as with women who were born in the US along with several generations of the­ir ancestors.15,16 Davis et al. set up a hypothe­sis in 1993 according to which xenooestro-gens could be a risk factor for the carcinogenesis of breast carcinoma in women and that prolonged exposure to these compo­unds could be considered one of the preven­table causes of this disease.4,17 In the last few years, several structurally different xenooe­strogens have been discovered which can, due to their tertiary structure and conformati­on, bind to oestrogenic receptors (ER) or in­duce oestrogenic responses in laboratory test systems, or can function using both mecha­nisms at the same time.18-20 Among xenooe­strogens are the halogenated organic compo­unds that were used until recently as pesticides. Some better known examples are kepone, toxaphene, endosulfan, dieldrin, o,p’­DDT, p,p’-DDE, some polychlorinated bi-phenyl (PCB) mixtures, hydroxy-PCB, non-lyphenol and some phthalates.4 Epidemiological studies of importance of xenooestrogens for breast cancer carcinogenesis Epidemiological research into the importance of xenooestrogens for breast cancer carcino-genesis represents only a part of research on the environmental risk factors that may influ­ence the occurrence and development of this disease, and this is despite a rising awareness of their importance.21 The studies conducted have mostly been case-control studies and in­vestigated the presence of organic halogeni­des, i.e. xenooestrogens in breast carcinoma patients compared to healthy control subjects. The hypothesis that claims xenooestrogens are a risk factor for breast cancer formation and development has been confirmed by so­me studies but disproved by others.22-28 Ac­cording to some earlier studies, no difference was observed in PCB and DDE concentrati­ons in the breast tissues of patients and con­trol subjects. However, PCB concentrations in necropsy samples of breast carcinoma pa­tients were higher than in the necropsy sam­ples of control subjects.22,23 A study publi­shed in 1992 by Falck et al. showed that PCB and DDE concentrations in breast carcinoma patients’ breast tissue were higher than con­centrations in healthy control subjects.24 A si­milar study published later by Dewailly et al. only found higher DDE concentrations in bre­ast tissue. Some groups of breast carcinoma patients had increased serum concentrations of DDE and PCB compared to healthy control subjects,25 whereas an extensive study publi­shed in 1994 by Krieger et al. failed to con­firm these differences.27 In one of the extensi­ve studies that followed, Henderson et al. found a large increase in the serum concen­trations of polybrominated biphenyls (PBB) in breast carcinoma patients compared to the control subjects.28 These epidemiological studies were unable to define the importance of xenooestrogens for the carcinogenesis of breast carcinoma, as higher serum concentrations of chlorinated organic compounds may have been, in some studies, caused by specific eating habits, sin­ce increased concentrations of these compo­unds were found in high-fat food as well as fish.4 It should be noted, however, that the re­sults of these and similar studies have in many cases led the laboratory scientists to se­ek to elucidate the role of xenooestrogens in the mechanisms of the breast cancer carcino-genesis. Studying the importance of xenooestrogens for breast cancer carcinogenesis in experimental in vitro conditions Several xenooestrogens that are able to bind to ER (Table 2) have been identified in the last few years using cell cultures in experimental in vitro conditions.4,18-20 By binding to ER, the xenooestrogens could act as sex hormones and accelerate breast carcinoma cell prolifera­tion. In this mitogenic effect, ER play the role of genetic transcription factors that release the block in the G1 phase of the cell cycle.1 Other mechanisms of the effects xenooe­strogens have on breast carcinoma cells have Table 2. Xenooestrogens that bind to oestrogenic re­ceptors (ER) (in vitro cell cultures) Toxaphene Endosulphan Dieldrin o,p’-DDT p,p’-DDE PCB (mixtures and PCB-like compounds) Hydroxy-PCB Bisphenol-A Nonylphenol Phthalates also been researched with the help of in vitro conditions. The results of some studies indi­cate that the xenooestrogens reduce the enz­ymatic activity of 17ß-estradiol 2-hydroxyla­se, and increase the enzymatic activity of E2 16a-hydroxylase, which leads to a change in the ratio of the two respective metabolites in the cell. After exposure to oestrogens, the concentration of 16a-hydroxyoestrone in the cells is increased and is higher than the con­centration of 2-hydroxyestrone, which is why the ratio of their concentrations is increa- sed.17,29 Previous studies also indicate the importance of the change of the ratio which showed that E2 16a-hydroxylase acts as a strong oestrogen whereas 17ß-estradiol 2­hydroxylase is a partial antagonist of the ER receptors.30,31 In the MCF-7 breast carcinoma cell line, many xenooestrogens (Table 3) have the aforementioned effect on the two hydrox­ylases,32 whereas the indole-3-carbinole (I3C), an ingredient of several vegetables, in­hibits the development and growth of breast carcinoma in in vitro as well as in vivo mo­dels.33,34 However, later studies have shown that a change in activity of E2 2-hydroxylase in MCF-7 cells is not caused by inducing the P 450 system but is instead a result of this system’s direct interactions with various che­mical substrates. Moreover, E2 2-hydroxylase activity was reduced after adding pure antio-estrogen ICI 164,384. These results show that Table 3. Xenooestrogens that reduce the enzymatic ac­tivity of 17-estradiole 2-hydroxylase and increase the enzymatic activity of 16-hydroxylase (in vitro cell cul­tures: MCF-7 cells) Endosulphan Kepone p,p’-DDE o,p’-DDE o,p’-DDT Atrazine 2,2’,4,4’,5 pentachlorobiphenyl 7,12-DMBA modulation of E2 2-hydroxylase activity in MCF-7 cells cannot serve as a reliable test for carcinogenic effects of oestrogenic pesticides and other compounds that are thought to promote the occurrence and development of breast carcinoma.4 Studying the importance of halogenated organic compounds in the development of breast carcinoma in experimental in vivo conditions Some studies of the importance of halogena­ted organic compounds and related xenooe­strogens in the occurrence and development of breast carcinoma were conducted using in vivo experimental models with animals (Ta­ble 4). Adding atrazine to Sprague-Dawley la­boratory rats decreased the latent period of breast cancer development;29 a similar study with Fisher laboratory rats showed no chan­ges.35 The results of the study on the Fisher laboratory rats also indicated that atrazine and related compounds influence the oestrus and regulation of synthesis of the luteinising hormone via non-oestrogenic pathways.35 Additional studies showed that atrazine and simazine have no oestrogenic effect,36 while a study done previously found that DDT cau­sed an increase in breast cancer incidence in male Sprague-Dawley rats that were given acetamidophenantrene at the same time.37 However, a much earlier study showed that DDT reduces the incidence of breast tumours induced by dimethylbenzanthracene (DM­BA).38 A review of these studies and examina­tions cannot