ADIOLOGY lllllJ NCOLOGY June 2005 Vol. 39 No. 2 Ljubljana ISSN 1318-2099 Editorial office RadiologtJ and OncologtJ June 2005 Institute of Oncologtj Vol. 39 No. 2 Zaloška 2 Pages 91-169 SI-1000 Ljubljana ISSN 1318-2099 Slovenia UDC 616-006 Phone: +386 1 5879 369 CODEN: RONCEM Phone/Fax: +386 1 5879 434 E-mail: gsersa@onko-i.si Aims and scope Radiologij and Oncology is a journal devoted to publication of original contributions in diagnostic and interventional radiology, computerized tomography, ultrasound, magnetic resonance, nuc/ear medicine, radiotherapy, c/inical and experimental oncologtj, radiobiology, radiophysics and radiation protection. Editor-in-Chief Editor-in-Chief Emeritus Gregor Serša Tomaž Benulic Ljubljana, Slovenia Ljubljana, Slovenia Executive Editor Editor Viljem Kovac Uroš Smrdel Ljubljana, Slovenia Ljubljana, Slovenia Editorial board Marija Auersperg Valentin Fidler MajaOsmak Ljubljana, Slovenia Ljubljana, Slovenia Zagreb, Croatia Nada Bešenski Be1a Fornet Branko Palcic Zagreb, Croatia Budapest, Hungary Vancouver, Canada Karl H. Bohuslavizki Tullio Giraldi ]urica Papa Hamburg, Gennany Trieste, Italy Zagreb, Croatia Haris Boka Andrija Hebrang Dušan Pavcnik Zagreb, Croatia Zagreb, Croatia Portland, USA Nataša V. Budihna Laszl6 Horvath Stojan Plesnicar Ljubljana, Slovenia Pecs, HunganJ Ljubljana, Slovenia Marjan Budihna Berta Jereb Ervin B. Podgoršak Ljubljana, Slovenia Ljubljana, Slovenia Montreal, Canada Malte Clausen Vladimir Jevtic Jan C. Roos Hamburg, Gennany Ljubljana, Slovenia Amsterdam, Netherlands Christoph Clemm H. Dieter Kogelnik Slavko Šimunic Munchen, Gennany Salzburg, Austria Zagreb. Croatia Mario Corsi Jurij Lindtner Lojze Smid Udine, Italy Ljubljana, Slovenia Ljubljana,Slovenia Ljubomir Diankov Ivan Lovasic Bonit Štabuc Sofia, Bulgaria Rijeka, Croatia Ljubljana, Slovenia Christian Dittrich Marijan Lovrencic Andrea Veronesi Vienna, Austria Zagreb, Croatia Aviano, Italy Ivan Drinkovic LukaMilas Živa Zupancic Zagreb, Croatia Houston, USA Ljubljana, Slovenia Gillian Duchesne Metka Milcinski Melbourne, Australia Ljubljana, Slovenia Publisher Association of Radiology and Oncology Affiliated with Slovenian Medica/ Association -Slovenian Association of Radiology, Nuclear Medicine Society, Slovenian Society far Radiotherapy and Oncology, and Slovenian Cancer Society Croatian Medica/ Association Croatian Society of Radiologij Societas Radiologorum H1111garoru111 Friuli-Venezia Giulia regional groups of S.I.R.M. (Italian Society of Medica/ Radiology) Copyright © Radiologij and Oncology. Ali rights reserved. Reader for English Mojca Cakš Vida Kološa Keywords Eva Klemencic Secretaries Milica Harisch Mira Klemencic Design Monika Fink-Serša Printed by Imprint d.o.o., Ljubljana, Slovenia Published quarterly in 700 copies Beneficiary name: DRUŠTVO RADIOLOGIJE IN ONKOLOGIJE Zaloška cesta 2, 1000 Ljubljana Slovenia Beneficianj bank account number: SI56 02010-0090006751 IBAN: SI56020100090006751 Our bank name: Nova Ljubljanska banka, d.d., Ljubljana, Trg republike 2, 1520 Ljubljana; Slovenia SWIFT: LJBASI2X Subscription fee for institutions EUR 100 (16000 SIT), individuals EUR 50 (5000 SIT) The publication of this journal is subsidized by the Ministry of Education, Science and Spori of the Republic of Slovenia. Indexed and abstracted by: BIOMEDICINA SLOVENICA CHEMICAL ABSTRACTS EMBASE / Excerpta Medica Sci Base This journal is printed on acid-free paper Radiology and Oncology is available on the internet at: http://www.onko-i.si ISSN 1581-3207 Ljubljana, Slovenia ISSN 1318-2099 June 2005 UDC 616-006 Vol. 39 No. 2 CODEN: RONCEM CONTENTS SONOGRAPHY, COMPUTED TOMOGRAPHY Chronic nonischemic ileo-ileo-colic intussusceptionc Roic G, Vrtar Z, Posaric V, Boric I, Cigit I 91 Osteosarcoma of the maxilla Sayin B, Yildirim N, Vural M, Dede D 95 Multislice computed tomography of pulmonary embolism: spectrum of findings Bešlic S, Dalagija F, Durovic V 101 ONCOLOGY Characterization of lung cancer patients, their actual treatment and survival: experience in Slovenia Debevec L, Debeljak A, Eržen], Kovac V, Kern I 115 Surgical treatment of malignant pleural mesothelioma. Experience in the interdisciplinary approach in Slovenia Eržen], Vidmar S, Sok M, Debeljak A, Kecelj P, Kovac V, Stanovnik M, Rott T, Kern I 123 Managing anemia with epoetin alfa in patients with rectal cancer Velenik V, Oblak I, Kodre V 133 Metastatic thymoma: a case report of an isolated, intra-abdominal metastasis causing asymptomatic spinal cord compression Gold DG, Miller RC 141 Rapid detection of most frequent Slovenian germ-line mutations in BRCAl gene using real-tirne PCR and melting curve analysis Novakovic S, Stegel V RADIATION PROTECTION Cytogenetic analysis of peripheral blood lymphocytes after arteriography (exposure to x-rays and contrast medium) Popova L, Hadjidekova V, Karadjov G, Agava S, Traskov D, Hadjidekov V SLOVENIAN ABSTRACTS 153 159 NOTICES 167 Radiol Oncol 2005; 39(2): 91-4. case report Chronic nonischemic ileo-ileo-colic intussusception Goran Roic1, Zvonimir Vrtar2, Vesna Posaric1, Igor Boric1, Irenej Cigit2 1Department of Pediatric Radiology, 2Department of Pediatric Surgery, Children's Hospital Zagreb, Zagreb, Croatia Background. Chronic intussusception is a prolapse of a portion of the bowel into the lumen of an immedi­ately adjacent segment of the bowel; it lasts for 14 days or more. The aim of the article is to present a rare cause of nonacute abdominal pain. Case report. We report about 14-year-old girl who presented with a one-month history of intermittent cramping lower abdominal pain and change in bowel behavior. Plain abdominal x-ray, ultrasonography and CT were performed. Laparatomy revealed an ileo-ileo-colic intusussception (70 cm long); invaginated Meckel's diverticulum was a prevailing anomaly. Conclusions. Atypical clinical presentation of chronic intussusception often results in delayed or inade­quate management of such cases because of the lack of suspicion of a correct diagnosis. Preoperative diag­nosis of invagination was based on ultrasonography and computed tomography (CT) which proved again as the most effective and useful preoperative diagnostic method. Surgical intervention is always needed in adults and older children because of high incidence of underlying lesions in them. Keywords: ileal diseases; intussusception; Meckel’s diverticulum Introduction Intussusception (invagination) is a prolapse of a portion of the bowel into the lumen of an immediately adjacent segment of the bowel. The acute type does not present as great a di­agnostic problem as does the chronic intus­susception. The chronic intussusception is Received 9 July 2004 Accepted 15 August 2004 Correspondence to: Goran Roic, M.D., Department of Pediatric Radiology, Department of Pediatric Surgery, Children,s Hospital Zagreb, Klaiceva 16, 10 000 Zagreb, Croatia; Phone: +385 1 4600231; Fax: +385 1 4600228; E-mail: goran.roic@zg.htnet.hr defined as intussusception lasting for 14 days or more.1 Adult intussusception is the cause of 1-5% of all bowel obstructions.2 A vast majority (95%) of intussusceptions occurs in children, whereas only 5% occur in adults.3 In adults, 80%–90% of cases have a demon­strable cause. Approximately 65% are due to a neoplasm, whereas nonneoplastic causes compose the remaining 15%–25% of cases with a known cause and include adhesions and postoperative complications, Meckel's di­verticulum, lymphoid hyperplasia and adeni-tis, trauma, celiac disease, duplications, and Henoch-Schönlein purpura.4 Treatment al­ways requires surgical excision.5 Case report A 14-year-old girl presented with a one-month history of intermittent cramping lower abdominal pain and change in bowel behav­ior. Due to menstrual problems, the patient was initially treated as dysmenorrhea. Abdominal ultrasonography revealed a soft-tissue mass with hypoechoic outer layer and central echogenic area; the peristalsis through invaginated ileum was active (Figure 1a). The characteristic US findings in a longi­tudinal plane were alternating hypoechoic and echogenic layers called the »sandwich« or »pseudokidney« sign (Figure 2b). Plain ab-dominal x-ray showed slightly dilated loops of the small bowel without air-fluid levels. CT of the abdomen showed concentric rings (»target« sign) with the thickening of the affected bowel and intraluminal areas of fat attenuation due to mesentery and Meckel's diverticulum drawn into the intussusception (Figures 2a, 2b). Laparatomy revealed an ileo-ileo-colic in-tusussception (70 cm long); the prevailing anomaly was invaginated Meckel's diverticu­lum. Discussion The classical presentation of intussusception consisting of pathognomonic triad of severe abdominal pain, bloody stool, and a palpable abdominal mass leads to the correct diagno­sis in the majority of the patients. Intus­susception can also be present in a subacute or chronic form with a long history of less se­vere symptoms.1,6 This form of »nonischemic« intussusception is a distinct entity with atyp­ical clinical presentation and often results in delayed diagnosis due to low index of suspi­cion.6 If one considers the possibility, chronic in-tussusception can be readily diagnosed by sonography; the CT appearances are pathog­nomonic.7-9 Ultrasonography of transverse sections shows a mass with a swirled appear­ance of sonolucent and hyperechoic bowel wall of the loop-within-a-loop. The character­istic US findings in a plane transverse to in-tussusception are a sandwichlike or pseudo-kidney appearance of the intussuscipiens and the intussusceptum with a hypoechoic ring surrounding an echogenic center; it appears as if multiple layers would build the walls of the intussuscepted bowel loops. Typical CT findings of intussusception are thickening of the affected bowel segment, ar­eas of fat attenuation within the abnormal bowel loop, concentric rings (»target« sign), and an intraluminal soft-tissue mass at the leading end of the intussusceptum.10,11 The »target« appearance is not specific for intus­susception, and it may also be seen in neu­tropenic colitis and cystic fibrosis.12 With in-tussusception, the mesentery invaginates the bowel and is trapped between the overlying layers of the bowel in the intussusceptum and intussuscipiens. In our case, CT and ultra-sonography findings were typical. Intussusception in adults must be man­aged by surgery, and intestinal resection is the procedure of choice.13 The laparoscopic approach offers both a diagnostic and thera­peutic option. Laparoscopy may be used as the final diagnostic or/and therapeutic tool for intussusception in adults.2 Chronic intestinal invagination is a rare cause of nonacute adult abdominal pain and Meckel's divertculum is a rare, though pre­vailing cause of intestinal invagination. Atypical clinical presentation of chronic in-tussusception often results in delayed or in­adequate management of such cases because of the lack of suspicion of a correct diagnosis. Preoperative diagnosis of invagination was based on ultrasonography and computed to­mography which proved again as the most ef­fective and useful preoperative diagnostic methods. Surgical intervention is always needed in adults and older children because of high incidence of underlying lesions in them. References 1. Chang ML, Cheung W, Ling YK, Chiu WW. Chronic intussusception in children: report of one case. Zhongua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi 1994; 35(4): 335-40. 2. Alonso V. Targarona EM, Bendahan GE, Kobus C, Moya I, Cherichetti C, et al. Laparoscopic treat­ment for intussusception of the small intestine in the adult. Surg Laparosc Endosc Pct Tech 2003; 13: 394-6. 3. Kuestermann SA, Saleeb SF, Teplick SK. General case of the day. Radiographics 1999; 19: 539-41. 4. Felix EL, Cohen MH, Bernstein AD, Schwartz JH. Adult intussusception: case report of recurrent in-tussusception and review of the literature. Am J Surg 1976; 131: 758-61. 5. Azar T, Berger DL. Adult intussusception. Ann Surg 1997; 226: 134-8. 6. Shekhawat NS, Prabhakar G, Sinha DD, Goyal RB, Gupta A, Sharma RK, et al. Nonischemic in-tussusception in childhood. J Pediatr Surg 1992; 27: 1433-5. 7. Baracchini A, Chiaravalloti G, Quinti S, Rosi A, Favili T, Ughi C, et al. Intestinal intussusception in children. Minerva Pediatr 1995; 47: 215-9. 8. Sachs M, Encke A. Entero-enteral invagination of the small intestine in adults. A rare cause of »un­certain abdomen«. Langenbecks Arch Chir 1993; 378(5): 288-91. 9. Kurtz B, Steidle B, Molzahn E. Invagination in adults. Rofo Forschr Geb Rontgenstr Neuen Bildgeg Verfahr 1993; 58: 314-9. 10. Lorigan JG, Dubrow RA. The computed tomo­graphic appearances and clinical significance of intussusception in adults with malignant neo­plasms. Br J Radiol 1990; 63: 257-62. 11. Gayer G, Apter S, Hofmann C, Nass S, Amitai M, Zissin R, et al. Intussusception in adults: CT diag­nosis. Clin Radiol 1998; 53: 53-7. 12. Merine D, Fishman E, Jonesa B. CT of the small bowel and mesentery. Radiol Clin North Am 1989; 27: 707-15. 13. Martin-Lorenzo JG, Torralba-Martinez A, Liron-Ruiz R, Flores-Pastor B, Miguel-Perello J, Aguilar-Jimenez J, et al. Intestinal invagination in adults: preoperative diagnosis and management. Int J Colorectal Dis 2004; 19: 68-72. Radiol Oncol 2005; 39(2): 95-9. case report Osteosarcoma of the maxilla Bige Sayin, Nilgün Yildirim, Murat Vural, Dog.an Dede Department of Radiology, Ankara Numune State Hospital, Ankara, Turkey Background. Maxillofacial sarcomas are rare tumours and osteosarcoma of the jaws is an exceptionally rare entity. Unlike osteosarcoma of the long bones, maxillofacial osteosarcomas are reported to occur in the third or fourth decades. Case report. We report an 18-year-old female patient with the histopathologic diagnosis of osteoblastic os­teosarcoma of the maxillary bone on the basis of computerized tomographic findings. Following the initial surgery and the adjuvant chemo-radiotherapy, a massive local recurrence developed in the facial region of the patient within two years. Conclusions. The radiographic evaluation of the osteosarcoma of the maxilla is important in the diagnosis and obtaining a complete surgical therapy. CT examination of this region after plain radiography plays a major role at the diagnosis. Key words: maxillary neoplasms – radiography; osteosarcoma Introduction Osteosarcoma is the most common primary malignancy of bone although only 6% to 10% of osteosarcomas occur in the craniofacial re­gion.1 Within the craniofacial region the mandible is usually reported as the most common site of the involvement, followed by the maxilla and skull.1,2 The average age at the onset of osteosarcoma of the maxillofacial region is about one or two decades later than that of osteosarcomas of other regions and Received 6 October 2004 Accepted 30 October 2004 Correspondence to: Bige Sayin MD, 96.sokak Yazikiri Sitesi B-2 Blok No:12, 06530 Ümitköy /Ankara, Turkey; Phone: +90 312 235 23 85; Fax: +90 312 363 22 89; E-mail: tamsay@hotmail.com the highest occurrence is found in the third to fourth decade of life. The patient we present is much younger than those in the literature. Case report An 18-year-old female patient was admitted to our hospital in September 2000 with the complaint of a painless swelling of her right cheek which was gradually enlarging for over two months. She also reported excessive tears in her right eye and loss of teeth on the right maxilla. By the physical examination, a 4 × 7 centimetre, hard, non-tender mass in­volving the right half of the maxillary region was found. No cervical lymphadenopathy was detected following the bilateral palpation of the neck. Her systemic examination did not reveal abnormal clinical findings. Chest X-ray, blood tests and abdominal ultrasonog­raphy were normal. A whole-body bone scan showed the increased activity in the right maxillary location. On the computerized to­mography it was seen that the tumour exhib­ited the invasion into the upper palatinum and infero-lateral wall of the maxillary sinus, and caused a development of a centimetre de­fect in the base of the orbital cavity, however, there was no descent of the orbital structures. Although the tumour was in close relation to the medial wall of the maxillary sinus, this re­gion appeared to be tumour-free. A punch biopsy of the lesion revealed the diagnosis of osteoblastic osteosarcoma of the maxilla. After the evaluation, a surgical exploration was performed and the patient underwent a wide excision of the tumour with hemimaxil­lectomy of the right side. The histopathologic examination of the specimen confirmed the diagnosis of the punch biopsy of osteoblastic osteosarcoma and the margins of the surgical resection were negative for the tumour. The nearest margin of the resection to tumour was three millimetres away. The patient re­ceived a total of 57 Gy adjuvant irradiation therapy with 60Co teletherapy equipment. The combination chemotherapy (adriamicine 500 mg/m2 and metotrexate 50 mg/m2) was given in six cycles in an adjuvant setting. In December 2001, she was free of symp­toms and both the control X-ray and CT did not detect any recurrent tumour in the relat­ed region. In June 2002, she was again admitted to our hospital with the complaint of a painful swelling in the operated area, difficulty in oral feeding and chemosis. Upon a clinical ex­amination, a massive recurrent lesion at the operated site was noted. The plain radiogra­phy demonstrated a densely ossified mass in the right hemifacial region (Figure 1). On CT scan examination, a 6 × 9 × 15 cm, mixed density, complex mass was seen at the primary site and also invaded the upper, lat­eral and inferior wall of the right orbita, the zygomatic bone, the infratemporal fossa, the masticatory muscles, and extended to eth­moid air spaces and narrowed the airway pas­sage. The inferior border of the right ramus was disrupted and the right bulbus oculi was pushed anteriorly by the tumour. The right masseter muscle was seemed to be thickened and heterogeneous with respect to the contra lateral side. The right parapharengeal fat tis­sue and lateral recessus was obliterated and the right sided narrowing of the nasopharyn­geal airway passage was noted. The mass had dense amorphous ossifications and showed the heterogeneous uptake of contrast materi­al (Figure 2). We also constructed three-di­mensional (3D) images so as to define the le­sion more precisely (Figure 3). The patient was evaluated for the possible metastasis and was negative. Because of lo­cally advanced and in-operable disease, a course of palliative external radiation therapy was administered with 60Co teletherapy equipment. Following a total dose of 20 Gy, there was an improvement in her symptoms but no regression of the lesion was noted. Discussion Osteosarcoma is the most common primary malignancy of bone, although only 6% to 10% of osteosarcomas occur in the craniofacial re­gion.1 Osteosarcoma of the craniofacial re­gion is a relatively rare disease.2,3 The mandible is usually reported as the most common site of involvement although there are some reports that mandibulary and max­illary osteosarcomas have been seen in the equal frequency followed by the skull.1,4,5 When compared with other locations, cranio-facial osteosarcomas are less aggressive, oc­cur in a more elderly population and prefer local invasion rather than distant metastases. The average age at the onset of osteosarcoma of the maxillofacial region is found in the third to fourth decade of life.6 While a slight male predominance is reported by some au-thors,1,4,7 some others propose it is more fre­quent in women.5 There are also reports with equal gender distribution.3 The histologic types are chondroblastic (41%), osteoblastic (33%) and fibroblastic (26%).2 The major risk factors for the development of osteosarcoma of the jaws are similar to those for osteosarcoma of the long bones, i.e., previous irradiation of facial region, Paget’s disease and fibrous dysplasia. Other bone ab­normalities, such as multiple osteochondro­matosis, chronic osteomyelitis, myositis ossi­ficans and trauma have also been proposed as risk factors.3,7 Our patient had no known ae­tiology of osteosarcoma. On plain radiographs, findings in osteosar-coma of the jaws are non-specific and these tumours have variable presentations, with the spectrum ranging from osteolytic through mixed osteolytic-osteoblastic to predominatly osteoblastic.8 It may have a completely radio lucent appearance, but it is often presented as a poorly-defined mixed radio lucent-ra­diopaque lesion.7,8 Plain radiography must be followed by the CT examination as the bone erosion, soft tissue infiltration and neoplastic tissue ossification can be showed superiorly. CT has come to play a large role as osseous changes in the jaws, distinguishing the lesion from surrounding or superimposed struc­tures, anatomy of the tumour and the degree of ossification can be precisely evaluated. The CT appearance of our case has been reported as being a mass of mixed radiopacity with a predominant soft tissue component, central calcification/ossification, and the aggressive destruction of the structures involved. Three radiographic presentations of osteosarcoma of the jaw are identified.5 The first is radiolu-cent, characterized by a total absence of bone formation within the tumour. In this type, the conventional radiology reveals a non-specific destruction of bone indistinguishable from the bone erosion caused by carcinoma. The second has a mottled appearance with small areas of amorphous ossification separated by non-ossified tumour tissue. In this type, the mottled ossification can be better or exclu­sively visualized by CT. The third, with lamel­lar ossification, is typically characterized by bony plates irradiating from a focus like a sunburst. In most cases, this type is visible with the conventional radiography; however CT separates fine lamellae from adjacent structures and makes the diagnosis easier in the less typical cases. The presented patient’s radiographic ap­pearance was in accordance with the third type identified above. This trabecular sunburst pattern, resulting from bony spicules extend­ing from cortex into the soft tissue, has been reported in 25% to 32% of jaw osteosarcomas.1 The sunburst pattern of periosteal bone for­mation in relation to a large soft tissue de­structive mass, is considered characteristic of the osteosarcoma but it is non-specific.9,10 It is clear that the complete resection of the primary lesion is ideal for the treatment of os­teosarcoma. A total maxillectomy is recom­mended at the time of the initial diagnosis of osteosarcoma as was in the patient present­ed.6 The surgical margin appears important in terms of prognosis. Patients with clear surgi­cal margins of greater than 5 mm demon­strate a better survival, fewer local recur­rences, and less metastatic disease than those with margins of less than 5 mm.7 Although such a wide rim of normal tissue is impracti­cal in the jaws, clear margins play a role in eradication of disease and limitation of in-tramedullary extension.6,7 In our patient, clear surgical margins were obtained at the initial therapy, but one margin was close to the tumour as previously described. Oste­osarcomas arising from the maxilla cannot al­ways be resected with sufficiently safe mar­gins as in the presented patient. This is re­flected by a relatively high local recurrence rate in some series.6 These tumours have usu­ally a tendency to spread with local inva-sion.2,3,5 Our patient had no detectable metas­tases in spite of the advanced, recurrent mass. Adjuvant treatments are considered effec­tive for preventing recurrence only when the primary lesion has been removed completely, although chemotherapy can be used for the control of occult distant metastases, as in os­teosarcomas of extremities.6,11 From available data, it appears that the introduction of chemotherapy for the treatment of craniofa­cial osteosarcomas did not lead to the im­provement in the survival statistics as it did with osteosarcomas of extremities.2 Some studies have shown radiation to be ineffective in the treatment of craniofacial osteosarco-mas.2,11 Delgado et al expressed that when surgical margins are not free of disease, the use of radiation does not improve the out­come.9 On the other hand, the ability of these tumours to spread through bone marrow dic­tates the establishment of surgical margins extending beyond the clinical and radiologi­cal presentation of the disease.2 Therefore, early diagnosis and radical surgery with wide surgical margins should be the most impor­tant part of primary treatment, as the residual tumour may show the aggressive local inva­sion of the tissues of the head and neck, as in our patient.1,4,12 High histological grade and incomplete resection or local recurrence sup­port a poor prognosis.2 In our view the presented case is interest-ing in terms of relatively early age onset of the tumour. Secondly, although the patient was free of symptoms and local recurrence with X-ray and CT 1.5 years after the therapy, she presented with a local, massive recur­rence in 6 months time. That’s why we be­lieve that the careful follow-up of these pa­tients for local recurrence is mandatory. In conclusion, osteosarcoma of the maxilla has an aggressive biological behaviour even in the case of applying adjuvant therapies. Therefore, early diagnosis and radical surgery with wide surgical margins are the keys to a good outcome. CT has an important role in the early diagnosis and the evaluation of its extent for the surgical planning. References 1. Barnes EL, Peel RL, Verbin RS, Goodman MA, Apple BN. Diseases of the bones and joints. In: Barnes EL, editor. Surgical pathology of the head and neck. New York: Marcel Dekker Inc; 1985. p. 985­99. 2. Mardinger O, Givol N, Talmi YP, Taicher S, Saba K, Hashomer T. Osteosarcoma of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001; 91: 445-51. 3. Oda D, Bavisotto LM, Schmidt RA, McNutt M, Bruckner JD, Conrad III EU, et al. Head and neck osteosarcoma at the University of Washington. Head Neck 1997; 19: 513-23. 4. Mark RJ, Sercarz JA, Tran L, Dodd LG, Selch M, Calcaterra TC: Osteogenic sarcoma of the head and neck: the UCLA experience. Arch Otolaryngol Head Neck Surg 1991; 117: 761-6. 5. Bianchi SD, Boccardi A. Radiological aspects of os­teosarcoma of the jaws. Dentomaxillofac Radiol 1999; 28: 42-7. 6. Okinaka Y, Takahashi M. Osteosarcoma of the maxilla: Report of a case and review of the litera­ture concerning metastasis. J Oral Maxillofac Surg 1997; 55: 1177-81. 7. August M, Magennis P, Dewitt D. Osteogenic sar­coma of the jaws: factors influencing prognosis. Int J Oral Maxillofac Surg 1997; 26: 198-204. 8. Cavalcanti MGP, Ruprecht A, Yang J. Radiological findings in an unusual osteosarcoma in the maxil­la. Dentomaxillofac Radiol 2000; 29: 180-4. 9. Delgado R, Maafs E, Alfeiran A, Mohar A, Barrera JL, Zinser Z, et al. Osteosarcoma of the jaw. Head Neck 1994; 16: 246-52. 10. Anderson D, Snyderman CH. Pathologic quiz case 2. High grade osteosarcoma of the maxilla. Arch Otolaryngol Head Neck Surg 1997; 123: 1355-6. 11. Van Es RJJ, Keus RB, Van der Waal I, Koole R, Vermey A. Osteosarcoma of the jaw bones. Int J Oral Maxillofac Surg 1997; 26: 191-7. Radiol Oncol 2005; 39(2): 101-14. Multislice computed tomography of pulmonary embolism: spectrum of findings Šerif Bešlic, Faruk Dalagija, Vesna Đurovic Institute of Radiology, Clinical Center, University of Sarajevo, Bosnia and Herzegovina Background. The purpose of this study is to analyse the contribution of multislice computed tomography (MSCT) as a diagnostic method in the diagnosis of pulmonary embolism (PE) and spectrum of findings in our material. Methods. During the period of one and a half year, we found PE in 25 patients (15 males and 10 females). The average age of the patients was 54.4 years (25 - 74). The examination was performed by »Somatom Volume Zoom« Siemens CT machine with four row detectors, with retrospective ECG gating, collimation 4 x 2.5 mm and reconstructed section with 0.8 mm. Contrast medium (130 ml) and 10 ml of saline was ap­plied, administered with a flow rate of 3.5 ml/s and with time delay of 22 seconds. Results. During the examination, we found embolism of the main branches of pulmonary artery in 14 (56%) patients, at the right branch in 10 (40%), at the left one in 4 (16%), and bilateral pulmonary embolism in 11 (44%) patients. Subsegmental pulmonary emboli were noticed in 8 (32%) patients. Pulmonary infarct was found in 12 (48%) patients, and was followed up with ipsilateral pulmonary artery dilatation in 11 (44%) cases, redistribution of the circulation and pulmonary artery branches dilatation in infarct zone in 9 (36%) cases, contrast enhanced consolidation of pulmonary parenchyma in 10 (40%), rag zones of ground glass attenuation in 15 (60%), haemorrhage in 21 (84%), striped and reticular pulmonary drawing in 11 (44%), and mosaic olighemy in 3 (12%)cases. Thrombi were rare, found only in the R/L atrium in 2 (8%)cases, pericardial haemorrhage in 1 (4%), mediastinal lymph nodes in 1(4%) case, sudden cut off of peripheral branch leading to infarct apex in 1 (4%), and haemoptysis in 1 (4%) case. In addition to deep vein thrombosis, heart failure was found as aetiology factor in 7 (28%) and malignancy in 3 (12%) cases. Conclusions. MSCT is an excellent non-invasive method for visualization of thrombus in the pulmonary artery. In our study, we have more often found embolism of the right branch of pulmonary artery, and pleu­ral effusion, infarct contrast enhanced consolidation of pulmonary parenchyma, ground glass attenuation zone, ipsilateral pulmonary artery dilatation, circulation redistribution with pulmonary artery branches di­latation nearby infarct zone. This diversity of findings cannot be noticed by any other method, with the pos­sibility of making alternative diagnosis, which has led MSCT in the foreground when pulmonary embolism diagnostics is at stake. Key words: pulmonary embolism – diagnosis; X-ray computed - methods Correspondence to: Prof. Šerif Bešlic, MD, PhD, Institute of Radiology, Clinical Center University of Received 10 February 2005 Sarajevo, Bolnicka 25, Bosnia and Herzegovina; Fax Accepted 28 February 2005 +387 33 444 553; E-mail: sbeslic@bih.net.ba Introduction Pulmonary embolism (PE) is an obstruction of any pulmonary artery branch by clot which could be brought from varicose veins in legs, tendency to blood clotting (because of exist­ing malignancy, after prostate gland opera­tion, in gynaecologic diseases, in heart failure and arrhythmias, etc).1 It is a frequent disease in risk hospitalized patients. An embolus tears off from the deep leg veins, divides in fragments in the right heart, from where it is rinsed in the lung, where the emboli of different size splash the lung.2,3 PE can cause immediate death or the pa­tient is breathless, has chest pain, his face and body become blue, neck veins swell up, his breathing is low and rapid, has palpita­tions, coughs and coughs up white pus mixed with blood (sputum).1,4,5 Thrombosis can cause pain and swelling of the leg, red colouring, warmth and tension could occur, but clinical evaluation is mostly unreliable and can cause serious mistakes, and most of people with deep vein thrombo­sis (DVT) have no any symptoms.6 Sudden dyspnoea without changes on plain chest radiography could be one of the manifestations.1 PE prevalence found on autopsy is 15-26%, and it is greater than the one found in hospi­talized patients. Owing to organs hypoxia, especially brain, 1/6 patients lose consciousness (syncope). The embolism attacks can repeat several times, so high blood pressure in pulmonary circulation appears (pulmonary hyperten­sion), with bad prognosis and most patients die after 5 years.1 Due to the above, all cases of pulmonary embolism must be taken seriously. Vein thrombosis is a frequent disease, with an incidence of 1-2 persons/ per 1000/ per year. Approximately 3000 persons get vein thrombosis in Slovenia every year. Non-treated thrombosis of popliteal and/or femoral vein will lead to PE in approximately 50% patients, of whom 10% patients die of pulmonary embolism.3 PE is the third most frequent cause of death in US with almost 50 000 deaths every year, with annual frequency of 300 000 to 600 000 (on average about 500 000) accidents. Many of PE events passed undiscovered be­cause clinical indications and PE symptoms are non-specific. A fast and accurate diagno­sis can save 100 000 lives every year. An ac­curate diagnosis is therefore a great chal­lenge.7,8 The mortality caused by PE is high, partly because of relapse. The mortality in non-treated patients is 30%, and in the patients with anticoagulation therapy, 10%. Repeated PE appears in 0.4-0.5% patients with acute PE. Access to the treatment of patients with PE has to be fast and interdisciplinary. Clinical suspicion of PE has to be confirmed or denied by diagnostic methods, preferably with non-invasive, precise and easily accessi­ble methods. It is important to exclude PE, because of the haemorrhage which can occur during an­ticoagulant therapy. The haemorrhage risk in­creases by 2% every day during the anticoag­ulant therapy.3 It is known that 20% of DVT of the calf will have propagation proximately, but some­times thrombosis staying in the calf should not lead to embolism. Should we wait and look at the insurance policy in situation like that, or should we start with diagnostic imag­ing of the affected extremity? Differential diagnosis of PE is very wide and includes many conditions, from life-en­dangered diseases to anxiety.3 There is no any warning signs, symptoms or laboratory tests, which suggest PE.2 In 2/3 of patients with the suspicion of PE, other diseases were diagnosed.9 PE diagnosis is clinical, laboratory (simple test in bed D-Dimmer essay), ECG, plain ra-diography of chest (RTG), gas analysis in ar­terial blood, lung scintigraphy with tech­netium 99, transthoracic or transesophageal US of the heart and veins, angiography of pulmonary artery, which until recently, was the most reliable diagnostic method, and sometimes the therapy method as well.1,3,8 The chest angiographies were normal in 10% cases, and most of its abnormalities were non-specific. Non-specific shade, pleural ef­fusion, atelectasis or elevation of hemidi­aphragm, and vascular alternation, i.e. focal ipsilateral pulmonary artery enhancement (Fleschner’s sign or so called the ankle sign) could be found. The pulmonary artery branch embolism can be seen as the lung infarct, a wedge shaped shadow with its top oriented centrally and base peripherally. Usually, the right interlobar pulmonary artery is affected. Because of the clot presence, focal olighemy may occur, but is very rare and results from the vascular obstruction (Westermarks sign). Lung infarct can develop immediately or in 2-3 days after embolism, usually peripher­ally or in the lower lung zones, frequently as­sociated with small pleural effusion. At the beginning, it is ill-defined, but with time, it becomes sharp, the so-called Hampton’s hump in the peripherally wedge-shaped shade with curvy peak headed to the hilus. The infarct healing, or the so-called »melt­ing«, demonstrates as keeping its shape and, with time, reducing in size. Pneumonia and oedema usually »disappear – fade away« gradually.1,2,10 In big branch embolism, the whole lobe of the lung can »fall out« of function, so, the pul-monary-blood vessel bed or pulmonary tissue cannot be seen with chest X-ray.1 The lung scintigraphy with technetium 99 (V/Q) has been preferred for a long time as screening test for detecting clinically signifi­cant pulmonary embolism was. It shows »fall out« of lobe of a lung or part of it. A segmen­tal or greater perfusion defect is present with normal ventilation in that zone (V/Q discord) indicates a high possibility of pulmonary em­bolism.1,10 V/Q scanning findings are indirect indica­tors of a clot, not visualized directly, so it has a high sensitivity, but low method specificity, especially in the patients with other lung dis­eases. Because of that, the interpretation of perfusion scintigraphy results is difficult.2,3,10 PIOPED study results show that only 41% PE can be confirmed with this method, also the accordance in the interpretation of find­ings among different examiners is poor (30%).2,3 Until recently, the most reliable method has been diagnostic pulmonary angiography, sometimes it is therapeutical as well (local thrombolysis, fragmentation, embolecto­ my).1,11 Angiography has been considered the most precise examination, but it is invasive (morbidity 6%, mortality 0.5%), and it is not available everywhere.3 The pulmonary angiography findings were considered a gold standard; however, they show 25% false negative results for small sub-segmental emboli, and the accordance in in­terpretation of findings among different ex­aminers is poor (<30%). This investigation is rarely performed in clinical practice.2 The technology revolution in diagnostic approach to suspicious pulmonary embolism has been happening in the last 10 years by in­troducing spiral computed tomography (SCT).2,12 In 1978, Sinner was the first who de­scribed PE diagnosed with CT. In 1980, Godwin and co-operators showed directly en-dovascular emboli. In 1992, the first compar­ative analysis of SCT and PA was made, and in the next years, Teigen and co-operators used electron beam CT (EBCT).7 In the last 10 years, CT reached a high ac­curacy in the pulmonary embolism evalua­tion.7 Spiral or electron beam CT findings have revolutionized the pulmonary embolism diag-nosis and made possible the direct visualiza­tion of a clot in the central pulmonary artery.2 CT provides, with high sensitivity and speci­ficity (>90%), a direct visualization of ob­structing emboli together with their vascular and pleuroparenchymal sequels (cardio pul­monary status). An insufficient contrast bo­lus, hilar limphadenopathy and hilar calcifi­cations, respiration artefacts can cause diag­nostic problems, e.g. subsegmental emboli can be overlooked, oblique arteries may de­mand oblique reconstructions for better visu­alization, etc. It can be combined with the pelvis and extremities scanning for analyzing sources of thromboembolism (CT flebogra­phy). The consequences of a negative CT an-giogram are favourable, with DVT or PE in 0.5%, and fatal embolism occurs in 0 to 0.7% cases.2,13 The comparisons of SCT pulmonary an-giographies (SCTPA) with V/Q scans proved higher punctuality of SCTPA than V/Q; SCT was correct in 92%. CT, in comparison with V/Q scan, shows a reliability of 90% to 54%, respectively. SCT has a higher sensitivity (77­81%) than V/Q (41%), and a similar propor­tion has been observed in specificity. In total, SCT is more punctuate than V/Q. Various studies in several European centres proved a higher specificity of CT than that of V/Q, and better accordance in the interpretation of CT findings between different examiners. In that way, SCT has put into question the role of ventilation-perfusion scintighraphy and has thrown suspicion on pulmonary an-giographies as a gold standard.8 Moreover, CT allows the visualization of other changes in the thorax, which may be the cause of patient’s condition and symp­toms. In 65% of patients, various changes are discovered by CT, upon which an alternative diagnosis was made in the patients suspi­cious for PE. Neither scintigraphy nor angiog­raphy has these possibilities. The introduction of the multislice CT (MSCT) has brought significant advantages, such as the possibility to examine dyspnoeic patient in an emergency situation in a few seconds, covering broad volumes with a low collimation, the possibility of a precise analy­sis of peripheral pulmonary arteries and of a detailed whole lung exploration. The com­bined CT venography and pulmonary CT an­giography, using one injection of contrast medium, reduces the examination time and excludes additional examinations. Finally, by the evaluation of the right heart, the load and distension of the right-side cavities can be es­timated. In that way, the multislice CT ex­posed one of its most important applica­tions.6,12 Risky and symptomatic patients are often exposed to ascendant venography, which is considered as a gold standard fort he detec­tion of small deep thrombi in the vein system, but this technique is invasive, so radiologists are looking for a replacement. Ultrasound (US) B mod and Colour Doppler are fast and reliable methods, but need experienced examiners. MRI is also a promising method, but so far, it has not been used widely in urgent situations and in seri­ously ill patients, mostly because of long-term examination, monitoring problems, high costs and limited availability.7,11 The time of flight and phase contrast im­aging proved to be highly accurate in some research studies on imaging of the blood cir­culation in the proximal vein system, and al­so provides a direct visualization of a clot in the pulmonary artery or extremities veins. In pregnant women and the patients with plas­ter cast, the acute clot can be differentiated from the chronic clot and from imitating pathology. MRI is an expensive screening method. It has some deficiencies, e.g. every patient cannot fit in the machine (over­weight), and for the time being, the clot visu­alization below the knee is not satisfactory.6 The treatment of PE presumes usage of an­ticoagulants and fibrinolitics.2 The therapy of blood clotting lasts usually 6-12 months and is accompanied by hemor­rhagic complications in 2-15% cases; a throm­botic vein can be surgically separated from the thrombosis place, or a special device is in­serted (IVC filter) in which the clots are kept not to go in the right heart, more exactly, in the pulmonary circulation.1 They are used when the contraindication for anticoagulation therapy is present. Pulmonary thromboendarterecotmy can be used in vitally endangered patients.13 The prognosis is good with adequate ther­apy. However, there is a high level of suspi­cion on fatal result (about 20%) in non-treated subjects. Hardly noticed subsegmental em-boli present a problem. The consequences for non-treated subsegmental emboli are un­known, while the consequences of following up the negative pulmonary angiograms or SCTPA are favourable.2 The goal of this study is to analyze the con­tribution of MSCT in the detection of pul­monary artery embolism in our material, as well as to review the frequency of findings spectrum that follows it, and which can be di­agnostically important. Methods In the period of one year and a half, we found PA embolism in 25 patients (15 male and 10 female) during MSCT scanning. The youngest patient was 25 and the oldest one was 74. Average age of patients was 54.4 years. After the native CT serial, which included the whole thorax and upper abdomen, the contrast serial was made in the area from the arcus of the aorta to 2 cm below the mouth of the lower pulmonary veins. Scanning was performed on the »Somatom Volume Zoom« Siemens device, MSCT with 4 rows of detectors, with retrospective ECG-gating, thick layer of 3 x 2.5 mm and section width of 0.8 mm. The contrast medium (CM) 130 ml and 10 ml of physiological solution were injected by automatic syringe in the cubital vein with a flow rate of 3.5 ml/s and with a delayed time, determined mostly empirically and ranging from 22 to 25 sec, depending on the cardiac status and patient’s age. The analysis of the following findings was made: embolism frequency and dilatation of central and segmental branches, frequency of pulmonary circulation redistribution, infarct, contrast enhanced consolidation of pul­monary parenchyma, zone opacification type ground glass, olighemy mosaic, septal bumps and reticular drawing, pleural reaction and pericardial effusion, the right heart dilatation, heart failure signs, frequency of clots in the heart, haemoptysis, appearing of enhanced mediastenal lymph nodes, and frequency of malignant process coincidence and pul­monary embolism. Results During the examination we found pulmonary artery embolism in 25 (100%) patients. Among them, 15 (60%) were male and 10 (40%) female. The spectrum and frequency of CT findings in examined patients are shown in Table 1. From the given chart, we can see that PE was more often followed by pleural effusion, which was found in 21 (84%) patients, zone opacification ground glass found in 15 (60%) patients, central pulmonary artery branches embolism in 14 (56%) patients, pulmonary in­farct in 12 (48%) patients, bilateral PE, ipsilat­eral pulmonary artery enhancement, and striped and reticular pulmonary drawing in 11 (44%) patients, contrast enhanced pul­monary parenchyma consolidation and PE of the right branch of pulmonary artery in 10 (40%) patients. Other CT findings were rare, or harder to notice. Table1. Patient data: spectrum of findings in pulmonary embolism Features Number of patients Bilateral PE 11 (44%) Central branches embolism 14 (56%) PE R.Branch 10 (40%) PE L.Branch 4 (16%) Subsegmental PE 8 (32%) Ipsilateral pulmonary artery enhancement 11 (44%) Dilation R.Branch 8 (32%) Dilation L.Branch 3 (12%) Circulation redistribution and branch dilation in infarct zone 9 (36%) Sudden failure of peripheral pulmonary artery leading to infarct apex 1 (4%) Infarct 12 (48%) Contrast enhanced pulmonary parenchyma 10 (40%) United Infarct and contrast enhanced consolidation pp 6 (24%) Rag zone of ground glass opacification 15 (60%) Olighemy mosaic 3 (12%) Striped and reticular pulmonary drawing 11 (44%) Effusion and adjacent pleura reaction 21 (84%) Presence of previous heart failure indications 7 (28%) Clot in R/L atrium 2 (8%) Malignance (1 Ca. Recti,2 Ca pulmo) 3 (12%) Haemoptysis 1 (4%) Pericardial effusion 1 (4%) Boundary lymph nodes in mediastinum 1 (4%) Discussion Obstruction of any pulmonary artery branch, mostly with blood clot, is called pulmonary embolism. The pulmonary embolism is the final result of thrombosis in the peripheral veins of low­er extremities and is considered the third most frequent cause of death. The risk factors are prolonged staying in bad, varices in lower extremities, trauma, re­cent surgical treatment, obesity, pregnancy, de­ficiency of antithrombin III, deficiency of S pro­tein, increased blood clotting in the patients with malignant disease, migrant trombo­phlebithis, deep vein thrombosis in pelvis, acute heart attack, serious heart impairment, central vein catheters, congestive