prove the validity of the hypo­thesis of the important role of xenooestro-gens in breast carcinoma carcinogenesis, as some halogenated organic compounds and xenooestrogens can both inhibit and accelera­te it in in vivo conditions. Halogenated organic compounds with antioestrogenic activity Several of the numerous studies on the im­portance of xenooestrogens for carcinogene-sis and the development of breast carcinoma found that there were some halogenated or­ganic pollutants whose effects were directly opposite to those of oestrogens. One such an-tioestrogenic compound is 2,3,7,8-tetrachlo­rodibenzo-p-dioxine (TCDD), which accor­ding to some studies slows the occurrence of spontaneous breast and uterus tumours in fe­male Sprague-Dawley rats and the occurrence of breast tumours in immunosupressed B6D2F1 mice with xenografts of the MCF-7 cells.39-41 Additional studies confirmed the antioestrogen and antitumor effect of TCDD and some halogenated aromatic hydrocar­bons (HAH) in human breast carcinoma cell lines in in vivo as well as in vitro conditions (Table 5).42 Table 4. Halogenated organic compounds that play a role in breast cancer development (animal experimental mo­dels – in vivo) Compound Animal model Result Reference Atrazine Rats (female) A decrease in the latent period of breast 29 (Sprague-Dawley) cancer development Atrazine Rats (female) (Fischer) No change in the latent period of breast 35 cancer development ACTDP and DDT Rats (male) Increased breast tumour incidence 37 (Sprague-Dawley) DDT Rats (female) (Fisher) A decrease in DMBA-induced breast 28 tumour incidence ACTDP = acetamidophenantrene; DMBA = dimethylbenzanthracene Table 5. Halogenated organic compounds that act as antioestrogens (in vitro cell cultures and in vivo animal ex­perimental models) Compound Animal model Result Reference TCDD Rats (female) A decrease in the occurrence 39 (Sprague-Dawley) of spontaneous breast and uterine tumours TCDD Rats (female) Inhibition of breast tumour carcinogenesis 40 (Sprague-Dawley) TCDD Mice (immunosupressed A decrease in the occurrence 41 with MCF-7 xenografts) of spontaneous tumours TCDD and HAH Human breast cancer Lower activity of peroxydases and binding 42 cell lines of EGRF receptors, smaller amounts of m-RNA TCDD = 2,3,7,8-tetrachlorodibenzo-p-dioxine; HAH = halogenated aromatic hydrocarbons TCDD acts similarly to the “pure” antioe­strogen ICI 164,384, which binds competiti­vely to ER and is an ER antagonist.43 Both compounds inhibit some of the oestrogenic responses and reduce concentrations of oe­strogen-associated proteins in MCF-7 cells. However, TCDD does not bind to ER or re­ceptors for other steroid hormones. Like the various classes of HAH and polychlorinated aromatic hydrocarbons (PAH), it binds to the aryl-carbohydrate receptors that trigger si­gnal pathways similar to those triggered by the other ligand-induced transcription fac­tors.4, 42 Aryl-carbohydrate receptor agonists, which in addition to TCDD and similar pollu­tants from the class of halogenated hydrocar­bons also include I3C and related hetero-PAH found in vegetables and PAH released with the cooking of fish and meat,4 inhibit the growth-factor-induced growth of human bre­ast carcinoma cells.44-45 Various oestrogenic and antioestrogenic compounds in the diet An assessment of the influence of the dietary intake of xenooestrogens on breast carcinoma incidence should also include other compo­unds with oestrogenic and antioestrogenic ef­fects that may be present in the diet. The cha­racteristics of exposure to halogenated orga­nic compounds with a weak oestrogenic ef­fect are not known. However, there are esti­mates for average daily exposure to oestroge­nic compounds in the diet according to regu­lar measurements of their concentrations in various kinds of food. As reported by Safe and McDougal, the average daily intake of DDT, DDE, toxaphene and dieldrin is about 2.5 micrograms per day;4 the average daily in­take for other xenooestrogens is not known.46 Bioflavonoids are an important dietary source of compounds with oestrogenic activity and can be found in most fruits, vegetables, wal­nuts and hazelnuts. The estimated dietary in­take of oestrogenic bioflavonoids may reach up to 1000 milligrams per day. However, the concentrations of oestrogenic lignans in vari­ous kinds of foods, which have been found in human serum, are as yet unknown.46-48 Besi­des these xenooestrogens, the usual diet con­tains compounds with antioestrogenic effects, as well as compounds that reduce the proba­bility of breast carcinoma occurrence with other mechanisms. Some of them include va­rious cell antioxidants and terpenoids.4,46 Estimates have been made of the dietary con­centrations of other halogenated organic com­pounds with antioestrogenic effects and other compounds that act as aryl-carbohydrate re­ceptor antagonists, such as TCDD, HAH, PAH, and I3C.49-51 An assessment of the importance of xenooestrogens for breast carcinoma carcinogenesis Studies of the occurrence and development of breast carcinoma in the last three decades ha­ve implicated exposure to natural or synthetic oestrogens as a risk factor for the occurrence of breast carcinoma in women.1,4 Since 1993, when Davis et al. set up a detailed hypothesis according to which prolonged exposure to xe­nooestrogens could be considered a preventa­ble cause for the occurrence of this disease in women, several epidemiological and experi­mental studies in in vivo as well as in vitro conditions have been conducted to ascertain the validity of this hypothesis.17 It is impossi­ble to either prove or deny it even with the collected results of a large number of studi­ es.4,17 No increase in breast carcinoma incidence could be found in women who were exposed to relatively high concentrations of PCB and DDT for extended periods.52 The small quan­tities of these compounds that are present in the environment probably cannot act as etio­logical agents for the occurrence of this dise­ase. It should also be noted when studying the prolonged exposure of women to xenooe­strogens that an ordinary diet contains seve­ral compounds that have been shown to pre­vent the occurrence and development of breast carcinoma in in vivo and in vitro condi­tions. Other xenooestrogen-like pollutants, in addition to various cell antioxidants and ter­penoids, have been discovered in the diet, such as TCDD and HAH; these have been shown to act as antioestrogens, unlike other pesticides from the class of halogenated hydrocarbons.4,49,53 Also noteworthy is the fact that the intake of weakly oestrogenic pesticides from the class of halogenated hydrocarbons, whether in the diet or in some other way, represents only a minor part of daily exposure to oestro-gens. Several women receive relatively high quantities of potent oestrogenic drugs either through hormone contraception or hormone replacement therapy, yet their risk of breast carcinoma is minimal.16 Xenooestrogens and breast carcinoma – a public health perspective The environment we live in and depend on can influence our health for better or worse.21 An increasing incidence of breast carcinoma has been observed in most industrially and agriculturally developed countries in the last three decades,2,5-9 the causes of which are su­bject to a large number of epidemiological and clinical studies, as well as studies in ex­perimental in vivo and in vitro conditions. Sin­ce pesticides have achieved widespread use in this period due to intensive agricultural production, a study of these industrially ma­de compounds as risk factors is part of these ongoing research projects. Some of these compounds are called xenooestrogens due to the fact that they are a part of the environ­ment and because of their weakly oestrogenic effects.4,5,17,52-54 The number of breast carcinoma casualties and their relative five-year survival rate after the diagnosis of the disease have not changed much despite advances in treating the symptomatic disease.1-3 Although screening programmes using mammography are relati­vely expensive, several randomised studies have shown that a well-considered applicati­on of these programmes reduces the morta­lity rate of breast carcinoma patients.1, 2, 10, 11 However, since these programmes cannot le­ad to an immediate reduction in the mortality rate,55 it is important that the possibilities of improving the overall situation by applying primary prevention methods are taken into consideration. The fact that several cancer re­search and treatment institutions are conduc­ting a number of studies on the efficacy of va­rious pharmacological approaches to breast carcinoma prevention is also important. The publication of results of studies on the che­moprevention of this carcinoma with Tamoxi­phen has aroused considerable professional and public interest.56 A large part of the well-informed public shows concern about the possible influence environmental risk factors may have on the occurrence of various diseases. Part of this public is particularly concerned about pro­blems relating to the occurrence of breast car­cinoma and other cancerous diseases in rela­tion to xenooestrogens.4 Unfortunately, the results of studies of the influence of xenooe­strogens on breast cancer occurrence are am­biguous, which makes educating the general public through clear and simple data rather complicated. In spite of this, doctors and oth­er medical professionals in the primary health network should help breast carcinoma pati­ents and everyone else to interpret the danger posed by the presence of xenooestrogens in their environment. They should also consider the possibility, when conducting clinical exa­minations and examining a medical history, that this disease forms due to a possible pro­longed exposure to these chemicals.1, 2 Suggestions have been made regarding the sequence of studies and measures that sho­uld be taken to assess the importance of envi­ronmental risk factors. It is necessary to iden­tify the compound – in this case, one or more xenooestrogens which, due to their presence in the environment, may represent a risk fac­tor. Next, the time of exposure to one or mo­re xenooestrogens, the number of such episo­des, and their duration and intensity must be determined. The third step towards such an estimate is to identify the characteristics of acute or chronic exposure to xenooestrogens with regard to breast carcinoma carcinogene-sis. Especially important is experimental work in laboratories. The characteristics and importance of the link between exposure to xenooestrogens and the predicted results of exposure must be determined. Finally, the risk of breast carcinoma carcinogenesis in every woman that has been exposed to envi­ronmental xenooestrogens must be defined, as must be the probable consequences of such exposure for a larger population over a longer time period and a calculation of popu­lation attributive risk, population attributive risk in percentages and odds ratios. By stud­ying xenooestrogens’ role in breast carcinoma carcinogenesis, such an estimate would be difficult to make, since the possible effects of exposure to relatively small concentrations of these compounds in the environment and in the routes of entry should be taken into acco­unt. Despite these potential problems, it is necessary to obtain such estimates so they can be used when promoting healthy lifest­yles and also in order to introduce and justify all public and individual measures that must be taken to remove or at least reduce the pre­sence of xenooestrogens in the environment. A further reduction in breast carcinoma inci­dence, and consequentially mortality due to breast carcinoma, could thus potentially be achieved.1-5,11,46-50,52-54,57 References 1. King RJB. Cancer biology. London: Addison Wesley Longman Limited; 1996. 2. Jekel JF, Elmore JG, Katz DL. Epidemiology, biostati­stics and preventive medicine. Philadelphia (PA): W. B. Saunders Company; 1996. 3. South Australian Cancer Registry. Epidemiology of cancer in South Australia. Incidence, mortality and sur­vival 1977 to 1995 analysed by type and geographical location – nineteen years of data. Adelaide: South Australian Health Commission; 1996. 4. Safe SH, McDougall A. Environmental factors and breast cancer. Endocr-relat cancer 1997; 4: 113-123. 5. Lipmann SM, Lee JJ, Sabichi AL. Cancer chemo-prevention: progress and promise. J Natl Cancer Inst 1998; 90: 1514-28. 6. Parkin DM, Pisani P, Ferlay J. Estimates of wor­ldwide incidence of eighteen major cancers in 1985. Int J Cancer 1993; 54: 594-606. 7. Pisani P, Parkin DM, Ferlay J. Estimates of the worldwide mortality from eighteen major cancers in 1985. Int J Cancer 1993; 55: 891-903. 8. Parkin DM, Whelan SL, Ferlay J, Raymond L, Yo­ung J. Cancer incidence in five continents. Lyon: In­ternational Agency for Research in Cancer; 1997. 9. Kricker A, Jeffs P. Breast cancer in Australian wo­men. Canberra: Australian Institute of Health and Welfare; 1996. 10. Gillet D. Early breast cancer: surgical treatment. In: Bishop JF, editor. Cancer facts. A concise onco­logy text. Amsterdam: Harwood Academic Publi­sher; 1999. p. 133-41. 11. Williams CJ. Gynaecological cancers. In: Williams CJ, editor. Cancer biology and management: An intro­duction. Chichester (England): John Wiley & Sons Ltd; 1990. p. 285-320. 12. Plesnicar A, Kovac V. Breast metastases from cu­taneous melanoma. A report of three cases. Tumo­ri 2000; 86: 170-73. 13. Sondik EJ. Breast cancer trends. Incidence, morta­lity, and survival. Cancer 1994; 74: 995-9. 14. Ries LAG. Stat bite: top 5 cancers for females and males in the US. J Natl Cancer Inst 1995; 87: 867. 15. Pike MC, Bernstein L, Spicer DV. Exogenous hor­mones in breast cancer. In: Niederhuber JE, editor. Current therapy in oncology. St Louis: CV Mosby; 1993. p. 292-303. 16. Hulka BS, Liu ET, Lininger RA. Steroid hormones and risk of breast cancer. 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Organochlorine compounds in human bre­ast fat from deceased with and without breast can­cer and in biopsy material from newly diagnosed patients undergoing breast surgery. Environ Res 1984; 34: 24-8. 23. Mussalo-Rauhamaa S, Häsänen E, Pyysalo H, An-tervo K, Kauppila R, Pantzar P. Occurence of (-he­xachlorocyclohexane in breast cancer patients. Cancer 1990; 66: 2124-8. 24. Falck F, Ricci A, Wolff MS, Godbold J, Deckers P. Pesticides and polychlorinated byphenil residues in human breast lipids and their relation to breast cancer. Arch Environ Health 1992; 47: 143-6. 25. Wolff MS, Toniolo PG, Leel EW, Rivera M, Dubin N. Blood levels of organochlorine residues and risk of breast cancer. J Natl Cancer Inst 1993; 85: 648-52. 