heart disease, arrhythmias, atrial fibrillation, etc.1,2,10,11,14 Sudden death occurs most frequently when the obstruction happens at the bifurca­tion of the pulmonary artery. When the dis­tant branches are occluded, the patient is breathless, becomes blue in the face and body, the veins of the neck are swollen, breathing is superficial and accelerated (>21/min), the blood flow rate through the lung is decreased, all organs suffer from ischemia, especially the brain, so, in 1/6 of patients, syncope devel­ops. If the patient stays alive, acute pul­monary heart will develop, with strong chest pain bellow the sternum. The prognosis is de­pendent on the heart condition and quick in­tervention. The embolus in the intermediate artery causes the deterioration of the patient’s con­dition, chest pain, cough, blood-stained cough up, feeling of choking, tachypnea and superficial breathing. Symptomatology can be divided in few phenomena, such as the pulmonary infarct syndrome (pleural pain or haemoptysis), iso­lated dyspnoea syndrome (dyspnoea in ab­sence of pleural pain, haemoptysis or circula­tory collapse) and circulatory collapse syn­drome (losing consciousness or blood pres­sure <80mmHg) and can be met in 65%; 22% and 8% patients, separately. The emboli in the central branches are most often and most easily detected (Figure 1). In this study, it was found in 14(56%) cas­es; PE of the right branch in 10(40%), in the left branch in 4(16%), and bilateral PE in 11(%). The average age of the patients was 54.4 years. It was more frequent in men (60%) than in women (40%). As shown in Table 1, PE in the subseg-mental artery were found in 8 (32%) exam­ined patients (Figure 2). PE divides in 3-11 parts, on average, when it comes in the heart. One or few fragments are big enough to be detected.3 One third of PE causes or contributes to the patient’s death where clinical diagnosis of suspected PE is unreliable; so, over 70% of cases are not clinically suspected. These re­sults have not changed for 3 decades in spite of the progresses in medicine and prophylax­is. Approximately 10% of the patients do not survive the initial stage of PE. PE is fatal if it is not treated in 30%, and this can be reduced to 2-10% if diagnostic and treatment with antico­agulants are quick enough. This therapy is ac­companied with complications in 10-30%. The estimation frequency of isolated sub-segmenal PE is very significant because they can be indicator of a silent deep vein throm­bosis (DVT), which potentially indicates harder embolic accidents. The detection of a small embolus can be relevant for a chronic pulmonary hypertension diagnosis in the pa­tients with thromboembolism disease, and may represents a »tip of the iceberg«. This problem may not be solved for a long time. The only solution to solve the problem of these small missed or potentially missed clots is to evaluate consequences of patients with negative SCT pulmonary angiographies (SCT­PA), in other terms, to determine the subse­quent PE rate (negative predicting value). Different authors cite different results for the main, lobar, segmental and subsegmental branches: sensitivity 88-91%, specify 81.5­86%, positive 75.81.5% and negative predict­ing value 91-94%.20 Some authors reported the sensitivity of 90%; specificity 94%, positive and negative predicting value 90 and 94%.4 According to certain authors, the sensitivi­ty at segment level is 91-96% and specifity 78­100%, the subsegment sensitivity 63% and specificity 89% and, recently, the sensitivity and specifity ranges of 88-96% and 94-100%, repsectively. In that way, CT is kept busy with angiographies on subsegmental level. According to these authors, angiographies have some lower results at subsegmental lev­el, so it cannot be used as a reference method for success evaluation.3 A one-mm breath hold collimation results with significant greater percentage of em­bolism detection in subsegmental pulmonary arteries, and greater harmony between differ­ent readers than using thicker cross sections. Using one-mm cross vs. opposite 3mm ones, the number of indefinite cases reduces to 70%.21 Also 54% subsegmental arteries are identi­fied after using pulmonary window, and they are correctly visualised using mediastinal window.18 The prevalence of isolated subsegmental embolism, according to different studies, is between 5 and 30%. If satisfied, the subseg-mental branches don't show during examina­tion. The pulmonary diagnosis can be pre­dicted in 5-30%. This is especially important in the patients with accompanying lung and heart diseases, in whom they may be warning signs for developing recurrent potentially mortal embolism.3 Only relatively specific PE finding is wedge shaped pulmonary consolidation, which most probably represents pulmonary infarct, although in PE patients, this finding is very rare and, according to some authors, varies between 10%, 25% and 62%.3,13 A similar image may appear in 5% of pa­tients who have not PE (It is often seen in pneumonia, tumours, pulmonary fibrosis, haemorrhage, oedema).3 In this investigation, pulmonary infarct was found in 12 (48%) patients. We believe that it is more frequent than reported in liter­ature and that the advance of diagnostic methods will contribute to a more frequent revealing (Figure 3). Pulmonary infarcts can be any shape or size, like peripheral opacification, lobular or wedge-shaped image, irregular polyhedral, depending on the number and location of af­fected secondary pulmonary lobules with cut apex, when the lobules lay just right opposite embolus and they are divided adequately from bronchial collateral vessels. The infarct can include central regions of low attenuation, which show the combination of opaque glass shade and reticulation below and that represent no infarct secondary pul­monary lobules, which in time of embolism cannot be per funded. Alternatively, they can be supplied from nonembolised pulmonary arteries, retrograde circulation from pul­monary veins, or from bronchial collateral vessels. The contrast enhancement of lesion after the fourth injection of contrast medium is connected with pulmonary haemorrhage (76%), and non-enhanced lesion suites pul­monary infarct. However, a drop in enhance­ment in the collapsed lung is not a specific sign of pulmonary infarct, because it can be seen in some kinds of pneumonia.7 The contrast enhanced consolidation of pulmonary parenchyma was, in this investi­gation, found in 10 (40%) cases. In 6 (24%) cases it was related to the infarct (Figure 4). In radiology literature, these two categories are not adequately distinguished. The presence of vascular sign, associated with the vessel bump leading to shade apex, increases the possibility that the lesion repre­sents infarct, but this sign is not frequent and therefore hard to recognize. The enhancement of ipsilateral pulmonary artery in this investigation was found in 11 (44%) cases, 8 (32%) on the right and 3 (12%) on the left branch. Circulation redistribution and branch dilation in the infarct region are found in 9 (36%) cases, and a sudden break of the peripheral pulmonary artery leading to in­farct apex only in 1 (4%) case. This sign is dif­ficult to recognize and requires a meticulous analysis.10,13,15 The obstruction exceeding 30% of pul­monary circulation causes a sufficient in­crease in pulmonary vascular resistance to produce significant pulmonary hypertension which results in overloading the right ventri­cle (RV), which increases and dilates. The in-terventricular septum moves to the left, com­pressing the left ventricle (LV). It was found that small acute pulmonary embolism was re­lated to short axis (RV/LV) under 1.1/1. In all serious acute PE cases, the relation was greater than 1.5/1. Straightening or left move­ment interventricular septum and contrast re­flux in the vena cava inferior (VCI) can be seen, but it is more difficult to quantify. An acute dilation of RV can be a useful sign to evaluate physiology effect PE difficulty, be­cause revealing vasoactive agents can in­crease pulmonary vascular resistance to a re­flexive pulmonary vasoconstriction followed by mechanical obstruction with intravascular clots.3 Chemodynamic consequences are the re­duction >50% vascular trough leads to pul­monary hypertension and failure right-site heart, and 1% ill patients with acute pulmonary embolism will become chronically ill.2,15 An earlier diagnosed heart failure as in­farct source is often present, and in our study, it was found in 7 (28%) cases, of which the clot was found in left/right atrium in 2 (8%) cases. A malignant process as infarct source, found in 3 (12%) cases, was not sig­nificant in this small serial. Accompanying effusions develop sudden­ly and usually are small and unilateral, reach­ing the maximum length in the first three days. These effusions are often hemorrhagic and connected with inflammatory response, following pulmonary necrosis. High effusion frequency was also confirmed in this investi­gation. It was found in 21 (84%) patients; in only one patient (4%), pericardial effusion was found. Incremental mediastinal lymph nodes were rare, too, only 1 (4%) case. Pleural effusion, as it has been reported, is the most frequent in the group with pul­monary embolism, and segment consolida­tion which morphology easily can represent pulmonary infarct, until mosaic sample and enhanced mediastinal lymph nodes can meet rarely. Except the mentioned parenchymal and pleural changes, pulmonary thromboem­bolism can result in haemorrhage without in­farct, and on CT, the haemorrhage is viewed as a ground glass opacification, or as an air ways consolidation, not differing from pneu­monia or oedema.13 Vascular occlusion of small arteries, which supply secondary pulmonary lobules, makes inhomogeneous pulmonary parenchyma at­tenuation on CT. This is called mosaic olighe-my. These limited regions of changed pul­monary parenchyma attenuation (mosaic sample) are a specific sign of perfusion obsta­cle and are helpful in diagnosing pulmonary embolism.3,13 Our investigation showed the existing ground glass opacification in 15 (60%) cases, and in 3 (12%), mosaic olighemy. The detec­tion of this sign takes a lot of patience. When we talk about diagnostic approach, a relatively great number of indefinite inves­tigations stand out, especially in the patients with chronic pulmonary diseases or paren­chyma abnormalities on chest radiography. Chest X-Ray (RTG) is mostly non-specific and normal only in 10%.2,10 Although CT is more sensitive for addi­tional signs than RTG, the absence of abnor­malities on CT does not exclude PE, because 29% of patients with PE had no pleuropul­monary abnormalities described on CT.7 The majority of late PE occurs in the first weeks after treating or excluding PE: 50% of PE have relapse, and 90% of PE are fatal with­in the first 1-2 weeks. So, an average follow­up of 3 months is acceptable to differentiate the missed PE. A vein fatal PE occurs in 0­0.9%. In CT examinations with the 3mm colli­mation, the vein thromboembolism frequen­cy (VTE) was 0.5% and fatal PE 0.3%.3 The lower extremities investigation on DVT can be used as an alternative method in some patients with adequate cardiopul­monary reserve or low or moderate clinical suspicion on VTE. Pulmonary vessels analysis is based on dif­ferent algorithms depending on accessible equipment quality. As it is mentioned in the introduction part, beside chest x ray in PE diagnostic, oth­er methods are used, such as SCT angiogra­phies (SCTA), which came into the first im­aging line in PE studies, followed echocar­diography and ventilation/perfusion (VQ) scinthigraphy, pulmonary angiographies (PA), venography and often D-dimmer test.16 Normal V/Q scanning excludes PE, and consequently, V/Q scanning diagnoses of PE with possibility over 90%. However, investi­gations show that 60-70% V/Q scanning are not diagnostic and ask for additional tests. Studies, which compare V/Q scanning and SCTPA, show that, in scintigraphy, the diag­nosis has been made in 74% and on CT in 92% samples.7,8 It has been published that unsuccessful or indefinite SCTPA rate is between 2 and 13%. This is in contrast to V/Q scanning rate with­out diagnosis, which vary a lot (30-80%), and in the same range, it is not diagnostic for PA (0-17%).3 CT showed itself superior to V/Q scintig­raphy in the estimation of embolus maturity.7 The duration of investigation in SCT is ap­proximately 10min, and in V/Q scanning 45 min, which can be extremely important in se­riously ill patients who need special care and monitoring. CT has better results than scintigraphy, and in many things, it is equal to angiogra­phies. It is non-invasive, fast, widely accessi­ble, especially in the institutions where pul­monary scintigraphy and angiographies are not accessible, and presents imaging method of choice, if it is carefully composed as a whole diagnostic procedure. When CT is op­timal to subsegmental branches, angiogra­phies are not necessary.3 Studies reported on 2002 RSNA meeting found a significant decrease in using ventila­tion-perfusion (V/Q) pulmonary scintigraphy and pulmonary angiographies during the last decade. The usage of CT pulmonary arteriog­raphy did not only increase during the same period, but it replaced V/Q scanning as a standard test.9,12 Negative SCT can exclude clinically sus­pected pulmonary embolism as precisely as normal pulmonary scintigraphy or negative pulmonary angiographies.17 Pulmonary angiography was a method of choice for a long time, high sensitive and spe­cific (gold standard) for pulmonary embolism detection, such as intraarterial defect of fill­ing or sudden break (totally obstruction) of pulmonary vessels. It is indicated when the radionucleid scan is indefinite or indirectly possible when the patient is candidate for operation (for em-bolectomy) or in extremely high risk of using anticoagulants.2,10 Angiographies are indicated in case of high PE suspicion, in normal CT and negative extremity US, and in low-quality CT image of peripheral pulmonary circulation.3 In recent studies SCTPA found more sub-segmental PE than PA (92 to56%). In this role, SCTPA proved to be better than PA.7 Depending on slice thickness, the litera­ture cites different results about SCTPA ef­fect, from 53 to 100%. The comparison of SCTPA with the 1 mm collimation and pul­monary angiographies showed that both tech­niques were comparative for discovering sub-segmental size emboli. Thinner slice has an advantage in CT. The 1mm-thick reconstruc­tive scan allows detection 14 to 40% addition­al subsegmental PE comparing with 2 and 3mm-thick reconstructive cross sections.7 Spiral CT gives possibility for making al­ternative diagnosis; its findings percentage varies from 11-85%. Alternative diagnoses in the patients with­out PE included pneumonia, atelectasis, pneumothorax, pneumomediastinum, peri­cardial or pleural haemorrhage, aortal dissec­tion, cardiovascular disease, interstitial pul­monary disease, traumatic changes, postoper­ative changes, abscess, esophagitis, mycosis cork, bronchial infection, chronic obstructive pulmonary disease, bronchopleural fistula, mediastinitis, pulmonary artery hyperten­sion, aspirate pneumonia, septical embolism, diaphragm hernia, oesophageal rupture and malignant tumours. Alternative finding can be met with or without PE. Other SCTPA advantages are that it is a strategy with the lowest rate of mortality, with the lowest total price per saved life, usu­ally in combination with leg examination by US-Doppler. The chipper approach was using leg US, followed with SCTPA.7,8 SCTPA is a routine widely spread 24-hour technique, more accessible than nuclear stud­ies, which is one of the main reasons that SCT is the first choice in diagnosing PE at many institutions.3 Researches and technology progress made multislice SCT (MSCT) de facto a gold stan­dard for imaging pulmonary embolism. CT has become accepted as the first-line method for imaging pulmonary circulation in the pa­tients with suspective pulmonary embolism in daily clinical practice. However CT has not accepted yet univer­sally as gold standard, especially in internists and pulmologists, although these CT critics prefer to send patients regularly on CT than on V/Q. However, many clinicians do not accept SCTPA as definitive method for excluding PE because of some interpretation mistakes. But, minimum experience and knowledge in inter­pretation mistakes (technical, anatomical, connected with patients, inadequate parame­ters of injection, flow rate, concentration and time delay, or insufficient apnoea lasting, what could have result as pseudo defects of loading) are needed. The best compromise must be found among high longitudinal space resolution and short time apnoea. Breath hold artefacts can result in an inhomogeneous opacification of pulmonary arteries, with hypodense doubling or steaming up of vessel contours. Artefacts beams from contrast in the vena cava superi­or (VCS) can create defects of pseudo-loading in pulmonary arteries of right upper slice. These artefacts can be reduced with the saline thrust right after the injection of contrast medium, which rinses the contrast into VCS. Anatomical limiting factors and variants should be known for accurate interpretation. VCS obstruction, cardiomiophaty, focal or global enhancement pulmonary and cardiac resistance, or pulmonary shunts can request longer delay time, until circumferential per vascular oedema or mycosis corks of small bronchi can simulate PE. Changing windows and levels can increase the confidence in in­terpretation of suspect loading defect, but that also can increase obvious artefacts caused by image noise, solid beam and mov­ing. An additional follow-up of the patient’s condition is also possible with CT, usually with perfusion pulmonary scans. The chang­ing of perfusion image can be unnoticeable in some patients with central clots. Dissolving and fragmentation of central embolus with peripheral migration can lead to obvious dete­rioration of perfusion defects with chest pain and missing repeated PE diagnosis. With CT venography, stratifying contrast medium ad­vances from slow blood circulation in varicose veins, proceeds to the obstacles and harden­ing artefacts, which can be made from bones, orthopaedic material and calcifications, thus averting accurate diagnosis.6 Contrast extravasation can appear on the injection place, as undesired reactions to con­trast; teophilinum can be given as prophylac­tic therapy.3 Technical problems, which could lead to investigation without conclusion, were met in less than 3% of patients, and usually they are connected with breathing artefacts (hard dys­pnoeic patients), bad relation signal-noise, and insufficient opacification of pulmonary arteries, which may occur in 1-10% cases.7 CT provides a quantitative estimation of PE effects on tissue perfusion, with an addi­tional direct embolus visualization, which has a significant influence on treatment plan­ning.9 As it has been seen in the last years, CT has become a method of choice for central pulmonary embolism (PE) diagnosis to the level of segmental arteries. Multiplanar and 3D reconstruction and colour delineation of perfusion defect, ROI measuring of arterial proceeds for pulmonary blood circulation es­timation, 1 mm collimations, axial and 3D SSD image reconstruction and analysis of sub segmental arteries by mediastinal and pul­monary window, contribute those.13,14,18,19 On the basis of these experiences, the pa­tients with negative CTPA made with 3 mm collimation, can be without anticoagulant therapy if they are not seriously ill and if they have no limited cardiopulmonary reserve and/or if there is no high clinical suspect on PE.22 For those who can't keep breathing is sug­gested to breath low; however, the survey of segmental and subsegmental emboli is not optimal.3 Using monitoring reading became impor­tant for pulmonary arteries analysis, using cine-mod scanning, resulted in an enhanced detection PE rate. Monitors are also helpful for Multiplanar reconstruction (MPR) to dif­ferentiate infra and extra vascular structures and to improve diagnostic reliability. Double-screen monitors show simultaneously the mediastinal and parenchymal window, thus providing a more precise diagnosis; prevent­ing false-positive may cause respiratory or vascular artefacts. Windows sets also should be adapted according to vascular reinforce­ment, intending not to miss small emboli. Large number of images is a problem, be­cause it slows down the work. The total num­ber of SCTPA images is in range from 100-200 for single SCT (SSCT) and 500-1000 for MSCT.7 With reference to irradiation quantity, it must be said that SCTPA is responsible for high effective radiation dose, larger than the radiation dose in chest X ray and venography. Today, SCTPA is the most used primary method in suspected PE in Austrian hospi­tals.16 It is a diagnostic procedure of choice in clinical practice with high accordance among different examiners for main, lobar and seg­mental zones.11,20 For exclusion of pulmonary embolism, SCT is used as a transitive step, leaving pul­monary angiographies for cases with no reli­able results. The following protocol was sug­gested: when CT is positive, stop; when it is negative, lower than subsegmental branches, other examinations are not needed.8 In the arsenal of diagnostic examinations, except the mentioned ones, echocardiogra­phy in bed is obviously appropriate initial di-agnostic test to evidence the overloading of RV, which is frequently united with massive PE, and to show clots in the heart cavities or central pulmonary arteries or other disorders, as pericardial tamponade, acute valvular dis­ease, infarct of myocardium or aorta dissec­tion. US examination is also priceless with classical flexography for examining the vein system of lower extremities.7 MRI has significant role in diagnostic arse­nal, too.23 Which of these diagnostic procedures will triumph at the end, will be seen, taking into consideration a permanent technological in­novation. Conclusions MSCT is easily accessible and excellent non­invasive method for the clot visualization in pulmonary artery. As the investigations show, it has become effective at the subseg-mental level, and in many respects, sur­passed pulmonary angiographies. It provides information about the whole spectrum of findings which can be seen in pulmonary em­bolism; so far, no other method could provide it. Moreover, it also allows alternative diagno­sis. Pulmonary artery embolism is, in most cases, associated with the changes in the pul­monary parenchyma and with indications for heart failure. In this investigation, pulmonary embolism was mostly followed by the find­ings of pleural effusion, enhanced attenua­tion ground glass type, pulmonary infarct, contrast enhanced consolidation pulmonary parenchyma, and striped and reticular septal bumps. The right pulmonary artery embolism was found more often than the left branches embolism. It is harder to detect other signs described in literature or they are very rare. An investigation on greater serials with new MSCT devices with 16, 32 and 64 detector lines will probably bring new significant in­formation. References 1. Durakovic Z. Plucna embolija. Medix 1998; 4(17/18): 77-80. 