26. Dewailly E, Dodin S, Verreault R, Ayotte P, Sauvé L, Morin J, et al. High organochlorine body burden in women with estrogen receptor-positive breast cancer. J Natl Cancer Inst 1994; 86: 232-4. 27. Krieger N, Wolff MS, Hiatt RA, Rivera M, Vogel-man J, Orentreich N. Breast cancer and serum or-ganochlorines: a prospective study among white, black, and Asian women. J Natl Cancer Inst 1994; 86: 589-99. 28. Henderson AK, Rosen D, Miller GL, Figgs LW, Zahm SH, Sieber SM, et al. Breast cancer among women exposed to polybrominated byphenils. Epi­demiology 1995; 6: 544-6. 29. Davis DL, Bradlow HL. Can environmental estro­gens cause breast cancer? Sci Am 1995; 273: 166­71. 30. Schneider J, Huh MM, Bradlow HL, Fishman J. Antiestrogen action of 2-hydroxyestrone on MCF­7 human breast cancer cells. J Biol Chem 1984; 259: 4840-5. 31. Swaneck GE, Fishman J. Covalent binding of the endogenous estrogen 16a-hydroxyestrone to estradiol receptor in human breast cancer cells: characterization and intranuclear localization. Proc Natl Acad Sci 1988; 85: 7831-5. 32. Bradlow HL, Davis DL, Lin G, Sepkovic D, Tiwari RK. The ratio of 16a/2-hydroxyestrone as a biolo­gic marker of breast cancer risk. Environ Health Persp 1995; 103: 147-50. 33. Bradlow HL, Michnowicz JJ, Telang NT, Osborne MP. Effects of dietary indole-3-carbinol on estradi­ol metabolism snd spontaneous mammary tumors in mice. Carcinogenesis 1991; 12: 1571-4. 34. Tiwari RK, Guo L, Bradlow HL, Telang NT, Osbor­ne MP. Selective responsiveness of breast cancer cells to indole-3-carbinol, a chemopreventative agent. J Natl Cancer Inst 1994; 86: 126-31. 35. Wetzel LT, Luempert LG, Breckenridge CB, Tisdel MO, Stevens JT, Thakur AJ, et al. Chronic effects of atrazine on estrus and mammary tumor forma­tion in female Sprague Dawley and Fisher 344 rats. J Toxicol Env Health 1994; 43: 169-82. 36. Connor K, Howell J, Chen I, Liu H, Berhane K, Sci-aretta C, et al. Failure of chloro-s-triazine-derived compounds to induce estrogen receptor-mediated responses in vivo and in vitro. Fund Appl Toxicol 1996; 30: 93-101. 37. Scribner JD, Mottet NK. DDt acceleration of mam­mary gland tumors induced in the male Sprague-Dawley rat by 2-acetamidophenantrene. Carcinoge­nesis 1981; 2: 1235-9. 38. Silinskas KC, Okey AB. Protection by 1,1,1-trichlo­ro-2,2bis(p-chlorophenyl)ethane (DDT) against mammary tumors and leukemia during prolonged feeding of 7,12-dimethylbenz(a)anthracene to fe­male rats. J Natl Cancer Inst 1975; 55: 653-7. 39. Kociba RJ, Keyes DG, Beger JE, Carreon RM, Wa­de CE, Dittenber DA, et al. Results of 2-year chro­nic toxicity and oncogenicity study of 2,3,7,8-tetra­chlorodibenzo-p-dioxin in rats. Toxicol Appl Pharmacol 1978; 46: 279-303. 40. Gierthy JF, Bennet JA, Bradley LM, Cutler DS. Cor­relation of in vitro and in vivo growth suspension of MCF-7 human breast cancer by 2,3,7,8-tetra­chlorodibenzo-p-dioxin. Cancer Res 1993; 53: 3149­53. 41. Holcomb M, Safe S. Inhibition of 7,12-dimeth­ybenzanthracene-induced rat mammary tumor growth by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Cancer Lett 1994; 82: 43-7. 42. Safe S. modulation of gene expression and endo­crine response path ways by 2,3,7,8-tetrachlorodi­benzo-p-dioxin and related compounds. Pharmacol Therapeut 1995; 67: 247-81. 43. Wakeling AE. Use of pure antiestrogens to eluci­date the mode of action of oestrogens. Biochem Pharmacol 1995; 49: 1545-9. 44. Fernandez P, Safe S. Growth inhibitory and anti-mitogenic activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in T47D human breast cancer cells. Toxicol Lett 1992; 61: 185-97. 45. Liu H, Biegel L, Narasimhan TR, Rowlands C, Sa­fe S. Inhibition of insulin-like growth factor-I res­ponses in MCF-7 cells by 2,3,7,8-tetrachlorodiben-zo-p-dioxin and related compounds. Mol Cell Endocrinol 1992: 87: 19-28. 46. Winter CK. Dietary pesticide risk assessment. Rev Environ Contam Toxicol 1992; 127: 23-67. 47. Verdeal K, Ryan DS. Naturally-occuring estrogens in plant foodstuffs – a review. J Food Protect 1979; 42: 577-83. 48. Aldercreutz H, Markkanen H, Watanabe S. Pla­sma concentrations of phytooestrogens in Japane­se men. Nature 1993; 342: 1209-10. 49. US Environmental Protection Agency. Health asses­sment for 2,3,7,8-TCDD and related compounds. Ex­ternal review draft 1994; EPA/600/BP-92/001 a-c. 50. Vaessen HAMG, Jekel AA, Wilbers AAMM. Die­tary intake of polycyclic aromatic hydrocarbons. Toxicol Environ Chem 1988; 16: 281-94. 51. Bjeldanes LF, Kim JY, Grose KR, Bartholomew JC, Bradfield CA. Aromatic hydrocarbon responsive­ness – receptor agonists generated from indole-3­carbinol in vitro and in vivo – comparisons with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Proc Natl Acad Sci 1991; 88: 9543-7. 52. A °hlborg UG, Lipworth L, Titusernstoff L, Hsieh CC, Hanberg A, Baron J, et al. Organochlorine compounds in relation to breast cancer, endome-trial cancer, and endometriosis: an assessment of the biological and epidemiological evidence. Crit Rev Toxicol 1995; 25: 463-531. 53. Ames BN, Gold LS, Willet WC. The causes and prevention of cancer. Proc Natl Acad Sci 1995; 92: 5258-65. 54. Ma L, Selim HM. Atrazine retention and transport in soils. Rev Environ Contam Toxicol 1996; 145: 129­73. 55. Burton CR, Giles GG. Cancer prevention, scree­ning and early detection. In: Bishop JF, editor. Can­cer facts. A concise oncology text. Amsterdam: Har-wood Academic Publisher; 1999. p. 28-32. 56. Decensi A, Costa A. Recent advances in cancer chemoprevention, with emphasis on breast and colorectal cancer. Eur J Cancer 2000; 36: 694-709. 57. Plesnicar S, Plesnicar A. Cancer, a reality in the emerging world. Semin Oncol 2001; 28: 210-16. Radio/ 0/lcol 2002; 36(1 ): 1-4. Primarni ne-Hodgkinov limf om v cekumu: prikaz primera Kropivnik M, Jamar B, Cernelc B Izhodišca. Primarni limfam širokega crevesa je redek, predstavlja le 0,4 % primarnih rnaligno­mov v širokem crevesu, obicajno pa zajame cekum ali rektum. V clanku želimo prikazati pomen rentgenske preiskave širokega crevesa v diagnosticnem po­stopku. Prikaz primera. 77-letni bolnik je bil sprejet zaradi bolecin in suma na septicno vnetje v levem kolku, kjer je imel deset let prej vstavljeno totalno endoprotezo. Iz punktata so izolirali Listerio monocytogenes. Dvajset let prej so mu odstranili levo ledvico zaradi hipernefroma. Ob spreje­mu je bil febrilen in anemicen. Zakljucki. Pri bolniku so opravili vec preiskav: ultrazvocno in racunalniško tomografsko prei­skao trebuha, scintigrafijo in jejunoileografijo Z dvojno kontrastno rentgensko preiskavo široke­ga crevesa smo prikazali tumor v predelu ileocekalne valvule. Diagnozo ne-Hodgkinovega lim­fama so postavili histološko po biopsiji ob koloskopiji. Rndiol 011col 2002; 36(1): 5-12. Karotidna angioplastika z uporabo sredstev za zašcito možganov Miloševic Z, Žvan B, Zaletel M, Šurlan M Izhodišca. Karotidna endaterektomija (CEA) je kirurško zdravljenje zožitev notranje karotidne arterije, ki se v svetu in pri nas veliko uporablja. Pri CEA je v vecini primerov potrebna splošna anestezija bolnika. Zapleti pri zdravljenju s CEA so možganska kap, paraliza obraznih živcev, hematom v pooperativnem podrocju in zapleti pri delovanju srca. Tveganje je vecje pri bolnikih s ponovnimi zožitvami po CEA, pri bolnikih po radioterapevtskem obsevanju v podrocju vratu