2. Gurney JW, Winwr-Muram HT. Chest.pulmonary embolism. In: Amirsys, editor. Pocket Radiologist. Salt Lake City: W.B. Saunders Company; 2003. p. 273-5. 3. Rainer S, Benko D. Spiralna CT preiskava pljucnih arterij v diagnostiki pljucne embolije. Zdrav Vestn 2000; 69: 317-23. 4. Qanadli SD, Hajjam ME, MesurolleB, Barre O, Bruckert F, Joseph T, et al. Pulmonary embolism detection: prospective evaluation of dual-section helical CT versus selective pulmonary arteriogra­phy in 157 patients. Radiology 2000; 217: 447-55. 5. Raptopoulos V, Boiselle PM. Multi-detector row spiral CT pulmonary angiography: comparison with single-detector row spiral CT. Radiology 2001; 221: 606-13. 6. Gould P. MRI gains favor for early, accurate DVT diagnosis. Diagnost Imaging Europe 2003; 19: 7-8. 7. Ghaye B, Remy J, Remy-Jardin M. Non-traumatic thoracic emergencies: CT diagnosis of acute pulm-nary embolism: the first 10 years. Eur Radiol 2002; 12(8): 1886-905. 8. Marchant J. Spiral CT advances in pulmonary em­bolism. Diagnost Imaging Europe.2000; 2: 9-10. 9. Abella H. CT gains favor for imaging pulmonary embolism. Diagnostic Imaging 2003; 25: 16-7. 10. Eisenberg RL, Margulis AR. Pulmonary embolism. In: Radiology pocket reference. Philadelphia: Lippincott-Raven; 1996. p. 51-2. 11. Thieme T, Kleber FD, Mutze S. Pulmonary em­bolism. In: Schering diagnostics. Ultravist; 2001. p. 12-3. 12. Laurant F. Pulmonary embolism. Eur Clin Radiol 2002; 12(Suppl 1): 58. 13. Greaves SM, Hart EM, Brown K, Young DA, Batra P, Aberle DR. Pulmonary thromboembolism: spec­trum of findings on CT. AJR Am J Roentgenol 1995; 165: 1359-63. 14. Schoepf UJ, Bruening R, Konschitzky H, Becker ChR, Knez A, Weber J, et al. Pulmonary embolism: comprehensive diagnosis by using electron-beam CT for detection of emboli and assessment of pul­monary blood flow. Radiology 2000; 217: 693-700. 15. Gurney JW, Winer-Muram HT. Pulmonary hyper­tension. In: Amirsys, editor. Pocket radiologist, chest. Salt Lake City: W.B. Saunders Company; 2003. 276-8. 16. Schibany N, Fleischmann D, Thallinger C, Schibany A, Hahne J, Ba-Ssalamah A, et al. Equipment availability and diagnostic strategies for suspected pulmonary embolism in Austria. Eur Radiol 2001; 11: 2287-94. 17. Gottsater A, Berg A, Centergard J, Frennby B, Nirhov N, Nyman U. Clinically suspected pul­monary embolism: it is safe to withhold anticoag­ulation after a negative spiral CT? Eur Radiol 2001; 11: 65-72. 18. Coche E, Pawlak S, Dechambre S, Maldague B. Peripheral pulmonary arteries: identification at multi-slice spiral CT with 3D reconstruction. Eur Radiol 2003; 13: 815-22. 19. Schoepf UJ, Kessler MA, Rieger CT, Herzog P, Klotz E, Wiesgigl S, et al. Multislice CT imaging of pulmonary embolism. Eur Radiol 2001; 11: 2278-86. 20. Ruiz Y, Caballero P, Caniego JL, Friera A, Olivera MJ, Tagarro D, et al. Prospective comparison of helical CT with angiography in pulmonary em­bolism: global and selective vascular territory analysis. Interobserver agreement. Eur Radiol 2003; 13: 823-9. 21. Schoepf UJ, Holzknecht N, Helmberger TK, Crispin A, Hong C, Becker CR, et al. Subsegmental pulmonary emboli: improved detec­tion with thin-collimation multi-detector row spi­ral CT. Radiology 2002; 222: 483-90. 22. Nilsson T, Olausson A, JohnssonH, Nyman U, Aspelin A. Negative spiral CT in acute pulmonary embolism. Acta Radiologica 2002; 43: 486-91. 23. Coche EE, Hammer FD, Goffette PP. Demon­stration of pulmonary embolism with gadolinium-enhanced spiral CT. Eur Radiol 2001; 11: 2306-9. Radiol Oncol 2005; 39(2): 115-21. Characterization of lung cancer patients, their actual treatment and survival: experience in Slovenia Lucka Debevec1, Andrej Debeljak1, Janez Eržen2, Viljem Kovac3, Izidor Kern1 1University Clinic of Respiratory and Allergic Diseases Golnik, 4204 Golnik, Slovenia 2Department of Thoracic Surgery, Clinical Centre, 1000 Ljubljana, Slovenia 3Institute of Oncology, 1000 Ljubljana, Slovenia Background. The aim of the study was to establish characteristics of lung cancer patients diagnosed at the University Clinic of Respiratory and Allergic Diseases Golnik in 1996, their selected and realized therapy, and survival. Methods. The retrospective study comprises 345 patients aged from 37 to 90 years (mean 65), 285 males and 60 females. Performance status (Karnofsky): > 80 in 171 patients, 60-80 in 130 and <60 in 44 patients. Microscopically confirmed tumour in 97%: by bronchoscopy 281, transthoracic needle biopsy 23, peripher­al lymph nodes biopsy 12, sputum cytology 7, pleural (effusion) cytology 4, distant metastases biopsy 2, me-diastinoscopy 1, autopsy 4 patients. Histology and/or cytology: squamous 131, adenocarcinoma 86, large cell 63, small cell 51, non-small cell 1, unclassified 2. Clinical staging of non-small cell lung cancer (NSCLC): stage I 63, stage II 32, stage IIIA 48, stage IIIB 59, stage IV 77, undeterminable 2 patients. Staging in small cell lung cancer (SCLC): limited disease 24, extended disease 27 patients. Results. The selected primary oncological therapy was changed in 11%. Realized primary therapy: radio­therapy 102 (30%), surgery 77 (23%), chemotherapy 47 (14%), supportive treatment 111 (33%). In resect-ed patients staging was correct in 46%, underestimated in 44%, overestimated in 10%. The overall five-year survival was 7.8% (median 6.2 months) and the five year survival of resected patients was 41.9% (median 33 months). The median survival of irradiated patients was 5.7 months, of supportively treated patients 2.5 months. The survival was significantly different according to the performance status and stage. Conclusions. The selected oncological therapy was actually realized in 89%. In our patients there was a low percentage of NSCLC treated by chemotherapy. Among five-year survivors there were 26 resected and one supportively treated patient, that confirms surgery as the most effective therapy in our lung cancer patients. Key words: lung neoplasms – diagnosis – therapy; survival analysis Received 3 March 2005 Accepted 18 March 2005 Correspondence to: Lucka Debevec, M.D., University Clinic of Respiratory and Allergic Diseases Golnik, 4204 Golnik, Slovenia; Phone: +386 4 2569 171; Fax: +386 4 2569 117; E-mail address: lucka.debevec@klini­ka-golnik.si Introduction In recent years there were among 2 million in­habitants in Slovenia approximately one thousand new primary lung cancer patients per year. The data of Cancer Registry of Slovenia presented 958 new cases in 1996, with the incidence rate of 82 per 100.000 pop­ulation for men and 17 per 100.000 popula­tion for women. During that year the lung cancer was the most common cancer in men and the sixth most common cancer in women (after cancer of the breast, skin, corpus uteri, colon and cervix uteri).1 More than a third of lung cancer patients were diagnosed at the University Clinic of Respiratory and Allergic Diseases Golnik. The study presents the eval­uation of routine management and survival of 345 lung cancer patients. This number in­volves all lung cancer patients diagnosed in 1996, and among them some were also treat­ed by chemotherapy at this institution. Surgery was applied at the Department of Thoracic Surgery, Clinical Centre, Ljubljana, Figure 3. Survival of irradiated and supportively treat­ed patients. and radiotherapy at the Institute of Oncology, Ljubljana. The purpose of the study was to establish characteristics of patients and their tumours, the selected and realized therapy, and the survival. Methods The retrospective study comprises 345 pa­tients. The characteristics of patients and their tumours are evident in Table 1 and Table 2. After the diagnostic procedure 337 of 345 patients were presented at a lung cancer meeting (pulmologist, surgeon, radiation oncologist, pathologist, radiologist) where a treatment modality for each patient was se- Figure 4. Survival of NSCLC and SCLC patients. Table 1. Characteristics of patients Number of patients 345 Gender male 285 female 60 Age (years) 37 – 90 (mean 65) Predominant symptoms and signs at the time of admittance cough, dyspnoea, with or without hemoptysis 119 bronchitis, pneumonia 83 haemoptysis, haemopthoe 30 chest pain 30 brachialgia 11 bone pain 10 Syndrome venae cavae sup., dysphagia, paresis n. recurrentis 13 central nerve system symptoms 14 weight loss, weakness 13 digestive disorders 8 peripheral lymph nodes enlargement 4 asymptomatic 10 Performance status (Karnofsky) >80 171 (49%) 60 - 80 130 (38%) <60 44 (13%) Clinical stage (332 patients with classified tu­ mour) Non-small cell cancer stage I 63 (22.5%) stage II 32 (11.5%) stage III.A 48 (17%) stage III.B 59 (21%) stage IV 77 (27%) Small cell cancer limited disease 24 (47%) extended disease 27 (53%) Undeterminable 2 (1%) lected. Thereafter it was presented to the patient. For various reasons the actual pri­mary treatment in some patients was changed. Staging of non-small cell lung cancer (NSCLC) was made according to TNM classi-fication,2 while the one of small cell lung can­cer (SCLC) was made according to limited Table 2. Characteristics of tumours Microscopically confirmed tumour 334 (97%) Not confirmed 11 (3%) Diagnostic investigations for verification bronchoscopy 281 ransthoracic needle biopsy 23 peripheral lymph node needle biopsy 12 sputum cytology 7 pleural (effusion) cytology 4 distant metastases biopsy 2 mediastinoscopy 1 autopsy 4 Histology and/or cytology squamous cell 131 (39%) adenocarcinoma 86 (26%) large cell 63 (19%) small cell 51 (15%) non-small cell 1 (0.3%) unclassified 2 (0.6%) Table 3. Selected and realized primary treatment modality of patients Primary treatment Selected Realized Surgery 93 (28%) 77 (23%) Radiotherapy 110 (32%) 102 (30%) Chemotherapy 50 (15%) 47 (14%) Supportive treatment 84 (25%) 111 (33%) Total 337(100%) 337 (100%) No therapy (death before selection) 8 / 345 disease (LD) and extended disease (ED). The diagnostic procedure from admittance day to microscopic verification took 1 to 75 days, mean 7 days. The zero time for the calculation of the sur­vival was the date of admittance to the insti­tution until death or until the end of the fol­low-up period on December 31st 2001. All liv­ing patients were confirmed to have been alive at this date. The minimal follow-up time for all patients was 5 years. The survival was calculated according to Kaplan-Meier’s method, differences were confirmed by the log-rank test. Results The selected and realized primary treatment modality is evident in Table 3. The therapy was most frequently not realized in patients selected for surgery. The overall primary on-cological therapy was changed in 27 of 253 (11%) patients. The overall survival of 345 patients is pre­sented on Figure 1. The median survival was 6.2 months. After five years 27 (7.8%) pa­tients were still alive. There was no difference in survival ac­cording to gender (p=0.127). Eighty-eight of 93 patients selected for sur­gery were admitted for thoracic surgery. Afterwards 4 patients refused the interven­tion while 7 patients were rejected by the surgeon. In 77 surgically treated patients 35 had lobectomy, 5 bilobectomy, 22 pneu­monectomy, 9 exploratory thoracotomy, 6 mediastinoscopy (mediastinotomy). In 62 re-sected patients staging was correct in 46%, underestimated in 44% and overestimated in 10%. The survival of resected patients is pre­sented on Figure 2. Their median survival was 33 months. The five-year survival of resected patients was 41.9%, stage I 51.2%, stage II and IIIA 23.5% and 25% respectively, considering the clinical TNM staging. In patients with ex­ploratory thoracotomy the median survival was 14.1 months. In irradiated patients the median survival was 5.7 months and in supportively treated patients 2.5 months (p=0.0001), Figure 3. In NSCLC patients the median survival was 6.3 months, in SCLC patients 7.5 months, however, the long-term survival was significantly better in NSCLC patients (p=0.0153), Figure 4. The survival according to the stage was sig­nificantly different in NSCLC (p<0.0001), Figure 5, and in SCLC patients (p=0.0004), Figure 6. The survival according to the performance status is different as well (p<0.0001), Figure 7. Discussion Of registered predominant symptoms and signs the pulmonary ones were present in two thirds of our patients. Only 3% of pa­tients were asymptomatic. Hawson et al.3 re­ported 15% asymptomatic patients in NSCLC and 5% in SCLC among 1024 lung cancer pa­tients. Haber4 established the increase of asymptomatic patients in Queensland of 7% in 1964 to 13% in 1990. Lee et al.5 established 7.2% asymptomatic in 3794 Korean lung can­cer patients. The frequency of discovery of patients still at an asymptomatic stage could indicate the efficiency of detection. Bronchoscopic samples most commonly enabled the microscopic confirmation of tu­mour. In 4 patients tumour was proven by au­topsy. In 11 (3%) patients tumour was micro­scopically not confirmed. These were patients with a low performance status, not capable for diagnostic procedures or capable for a supportive treatment only. The Cancer Registry of Slovenia in 1996 reported 92% mi­croscopically confirmed lung cancer in male and 91% in female.1 The percentage of un­confirmed lung cancer, named also radiologi­cal lung cancer, is rarely reported. Lung6 pub­lished a study of 16 Turkish centres and 3.8% radiological cancer among 11849 lung cancer patients. Juhasz et al.7 reported 11% of uncon­firmed tumours in 499 NSCLC patients, so they concluded that there were no SCLC among their patients. Squamous cell is the most common type of lung cancer, 30%8 to 50%9 of all lung cancer. The increase of adenocarcinoma in some countries over the last two decades is most likely to be attributable to the increased use of milder, filter-tip cigarette, the smoke from which is inhaled deeply, causing adenocarci­noma of the periphery of the lung.10 Small cell lung cancer is less frequent, 15%11 to 30%.12 In our patients there were 39% squa­mous cell and only 15% small cell, 26% ade­nocarcinoma and 19% large cell, meanwhile the Cancer Registry of Slovenia published 32% squamous, 17% small cell, 24% adenocar­cinoma and no specified data for large cell carcinoma in 1996.1 The valid TNM classification since 1997 range T3N0M0 tumours in IIB stage, it was al­ready considered in the analysis. It was not possible to distinguish A and B in I and II stage. Based on the present data we were able to determine the clinical stage in 99% of pa­tients. Only in resected patients it was possi­ble to compare clinical TNM and postsurgi-cal-pathomorphological TNM stage that has a better survival.13 Clinical TNM stage was cor­rect in almost half of our patients, very simi­lar to the published data.14,15,16 In our pa­tients 13% had exploratory thoracotomy, also as a consequence of tendency to enable the resection for all patients without the proven inoperability. As exploratory thoracotomy yields no benefit to the patient in terms of survival or palliation, the goal of thoracic sur­geons should be to eliminate such interven­tion.17 Consistent and precise staging en­abled diminishing of exploratory thoracoto-my from 15.1 to 2.1%.16 The duration of a diagnostic procedure in our patients was mostly about one week and did not essentially influence a therapy delay. The realization of therapy depends on the pa­tient’s motivation for therapy, confidence in the doctor, fear of therapy modality, access to the treatment and financial possibilities. The latter is not the case in Slovenia, because all citizens have health insurance that includes the whole cancer management. The differ­ence between the selected and realized thera­py was mostly the consequence of waiting for the radiotherapy up to two weeks and for the surgery about one month. During the waiting time the patient’s situation can deteriorate and a primarily selected therapy may not be suitable any more. It can be also considered that the selected therapy modality was not al­ways adequate. All of 110 patients referred to radiotherapy came to the Institute of Oncology18 and 93% of them were irradiated, i.e. 30% of all pa-tients. This percentage included primarily ir­radiated patients with curative and palliative intent, but not irradiated after thoracotomy or chemotherapy. Hawson et al.3 reported 40%, Skrickova et al.19 32.2% irradiated cancer pa­tients, both in NSCLC only. Of 93 patients selected for surgery 83% of them were operated (cervical mediastino­scopy and parasternal mediastinotomy as the initiation of surgical intervention included). Five percent of patients refused the surgery after coming to the thoracic surgeon, while 9% were rejected because of signs of inoper-ability or deterioration of a general condition. Chemotherapy was performed in 44/47 se­lected SCLC and 3/3 selected NSCLC pa­tients. That minimal use of chemotherapy in NSCLC (1%) was also due to the insufficient payment of modern expensive drugs by the health insurance. Hawson et al.3 reported the same use of chemotherapy in 873 NSCLC, but in 1990. Of 337 treated patients 111 (33%) were get­ting a supportive care. One of them, periph­eral large cell carcinoma stage I, without symptoms, unfit for the resection, survived for more than five years. A similar percentage of a supportive treatment is reported by oth- ers.3,19 The presented survival figures are factual and not calculated. They do not exclude peri-operative and general mortality. Almost 8% of patients survived for 5 years, all but one were resected. Conclusions The selected oncological therapy was actually realized in 89%. In our patients there was a low percentage of NSCLC treated by chemo­therapy. Among five-year survivors there were 26 resected and one supportively treat­ed patient, that confirms the surgery as the most effective therapy in our lung cancer pa­tients. References 1. Institute of Oncology Ljubljana, Cancer Registry of Slovenia. Cancer Incidence in Slovenia 1996. Report No.38. Ljubljana: Institute of Oncology; 1998. 2. UICC International Union Against Cancer. TNM classification of malignant tumours. Sobin LH, Wittekind Ch, editors. Sixth edition. New York: Wiley-Liss; 2002. p. 99-103. 3. Hawson G, Zimmerman PV, Ford CA, Johnston NG, Firouz-Abadi A. Primary lung cancer: charac­terization and survival of 1024 patients treated in a single institution. Med J Aust 1990; 152: 230-4. 4. Haber RW. Primary lung cancer in Queensland. [Comment]. Med J Aust 1991; 154: 429. 5. Lee C, Kang KH, Koh Y, Chang J, Chung HS, Park SK, et al. Characteristics of lung cancer in Korea, 1997. Lung Cancer 2000; 30: 15-22. 6. Lung T. The retrospective analysis of lung cancer patients in Turkey, a country where smoking is highly prevalent. [Abstract]. Lung Cancer 2000; 29 (Suppl 1): S235. 7. Juhasz E, Temesi G, Myhali E, Maroti A. Analysis of survival data in non small cell lung cancer 1992­1997. Lung Cancer 1999; 25 (Suppl 1): S33-4. 8. Ginsberg RJ, Vokes EE, Raben A. Non-small cell lung cancer. In: DeVita VTJ, Hellman S, Rosenberg SA, editors. Cancer: principles and prac­tice of oncology. 5th ed. Philadelphia: Lippincott – Raven; 1997. p. 858-911. 9. Neal AJ, Hoskin PJ. Clinical oncology: basic princi­ples and practice. London: Arnold; 1997. p. 42-55. 10. Thun MJ, Lally CA, Flannery JT, Calle EE, Flanders WD, Heath CW Jr. Cigarette smoking and changes in the histopathology of lung cancer. J Natl Cancer Inst 1997; 89: 1580-6. 11. Ihde D, Pass H, Glatstein E. Small cell lung cancer. In: DeVita VTJ, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 5th ed. Philadelphia: Lippincott – Raven; 1997. p. 911-49. 12. Hansen HH, Pappot H. Primary malignant tu­mours of the lung and pleura. In: Cavalli F, Hansen HH, Kaye SB, editors. Textbook of medical oncology. London: Dunitz; 2000. p. 245-69. 13. Mountain CF. Lung cancer staging. When the rules don’t fit and other considerations. In: Motta G, editor. Lung cancer. Frontiers in science and treat­ment. Genoa: Grafica; 1994, 99-116. 14. Marel M, Melinova L, Stastny B, Skacel Z, Cermak S, Demes R, et al. The results of surgical treatment of non-small cell lung cancer at the Pneumological Clinic in Prague, Czech Republic 1985-1990. Lung Cancer 1994; 11: 293-8. 15. Vidmar S. Accordance of clinical versus patholog­ical stage (pTNM) in patients with surgically treat­ed non-small cell lung cancer. Radiol Oncol 1994; 28: 337-40. 16. Neef H. Clinical experience in staging of lung can­cer at Martin-Luther University Halle-Wittenberg. Ann Ital Chir 1999; 70: 909-12. 17. Steinbaum SS, Uretzky ID, McAdams HP, Torrington KG, Cohen AJ. Exploratory thoracoto-my for nonresectable lung cancer. Chest 1995; 107: 1058-61. 18. Debevec M. The role of radiotherapy in lung can­cer treatment. Report from Slovenia. Radiol Oncol 1994; 28: 376-81. 