in pri srcnih bolnikih. Karotidna angioplastika s postavitvijo žilne opornice (CAS) je novejša in manj invazivna metoda zdravljenja zožitev notranje karotidne arterije. Metoda je zlasti primer­na pri ponovnih zožitvah po CEA in pri distalnih zožitvah notranje karotidne arterije, ki so manj dostopne za CEA. Pri CAS ni potrebna splošna anestezija bolnika, zato je primernejša za težje srcne bolnike. Zapleti CAS so možganska kap zaradi distalne embolije plaka ali krvnega strdka med posegom, akutna zapora, disekcija ali vazospazem zdravljene arterije in ponovna zožitev zaradi hiperplazije intime arterijske stene. Ker je CAS relativno nova metoda, je potrebno opre­deliti ucinkovitost in varnost metode, preden se široko uvede v klinicno prakso. Bolniki in metode. V Sloveniji smo uvedli CAS v okviru raziskave Slovenian Carotid Angioplasty Study (SCAS). CAS smo izvedli pri 17 bolnikih (12 moških in 5 žensk), ki so bili stari od 69 do 82 let. Vsi bolniki so imeli simptome zožitve arterije karotis, stenoza pa je bila vecja od 70 %. Rezultati. CAS je bila tehnicno uspešna pri vseh 17 bolnikih, saj smo pri vseh zmanjšali steno­zo karotidne arterije in je bila po posegu manjša od 30 %. Pri 14 bolnikih stenoze nismo vec ugo­tovili, pri 2 je bila 15 % in pri enem 30 %. Pri 15 bolnikih po CAS nismo opazili zapletov, ena bol­nica je imela znake hiperperfuzijskega sindroma, ena pa znake crebrovaskularnega inzulta. Zakljucki. Glede na naše zacetne izkušnje bo CAS lahko imela pomembno vlogo v okviru pre­precevanja možganske kapi, predvsem s pravilnim izborom bolnikov in z uporabo sredstev za­šcite možganov med posegom. Radio/ 011col 2002; 36(/): 13-22. Ultrazvocni prikaz analnega sfinktra po kolostomiji Sudol-Szopiriska I, Szczepkowski M, Panorska A, Jakubowski W Izhodišca. Namen raziskave je bil z analnim ultrazvokom (AUS) prikazati spremembe na anal­nem sfinktru pri bolnikih po kolostomiji. Želeli smo tudi najti in razcleniti vzroke ugotovljenih sprememb. Bolniki in metode. AUS smo izvedli po kolostomiji pri 25 bolnikih in uporabili endorektalno sondo z 7.0 MHz. Okvare notranjega analnega sfinktra smo ovrednotili in za statisticno analizo uporabili metodo variance (ANOVA). Rezultati. Notranji analni sfinkter je bil stanjšan pri 22 bolnikih (88 %), srednja debelina pa je bi­la 1.62 mm. Krožno stanjšanje celotne dolžine je imelo 20 bolnikov (90.9 %). Povecano ehogenost notranjega analnega sfinktra smo ugotovili pri 15 bolnikih (60 %) in pri 10 od njih (66.6 %) je ob­segala celotno dolžino in obod sfinktra. Robove notranjega analnega sfinktra ni bilo mogoce do­bro dolociti pri 10 bolnikih (40 %). Statisticno znacilno povezavo smo našli med casom trajanja stomije in okvaro ehogenosti notranjega analnega sfinkterja (p = 0.0001). Pri ostalih spremem­bah pa ni bilo najti statisticno znacilne povezave. Zakljucki. Pri bolnikih po kolostomiji smo ugotovili zmanjšano debelino in povecano ehogenost notranjega analnega sfinktra. Pri nekaterih bolnikih ni bilo mogoce prikazati robov sfinktra. Sta­tisticno znacilno povezavo smo našli le med casom trajanja stomije in okvaro ehogenosti notra­njega analnega sfinktra. Radio/ 011col 2002; 36(1): 23-3-i. Endoskopska ultrazvocna preiskava puborektalne mišice -primerjava izsledkov analne in vaginalne ultrazvocne preiskave dveh preiskovalcev Sudol-Szopiriska 1, Szczepkowski M, Panorska A, Sarti D, Jakubowski W Izhodišca. Z raziskavo smo želeli primerjati rezultate analne in transvaginalne ultrazvocne prei­skave. Primerjali smo tudi ocene razlicnih izvajalcev pri obeh preiskavah. Zanimala nas je razli­cna vizualizacija kot tudi ocena dinamike puborektalne mišice. Bolniki in metode. Analno in transvaginalno ultrazvocno preiskavo smo opravili pri 25 bolnicah, starih od 20 do 72 let (povprecna starost 42 let). Pri vseh preiskavah smo uporabili naprave Brnel &Kjaer s 7,0 MHz vrtljivo sondo s trdo konico, napolnjeno z vodo. Vse bolnice sta pregledala dva preiskovalca z analno in transvaginalno preiskavo. Rezultati. Pri 15 (60 %) od 25 bolnic je bila puborektalna mišica natancneje dolocena s transva­ginalno preiskavo kot z analno. Oba preiskovalca sta se strinjala v tej ugotovitvi. Njuni zakljuc­ki pa so se razlikovali pri oceni funkcionalnosti puborektalne mišice pri obeh metodah raziska­ve: pri 4 bolnicah (16 %) sta oba preiskovalca ugotovila razlike med metodama (16 %), pri 3 pa le prvi preiskovalec (28 %). V vseh primerih sta funkcijo puborektalne mišice ocenila boljše s tran­svaginalno ultrazvocno preiskavo kot z analno. Zakljucki. Z analno in transvaginalno ultrazvocno preiskavo ocenjujemo morfologijo in dinami­cno funkcionalnost puborektalne mišice. V vecini primerov (60 %) je bila vizualizacija puborek­talne mišice boljša pri transvaginalni metodi kot pri analni. Pri oceni funkcionalnosti puborek­talne mišice so bili rezultati prvega preiskovalca pri obeh metodah protislovni v 7 primerih (28 %), rezultati drugega preiskovalca pa v 4 primerih (16 %). V vseh primerih pa je transvaginal­na preiskava natancneje prikazala funkcionalnost puborektalne mišice kot analna metoda. V 3 primerih (12 %) smo med prvim in drugim preiskovalcem ugotovili razlike v njunih ocenah funk­cionalnosti puborektalne mišice. Radio/ 011col 2002; 36(1): 73-9. Radio/ 011co/ 2002; 36(1): 33-40. Uravnavanje odgovora normalnega tkiva na radioterapijo in kemoterapijo zaradi preprecevanja stranskih ucinkov Plevova P Izhodišca. Ionizirajoce sevanje in citostatske ucinkovine, ki jih uporabljamo pri zdravljenju ra­ka, povzrocajo imunski odgovor normalnega tkiva. Ta imunski odgovor je uravnavan s citokini in adhezijskimi molekulami in ce vplivamo na njih, lahko zmanjšamo stranske ucinke zdravlje­nja. V clanku podajamo pregled objavljenih podatkov o tej tematiki. Zakljucki. Nacini, s katerimi lahko vplivamo na imunski odgovor tkiva, da bi omejili stranske ucinke kemoterapije in radioterpije, so si nasprotni. Nekateri zavirajo odgovor na zdravljenje, saj bi pretirana odzivnost zdravega tkiva lahko imela škodljive posledice. To so na primer korti­kosteroidi, nesteroidni antirevmatiki, lizofilin, protitelesa proti citokinom, oligonukletidi, analo­gi sialila Lewis X. Druge ucinkovine pa spodbujajo odzivnost s pospeševanjem endogenega pro­izvajanja citokinov (AS101) ali pa uporabljajo rekombinantne oblike ustreznih citokinov, ki že sodelujejo v odgovoru na zdravljenje in zato še bolj stopnjujejo fiziološki odgovor tkiva na zdrav­ljenje. V klinicni praksi je uporaba kortikosteroidov in nestreroidnih antirevmatikov že mocno uveljavljena, medtem ko je uporaba ostalih ucinkovin še vedno v preizkusni fazi. Rndiol 011co/ 2002; 36(1): 41-6. Limf angioleiomiomatoza Anderluh F Izhodišca. Limfangioleiomiomatoza je redka bolezen neznanega vzroka, za katero zbolevajo žen­ske v rodnem obdobju. Za bolezen je znacilna neneoplasticna proliferacija a,tipicnih gladkomiši­cnih celic v pljucnem parenhimu, limfnih žilah ter mediastinalnih in abdominalnih bezgavkah. V klinicni sliki se pojavljajo spontani pnevmotoraksi, dispneja, hemoptize in hilotoraks. Zakljucki. Racunalniška tomografija visoke locljivosti in imunohistološke metode v biopticnih vzorcih pljucnega tkiva nam omogocajo pravilno postavitev diagnoze. Nacini zdravljenja so ra­zlicni, obicajno hormonski, vendar je zaenkrat njihov uspeh še vprašljiv, prognoza bolnikov pa slaba. Radio/ 011co/ 2002; 