19. Skrickova J, Špelda S, Svobodnik A, Kaplanova J, Palkova J, Babickova L, et al. A realistic view of the treatment of non-small cell lung cancer (NSCLC): an analysis of 348 consecutive patients. [Abstract]. Lung Cancer 2001; 32 (Suppl 1): S47. Radiol Oncol 2005; 39(2): 123-31. Surgical treatment of malignant pleural mesothelioma. Experience in the interdisciplinary approach in Slovenia Janez Eržen1, Stanko Vidmar1, Miha Sok1, Andrej Debeljak2, Peter Kecelj2, Viljem Kovac3, Marjeta Stanovnik3, Tomaž Rott4, Izidor Kern3 1Department of Thoracic Surgery, Clinical Centre, 1000 Ljubljana, Slovenia 2University Clinic of Respiratory and Allergic Diseases Golnik, 4204 Golnik, Slovenia 3Institute of Oncology, 1000 Ljubljana, Slovenia 4Institute of Pathology, Medical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia Background. The aim of the study was to identify perioperative morbidity and mortality, the category and mode of adjuvant treatment, local recurrence and survival in patients treated by extrapleural pneumonecto-my (EPP) for malignant pleural mesothelioma (MPM). Methods. From 2000 to 2003, 18 patients with MPM were referred to the Department of Thoracic Surgery in Ljubljana, and 17 of them were operated on. Two patients underwent explorative thoracotomy, and 15 patients were evaluated. Five female and nine male patients (aged 52-68 years) were treated by EPP and one male patient by pleurectomy. Eight patients received both adjuvant chemotherapy (ChT) and radiotherapy (RT), with cisplatin 100 mg/m2 + mitomycin C 6-10 mg/m2 or gemcitabine 1000 mg/m2 and external beam radiation with 24 Gy - 58 Gy respectively, three patients received no adjuvant therapy, three patients were treated by adjuvant ChT, two of them were given cisplatin 100 mg/m2 + mitomycin C 6-10 mg/m2, and one patient cisplatin 100 mg/m2 on the first day and gemcitabine 250 mg/m2 in prolonged 6 hours infusion on the first and on the eighth day. One patient was treated only by adjuvant RT. Results. There were no perioperative deaths and the postoperative morbidity was 42%. Of the 15 evaluable patients, and in the median follow up of 40 months (28-64), we noticed nine (60.0%) recurrences, seven local and two abdominal. Eight (53.3%) patients died, all because of the local progress of disease. Of the 3/15 patients without adjuvant treatment, one patient (T1bN0M0) is well 46 months after the operation, one patient (T2N0M0) got recurrence in abdomen, was treated with ChT and reoperation, and is still alive 31 month after the first surgical treatment. One patient (T2N0M0) died two months after the surgery due to local recurrence. In ChT+RT group, 6/8 patients died: the patient at stage T1aN0M0 died after nine months, the patient at stage T1bN0M0 died after nine months, two patients at the stage T2N0M0 died af­ter four and 23 months respectively, the patient at stage T3N0M0 after 11 months, and the patients at stage T3N2M0 died seven months after the operation. Two out of eight patients are alive: the patient at stage T1bN0M0 is alive 43 months, and the patient at stage T2N0M0 is alive 28 months after the operation. In the ChT group, 1/3 patient (T2N0M0) died 6 months after the operation, 2/3 patients (T2N0M0 and T3N0M0) are well after 43 and 20 months respectively. The patient treated with adjuvant RT only is well 50 months after the surgical treatment. The median survival time was 20 months for the whole group of pa­tients operated on, the 1-year survival rate was 53.3% and 2-year survival rate was 46.7%. Conclusions. In selected patients with MPM, complete surgical resection is indicated, followed by chemotherapy and radiotherapy. The operation could be performed safely with acceptable mortality and morbidity. Our group of patients is too small, the adjuvant therapies were too different to favour any of the treatment mode applied. Further randomised studies and standardised protocols are needed to evaluate the best mode of treatment for each patient. Key words: pleural neoplasms; mesothelioma – surgery – drug therapy - radiotherapy Received 30 May 2005 Accepted 5 June 2005 Correspondence to: Assist. Janez Eržen, MD, MSc, Clinical Department for Thoracic Surgery, Clinical Centre, Zaloška 7,1525 Ljubljana; Phone +386 1 522 21 64; E-mail: janez.erzen@mf.uni-lj.si Introduction Malignant pleural mesothelioma (MPM) is a rare disease and it is rarely curable. Most fre­quently the patients with mesothelioma had been exposed to asbestos. Recently, the pres­ence of a DNA tumour virus (simian virus 40) in tumour cells has suggested a connection between the simian virus 40 and human mesothelioma.1,2 Mineral oils, liquid paraffin, recurrent pulmonary infections, tuberculous pleuritis, exposure in leather and petrochem­ical industry, environmental exposure to cop­per, nickel and glass fibres are cited as non-asbestos risk factors.3 MPM grows from the visceral or parietal pleura. For a long period of time it can be lo-calised at the pleura, but later it infiltrates the lung parenchyma, the diaphragmatic muscle, the endothoracic fascia, the mediastinal fat, the soft tissues of the chest wall, and even the ribs and the pericardium. It usually involves the lower part of thoracic cavity and the low­er pulmonary lobe.4 MPM is more frequent in males, who usu­ally fall ill between the ages 50 and 70 years. In 80% of patients, the illness starts with dys­pnea, chest pain and pleural effusion.5 Patients often suffer from irritating cough and fever. MPM grows up from multipotential mesothelial or subserous cells. The tumour histology affects the survival prognosis, which makes it important to diagnose the ep­ithelial, mixed or sarcomatous type of tu­mour.3 Occasionally the mesothelioma is hard to distinguish from metastatic adenocar­cinoma and the early stage of the benign mesothelial hyperplasia.3 Immunohisto-chemical studies are required, and in same cases even electron microscopy, to establish a conclusive diagnosis. Due to slowly evolving symptoms and non-specific clinical picture, the diagnosis is frequently delayed. The average time interval between the first symptoms of the disease and the diagnosis is from three to six months. A sufficient amount of tissue is needed for diagnosis, and it is obtained by thoracoscopy, videothorascopic procedure or needle punc­ture. An invasive diagnostic procedures may causes a malignant seeding.6 The prognosis of the disease is poor. Median survival of untreated patients is four to twelve months.7,8 Nevertheless, it can stretch up to five years for 10-15% of patients, in whom the progression of the disease is, for unknown reasons, slow.3 Surgical treatment promises the most, but only for selected patients. It is appropriate for patients with the epithelial tumour, stage I or II. The prognosis is more favourable for pa­tients who are in good condition, younger than 50 years and not in pain.4 The nature of the tumour, which spreads over anatomically large and heterogeneous area, makes the mi­croscopically complete resection rarely possi-ble.9 The operation alone is usually not suffi­cient. Additional methods are applied prior to, in the course of, or after the surgical re­moval of the tumour. Postoperative irradia­ tion,5,10,11 systemic12,13 and intrapleural chemotherapy14-16 are very common. Modern methods of treatment, such as photodynamic therapy,17,18 immunotherapy, genetic treat­ment and intracavitary chemotherapy with heat, seem promising, but are yet to produce permanent improvement.19 For the majority of patients, the surgical treatment of MPM is not viable and it is hard­ly ever successful. Only 10-15% of patients with MPM are operated on. A typical candi­date for the operation is a patient in stage I or II of the disease, with the epithelial type of MPM. Two methods of surgical treatment are used: pleurectomy and extrapleural pneu­monectomy (EPP). Pleurectomy is the more frequent of the two methods, with less complications, and lower postoperative mortality rate. This oper­ation is less radical, and localised recurrences are more common.3,20 Nevertheless, the oper­ation is equally successful, if the tumour can be completely resected.21 EPP is a more radical operation than pleurectomy, more difficult for the patient, with higher postoperative mortality and mor­bidity rates. Its long-term survival prognosis improves when combined with radiotherapy and chemotherapy.22 The surgical procedure involves a complete resection of the lungs, parietal pleura, pericardium, and diaphragm. Regional lymph nodes are removed as well. The early postoperative mortality should not exceed 10%. Methods The four-year period of surgical treatment of MPM has been retrospectively analysed at the Clinical Department of Thoracic Surgery of the Clinical Centre in Ljubljana. The data were obtained from the medical records pro­vided by the University Clinic of Respiratory and Allergic Diseases Golnik, by the Department of Thoracic Surgery of the Clinical Centre, and by the Institute of Oncology in Ljubljana. The data pertaining to survival were obtained from the Cancer Register at the Institute of Oncology, and through telephone contacts with patients and their family physicians. During the period between the years 2000 and 2003, the Clinical Department of Thoracic Surgery, Clinical Centre Ljubljana, admitted 18 patients diagnosed with MPM. They were aged between 32 and 68 years, the average age was 58.5 years. Seven of them were females, eleven were males. Ten patients had been exposed to as­bestos, or had been diagnosed with asbesto-sis of lungs. All of them came from the region of Gorica, four of them from Kanal, a place with merely 1500 inhabitants.23 All but three patients had been diagnosed with MPM prior to the admission to our de­partment. In nine cases the diagnosis was based on needle biopsy, in five cases addi­tional thoracoscopy24 was performed to con­firm the inconclusive needle biopsy-based di­agnosis. The diagnosis based on thora­coscopy was always conclusive. One patient was diagnosed by thoracoscopy, without pre­vious needle biopsy. Two patients were diag­nosed by minithoracotomy at our depart­ment, one with the help of video-thora­coscopy. All patients had a history of chest pain on the affected side and/or dyspnea. Other symptoms were: irritating cough (3), general discomfort and fatigue (3), loss of weight (2) and fever. All except one had thoracic effu­sion. Surgical treatment was chosen in the case of epithelial type of tumour, stage I, II or III according to IMIG (International Mesothe­lioma Interest Group) classification,3 if the patient's status made the procedure possible. In addition to usual blood tests and ECG, bronchoscopy, pulmonary function tests, the ultra-sound of liver, and computerised to­mography (CT) of the thorax and of the upper abdomen were performed in all patients. Results Of the 18 patients chosen for the operation, one female patient did not undergo it due to her rapidly deteriorating general condition. In two patients, only explorative thoracotomy was performed, the other 15 patients were evaluated. EPP was performed on 14 patients, one patient underwent pleurectomy. None of the patients died in the first 30 days after the operation. Six of the radically operated patients (42%) developed minor post­operative complications, which were not life-threatening, nor did they affect further treat­ment or length of hospitalisation (Table 1). Most of the radically operated patients had major posterolateral thoracotomy performed, with the removal of the 6th rib, and in three patients double thoracotomy was indicated. Goratex fabric was used for the reconstruc­tion of the diaphragm and of the pericardium, except in one patient, whose diaphragm was replaced with a Vycril net. The patients remained in hospital from 6 to 14 days, 10 days on the average. Thirteen radically operated patients had the epithelial, and two the mixed type of mesothelioma. Most of them were at stage I and II of the disease (Table 2). Table 1. Type and number of operative complications in patients with malignant pleural mesothelioma, treated by the extrapleural pneumonectomy and pleurectomy Type of complications Number Tahiarrythhmia 3 Unexplained fever 1 Chylothorax 1 Bronchial fistula 1 Table 2. Stage in radical operated patients with malig­nant pleural mesothelioma Stage – IMIG classification Number T1aN0M0 1 T1bN0Mo 6 T2N0M0 4 T3N0M0 3 T3N2M0 1 None of the patients received neoadjuvant treatment. The patients who underwent ex-plorative thoracotomy and not the operation were treated differently. One of them re­ceived chemotherapy and radiotherapy, the second one just chemotherapy. The patient who was not operated was treated for symp­toms only. Three operated patients in stage I had no adjuvant treatment. Eight patients underwent chemotherapy and radiotherapy, three patients just chemotherapy, one patient only radiotherapy (Table 3). Of the patients who took cytostatic drugs after the operation during the first three years, four were given mitomycin C 6-10 mg/m2 and cisplatin 100 mg/m2 each three weeks. The treatment was often adjusted to the patien's condition, side effect of drugs, and the response to treatment. On the aver­age, it lasted three months, in one case only a month, and in another case five months. One of the patients was given cisplatin, metotrax-at, adriamycine and gemcitabine because of an early extensive progression. In the course of further treatment, three patients were given gemcitabine 1000 mg/m2 instead of mitomycin C during the last year, Table 3. Mode of the treatment and survival Mode of the treatment Number Median Alive of patients survival in month OP + CT + RT 8 10 4 OP + CT 3 20 2 OP 331 2 OP + RT 1 50 1 Total 15 20 7 OP = operation; CT = chemotherapy; RT = radiotherapy Table 4. Type and mode of adjuvant treatment of the operated patients Patient Start of CT Completed CT CT Start of RT Completed Tumour dose RT in Gy F.K. 17.04.00 07.09.00 Mito C+Cispl 23.10.00 22.11.00 40 E.S. 26.06.00 24.09.00 Cispl+MTX+Adria+Gemz 07.07.00 04.10.00 58 S.B. 08.05.01 08.06.01 54 B.P. 13.11.01 13.03.02 Mito C+Cispl 18.03.02 27.03.02 27 F.Z. 26.01.02 20.03.02 Mito C+Cispl J.B. 07.01.02 09.04.02 Mito C+Cispl 02.07.02 31.07.02 50 V.K. 25.02.02 14.05.02 Mito C+Cispl 29.07.02 08.08.02 41 A.M.M. 15.10.02 02.12.02 Mito C+Cispl 06.02.03 12.03.03 50 I.L. 25.09.02 23.12.02 Mito C+Cispl D.S. 23.04.03 01.07.03 Cispl+Gem 21.07.03 19.09.03 54 I.P. 12.06.03 27.08.03 Cispl+Gem 15.10.03 06.11.03 24 B.R. 08.12.03 03.02.04 Cispl+Gem in prolong inf. KT = chemotherapy; RT = radiotherapy; Mito C = mitomycin C; Cispl = cisplatin; MTX = Methotrexat; Adria = adriomycine; Gem = gemcitabine while the dosage of cisplatin remained the same. The above eight patients had postoperative radiotherapy of hemithorax, at the dosage from 24 to 58 Gy. Three patients took cytostatic drugs with­out radiotherapy. Two patients were adminis­tered cisplatin 100 mg/m2 and gemcitabine 1000 mg/m2, one patient cisplatin 100 mg/m2 and gemcitabine 250 mg/m2 in prolonged 6­hour infusion on the first and on the eighth day. One female patient underwent radio­therapy and no chemotherapy (Table 4). The median survival of all operated pa­tients, regardless the adjuvant treatment, was 20 months. One-year survival rate was 53.3%, and two-year survival rate was 46.7%. The median survival of the patients who received postoperative chemotherapy and ra­diotherapy, as well as of those treated with chemotherapy without radiotherapy, was 11 months, while the patients without adjuvant treatment had median survival of 31 months. The female patient who underwent radiother­apy after the operation (Table 3) survived longest (50 months). The patients with explo­rative thoracotomy and adjuvant ChT and RT, as well as the patient treated for symptoms only, survived for a little over 8 months. Discussion The exposure to asbestos and lung asbestosis were definitely established in 10/18 (55%) pa­tients, and very probable in two other cases (65%). It is especially distressing that most of them came from a geographically small re­gion of Gorica, and that Kanal, a small place with about 1500 inhabitants, drastically stands out.23 Asbestos, a primary etiological agent of MPM, was present in 66% of pa­tients, which is a little lower than the per­centage reported by other authors.1-3 Other etiological factors, such as the infection with the simian virus 40, were not explored. Two of the patients, however, had been employed in petrochemical industry. The symptoms had been present for sever­al months, up to half a year, on the average. Only in one female patient had the x-ray ex­amination revealed changes a year before, and adenocarcinoma of lungs had been ini­tially diagnosed. The disease affects males more than fe­males. Other studies report ratios even more detrimental for males3,5 than is the case in our study (1 : 2.4). The disease usually starts with dyspnea and pleural effusion, as well as chest pain in Radiol Oncol 2005; 39(2): 123-31. the affected side.3,5,7 All patients had the his­tory of one or more of these symptoms. The diagnosis is not easy, since symptoms such as chest pain, dyspnea, fatigue and cough are non-specific, and, on the other hand, histopathologist can find it difficult to distinguish MPM from adenocarcinoma.3,5 In our group, needle biopsy was in five cases in­sufficient for a definite diagnosis. In order to determine the stage of the dis­ease, the CT of the thorax and of the upper abdomen was performed on all candidates for the operation. The CT was underestimated only in two patients (13.3%). In both cases the tumour had spread to mediastinal organs and was consequently inoperable. No MRI was performed, although it is recommended, since it is more precise than CT in determin­ing the penetration of the tumour in the me-diastinum and in the diaphragm.5 In the course of the four years, EPP was performed on 14 patients, which is more than in the previous period of time. In the analysis of the MPM patients in Slovenia between 1980 and 1977, Debevec et al report that only 24 of 156 patients with MPM were operated on. Explorative thoracotomy was done for half of them, and EPP only for five patients.25 In most cases, extensive posterolateral tho-racotomy was performed, with the resection of a rib. Double thoracotomy was performed in three patients, which was mostly the sur­geon's choice. The approach must provide grounds for a safe and radical surgery on ex­tensive area involving vital and sensitive structures such as functional pulmonary veins, the heart and the inferior vena cava. When performing EPP, we try to resect parietal pleura, lungs, pericardium and di­aphragm in one piece, without opening the pleural cavity. This is achieved only rarely be­cause of its adhesion to the thoracic wall, me-diastinum, pericardium and diaphragm, as well as due to previous diagnostic procedures in the pleural cavity. The defect of the peri­cardium and of the diaphragm was in all but one patients restored with a Goretex patch. This fabric is very suitable, it causes no com­plications, but it is very expensive. A Vycril net used in one operated patient proved sat­isfactory as well, and is frequently being used. In each operation, the canal made by previous diagnostic biopsies was radically re-sected, either as a separate procedure or dur­ing the thoracotomy. None of the operated patients died during the early postoperative period, which is a very good result. At present, the early post­operative mortality is 5-10%.3,5,10,22,26 Early postoperative deaths are mostly due to sud­den drop of blood pressure because of the dislocation of mediastimun and blood in-put disorders, haemorrhage, infection of the re­maining pulmary lobes, bronchial fistula and the subsequent empyema in the pleural cavity, and mediastinitis. Herniation of the heart can result from the defect of the pericardium, un­less it has been meticulously reconstructed.5 Various postoperative complications are re­ported for EPP. They occur in 50% and even more patients. In our group, 42% of patients experienced complications, but none of them was extensive. Only one female patient had to be readmitted because of a bronchial fistula. Pleurectomy is a less demanding proce­dure, with fewer complications and low early postoperative mortality, but it is also less rad­ical than EPP. The median survival after this operation is from 9 to 20 months, as reported by different authors.7 Radical resection from the visceral pleura, where the disease usually recurs, is problematic.9 Local recurrence is 10% for EPP, and 52% for pleurectomy.27 Decortication always indicates adjuvant treat­ment. It was performed in only one female patient at the stage T1aN0M0. After the oper­ation, she underwent adjuvant treatment in­volving chemotherapy and radiotherapy. The patient died nine months after the operation due to local progress of mesothelioma. Most authors agree that EPP alone is not sufficient, and that adjuvant treatment is nec- essary.3,5,11,20 Median survival after EPP is from 9 to 19 months,7 not unlike the survival after decortication. This is due to the fact that decortication is more frequently indicated at lower stages of the tumour. Not all of the authors report such opti­mistic results. Mattson reports that 100 oper­ated patients, who underwent adjuvant treat­ment involving five different modes of irradi­ation and systemic chemotherapy, had the median survival of 8 months and only 20% had two-year survival.11 Adjuvant treatment most frequently in­volves chemotherapy and irradiation of com­plete hemithorax at high tumour dose,5,11 or only irradiation of hemithorax at high tumour dose.10 Median survival of the whole group of our operated patients was 20 months, which is significantly better than the survival of pa­tients in the same period and who were not operated on28 and whose median survival was 11 months. The groups were not ran-domised. Patients who were not operated on were probably at a higher stage of the disease, had different histological type of tumour, and were in worse performance status than the patients operated on, so that the two groups cannot be validly compared. Most of our patients (12/15) received adju­vant treatment after the operation, but not in the same mode. They were prescribed differ­ent cytostatic drugs, different dosages, differ­ent number of cycles, as well as different ra­diation doses. Five recent patients were treat­ed with a cytostatic drug of the 3rd generation, which shows better results.29-31 The IMRT method of irradition, which could be very ef-fective,32,33 was not available in our case. A small number of patients (3) had no adjuvant treatment. The small size of the sample of treated patients makes any evaluation of the efficiency of individual methods of treatment unreliable. There are indications that the re­sults tend to be the same as those reported by DaValle34 that in a group of 17 patients the survival length showed no correlation with the adjuvant treatment. His study, however, was not controlled and randomised. At least one more year of follow-up observation would be needed for a valid evaluation of our methods of treatment. Different and multiple methods of treat­ment indicate that the MPM disease is still unmanageable, fatal for most patients, irre­spective of how it is treated. In spite of ag­gressive local treatment, loco-regional recur­rences of the tumour are almost inevitable, if the rest of the pleural cavity, pericardium and abdomen are considered loco-regional. Better results are obtained in carefully selected pa­tients at initial stage, who are treated with a radical local resection of the tumour and ad-juvant radiotherapy. In future, neoadjuvant cytostatic treat­ment, applied and recommended by Stama-tis,35 who reports 31% of three-year survival, will have to be considered. The same author points out that the use of cytostatic drugs af­ter EPP can be detrimental to the other side of the lungs. For that reason he recommends that the treatment starts with three cycles of cisplatin and gemcitabine medication, radical resection after three to four weeks, and radio­therapy of hemithorax after four to six weeks. Conclusions The incidence of MPM has been growing. In patients with epithelial tumour at stage I and II, surgery is indicated besides the oncological treatment. If sufficient, or if the disease is strictly localised, pleurectomy is performed. EPP is a more radical procedure, relatively safe and with acceptably low postoperative mortality and morbidity. It is crucial that the best method of neoaduvant and/or adjuvant treatment after a radical operation is agreed upon. References 1. McDonald JC, McDonald AD. The epidemiology of mesothelioma in historical context. Eur Respir J 1996; 9: 1932-42. 2. Pass HI, Donington JS, Wu P, Rizzo P, Nishimura M, Kennedy R, et al. Human mesotheliomas con­tain the simian virus-40 regulatory region and large tumor antigen DNA sequences. J Thorac Cardiovasc Surg 1998; 116: 854-9. 3. Rusch VW. Mesothelioma and less common pleu­ral tumors. In: Pearson FG, Ginsberg RJ, Cooper JD, Hiebert CA, Deslauriers J, Patterson GA, et al, 2nd editors. Thoracic surgery. edition. New York: Churchill Livingstone; 2002. p. 1241-63. 4. Roberts JR. Surgical treatment of mesothelioma: pleurectomy. Chest 1999; 116: 446S-9S. 5. Sugarbaker DJ, Garcia JP. Multimodality therapy for malignant pleural mesothelioma. Chest 1997; 112: 272S-5S. 6. Boutin C, Rey F, Viallat RJ. Prevention of malig­nant seeding after invasive diagnostic procedures in patients with pleural mesothelioma: a random­ized trial of local radiotherapy. Chest 1995; 108: 754-8. 7. Ruth S, Baas P, Zoetmulder FA. Surgical treatment of malignant pleural mesothelioma. A review. Chest 2003; 123: 551-61. 