36(1): 47 -51. Infantilna miofibromatoza maksile. Prikaz primera Ihan Hren N Izhodišca. Infantilna miofibromatoza je redek benigni tumor otrok. Znacilne so cvrste mase v mehkih tkivih, kosteh ali notranjih organih. Pogosto se pojavlja na glavi in vratu. Poznane so tri oblike: solitarna, multicentricna in visceralna miofibromatoza. Zadnja oblika je lahko smrtna, ostale imajo odlicno prognozo. Znana je spontana regresija. Prikaz primera. Opisan je manj znacilen primer najstnika z obsežno solitarno miofibromatozo zgornje celjustnice. Zakljucki. Pri diagnosticiranju infantilne miofibromatoze je potrebna posebna pozornost zaradi diferencialno diagnosticne podobnosti s fibrosarkomom, leomiosarkomom, histiocitozo. Radio/ Oncol 2002; 36(1): 53-62. Kratek pregled priprave tumorskih vakcin v zadnjem desetletju Novakovic S, Jezeršek Novakovic B Kako bi lahko unicili tumorske celice, ne da bi ob tem prizadeli tudi normalne celice v organi­zmu? Kako bi lahko spremenili sedanje pristope sistemskega zdravljenja, ki temelji predvsem na uporabi citostatikov, da bi le-to delovalo samo na tumorske celice in ne bi prišlo do pojava ne­obcutljivih celicnih klonov? Takšnih in podobnih vprašanj je pri zdravljenju raka veliko in pred­stavljajo osnovo za nove predklinicne in klinicne raziskave s skupnim ciljem odkriti ucinkovito zdravilo ali nacin zdravljenja rakastih bolezni. Ceprav so še pred nekaj leti nesporno prevlado­vali citostatiki kot najucinkovitejše orožje v boju proti raku, se v zadnjih 25 letih na tem podro­cju vse bolj uveljavlja biološka terapija. Posebej obetavna med biološkimi terapijami je priprava in uporaba tumorskih vakcin. Na osnovi novejših spoznanj s podrocij imunologije, tumorske fi­ziologije in molekularne biologije so raziskovalci oblikovali razlicne nadvse zanimive pristope k oblikovanju tumorskih vakcin. Pricujoci clanek predstavlja kratek pregled nekaterih od navede­nih pristopov. Radio/ Oncol 2002; 36(1): 63-72. Ksenoestrogeni in njihova vloga pri nastanku in razvoju karcinoma dojke Plesnicar A, Družina B, Kovac V, Kralj B Izhodišca. Petletno preživetje bolnic s karcinomom dojke se v razvitih državah v zadnjih dese­tletjih ni bistveno izboljšalo. Za cim vecjo uspešnost pri preprecevanju in zdravljenju karcinoma dojke je zato nujno temeljiteje poznati pogoje in mehanizme nastanka in razvoja te bolezni. Še posebej je potrebno oceniti vlogo najrazlicnejših dejavnikov tveganja iz okolja, med njimi tudi ksenoestrogene. Ksenoestrogeni so strukturno raznoliki in se vežejo na estrogenske receptorje izpostavljenih celic v tkivih dojke in/ali sprožajo estrogenicne odgovore na laboratorijskih te­stnih sistemih. Zato je bila že pred nekaj leti postavljena hipoteza, da je lahko dogotrajna izpo­stavljenost žensk ksenoestrogenom dejavnik tveganja pri razvoju raka dojke oz., da so ksenoe­strogeni eden od možnih vzrokov nastanka te bolezni. Vendar z doslej zbranimi rezultati epidemioloških in laboratorijskih raziskav vloge in pomena ksenoestrogenov pri nastanku kar­cinoma dojke ni bilo mogoce natancno opredeliti. Tako posamezni polutanti med kloriranimi ogljikovodiki, ki so jih uporabljali kot pesticide, na primer TCDD in indol-3-karbinol, delujejo celo v nasprotju z odgovori, ki jih v celicah sprožajo estrogeni in ucinkujejo kot antiestrogeni. Zakljucki. Ksenoestrogeni imajo šibke ucinke, v vsakdanjem življenju jih zaužijemo ali prejme­mo z drugacnimi aplikacijami le v zelo majhnih kolicinah. Njihova vloga pri nastanku raka doj­ke je nejasna. Celo pri ženskah, ki vec let prejemajo sorazmerno velike kolicine estrogenih zdra­vil s kontracepcijo in hormonsko nadomestno terapijo, je ugotovljeno tveganje nastanka raka dojke minimalno. Tako je seveda tudi edukacija bolnic otežkocena in je potrebno previdno in­terpretirati morebitno nevarnost izpostavljenosti ksenoestrogenom v njihovem okolju. Kljub tem problemom priporocajo ukrepe, ki bi zmanjšali prisotnost ksenoestrogenov v okolju, kakor tudi nadaljnje vecstopenjske raziskave o njihovem vplivu na karcinogenezo. Notices Notices submitted Jor publication shou/d contain a mailing address, phone and/ or Jax number and/or e-mail oj a Contact person or department. Lung cancer March 14-15, 2002 The IASLC international workshop "Early Invasive Lung Cancer. New Diagnostic Tools & Treatment Stra­tegies" will be offered in Turin, ltaly. Contact Organising Secretariat, CCI Centro Congressi lnternazionale srl, Via Cervino 60, 10155 Turin, ltaly; or call +39 011 244 69 16; or fax +39 011 244 69 00; or e-mail info@lcongressiefiere.com Gastroenterology and hepatology Marc/1 14-16, 2002 The teaching course "Gastroenterology and Hepa­tology" will take place in Las Croabas, Puerto Rico. Contact Program Coordinator, John Hopkins University, Turner 20/720 Rutland Avcnue, Baltimore, Maryland 21205, USA; or call +1 410 955 2959; or fax +1 410 955 0807; or e-mail cmenettin.it; or see http://www.cancerworld.org Breast cancer Marc/1 19-23, 2002 The 3rd European Breast Cancer Conference will be offered in Barcelona, Portugal. See http://www.fecs.be/conferences/ebcc3 Brachytherapy March 24-26, 2002 The ESTRO teaching course "Endovascular Brachy­therapy" will take place in Vienna, Austria. Contact ESTRO office, Av. E. Mounier, 83/4, B-1200 Brussels, Belgium; or call +32 7759340; or fax +32 2 7795494; or e-mail info«Destro.be; or see http://www.estro.be Breast cancer April 5-6, 2002 The teaching course "Current Concepts in the Multidisciplinary Managernent of Early-Stage Breast Cancer" will take place in Baltimore; Maryland, USA. Contact Program Coordinator, John Hopkins University, Turner 20/720 Rutland Avenue, Baltimore, Maryland 21205, USA; or call +1 410 955 2959; or fax +1 410 955 0807; or e-mail cmenet«lljhrni.edu; or see http://www.med.jhu.edu/cme Head and neck April 8-13, 2002 The master course about cancer in oral cavity and oropharynx will take place at European Institute of Oncology in Milan, ltaly. Call P. Lonati, +39 02 5748 9490; or fax +39 02 5748 9491; or e-mail head&neck@1ieo.it Thoracic surgery April 11-12, 2002 The "5th lnternational Meeting on General Thoracic Surgery" will be offered in Barcelona, Spain. Contact RCT, C/ Aulestia i Pijoan, 12 Baixos 98012, Barcelona, Spain, or call +34 93 415 69 38; or fax +34 415 69 04; or e-mail rctestro.be; or see http://www.es­tro.be Oncology Ju11e 30 -July 5, 2002 The "18th UICC lnternational Cancer Congress" will be offered in Oslo, Norway. Contact Norwegian Cancer Society, P.O. Box 5327 Majorstua, N-0304 Oslo, Norway, or call +47 22 59 30 00; or fax +47 22 60 69 80; or e-mail cancer@oslo2002.org Radiology July 1-5, 2002 The "22nd International Congress of Radiology (ICR 2002)" will take place in Cancun, Mexico. Contact B.P. Servimed, S.A. de C.V., at lnsergentes Sur No. 1188 50 piso, Col. Del Valle, 03210 Mexico DF, Belgium; or call +525 575 9931; or fax +525 559 9407; or e-mail fmricr@Jservimed.com.mx Notices 83 Oncology July 3-5, 2002 The ESO course "Cancer Economics and Evidence­Based Medicine" will take place in Sapporo, Japan. Contact ESO Office, Viale Beatrice d'Este 37, 20122 Milan, ltaly; or call +39 02 43359611; or fax +39 02 43359640; or e-mail csomi«Dtin.it; or sce http://www.cancerworld.org Clinical Oncology A11g11st 4-9, 2002 The "Masterclass in Clinical Oncology" will take place in Montecatini Terme, ltaly. Contact