8. Zellos L, Sugarbaker DJ. Current surgical manage­ment of malignant pleural mesothelioma. Curr Oncol Rep 2002; 4: 354-60. 9. Lee YC. Light RW, Musk AW. Management of ma­lignant pleural mesothelioma: a critical review. Curr Opin Pulm Med 2000; 6: 267-74. 10. Rusch VW, Rosenzweig K, Venkatraman E, Leon L, Raben A, Harrison L, et al.A phase II trial of sur­gical resection and adjuvant high-dose hemitho­racic radiation for malignant pleural mesothe­lioma. Thorac Cardiovasc Surg 2001; 122: 788-95. 11. Mattson K, Holsti LR, Tammilehto L, Maasilta P, Pyrhonen S, Mantyla M, et al. Multimodality treat­ment programs for malignant pleural mesothe­lioma using high-dose hemithorax irradiation. Int J Radiat Oncol Biol Phys 1992; 24: 643-50. 12. Huncharek M, Kelsey K, Mark EJ, Muscat J, Choi N, Carey R, et al. Treatment and survival in diffuse malignant pleural mesothelioma: a study of 83 cas­es from the Massachusetts General Hospital. Anticancer Res 1996; 16: 1265-8. 13. Hasturk S, Tastepe I, Unlu M, Cetin G, Baris YI. Combined chemotherapy in pleurectomized ma­lignant pleural mesothelioma patients. J Chemother 1996, 8: 159-64. 14. Rusch V, Saltz L, Venkatraman E, Ginsberg R, McCormack P, Burt M, et al. A phase II trial of pleurectomy/decortication followed by intrapleur­al and systemic chemotherapy for malignant pleu­ral mesothelioma. J Clin Oncol 1994, 12: 1156-63. 15. Lee JD, Perez S, Wang HJ, Figlin RA, Holmes EC. Intrapleural chemotherapy for patients with in­completely resected malignant mesothelioma: the UCLA experience. J Surg Oncol 1995; 60: 262-7. 16. Colleoni M, Sartori F, Calabro F, Nelli P, Vicario G, Sgarbossa G, et al. Surgery followed by intracavi­tary plus systemic chemotherapy in malignant pleural mesothelioma. Tumori 1996; 82: 53-6. 17. Pass HI, Temeck BK, Kranda K, Thomas G, Russo A, Smith P, et al. Phase III randomized trial of sur­gery with or without intraoperative photodynamic therapy and postoperative immunochemotherapy for malignant pleural mesothelioma. Ann Surg Oncol 1997; 4: 628-33. 18. Moskal TL, Dougherty TJ, Urschel JD, Antkowiak JG, Regal AM, Driscoll DL, et al. Operation and photodynamic therapy for pleural mesothelioma: 6-year follow-up. Ann Thorac Surg 1998; 66. 1128­33. 19. Kaiser LR. New therapies in treatment of malig­nant pleural mesothelioma. Semin Thorac Cardiovasc Surg 1997; 9: 383-90. 20. Soysal O, Karaoglanoglu N, Demiracan S, Topcu S, Tastepe I, Kaya S, et al. Pleurectomy/decortica­tion for palliation in malignant pleural mesothe­lioma: results of surgery. Eur J Cardiothorac Surg 1997; 11: 210-3. 21. Rusch VW, Venkatraman ES. Important prognos­tic factors in patients with malignant pleural mesothelioma, managed surgically. Ann Thorac Surg 1999; 68: 1799-804. 22. Grondin SC, Sugarbaker DJ. Pleuropneumo­nectomy in the treatment of malignant pleural mesothelioma. Chest 1999; 116: 450-4. 23. Krajevni leksikon Slovenije. Ljubljana: DZS; 1995. p. 182. 24. Debeljak A, Kecelj P, Kern I, Eržen J, Kovac V, Rott T. Medical thorascopy in pleural malignant mesothelioma. In: Zaltloukal P, Petruželka L, edi­tors. Lung Cancer. Current Topics. Prague: Monduzzi Editore; 2001. p. 81-6. 25. Debevec M, Kovac V, Debeljak A, Eržen J, Remškar Z, Kern I. Maligni plevralni mezoteliom. Analiza bolnikov v Sloveniji 1980-1997. Zdrav Vestn 2000; 69: 599-606. 26. Aziz T, Jilaihawi A, Prakash D. The management of malignant pleural mesothelioma; single centre experience in 10 years. Eur J Cardiotorac Surg 2002; 22: 298-305. 27. Baldini EH, Recht A, Strauss GM, DeCamp MM Jr, Swanson SJ, Liptay MJ, et al. Patterns of failure After trimodality therapy for malignant pleural mesothelioma. Annal Thorac Surg 1997; 63: 334-8. 28. Debeljak A, Kecelj P, Kern I, Triller N, Remškar Z, Eržen J, et al. Diagnoza malignega plevralnega mezotelioma. In: Debeljak A, Turel M, editors. Simpozij bolezni plevre in simpozij presaditev pljuc. Nova Gorica, 2.-3. april 2004. Celje: Združenje pneumologov Slovenije, 2004. p. 27-34. 29. Lee Kindler H. Systemic therapy for mesothe­lioma: old and new. Lung Cancer 2003; 41(Suppl 3): S54. 30. Nowak AK, Byrne MJ, Williamson R, Ryan G, Segal A, Fielding D, et al. A multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma. Br J Cancer 2002; 87: 491-6. 31. Kovac V, Zwitter M, Smrdel U, Debeljak A, Cesar R. Low-dose gemcitabine in prolonged infusion and cisplatin for malignant pleural mesothelioma: a phase I – II trial. In: Jassem J, editor. Gdansk: Medimond S.r.l., Monduzzi Editore; 2004. p. 131­4. 32. Ahamad A, Stevens CW, Smythe WR, Liao Z, Vaporciyan AA, Rice D, et al. Promising early local control of malignant pleural mesothelioma follow­ing postoperative intensity modulated radiothera­py (IMRT) to the chest. Cancer J 2003; 9: 476-84. 33. Baldini EH. External beam radiation therapy for the treatment of pleural mesothelioma. Thorac Surg Clin 2004; 14: 543-8. 34. DaValle MJ, Faber LP, Kittle CF, Jensik RJ. Extrapleural pneumonectomy for diffuse malig­nant mesothelioma. Ann Thorac Surg 1986; 42: 612­8. 35. Stamatis G. Malignant pleural mesothelioma.The role of surgical resection. Highlights in thoracic surgery. Monday 13th October. 2nd EACTS/ESTS Joint Meeting, Vienna, Austria 12-15 October 2003. Radiol Oncol 2005; 39(2): 133-40. Managing anemia with epoetin alfa in patients with rectal cancer Vaneja Velenik1, Irena Oblak1, Veronika Kodre2 1Department for Radiotherapy, Institute of Oncology, Ljubljana, Slovenia 2Janssen-Cilag Slovenia, Division of Johnson & Johnson d.o.o., Ljubljana, Slovenia Background. Anemia is one of the most challenging problems in clinical oncology due to its high prevalence among the patients with malignant diseases. The purposes of our study were: (1) to assess the potential of epoetin alfa therapy to prevent the decline in Hb concentrations that typically accompanies chemothera­py/radiotherapy (ChT/RT) of the patients with rectal cancer; (2) to test the hypothesis that the use of epo­etin alfa significantly reduces the transfusion requirements in the patients with rectal cancer treated with ChT/RT after surgery, and (3) to evaluate the safety profile of the administration of epoetin alfa in the clin­ical setting. Methods. Sixty patients who underwent surgery for rectal cancer were prospectively enrolled. Group A consisted of 39 patients with Hb concentrations =13 g/dl at the start of ChT/RT following surgery, and group B of 17 patients with Hb concentrations >13 g/dl at the start of ChT/RT following surgery, but whose Hb concentrations fell below 13 g/dl during the ChT/RT protocol. The starting dose of epoetin alfa in both groups was 10,000 IU subcutaneously (sc) three times a week (tiw). The following major parameters were evaluated: (1) change in Hb concentrations relative to the baseline as measured at 4-week intervals, (2) al­logenic blood transfusion requirements in relation to Hb concentrations, and (3) incidence and severity of adverse events and their potential relationship to epoetin alfa administration. Results. The study protocol was completed in 56/60 patients. In group A, a statistically significant increase in Hb concentration (p<0.001) was observed after the first 4 weeks of epoetin alfa treatment compared to the baseline values, with the mean increase of Hb concentration of 1.97 g/dl ± 0.91 g/dl and Hb concen­trations remained significantly increased through the whole study (p=0.0017). In group B, a continuous de­crease in Hb concentrations was observed during the first weeks of therapy, reaching the level of statistical significance after 3 weeks of postoperative treatment. After the initiation of epoetin alfa treatment, an in­crease of Hb concentrations and their maintenance at =12 g/dl was observed also in group B. Not a single patient enrolled in the study needed transfusion. None of described adverse events was connected to the epo­etin alfa treatment. Conclusions. The results of the present study show that epoetin alfa is safe and effective in maintaining Hb concentrations during the adjuvant therapy in rectal cancer patients. It significantly increases Hb con­centrations and reduces transfusion requirements in the patients receiving chemoradiotherapy after surgery for rectal cancer. Key words: rectal neoplasms – radiotherapy – drug therapy; anemia – drug therapy; epoetin alfa Received 3 May 2005 Accepted 18 May 2005 Correspondence to: Vaneja Velenik, M. D., Department of Radiation Oncology, Institute of Oncology, Zaloška 2, SI-1000 Ljubljana, Slovenia; Phone: +386 1 232 3063; Fax: +386 1 431 41 80; E-mail: vvelenik@onko-i.si Introduction Anemia is one of the most challenging clinical problems in clinical oncology due to its high prevalence among the patients with malig­nant diseases.1,2 It is now recognized as an in­dependent prognostic factor for patient’s sur­vival3-12 and can also have a considerable neg­ative effect on patient’s quality of life.7,13-17 Generally, clinical studies have shown that recombinant human erythropoietin (epoetin alfa) administered once weekly or three times a week improves hemoglobin (Hb) levels, de­creases transfusion requirements,1,4,7,12-20 im­proves quality of life,14-17,21-24 and may also improve the survival in the patients with can­cer-related anemia.4,7,25-27 However, despite such efficient approach to the anemia man­agement, a comprehensive survey28 indicated that only 36% of patients with solid tumors who were anemic received treatment for their anemia. Moreover, treatment of anemia was initiated at lower Hb levels than recommend­ed (mean Hb level of 9.6 g/dl for solid tu-mors).28 Accordingly, it is mandatory to assess the feasibility and safety of the administration of Table 1. The study population epoetin alfa in each individual type of cancer. The purposes of our study were: (1) to assess the potential of epoetin alfa therapy to prevent the decline in Hb value that typically accom­panies chemotherapy/radiotherapy (ChT/RT) of the patients with rectal cancer; (2) to test the hypothesis that the use of epoetin alfa sig­nificantly reduces the transfusion require­ments in the patients with rectal cancer treat­ed with ChT/RT after surgery, and (3) to eval­uate the safety profile of administration of epoetin alfa in the clinical setting. Methods Sixty patients who underwent rectal cancer surgery were prospectively enrolled in the study between March 2002 and December 2003 (Table 1). The following inclusion crite­ria were used: - histologic confirmation of adenocarcino-ma of the rectum (pathohistological stage II and III) that were amenable to postoperative ChT/RT; - age above 18 years; - WHO performance status 0-2; - Hb level =13 g/dl; -serum transferrin saturation (TSAT) >20%. Exclusion criteria were: uncontrolled or se­ vere cardiovascular disease, including recent (<6 months) myocardial infarction; uncon­trolled hypertension (diastolic blood pressure >95 mm Hg); congestive heart failure; uncon­trolled or unexplained seizures; major illness Group N Description Mean age/Range (years) Gender (male/female) A 39 Hb level = 13 g/dl at the start of the Cht/RT treatment following surgery; enrolled at the start of the Cht/RT 64.8±14 19 M/20 F B 17 Hb level >13 g/dl at the start of Cht/RT treatment following surgery; enrolled during the Cht/RT 68.5±9.5 11M/6F All 56 Patients with Hb=13 g/dl treated for rectal cancer with Cht/RT after surgery 66.6±11.7 30 M/26 F ChT/RT – chemo-radiotherapy; N – number of patients or infection within the preceding month, his­tory of thrombotic or other vascular events during the preceding 6 months; known hy­persensitivity to epoetin alfa or one of its components; pregnancy, lactation, or inade­quate method of contraception in females with childbearing potential. Surgical procedures were as follows: ab-dominoperineal resection (APR; 23 patients), low anterior resection (LAR; 28 patients), an­terior resection (RRA; 6 patients), Hartman’s palliative resection (2 patients) and coloanal anastomosis (CA; 1 patient). After surgery, all patients were treated on adjuvant setting at the Institute of Oncology in Ljubljana, Slovenia, following the protocol outlined below and approved by the Protocol Review Board and Committee for Medical Ethics at the Institute of Oncology. All patients were informed about the study protocol. At the enrolment, baseline data (history, physical and laboratory tests) were collected in all patients, including complete blood cell count, reticulocyte count, levels of serum iron, folate and vitamin B12, transferin satu­ration (TSAT) and ferritin. On the basis of Hb concentration, the pa­tients were divided into two groups. Group A consisted of 39 patients with Hb level =13 g/dl at the start of the ChT/RT, and group B of 17 patients with Hb level >13 g/dl at the start of the ChT/RT following surgery, but whose Hb fell below 13 g/dl during the ChT/RT. Chemo-radiotherapy protocol The patients were treated following the com­bined ChT/RT protocol as shown in Figure 1. During 25 weeks, the patients received 6 cy­cles of chemotherapy with 5-fluorouracil (5­FU), 425 mg/m2/day intravenously (iv), and Ca-folinat, 50 mg/day iv both during the days 1-5. Because of concomitant irradiation dur­ing the 4th cycle of ChT, the doses of 5-FU and Ca-folinat were reduced to 75% level for this cycle only. The cycles were repeated every 28 days. The patients were irradiated with 10-15 MV linear accelerator photon beams to a tumor dose of 50.4 Gy and daily fractions of 1.8 Gy, applied five-times/week. Epoetin alfa administration protocol In group A, the treatment with epoetin alfa started on day 1 of ChT/RT, whereas in group B, epoetin alfa was administered during the course of ChT/RT when a patient’s Hb concen­tration decreased below 13 g/dl. The starting dose of epoetin alfa was 10,000 IU subcuta­neously (sc) three times a week (tiw). Hb con­centration was monitored regularly at monthly intervals during chemotherapy and weekly during ChT/RT. If the Hb concentration in­creased by less than 1 g/dl from the baseline af­ter 4 weeks of initiating epoetin alfa, the dose of the drug was increased to 20,000 IU sc tiw. In case of the increase of Hb concentration by more than 2 g/dl per month, the dose of epoet-in alfa was reduced to 10.000 IU biw. ChT cycle: Chemotherapy cycle; RT: Radiotherapy Figure 1. Protocol of the study The administration of epoetin alfa was in­terrupted when Hb concentration increased above 14 g/dl and was initiated again when it fell below 12 g/dl at a dose of 10.000 IU twice a week (biw). The application of epoetin alfa was abol­ished if the treatment with epoetin alfa was not effective (no expected rise in Hb level af­ter dose escalation) or in cases of developing a severe adverse reaction related to epoetin alfa.29 All patients included in the study would be transfused if Hb concentration was <10 g/dl. Iron treatment, transfusion requirements and concomitant therapy The patient’s iron status, including transfer-rin saturation-TSAT (serum iron/iron binding capacity x 100; %) and serum ferritin (µg/L) was evaluated on weekly basis during ChT/RT, and on monthly basis during ChT. To avoid iron depletion of available stores and to support adequately erythropoiesis, stimulated by epoetin alfa, the patients with TSAT <20% and/or serum ferritin <100 µg/L required supplemental iron (300 mg elemen­tal iron orally per day). Follow up In the postoperative phase, the patients were followed on weekly basis for a total of 25 weeks. Safety evaluations were carried out by clinical laboratory tests and by assessing the incidence and severity of treatment-related side effects. Statistical analysis The following parameters were evaluated: (1) change in Hb concentration relative to the baseline as measured at 4-week intervals, (2) blood transfusion requirements in relation to Hb level, and (3) incidence and severity of ad­verse events and their potential relationship to epoetin alfa administration. Hb concentra­tion was presented as mean ± standard devi­ation (SD). Statistical analysis was performed using the two-sided paired t-test. A probabili­ty value of <0.05 was considered statistically significant. Results The study protocol was completed in fifty-six of sixty patients (56/60; 93.3%). The remain­ing four patients (4/60; 6.7%) included in the study were not included in statistical evalua­tions due to insufficient data. Forty-five of fifty-six patients (45/56; 80.3%) completed all six cycles of chemotherapy and radiation therapy as specified in the protocol. Eleven patients (11/56; 19.7%) received less than six cycles of ChT (5 cycles- 3 patients; 4 cycles- 5 patients; 2 cycles- 3 patients) due to the ap­pearance of adverse events (ileus, dehydra­tion, nausea, leucopoenia, febrile neutropoe­nia, infection, cardial decompensation, radio-proctitis, mucositis). Figure 2. Mean hemoglobin (Hb) concentrations in the patients treated with epoetin alfa in groups A and B. In group A, Hb levels were statistically increased from the enrolment in the study onwards. In group B, an initial decrease in Hb concentrations (weeks 0 through 3) was observed. After the initiation of the treatment with epoetin alfa, mean Hb concentrations in group B also reached the level of 12 g/dl till the end of the treatment. Hematological response In group A, a statistically significant increase in Hb concentration (p<0.001) was observed after the first 4 weeks of epoetin alfa treat­ment compared to the baseline values, with the mean increase of Hb concentration of 1.97 g/dl ± 0.91 g/dl. As shown in Figure 2, Hb concentrations remained significantly in­creased from the initial values through the rest of the treatment (p=0.0017). In group B, a continuous decrease in Hb concentrations was observed during the first weeks of the therapy, reaching the level of statistical sig­nificance after 3 weeks of postoperative treat­ment, (p=0.006). After the initiation of epoet-in alfa treatment, an increase of Hb concen­trations (on average 0.7 g/dl ± 0.4 g/dl/4 weeks) and their maintenance at =12 g/dl were observed (Figure 2). Figure 3 illustrates the frequency of Hb readings <13 g/dl in the patients from group A compared with those from group B during RT part of the protocol. In group A, a progressive­ly smaller share of patients with Hb values <13 g/dl was registered during RT. None of the pa­tients had Hb concentrations <13 g/dl at the Figure 3. Prevalence of patients with hemoglobin (Hb) concentration <13 g/dl during the RT part of the pro­tocol. In group A, a progressively smaller share of pa­tients with Hb concentrations <13 g/dl during RT was observed and with none of the patients with Hb val­ues 13 g/dl at the end of RT. In group B, the share of patients with Hb concentration <13 g/dl progressively increased during RT. 6th week of the irradiation. On the other hand, in group B, the share of patients with Hb con­centrations <13 g/dl progressively increased during RT. In this subgroup, epoetin alfa was typically initiated during the 3rd week of RT. Transfusion requirements Not a single patient enrolled in the study needed transfusion. Safety and tolerability of epoetin alfa Nine adverse events that occurred in 6 pa­tients who completed the study were record­ed: ileus, dehydration, nausea, leucopoenia, febrile neutropoenia, infection, cardial de-compensation, radioproctitis, and mucositis. None of the described adverse events was connected to the epoetin alfa treatment. Discussion In the present study, we tested the efficacy and feasibility of epoetin alfa administration in the patients receiving chemo-radiotherapy after surgery for rectal cancer. Our results demonstrate that, also in the patients with this type of cancer, epoetin alfa effectively in­creases and maintains Hb concentration dur­ing ChT/RT at the clinically requested level. None of the patients enrolled in our study re­quired transfusion despite the aggressiveness of the treatment protocol. The results of our study corroborate the findings of randomized controlled trials with epoetin alfa in the treatment of anemia in other solid and hematological malignancies. These studies have consistently shown an in­crease in Hb concentrations, a decrease in transfusion requirements, and an improve­ment in patient’s energy level, their ability to maintain daily activities, and their overall quality of life.1,4,7,13-19,21-24 Our results also confirmed an excellent safety profile of epoetin alfa. Although thrombotic/vascular events and hypertension have been reported previously in the patients treated with epoetin alfa,27 no such events were observed in our population of patients. Recent studies on ovarian and lung cancer patients receiving cisplatin-based chemother­apy have demonstrated that higher Hb con­centrations exerted a positive effect on pa­tient’s tolerability of chemotherapy.30-32 The patients with low Hb-concentrations due to either the disease itself or myelotoxicity of chemotherapy had a lower capacity to com­pensate for treatment toxicity.30 In addition, our results indicate that the epoetin alfa treatment is particularly benefi­cial in combined treatment protocols. The major challenge remains how to identify the patients who would most likely develop ane­mia during the combined therapy and who are candidates for prophylactic epoetin alfa treatment. The benefits of epoetin alfa pro­phylaxis in the context of current clinical guidelines, which recommend starting with epoetin therapy at the Hb concentration range of 10-11 g/dl,33,34 are yet to be defined. Anemia is a major cause of fatigue which is clinically manifested in 40-80% of patients with malignancies15,20,35-37 and usually criti­cally influences the quality of their lives. Indeed, fatigue is at least as common among the most reported bothersome symptoms in the patients with cancer as the pain is.13,15,17 On the other hand, many authors have re­ported that the problem of cancer-related fa­tigue is frequently not assessed adequately because it is not mentioned by patients, as­sessed by physicians, or not addressed to as an integral part of the treatment evaluation protocols.38 Obviously, it is of critical impor­tance to identify the fatigue in each individual patient and to offer him appropriate thera­peutic option to alleviate it. Hypoxia in the tumor has been recognized as a key regulator of tumor growth. Sustained hypoxic environment in a growing tumor may trigger changes that can result in a more aggressive phenotype of tumor cells.39-41 Many studies have demonstrated a reduced probability of local control and worse survival results in the patients with hypoxic tumors, treated with ChT and/or RT.42 In case of RT, the reduction in radiosensitivity of tumor cells should be seriously considered when the oxygen partial pressure in a tumor decreases below 25-30 mmHg. In general, a two- to threefold higher radiation dose is required to kill completely the hypoxic cells, compared with well-oxygenated cells, a difference re­ferred to as the oxygen enhancement effect.43 The increase in Hb concentrations, which im­proves the oxygen-carrying capacity of blood, is also correlated with better response to chemotherapy.44 To conclude, the results of the present study show that epoetin alfa is safe and effec­tive in maintaining Hb concentrations during the adjuvant therapy of rectal cancer pa­tients. It significantly increases Hb concen­trations and reduces transfusion require­ments in the patients receiving chemoradio-therapy after surgery for rectal cancer. Acknowledgements The authors wish to thank Aleš Ambrožic, PhD, Darja Ambrozic, MD, Rok Hren, PhD, Sanja Bizilj, MPhar, and Katarina Verhnjak, MSc Pharm for their assistance they offered during the preparation of this work. References 1. Groopman JE, Itri M. 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Meaningful survival in lung cancer patients. Semin Oncol 2002; 29: 125-31. 12. Pangalis GA, Siankantaris MP, Angelopoulou MK, Vassilakopoulos TP, Dimopoulou MN, Kontopidou FN, et al. Downstaging Rai stage III B-chronic lymphocytic leukemia patients with the administration of recombinant human erythropoi­etin. Haematologica 2002; 87: 500-6. 13. Cella D. Factors influencing quality of life in can­cer patients: anemia and fatigue. Semin Oncol 1998; 25(3 Suppl 7): 43-6. 14. Crawford J. Anemia and lung cancer. Lung Cancer 2002, 38: S75-8. 15. Curt GA, Breitbart W, Cella D, Groopman JE, Horning SJ, Itri LM, et al. Impact of cancer-related fatigue on the lives of patients: new findings from the Fatigue coalition. Oncologist 2000; 5: 353-60. 16. Del Mastro L, Venturini M. Strategies for the use of epoetin alfa in breast cancer patients. Oncologist 1998; 3: 314-8. 17. Demetri GD, Kris M, Wade J, Degos L, Cella D. Quality of life benefit in chemotherapy patients treated with epoetin alfa is independent of disease response or tumor type: results from a prospective community oncology study. J Clin Oncol 1998; 16: 3412-25. 18. Aapro M, Bajetta E, Freund M, Lttlewood TJ, Nortier JWR, Rapoport B. Is there a possible sur­vival benefit to increasing hemoglobin levels with epoetin alfa during chemotherapy? EJC Supple­ments 2004; 2: 20-8. 19. Abels R. Erythropoietin for anemia in cancer pa­tients. Eur J Cancer 1993; 29A(Suppl 2): S2-8. 20. Bentzen SM, Johansen LV, Overgaard J, Thames HD. Clinical radiobiology of squamous cell carci­noma of the oropharynx. Int J Radiat Oncol Biol Phys 1991; 20: 1197-206. 21. Gabrilove JL, Cleeland CS, Livingston RB, Sarokhan B, Winer E, Einhorn LH. Clinical evalu­ation of once-weekly dosing of epoetin alfa in chemotherapy patients: improvements in hemo­globin and quality of life are similar to three-times-weekly dosing. J Clin Oncol 2001; 19: 2875-82. 22. Glaspy J, Bukowski R, Steinberg D, Taylor C, Tchekmedian S, Vadhan-Raj S. Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. J Clin Oncol 1997; 15: 1218-34. 23. Shasha D, George MJ, Harrison LB. Once weekly dosing of epoetin ? increases hemoglobin and im­proves quality of life in anemic cancer patients re­ceiving radiation therapy either concomitantly or sequentially with chemotherapy. Cancer 2003; 98: 1072-9. 24. Thatcher N, De Campos ES, Bell DR, Steward WP, Varghese G, Morant R, et al. Epoetin alfa prevents anaemia and reduces transfusion requirements in patients undergoing primarily platinum-based chemotherapy for small cell lung cancer. Br J Cancer 1999; 80: 396-402. 25. Bohlius JF, Langesiepen S, Schwarzer G, Bennett CL, Engert A. Does erythropoietin improve overall survival in the treatment of patients with malig­nant diseases? Results of comprehensive meta-analysis. [Abstract]. Blood 2003; 102: 709. 26. Glaser CM, Millesi W, Kornek GV, Lang S, SchLll B, Watzinger F, et al. Impact of hemoglobin level and use of recombinant erythropoietin on efficacy of the preoperative chemoradiation therapy for squamous cell carcinoma of the oral cavity and oropharynx. Int J Radiat Oncol Biol Phys 2001; 50: 705-15. 27. Johnson & Johnson. Background information for Oncology Drugs Advisory committee meeting. 4 May 2004. Gaithesburg, MD. Safety of erythropoi­etin receptor agonists (ERAs) in patients with can­cer. At: http//:www.fda.gov/ohrms/dockets/ac/ 04/briefing/4037B2_02_JohnsonJohnson­Procrit.PDF. Accessed 23.09.2004. 28. Ludwig H, Birgegard G, Barret-Lee P, Birgegard G, Bokemayer C, Gascon P, et al. The European Cancer Anaemia Survey (ECAS): A large, multina­tional, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer pa­tients. Eur J Cancer 2004; 40: 2293-306. 29. ICH harmonised tripatite guideline for good clinical practice. Article 16. Brookwood Medical Publica­tions LTD; 1996. p. 87. 30. Fazekas JT, Scott C, Marcial V, Davis LW, Wasserman T, Cooper JS. The role of hemoglobin concentration in the outcome of misonidazole-sensitized radiotherapy of head and neck cancers: based on RTOG trial # 79-15. Int J Radiat Oncol Biol Phys 1989, 17: 1177- 81. 31. Tarnawski R, Skladowski K, Maciejewski B. Prognostic value of hemoglobin concentration in radiotherapy for cancer of supraglottic larynx. Int J Radiat Oncol Biol Phys 1997; 38: 1007-11. 32. Van Acht MJ, Hermans J, Boks DE, Leer JW. The prognostic value of hemoglobin and a decrease in hemoglobin during radiotherapy in laryngeal car­cinoma. Radiother Oncol 1992; 23: 229-35. 33. National Comprehensive Cancer Network (NC­CN). Clinical practice guidelines in oncology. Cancer-related fatigue. Version 1.2003. Available at http://www.nccn.org/physician_gls/f_guide­lines.html. 34. Rizzo JD, Lichitin AE, Woolf SH, Seidenfeld J, Bennet CL, Cella D, et al. Use of epoetin in pa­tients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol 2002; 19: 4083-107. 35. Blitzer PH, Wang CC, Suit HD. Blood pressure and hemoglobin concentration: multivariate analysis of local control after irradiation for head and neck cancer. [Abstract]. Int J Radiat Oncol Biol Phys 1984; 10(Suppl 2): 98. 36. Brizel DM, Sibley GS, Prosnitz LR, Scher RL, Dewhirst MW. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 1997; 38: 285-9. 37. Nordsmark M, Overgaard J. A confirmatory prog­nostic study on oxygenation status and loco-re­gional control in advanced head and neck squa­mous cell carcinoma treated by radiation therapy. Radiother Oncol 2000; 57: 39-43. 38. Turner R, Anglin P, Burkes R, Couture F, Evans W, Goss G, et al for Canadian Cancer and Anemia Guidelines Development Group. Epoetin alfa in cancer patients: evidence-based guidelines. J Pain Symptom Manage 2001; 22: 954-65. 39. Freedman LS, Honess DJ, Bleehen NM, Adams GE, Dische S, Henk JM. Does initial hemoglobin level modify the efficacy of radiosensitizers? An analysis of the MRC misonidazole studies in head and neck cancer and cervix cancer. Int J Radiat Biol Relat Stud Phys Chem Med 1987; 52: 965-7. 40. Horsman MR, Overgaard J. The oxygen effect. In: Steel GG, editor. Basic clinical radiobiology. London: Edward Arnold Publ; 1993. p. 81-8. 41. Kumar P. Tumor hypoxia and anemia: Impact on the efficacy of radiation therapy. Semin Hematol 2000; 4: 4-8. 42. Fyles AW, Milosevic M, Wong R, Kavanagh MC, Pintilie M, Sun A, et al. Oxygenation predicts ra­diation response and survival in patients with cervix cancer. Radiother Oncol 1998; 48: 149-56. 43. Denekamp J, Waitea A. The potential for improv­ing radiotherapy outcome by improving the oxy­gen supply to solid tumors. Strahlenther Onkol 1996; 172(Suppl.2): 22-3. 44. Vigario G, Kurohara SS, George FW. Association of hemoglobin levels before and during radiother­apy with prognosis in uterine cervix cancer. Radiobiology 1973; 106: 649-52. Radiol Oncol 2005; 39(2): 141-6. case report Metastatic thymoma: a case report of an isolated, intra-abdominal metastasis causing asymptomatic spinal cord compression Douglas G. Gold, Robert C. Miller Division of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA Background. Although thymomas are characterized histologically by a benign appearance, they have the potential for aggressive local invasion, and occasionally they metastasize. Case report. We describe a 47-year-old woman who recently presented to our clinic with asymptomatic spinal cord compression due to an intra-abdominal metastasis of a thymoma arising as the first site of metas­tasis 21 years after the primary tumour was resected. Conclusions. For the patient presented here, radiotherapy and surgery were chosen over systemic therapy as the primary treatment modalities at the time of recurrence for two reasons. First, the patient had a single, isolated metastasis that occurred after a 2-decade disease-free interval; thus, preoperative radiotherapy fol­lowed by resection was potentially curative. Second, it was thought, on the basis of the retroperitoneal lo­cation of the recurrent tumour immediately below the diaphragm, that it possibly was not a haemato­genously disseminated metastasis but a local pleural and lymphatic migration. Key words: thymoma; neoplasm metastasis – radiotherapy; spinal cord compression Introduction Thymomas are unusual tumours that typical­ly arise in the anterior mediastinum and are derived from thymic epithelial cells. Al­though the tumours are characterized histo-logically by a benign appearance, they have the potential for aggressive local invasion, Received 15 April 2005 Accepted 22 April 2005 Correspondence to: Robert C. Miller, MD, MSc, Division of Radiation Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; E-mail: miller.robert@mayo.edu ©2005 Association of Radiolog and Oncology and occasionally they metastasize.1 A 47­year-old woman recently presented to our clinic with asymptomatic spinal cord com­pression due to an intra-abdominal metasta­sis of a thymoma arising as the first site of metastasis 21 years after the primary tumour was resected. Case report In March 1983, when the patient was 25 years old, invasive thymoma of the anterior medi­astinum was diagnosed. At her most recent evaluation in 2004, only partial records were available about the evaluation and treatment in 1983. However, according to the existing medical records, the primary tumour, which involved the anterior mediastinum, had been resected piecemeal. She was referred for postoperative external beam radiotherapy be­cause of concern about residual tumour with­in the operative bed. A total radiation dose of 39.6 Gy in 22 fractions was administered to the mediastinum using opposed photon beams delivered by a 10-MV linear accelera­tor. A boost was delivered to a smaller vol­ume within the mediastinum for a total dose in that area of 54.0 Gy in 30 fractions. The maximum spinal cord dose was 40.2 Gy. The patient tolerated radiotherapy well and had no evidence of recurrence or treatment toxicity for more than 20 years. In March 2003, she noted a lower abdominal mass after a year of menorrhagia and sought medical evaluation. She subsequently underwent sim­ple hysterectomy. At the time of hysterecto­my, an omental mass, 18×12×9 cm, was resect-ed along with the uterus. Pathologic evalua­tion of the uterus demonstrated a subserosal, 0.5-cm leiomyoma; no other abnormality was noted. The omental mass was found to be an inflammatory myofibroblastic tumour. Immunohistochemical staining of the omental mass for anaplastic lymphoma kinase and smooth muscle actin was negative. Progressive left hip pain developed in ear­ly 2003. This worsened in 2004, and in October 2004, magnetic resonance imaging (MRI) showed an epidural mass that extend­ed from vertebral body T11 to L1, with com­pression of the left lateral thecal sac. A left paraspinal mass was also present, extending from the T11-12 interspace to L2. The two le­sions were connected at the T12-L1 neural foramen. There were no abnormalities of the vertebral bodies. The intimate relation be­tween the tumour and spinal cord is shown in Figure 1. Subsequent computed tomography (CT) of the chest, abdomen, and pelvis did not show abnormalities of concern other than a soft tissue mass arising in the left retroperi­toneum near the origin of the left psoas mus­cle and contiguous with an epidural mass ex­tending through the left T12 neural foramen. No bony destruction was apparent. The state of the tumour before radiotherapy is shown in Figure 2a. No evidence of local recurrence or new primary tumour was detected in the thorax. A nuclear bone scan did not show any abnormality. An incidental MRI finding was an incompletely imaged T2 hyperintense thy­roid nodule, 1.8×2.2×2.7 cm. A CT-guided needle biopsy was performed in October 2004 at an outside institution and repeated at a different site within the tumour at Mayo Clinic in early November 2004. Both biopsy specimens revealed metastatic thymo-ma. Immunohistochemical stains showed that the tumour contained a mixture of cytokeratin-positive epithelial cells and CD3­positive T cells. CD20 staining showed only a few reactive lymphocytes. Staining for S100 protein was negative. This staining pattern was thought to be consistent with the diagno­sis of metastatic thymoma, presumably relat­ed to the tumour resected from the chest in 1983. The original pathology slides from 1983 were not available for comparison with the metastatic lesion found in 2004. The omental tumour identified in 2003 was compared with the new lesion and the two tumours were his- Figure 2a. Computed tomographic images showing the paraspinal mass before radiotherapy. tologically different. A biopsy specimen from the thyroid lesion demonstrated a benign thy­roid nodule. The patient was in excellent health, with no major symptoms other than occasional mild left hip pain. Her past medical history was unremarkable. A detailed neurologic evaluation did not document a clinical myelopathy. No other neurologic deficits were present except for minimal loss of sen­sation over the left iliac crest in the region where she was experiencing pain. Optimal surgical management of the re­current thymoma would entail an en bloc re­section. However, because of the location of the tumour, its apparent adherence to the spinal cord, and its local invasion of sur­rounding bony and muscular structures, the patient was referred for preoperative radio­therapy. After a medical oncology evaluation, it was thought that chemotherapy was not in­dicated at that time. The patient received 50.4 Gy in 28 frac­tions of external beam radiation delivered with intensity-modulated radiotherapy. The gross target volume was determined from the patient’s MRI, which was fused with a treat-ment-planning CT scan. The clinical target volume was considered the gross tumour vol­ume as demonstrated on MRI plus areas where bone invasion was suspected on the basis of the CT scan. The patient’s previous radiotherapy fields were reconstructed to en- Figure 2b. Computed tomographic images showing the paraspinal mass approximately 4 weeks after ra­diotherapy. sure no overlap between those fields and the current treatment. The patient was carefully counselled about the potential risk of myelopathy from overlap of the two radio­therapy treatments. Intensity-modulated planning priorities were assigned to minimize the dose to the kidneys, followed by the small intestine (Figure 3). The spinal cord was not avoided because of the proximity of the tu­mour to the cord as well as the convex shape of the tumour, which surrounded one-half of the circumference of the spinal cord in some areas. Ninety-nine percent of the planning Figure 3. Isodose distribution from the intensity-mod­ulated radiotherapy plan showing the gross target vol­ume (shaded structure, which indicates macroscopi­cally evident tumor by fusion of the computed tomo­graphic and magnetic resonance imaging data sets) and the 49.5-Gy, 40-Gy, and 20-Gy isodose lines. (The clinical and planning target volumes have been delet­ed for clarity.) target volume, consisting of the clinical target volume plus a 1.0-cm margin, received a dose of 48.5 Gy or greater. The minimal planning target volume dose was 43.2 Gy. The maximal spinal cord dose was 50.9 Gy. Also, 17.6% of the right kidney and 37.3% of the left kidney were treated beyond the normal tissue toler­ance limit of 20 Gy. The patient tolerated the treatment well, without experiencing acute gastrointestinal tract or other toxic effects. Her hip pain re­solved during the final weeks of radiothera­py, suggesting an early response to radiother­apy as the left neural foramen at the T12-L1 level was decompressed. In January 2005, restaging studies were performed preoperatively, including MRI of the thoracic and lumbar spine and CT of the chest and abdomen. MRI demonstrated a marked decrease in the size of the paraspinal mass. CT also showed a decrease in the size of the lesion, with less encroachment on the spinal canal as compared with the imaging studies before radiotherapy (Figure 2b). No evidence of malignant disease was found elsewhere. In February 2005, laminectomy of T11-L1, posterior instrumented fusion of T5-L4, left thoracotomy with en bloc resection of the paraspinal metastasis, and T11-L1 corpec­tomies with titanium cage strut grafting were successfully performed. Pathologic evalua­tion of the resected specimen showed a 5.0×4.0×2.5-cm mass containing extensive fi­brosis and metastatic thymoma. All surgical margins were negative for tumour. Discussion The histologic classification of thymomas, which are derived from thymic epithelial cells, has been debated, and several classifi­cation systems have been proposed. However, it is generally accepted that the clinical degree of invasion of the tumour, not the presence of benign or malignant histolog­ic features, determines prognosis. This obser­vation led to the formulation of the Masaoka staging system, currently the most commonly used staging system.2 Masaoka stage I con­sists of encapsulated tumours. Stage II in­cludes tumours with macroscopic invasion of the surrounding mediastinal tissues or micro­scopic invasion of the capsule. Stage III in­cludes tumours with macroscopic invasion of nearby organs. Stage IVA includes pleural or pericardial dissemination, and stage IVB in­cludes lymphatic or haematogenously dis­seminated metastases.1,2 Surgical resection is the treatment of choice for most thymomas confined to the thoracic cavity, where the success of surgery and adjuvant therapy depends on the extent of resection and stage of disease.3 According to one report, the frequency of recurrence for stage I disease may be less than 5% after com­plete resection, whereas for stages II and III disease, the frequency of recurrence is 7% and 16%, respectively.4 Postoperative radio­therapy is often administered for stages II and III tumours because of the apparent local control and survival benefit reported in retro­spective series.5-7 Preoperative radiotherapy has been used for stage III disease to facilitate total or subtotal resection.8 Our current prac­tice is to consider adjuvant radiotherapy for resected Masaoka stage II tumours that pene­trate the capsule and for resected stage III tu­mours. However the decision depends on several factors, including the potential sites of tumour adherence or invasion, surgical ex­pertise and technique, and the patient’s un­derlying medical condition. Thymomas typically spread by direct inva­sion of nearby organs. Metastases may occur in the thorax as pulmonary nodules, pleural-based implants, diaphragmatic masses, or malignant pericardial or pleural effusions. Extrathoracic metastases are rare but may in­volve the kidney, bone, liver, and brain. Disease may spread directly from the thorax to the abdomen or retroperitoneum, as has been documented for mesotheliomas.1,3,4,9 Chemotherapy may be considered for un­resectable and metastatic thymomas. Single-agent chemotherapy, with various agents, has been studied, with ifosfamide appearing to be a promising agent. Multiagent chemotherapy regimens, with combinations of cisplatin, doxorubicin, cyclophosphamide, and vin­cristine, have produced response rates in ex­cess of 50%. Chemotherapy has also been giv­en neoadjuvantly as part of combined modal­ity therapy involving surgery and radiothera­ py.10-13 For the patient presented here, radiothera­py and surgery were chosen over systemic therapy as the primary treatment modalities at the time of recurrence for two reasons. First, the patient had a single, isolated metas­tasis that occurred after a 2-decade disease-free interval; thus, preoperative radiotherapy followed by resection was potentially cura­tive, whereas systemic therapy would not of­fer the possibility for a durable cure. Second, it was thought, on the basis of the retroperi­toneal location of the recurrent tumour im­mediately below the diaphragm, that it possi­bly was not a haematogenously disseminated metastasis. It was hypothesized that the spread of the tumour from the mediastinum to the retroperitoneum occurred through very slow-growing microscopic tumour deposited in the pleural space before or at the time of surgery in 1983. These microscopic tumour cells eventually migrated through lymphatic channels across the diaphragm, in a manner similar to that described for mesotheliomas. The absence of other identifiable sites of dis­tant metastatic disease lends support to this hypothesis. However, even if the underlying method of spread in this case was from an isolated, blood-borne metastasis rather than through local pleural and lymphatic migra­tion, the treatment strategy would have been the same because of the very long disease-free interval between the initial diagnosis and the development of the metastasis. Postoperatively, this patient did well. Adjuvant systemic therapy will not be admin­istered because of the absence of known residual malignant disease. Close observation with serial history and physical examinations and periodic CT of the chest and abdomen are planned for follow-up. References 1. Thomas CR, Wright CD, Loehrer PJ. Thymoma: state of the art. J Clin Oncol 1999; 17: 2280-9. 2. Masaoka A, Monden Y, Nakahara K, Tanioka T. Follow-up study of thymomas with special refer­ence to their clinical stages. Cancer 1981; 48: 2485­92. 3. Zhu G, He S, Fu X, Jiang G, Liu T. Radiotherapy and prognostic factors for thymoma: a retrospec­tive study of 175 patients. Int J Radiat Oncol Biol Phys 2004; 60: 1113-9. 4. Regnard JF, Magdeleinat P, Dromer C, Dulmet E, de Montpreville V, Levi JF, et al. Prognostic factors and long-term results after thymoma resection: a series of 307 patients. J Thorac Cardiovasc Surg 1996; 112: 376-84. 5. Curran WJ Jr, Kornstein MJ, Brooks JJ, Turrisi AT III. Invasive thymoma: the role of mediastinal irra­diation following complete or incomplete surgical resection. J Clin Oncol 1988; 6: 1722-7. 6. Urgesi A, Monetti U, Rossi G, Ricardi U, Casadio C. Role of radiation therapy in locally advanced thymoma. Radiother Oncol 1990; 19: 273-80. 7. Pollack A, Komaki R, Cox JD, Ro JY, Oswald MJ, Shin DM, et al. Thymoma: treatment and progno­sis. Int J Radiat Oncol Biol Phys 1992; 23: 1037-43. 8. Ohara K, Okumura T, Sugahara S, Akisada M, Yokose T, Ogata T, et al. The role of preoperative radiotherapy for invasive thymoma. Acta Oncol 1990; 29: 425-9. 9. Shin MS, Bailey WC. Computed tomography of in­vasive pleural mesothelioma. J Comput Tomogr 1983; 7: 389-94. 10. Highley MS, Underhill CR, Parnis FX, Karapetis C, Rankin E, Dussek J, et al. Treatment of invasive thymoma with single-agent ifosfamide. J Clin Oncol 1999; 17: 2737-44. 11. Fornasiero A, Daniele O, Ghiotto C, Piazza M, Fiore-Donati L, Calabro F, et al. Chemotherapy for invasive thymoma: a 13-year experience. Cancer 1991; 68: 30-3. 