Dr. Wolfgang Gatzermeier, ESO Office, Viale Beatrice d'Este 37, 20'122 Milan, ltaly; or call +39 0258317850; or fax +39 02 433 59640; or e-mail es­oweb@tin.it Radiation physics Augus/ 25-29, 2002 The ESTRO teaching course "Physics for Clinical Radiotherapy" will take place in Leuven, Belgium. Contact ESTRO office, Av. E. Mounier, 83/4, B-1200 Brussels, Belgiurn; or call +32 7759340; or fax +32 2 7795494; or e-rnail info«llestro.be; or see http://www.es­tro.be Radiobiology A11g11st 25-29, 2002 The ESTRO teaching course "Basic Clinical Radiobiology" will take place in St. Petersburg, Russia. Contact ESTRO office, Av. E. Mounier, 83/4, B-1200 Brussels, Belgiurn; or call +32 7759340; or fax +32 2 7795494; or e-rnail info«,iestro.be; or see http://www.es­ tro.be Oncohaematology August 29-30, 2002 The ESO course will take place in Buenos Aires, Argentina. Contact G. Farante, ESO Headquarters, ESO Latin Arnerica Office, Viale Beatrice d'Este 37, 20122 Milan, ltaly; or call +39 02 58317318; or fax +39 02 58321266; or e-rnail esolatin«,>tin.it; or see http://www.cancer­ world.org; or Argentina Office, A. Rancati, Florida 833 (1o), 1005 Buenos Aires; Phone +54 11 45118078; Fax +54 11 45118079. Oncohaematology Augus/ 31 -Septe111/Jer 1, 2002 The ESO course will take place in Bahia, Brazil. Contact G. Farante, ESO Headquarters, ESO Latin America Office, Vialc Beatrice d'Este 37, 20122 Milan, ltaly; or call +39 02 58317318; or fax +39 02 58321266; or e-mail esolatin«,'tin.it; or see http://www.cancer­world.org; or e-mail afrasson«llhotmail.com Prostate cancer Septe111ber 1-3, 2002 The ESTRO teaching course "Brachytherapy for Prostate Cancer" will take place in Utrecht, the Netherlands. Contact ESTRO office, Av. E. Mounier, 83/4, B-1200 Brussels, Belgiurn; or call +32 7759340; or fax +32 2 7795494; or e-rnail info«Destro.be; or see http://www.es­tro.be Lung cancer September 1-4, 2002 "8th The Central European Lung Cancer Conference" will be offered in Vienna, Austria. Contact Conference Sccretariat, Mondial Congress, Faulmanngasse 4, A-1040 Vienna, Austria; or call +43 1 588 04 O; or fax +43 1 586 91 85; or e-rnail con­gress@Jrnondial.at Lung cancer Septe111ber 8-12, 2002 The "JASLC Workshop on Progress and Guidelines in the Managernent of Non Srnall Celi Cancer" will be offered in Brugcs, Belgiurn. Contact Secretariat, P. van 1-loutte, Dept. Radiotherapy, Institute Jules Bordet, Rue Hcger­Bordet 1, B-1000 Brussels, Belgiurn; or call + 32 2 54 J 3830; or fax +32 2 538 7542; or e-rnail paul.van­houtte«,>bordet.be Medica! physics Seple111ber 9-B, 2002 The "lOth Jnternational Congress on Boron Neutron Capture Therapy" will take place in Essen, Gerrnany. Contact Dr. Ray Moss with e-rnail rnoss«ojrc.nl Radiation therapy Seple111ber 17-21, 2002 The 21st Annual ESTRO Meeting will take place in Prague, Czech Republic. Contact ESTRO office, Av. E. Mounier, 83/4, B-1200 Brusscls, Belgium; or call +32 7759340; or fax +32 2 7795494; or e-mail info«11estro.be; or see http://www.es­tro.be Oncology September 19-21, 2002 The ESO coursc "The Challenge of Cancer. A Central Role for General Practice" will take place in Dublin, Ireland. Contact ESO Headquarters, Viale Beatrice d'Este 37, 20122 Milan, Jtaly; or call +39 02 43359611; or fax +39 02 43359640; or e-mail esomi(del6.vsnl.net.in; or sec http://www.watch­2000.org Radiation therapy October 6-9, 2002 ASTRO Annual meeting will be held in New Orleans, Louisiana, USA. Contact American Society for Therapeutic Radiology and Oncology Office, 1891 Prcston White Dri ve, Res ton, V A 20191, USA; or see http://www.as­tro.org Salivary glands Oclober 7-12, 2002 The master course about cancer in salivary glands will take place at European Institute of Oncology in Milan, ltaly. Call P. Lonati, +39 02 5748 9490; or fax +39 02 5748 9491; or e-mail head&neck«Dieo.it Colorectal cancer Oclober 24-25, 2002 The "2nd Colorectal Cancer Conference" will take place in Rome, ltaly. Contact ESO Office, Viale Beatrice d'Este 37, 20122 Milan, ltaly; or call +39 02 43359611; or fax +39 02 43359640; or e-mail esomitin.it; or sce http://www.cancerworld.org Radiation oncology Marcil '/5-19, 2003 The "2nd International Conference on Translation Research and Pre-Clinical Strategies in Radiation Oncology, ICTR 2003" will be offcred in Lugano, Switzerland. Fax +41 91 820 9044, or e-mail jbernier«Dpop.eu­net.ch, or see http://www.osg.ch/ictr2003.html Radio/ 011co/ 2002; 36(1 ): 80-5. Nolices 85 Allergology and clinical immunology ]lll!C 7-11, 2003 1 The "22'"Congrcss of the Europcan Academy of Allergolo1,,y and Clinical lmmunology" take placc in Paris, France. Contact Congrex Sweden AB, Attn: EAACI 2003, Linnegatan 89A, P.0. Box 5619, SE-1'14 86 Stockholm, Sweden, or call +46 8 459 66 00; or fax +46 8 66'1 91 25; or c-mail eaaci2003ccocongrex.se; or see http://www.eaa­ci.org Lung cancer Augusl 70-14, 2003 The "10th World Conference of the lnternational Association for the Study of Lung Canccr" will bc of­fered in Vancouver, Canada. Contact 10th World Confercnce of Lung Cancer, c/o lnternational Conference Serviccs, 604-850 W cst Hastings, Vancouver BC Canada V6C 1E1, or call +1 604 681 2153; or fax +] 604 681 '!()49; or e-mail con­ference(a>2003worldlungcancer.org Radiation therapy Seple111ber 27-25, 2003 The ESTRO 22 / ECCO 12 Meeting will take place in Copenhagen, Denmark. Contact FECS office, Av. E. Mounier, 83/4, B-1200 Brussels, Belgium; or call +32 7759340; or fax +32 2 7795494; or e-rnail info«,>cstro.be; or sce http://www.fecs.be Radiation therapy Oc/o/Jer 19-23, 2003 ASTRO Annual rneeting will be held in Salt Lake City, Utah, USA. Contact American Socicty for Therapeutic Radiology and Oncology Officc, 1891 Preston White Drive, Reston, VA 20'l 91, USA; or sec http://www.as­tro.org Radiation therapy September 12-16, 2004 The 23rd Annual ESTRO Meeting will be held. Contact ESTRO office, Av. E. Mounier, 83/4, B-1200 Brussels, Belgium; or call +32 7759340; or fax +32 2 7795494; or e-mail info."estro.bc; or sce http://www.estro.be Radiation therapy Oc/ober 3-7, 2004 ASTRO Annual rnecting will be hcld in Atlanta, USA. Contact American Society for Thcrapeutic Radiology and Oncology Office, 189'1 Preston White Drivc, Res ton, VA 2019], USA; or scc http:// www.as­tro.org As a service to our rcaders, notices of n1eetings or courses will be inserted free of chargc. Pleasc sent information to the Editorial office, Radiology and Oncology, Zaloška 2, SI-] 000 Ljubljana, Slovenia. Radio/ Oucol 2002; 36(1): 80-5. 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 01 519 12 77 FAKS01 251 81 13 ŽR: 501 00-620-1 33-05-1 0331 1 5-2 14779 Activity of "Dr. J. Cholewa" Foundation for Cancer Research and Education -A Report for the First Quarter of 2002 The "Dr. J Cholewa" Foundation for cancer research and education is conccrned as the change in the donors' attitude towards the Foundation in the last rnonths of the year 2001 calls for the new ways to adapt to the given circurnstances. These new circurnstances and the difficulties and problems associated with them were taken into consideration and scri­ously discussed on ali lcvels of the Foundation. It is hoped that some of the new ap­proaches considered in contacts and communications with the donors will produce some tangible results in the near future. The activity of the Foundation is by now well established as a result of a relatively long and substantial experience, and through the hard work of its members it offers a certain guar­antee that the means from the possible donations will be spent in an efficicnt and impar­tial way. This attitude of the Foundation guarantces that the grants and supports are asso­ciated with excellent research work underway in Slovenia. The decision was also takcn to increase the amount of the "Dr. J Cholewa" Foundation for cancer research and education annual prize in order to give further incentive to young researchers in ali parts of Slovenia. It is a long-time held position of the Foundation that high quality research work in oncolo­gy and related scientific fields is taking place and should be further encouraged in ali parts of Slovenia where the interest to promote such research exists. The Foundation continues to support the regular publication of "Radiology and Oncology" international scientific journal that is edited, published and printed in Ljubljana, Slovenia. The Foundation has also received a number of grant applications and it has considered the merits of the proposed research work thoroughly. A nurnber of grants was awarded to ex­perts from various parts of Slovenia in order to attend various conferences and meetings in the field of oncology in Slovenia and around the world. The Foundation invited new members to its Executive council in order to better represent and understand the present currents and advances in the continuos development of can­cer research and education in Slovenia. The new members are Igor Bartenjev, MD, PhD, Janez Žagar, MD, PhD, and Rado Janša, MD, MSc. Tomaž Benulic, MD Borut Štabuc, MD, PhD Andrej Plesnicar, MD Conference Announcement Call For Papers BIOMEDICINE 2003 Fifth lnternational Conference on Simulations in Biomedicine 2 -4 April 2003, Ljubljana, Slovenia Organised by: Wessex Institute of Technology, UK University Medica! Centre Ljubljana, Slovenia Faculty of Computer and lnformation Science, Ljubljana, Slovenia klinicni"' center (C ljubljana Abstracts can be submitted at: www.wessex.ac. uk/conferences/2003/biomed03/ BIOMED 2003 provides an internationally recognised forum for disseminating the !atest bioengineering research and its applications. The conference topics will cover a broad spectrum including the application of computers to simulate biomedical phenomena. The conference will be held at the University Medica! Centre, the most important medica! institution in Slovenia and one of the leading modern medica! hospitals in Central Europe. The meeting aims to bring together medica!, physical scientists and engineers who are interested in the latest developments on simulations in medicine. It will also be relevant to professionals working in medica! enterprises, which are actively involved in this field. CALL FOR PA PERS Papers are invited on the topics outlined opposite and others falling within the scope of the meeting. Abstracts of no more than 300 words should be submitted as soon as possible. Abstracts should clearly stale the purpose, results and conclusions of the work to be described in the final paper. Fina! acceptance will be based on the full-length paper, which if accepted, must be presented at the conference. Each submitted paper is subject to a separate registration. We strongly encourage the submission of abstracts electronically. The language of the conference will be English. CONFERENCE SECRETARIAT Gabriella Gossutta, Conference Secretariat, BIOMEDICINE 2003, WESSEX INSTITUTE OF TECHNOLOGY, Ashurst Lodge, Ashurst, Southampton, SO40 7 AA. Telephone: 44 (O) 238 029 3223 Fax: 44 (O) 238 029 2853 Email: gcossutta@wessex.ac.uk TOPICS Simulation of Physiological Processes Computational Fluid Dynamics in Biomedicine Orthopaedics and Bone Mechanics Simulations in Surgery Data Acquisition and Analysis lmage Processing Design and Simulation of Artificial Organs Non-Conventional Therapy Computers in Medicine Expert Systems in Medicine Advanced Technology in Dentistry Gait and Motion Analysis Computer Technology for Disabled Cardiovascular System Virtual Reality in Medicine Electro-Magnetic Simulation Biomechanics VISIT THE CON FERENCE WEBSITE AT: www.wessex.ac.uk/conferences/2003/biomed03/ 22nd INTERNATIONAL CONGRESS OF RADIOLOGY ORGANIZED BY INTERNATIONAL SOCIETY OF RADIOLOGY ISR MEXICAN FEDERATION OF RADIOLOGY ANO IMAGING FMRI www.icr2002.org.mx ORGANIZING COMMITTEE 1 to 5 July 2002 PRESIDENTS CARL G. STANDERTSKJOLD-NORDENSTAM FINL. ISR CANCUN -MEXICO RAMIRO JOHNSON-VELA MEX. FMRI PRESIDENTS ELECT GEORGE KLEMPFNER AUSTRAL. ISR FRANCISCO AVELAR MEX. FMRI CATEGORICAL AND SECRET ARIES FRANCISCO ARREDONDO GUAT. ISR REFRESHER COURSES RAFAEL ROJAS-JASSO MEX. FMRI TREASURERS HANS RINGERTZ SWE. ISR SPECIAL FOCUS CONFERENCES JORGE HERRERA-CANTILLO MEX. FMRI EXECUTIVE DIRECTOR ISR OTHA LINTON EUA SYMPOSIA EDUCATION COMMITTEE ICR/ISR HOLGER PETTERSON SWE. SCIENTIFIC EXHIBITS CHAIRMAN ANO SCIENTIFIC COMMITTEE ICR-2002 JOSE LUIS RAMIREZ-ARIAS MEX. SCIENTIFIC LOCAL COMMITTEE WORKSHOPS JOSE LUIS RAMIREZ-ARIAS GUILLERMO ELIZONDO-RIOJAS BEATRIZ GONZALEZ-ULLOA JORGE HERNANDEZ-ORTIZ JANET TANUS-HAJJ INFORMATION B.P. Servimed, S.A. de C.V. lnsurgentes Sur 1188-507, 03210 Mexico, D.F. TEL. (525) 575-99-31 FAX. (525) 559-94-97 Web http//www.icr2002.org.mx E-mail fmricr@servimed.com.mx ENROLLMENT istcrto: Stcfaan arccfo. Ticlt B rn ail: mcdipoint(J: frcc or 251406 450 C includ ,yllabus ancl CD-RO oldin Europc A.G .. !3anlc C red it Suisse llahnhofstrasse 1 CH-6301 ZUG {Switzcrland) i\ccount o.627-92-l 3 SlC o.0823 1,ort codcl Octohcr), lunches, seminar focilitics. accompany pcrson sbaring thc room pay adclitional brcakl'ast only mcnt: AKTUA REJZEN (official trave! agent) E-:Vl ail: aktua@ idnct.bc Tei 325 l 4050 Fax +3251424059 Bank: Forti, bank. Dic,tscstecnwcg 430 B-3202 A,mchot 1B ium) Account No. 230-0379902-70 SWIFT:G BAB BB08A GENE RAL INFORMATION -, = .... 'III The course aims to teach musculo­skeletal ultrasound and is designed to learn the practice of standard ultrasound examinations. For that purpose, the key anatomic structures are discussed for each joint and emphasis is placed on training each participant individually in pratical sessions. This is guaranteed by tl1e presence of experienced teachers and by the limited number of pariicipants (maximum 21) accepted for each training session. Formal lectures provide an overview of current applications .An interactive multi-media CD-ROM on US anatomy -& pathology is provided to each practical hands-on training Wc do not process rcgistration 11·i1hont payment ( first in . fir,t scn·cd i ln case of written cancellation before October !O. the amount 11 ill be refundcd .bcyond this datc: 110 rcfund. o ultrasound course "ffl Hands on training in MUSCULO SKELETAL ULTRASOUND Grand Hotel Mercure Royal Crown * * * * * October 24-26 2002 (English speaking) STE AN ARCELIS TJEERD JAGER ICHEL DE AESENEER .... •• Q • U!mll'llll!l.'11\V --1 - - -_ ... _._-:m-:m-:m-:,· - kapsule v svetu najvec predpisovani sistemski( antimikotik edini peroralni sistemski antimikotik za zdravljenje vaginalne kandidoze, ki ga je odobril FDA Skrajšano navodilo Flukonazol je sistemski antimikotik iz skupine triazolov. Odmerjanje pri razlicnih indikacijah: vaginalna kandidoza 150 mg v enl