12. Loehrer PJ Sr, Chen M, Kim K, Aisner SC, Einhorn LH, Livingston R, et al. Cisplatin, doxorubicin, and cyclophosphamide plus thoracic radiation therapy for limited-stage unresectable thymoma: an intergroup trial. J Clin Oncol 1997; 15: 3093-9. 13. Shin DM, Walsh GL, Komaki R, Putnam JB, Nesbitt J, Ro JY, et al. A multidisciplinary ap­proach to therapy for unresectable malignant thy-moma. Ann Intern Med 1998; 129: 100-4. Radiol Oncol 2005; 39(2): 147-52. Rapid detection of most frequent Slovenian germ-line mutations in BRCA1 gene using real-time PCR and melting curve analysis Srdjan Novakovic and Vida Stegel Unit of Molecular Biology, Institute of Oncology Ljubljana, Slovenia Background. Detection of inherited mutations in cancer susceptibility genes is of great importance in some types of cancers including the colorectal cancer (mutations of APC gene in familial adenomatous polyposis - FAP, mutations in mismatch repair genes in hereditary nonpolyposis colorectal cancer – HNPCC), malig­nant melanoma (mutations in CDKN2A and CDK4 genes) and breast cancer (mutations in BRCA1 and BR­CA2 genes). Methods. This article presents the technical data for the detection of five mutations in BRCA1 gene in breast cancer patients and their relatives. The mutations - 1806C>T, 300T>G, 300T>A, 310G>A, 5382insC - were determined by the real-time PCR and the melting curve analysis. Results and conclusion. In comparison to direct sequencing, this method proved to be sensitive and rapid enough for the routine daily determination of mutations in DNA isolated from the peripheral blood. Key words: breast neoplasms – genetics; genes, BRCA1; mutation; polymerase chain reaction Introduction General screening for unknown mutations in the large genes such as BRCA1 and BRCA2 is time consuming and expensive. There is a whole range of procedures that should be performed prior to the final confirmation of the mutation. Habitually, the screening is Received 6 April 2005 Accepted 20 April 2005 Correspondence to: Srdjan Novakovic, PhD, Unit of Molecular 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 started by using the methods that provide in­formation about the region of the gene where the mutation is positioned (e.g. protein trun­cation test - PTT, single-strand conformation­al polymorphism analysis - SSCP, denaturing gradient gel electrophoresis - DGGE).1-3 Direct sequencing and determination of spe­cific changes in the nucleotide sequence aims at the final confirmation and identification of mutation. Yet, when the mutation is well determined and precisely described, then the detection can be performed in a less complicated and less expensive manner. One group of these methods comprises the analysis based on the determination of differences in the melting temperatures of perfectly matched base pairs and mutated variants.4-6 This article reports the determination of known BRCA1 muta­tions - 1806C>T, 300T>G, 300T>A, 310G>A, 5382insC using the real time PCR on Light Cycler and melting curve analysis. The sys­tem is programmed to monitor the melting curve analysis of the allele specific fluores­cent resonance energy transfer - FRET probes after the PCR, allowing direct typing of the sample without any further processing. Methods DNA was isolated from the peripheral blood using the DNA blood isolation kit (Quiagen, Hilden, Germany). The primers and probe sets for the detection of specific mutations were de­signed in our laboratory applying the Light Cycler Probe Design Software, Version 1.0, and synthesized by TIB Molbiol (Berlin, Germany). The real-time PCR and melting curve analy­sis at the Light Cycler instrument (Roche Molecular Biochemicals, Mannheim, Ger­many) was applied for the detection of muta­tions. PCR was performed according to the manufacturer's instructions (Light Cycler Fast Start master hybridization probes, Roche Molecular Biochemicals). Briefly, the DNA templates were selectively amplified in the PCR reaction (annealing temperature 52°C, 45 cycles) using specific primers described in Table 1. Beside specific primers, the specific hybridization probes conjugated with LC Red640 (Light Cycler Red 640 fluorescent dye) were added to the mastermix. At the end of PCR reaction, the melting curve analysis was performed through heating the mix to 95°C for 1 min followed by cooling in steps (58°C, 48°C, 40°C, 35°C) to 35°C and repeated gradual heat­ing to 85°C. The data were collected during the gradual heating phase (35°C - 85°C). Results and discussion Several cancers appear to be related to BRCA1 and BRCA2 mutations including breast, ovar­ian, pancreatic, prostate, fallopian tube, la- Table 1. The primers and probes used for the detection of mutations in BRCA1 gene. Mutation Primer and probe names Type and length of nucleotide s equence* 1806C>T BRCA1 F primer – forward (23bp) BRCA1 A primer - reverse (24bp) Senzor probe - senzor–FL (30bp) Anchor probe - LC Red640-anchor–PH (34bp) 300T>G BRCA1in4 F primer - forward (22bp) 300T>A BRCA1in5 B primer - reverse (20bp) C61G Sen G probe - senzor–FL (23bp) C61G Anch probe - LC Red640-anchor–PH (32bp) 310G>A BRCA1in4 F primer - forward (22bp) BRCA1in5 B primer - reverse (20bp) C64Y Sen G probe - senzor–FL (29bp) C64Y Anch probe - LC Red640-anchor–PH (30bp) 5382insC BRCA1in19 F primer - forward (21bp) BRCA1in21 S primer - reverse (22bp) 5382insC Sen probe - senzor–FL (22bp) Ex20 Anchor probe - LC Red640-anchor–PH (28bp) *the sequences of primers and probes are available through E-mail of corresponding author LC - Light Cycler Red 640 fluorescent dye, FL - Fluorescein, PH – phosphate Radiol Oncol 2005; 39(2): 147-52. ryngeal cancer, as well as adult leukemias and lymphomas.7 However, women with germ-line heterozygous mutations in BRCA1 or BRCA2 are primarily at increased risk of developing breast or/and ovarian cancer. The mutations in BRCA1 and BRCA2 predict the likelihood of breast cancer development by the age of 70 years of 45% to 87% and 26% to 84%, respectively. The odds of ovarian cancer for BRCA1 and BRCA2 mutation carriers are 16% to 63% and 10% to 27%, respectively.8 Even though the breast and ovarian cancers related to inherited mutations in cancer sus­ceptibility genes represent a small proportion of all cancers (less than 10%), it is of great im­portance for the clinician to detect the pa­tients who are carrying these mutations. Consequently, the determination of potential risk among the family members of the muta­tion carrier can be estimated and prevention measures can be undertaken. The criteria for the genetic testing of patients and relatives are based on the most common risk factors in hereditary cancer syndromes – early age can­cer onset, presence of the same cancer in multiple relatives, occurrence of multiple pri­mary cancers in one individual, development of an unusual type of cancer (e.g. breast can­cer in male), being a member of a specific eth­nicity.9,10 Considering the facts, that Slovenian population is ethnically relatively closed and that the breast cancer in Slovenia is the most common cancer type affecting women, we started, at the Institute of Onco­logy Ljubljana in 2001, with genetic counsel­ing and testing of individuals from families with multiple histories of breast and ovarian cancer. Laboratory of Medical Genetics - Vrije University Brussels, provided general muta­tion screening of BRCA1 and BRCA2 genes for Slovenian patients. From these results, it was evident that the most frequent mutations in hereditary breast (and ovarian) cancer were the Slovenian founder mutations IVS162A>G in BRCA2 and 1806C>T, 300T>G, 300T>A, 310G>A, 5382insC in BRCA1 gene. Almost 80% (precisely 77%) of all determined muta­tions in Slovenian patients were covered by this mutation profile. With the purpose of simplifying the detection of mutations in BR­CA1 gene, we applied the real-time PCR fol­lowed by melting curve analysis using hy­bridization probes. The primers and probes were designed on the sequences of BRCA1 gene covering the reported mutations ­1806C>T, 300T>G, 300T>A, 310G>A, 5382insC. For each type of mutation, the op­timal conditions were settled and the positive inner control was used. Figure 1. Detection of 1806C>T mutation in BRCA1 gene by real-time PCR and melting curve analysis. DNA was isolated from the blood of a normal person and of a carrier of mutation. A - normal DNA (wild-type); B - positive control (mutant DNA); C - patient’s DNA; wild type peak at 62°C; mutant peak at 58°C. Figure 2. Detection of 300T>G mutation in BRCA1 gene by real-time PCR and melting curve analysis. DNA was isolated from the blood of a normal person and of a carrier of mutation. A - normal DNA (wild-type); B - positive control (mutant DNA); C - patient’s DNA; wild type peak at 58.5°C; mutant peak at 67°C. Figure 3. Detection of 300T>A mutation in BRCA1 gene by real-time PCR and melting curve analysis. DNA was isolated from the blood of a normal person and of a carrier of mutation. A - normal DNA (wild-type); B - positive control (mutant DNA); C - patient’s DNA; wild type peak at 58°C. Heterozygous mutant product for 300T>A mutation did not show any addi­tional peaks. The homozygous (wild-type) PCR product designed for the detection of 1806C>T on BR­CA1 gene showed a single peak at 62°C, whereas the heterozygous products (mutant) showed an additional peak at 58°C (Figure 1). The homozygous (wild type) PCR product designed for the detection of 300T>G on BR­CA1 gene showed a single peak at 58.5°C, whereas the heterozygous products (mutant) showed an additional peak at 67°C (Figure 2). Unfortunately, the heterozygous product for 300T>A mutation did not show any addition- al-time PCR and melting curve analysis. DNA was iso­lated from the blood of a normal person and of a car­rier of mutation. A - normal DNA (wild-type); B - pos­itive control (mutant DNA); C - patient’s DNA; wild type peak at 60.5°C; mutant peak at 54.5°C. al peaks, thus making the mutation unde­tectable by this method (Figure 3). The reason for that was a too small difference (less than 2°C) between the melting temperatures of the wild type and mutated DNA sequence. The homozygous (wild type) PCR product designed for the detection of 310G>A on BR­CA1 gene showed a single peak at 60.5°C, whereas the heterozygous products (mutant) showed an additional peak at 54.5°C (Figure 4). The homozygous (wild type) PCR product designed for the detection of 5386insC on BR­CA1 gene showed a single peak at 62.5°C, whereas the heterozygous products (mutant) showed an additional peak at 67.5°C (Figure 5). The majority of mutations detected with the real-time PCR and melting curve analysis were further subjected to direct sequencing. The number of tested individuals and of mu­tation positive individuals is listed in Table 2. An absolute correlation between the direct se­quencing and the real-time PCR and melting curve analysis was obtained – the real-time PCR and melting curve analysis actually gave no false positive outcomes. The patient’s DNA that was negative for mutations by real-time PCR and melting curve analysis was not subjected to sequencing in all cases, which precludes any conclusions concerning the false negative results of the method. Table 2. Mutations in Slovenian patients detected by real-time PCR and melting curve analysis. Type of Number of Number of No. LC positive/No. mutation tested patients detected mutations direct sequencing positive* 1806C>T 87+90 12 10/10 300 T>G 5 2 2/2 300T>A 5 0 0/2 310G>A 2 1 1/1 5382insC 3 2 2/2 * number of positive samples detected by real-time PCR and melting curve analysis using Light Cycler (LC)/number of samples confirmed to be positive by direct sequencing However, positive misleading results may be obtained because of unknown polymor­phisms or a mutation within the target region affecting hybridization of probes and binding of primers, and consequently, the melting temperature of the product. It should also be mentioned that careful optimization of the re­action for each mutation is necessary before the analysis of the patients' DNA samples is performed in order to achieve an optimal sensitivity and specificity for the method. Especially important is to bear in mind that not only the physical features during the re­action, but also the nucleotide structure in the dimmer (e.g. higher melting temperature of the fragments that have higher percentage of GC) and the length of the dimmer frag­ment (the melting temperature of longer frag­ments is higher) affect the melting tempera­ture. In this study, the PCR was optimized in respect to annealing temperature, concentra­tion of Mg2+, and number of polymerization cycles; the reaction during the melting curve analysis was optimized in respect to the time and temperature differences in the intervals of cooling and heating steps. In view of the present results, it could be concluded that the primers and probes for the detection of 1806C>T, 300T>G, 310G>A and 5382insC mutations in BRCA1 gene were designed successfully. After the optimization, the real-time PCR and melting curve analysis using hybridization probes showed out to be an extremely sensitive method for the detec­tion of known mutations. Even though the designed primers and probes were specific for the mutation 300T>A, the method was not sensitive enough for this type of mutation. However, for the final conclusions about the sensitivity and specificity of the method, a larger number of samples should be included. Prior to this, possible false negative and posi­tive results should be taken in consideration. Acknowledgment The study was supported by the Ministry of Education, Science and Sport of the Republic of Slovenia, grant number J3-3501 and J3­6363. References 1. Roest PAM, Roberts RG, Sugino S, van Omen GJB, den Dunnen JT. Protein truncation test (PTT) for rapid detection of translation-terminating mu­tation. Hum Mol Genet 1993; 2: 1719-21. 2. Hayashi K, Wenz HM, Inazuka M, Tahira T, Sasaki T, Atha DH. SSCP analysis of point muta­tions by multicolor capillary electrophoresis. Methods Mol Biol 2001; 163: 109-26. 3. Myer RM, Lumelsky N, Lerman LS, Maniatis T. Detection of single base substitution in total ge­nomic DNA. Nature 1985; 313: 495-8. 4. Foy CA, Parkers HC. Emerging homogeneous DNA-based technologies in the clinical laboratory. Clin Chem 2001; 47: 990-1000. 5. Wilhelm J, Pingout A. Real-time polymerase chain reaction. Chembiochem 2003; 4: 1120-8 6. Gerard P, Pindolia MS, Worsham MJ. A rapid and sensitive approach to mutation detection using re-al-time polymerase chain reaction and melting curve analyses, using BRCA1 as example. Mol Diagn 1999; 4: 241-6. 7. DeVita TV, Hellman S, Rosenberg AS, editors. Principles and practice of Oncology 7th edition. Philadelphia: Lippincott Williams & Wilkins; 2005. 8. King MC, Marks JH, Mandell JB. Breast and ovari­an cancer risks due to inherited mutations in BR­CA1 and BRCA2. Science 2003; 302: 643-6. 9. Loman N, Johannsson O, Kristoffersson U, Olsson H, Borg A. Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast can­cer. J Natl Cancer Inst 2001; 93: 1215-23. 10. Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M, Timmerman MM, Brody LC, Tucker MA. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 1997; 336: 1401-8. Radiol Oncol 2005; 39(2): 153-8. Cytogenetic analysis of peripheral blood lymphocytes after arteriography (exposure to x-rays and contrast medium) Ljubomira Popova1, Valeria Hadjidekova1, Georgy Karadjov1, Savina Agova2, Danail Traskov3, Vassil Hadjidekov4 1National Center of Radiobiology and Radiation Protection, Sofia 1756, Bulgaria 2Department of Medical Genetics, Medical University, Sofia 1431, Bulgaria 3Coordinated Science Laboratory, University of Illinois, IL 61801, USA 4University Hospital Alexandrovska, Department of Radiology, Sofia 1431, Bulgaria Backgrounds. The purpose of our study is to investigate the cytogenetic analysis findings in peripheral blood lymphocytes of 29 patients who had undergone diagnostic radiography. Methods. Peripheral blood samples were taken from 22 patients submitted to renal arteriography and 7 pa­tients submitted to cerebral arteriography (17 male and 12 female, aged between 13-68 years). Cytogenetic analyses of peripheral lymphocytes were performed before the procedure, immediately after and 24 hours later. The entrance skin dose obtained during the whole diagnostic X-ray exposure was measured by ther­moluminescent dosimeters and varied between 0.03-0.30 Gy. Both low and high osmolarity contrast media were used. Chromosomal aberrations and micronuclei frequency were used as biomarkers of genotoxicity. Results. The estimated frequency of chromosomal aberrations and micronuclei in the peripheral blood lym­phocytes of patients after arteriography examination was significantly higher than the level before the di­agnostic exposure. The mean frequency of cells with chromosomal aberrations was nearly double after ex­amination and proved to be constant in the analysis after 24 hours. Conclusions. Radiological diagnostic procedures involving iodinated contrast media as arteriography may cause a significant increase in cytogenetic damage in peripheral blood lymphocytes. Key words: angiography – adverse effects; lymphocytes; chromosome aberrations; micronucleus tests Introduction Iodinated contrast media are largely needed in diagnostic radiology. In angiography and in- Received 17 October 2004 Accepted 11 November 2004 Correspondence to: Vassil Hadjidekov, MD, PhD, University Hospital Alexandrovska, Department of Radiology, Sofia 1431, Bulgaria; Phone: +359 888940801; E-mail: hadjidekov@yahoo.com terventional radiology, especially high diag­nostic doses are obtained - relatively long flu-oroscopy time plus serial radiography (several frames per second). Cytogenetic analysis find­ings of diagnostic doses of ×-rays and contrast media were investigated in experimental stud­ies on cell cultures in vitro.1,2 Parallel clinical investigations showed an increased genotoxi-city in the peripheral blood lymphocytes of the patients undergoing angiography.2-4 The results indicate that some contrast media can induce genotoxic effects alone, and when ap­plied in combination with X-rays, can in­crease, even double the radiation induced ge­netic damage. Radiological contrast media do not only increase the absorbed dose, but may also enhance the sensitivity of blood cells to the radiation induced cell damage.2-4 Cytogenetic analysis results are of great con­cern as they are involved in the mechanism of cancer genesis. It is generally accepted that chromosomal mutations are causal events in the development of neoplasia and it has been postulated that an increased cytogenetic dam­age may be an indication of an enhanced can­cer risk.5 The aim of the present study is to investigate the effects of contrast media and diagnostic ra­diation on cytogenesis of the peripheral blood lymphocytes of the patients undergoing arteri­ography. Chromosomal aberrations (CA) and micronuclei (MN) in the peripheral blood lym­phocytes are used as cytogenetic biomarkers. Methods Subjects investigated Twenty-nine patients with limited history of previous medical radiation exposures and un­dergoing angiography examination [22 renal arteriographies (RAr) and 7 cerebral arteri­ographies (CAr)] were selected for this study. In the selected group of patients, 17 were males and 12 females, ranging in age from 13 to 68 years (average age 41.6 years). A Philips Medical Systems angiographic equipment »PolyDiagnost C« was used with DSI viewing console and Easy Vision worksta­tion. The unit was operated at 60 - 90 kV range and up to 250 mA with a filtration of 2 mm Al. Blood samples were collected in sterile va­cationers with Li-heparin. Three samples were taken: (1) before angiographic run, (2) immediately after, and (3) 24 hours after the examination. The radiation exposure assess­ment was made by thermoluminescent dosimeters. The radiation exposure varied from 0.03 to 0.30 Gy (Table 1) and was esti­mated as skin entrance dose. The type and the volume of contrast material used are giv­en in Table 1. For all subjects, a questionnaire was completed to assess their general physi­cal condition, life style, previous ×-ray exami­nations, diets, use of medications. Cytogenetic endpoints Lymphocyte cultures were prepared in 5 ml RPMI-1640 medium supplemented with 10% fetal calf serum and phytochaemaglutinin P. For chromosomal aberration analysis, Colchicine 0.5 mkg/ml was added to the cul­tures 48 hours after incubation. The cells were harvested two hours later.6 Twenty-eight subjects were analyzed for chromoso­mal aberrations (CA). The cells scored per sample for structural chromosomal aberra­tions after staining with 10% Giemsa ranged from 100 to 400. For cytokinesis blocked micronucleus test, Cytochalasin B was added 44 hours after in­cubation. The cells were harvested after 72 hours (7). Ten patients were analyzed for the presence of micronuclei (MN) in binucleated lymphocytes immediately before (1) and after (2) radiodiagnostic examination. Two thou­sand cells per each sample were analyzed. Ethics Informed consent was obtained from all in­vestigated subjects after they had received an explanation of the study. The reports were re­viewed and approved by the local ethics com­mittee. The volume of the samples (1) and (2) is the blood collected during the air trapping prevention and catheters flushing. Statistical analysis Student t- test and . 2- test was applied before and after arteriography of patients to analyze statistical significance of the difference be­tween the frequencies of chromosomal aberra­tions and micronuclei formation, respectively. Results A total of 29 subjects submitted to angiogra­phy were investigated cytogenetically. Chro­mosomal aberrations were analyzed in 28 of them, and in 10 subjects, micronuclei forma­tion in binucleated lymphocytes was investi­gated (Table 2). The frequency of chromosomal aberra­tions was increased in most of the patients immediately after the examination and re­mained constant at the sampling after 24 hours (Table 2). Dicentric chromosomes, which are the most sensitive indicators of ra­diation exposure, were found in 7 cases. It must be noted that, despite selection, some of the patients underwent some kind of radiodi- Table 1. Characteristics of the investigated patients undergoing arteriography No Case Age Sex Smoker Type* Contrast Total Entrance Ro-exam. Sampling of agent volume skin dose in last time** examination (mg J/ml) (ml) (Gy) 1 year CA MN 1. GI 28 M yes CAr iodixanol 320 80 Head CT 1; 2 1; 2 2. KG 45 F CAr iodixanol 320 80 Head CT 1; 2 1; 2 3. DG 56 F no CAr iopromide 300 50 Head CT 1; 2 1; 2 4. RF 44 F RAr iopromide 370 40 IVU 1; 2 1; 2 5. DS 39 M yes RAr iohexol 350 40 no 1; 2 1; 2 6. SM 49 M yes CAr iohexol 350 50 Head CT 1; 2 1; 2 7. DK 36 M yes CAr iohexol 350 50 Head CT 1; 2 1; 2 8. ED64 F no CAr iohexol 350 50 Head CT 1; 2 9. MP 50 M CAr iopromide 300 80 Head CT 1; 2 1; 2 10. PD35 M yes RAr diatrizoate 370 58 0,09 IVU 1; 2; 3 11. II 65 F no RAr diatrizoate 370 52 0,08 Abdominal CT 1; 2; 3 12. EL 60 F no RAr ioxaglate 320 50 0.20 IVU 1; 2; 3 13. PX 42 M RAr diatrizoate 370 46 no 1; 2; 3 14. HI 33 M no RAr diatrizoate 370 46 0,20 no 1; 2; 3 15. SV 13 F no RAr diatrizoate 370 48 0,19 IVU 1; 2; 3 16. HS 17 F no RAr diatrizoate 370 18 0,05 no 1; 2; 3 17. ML 33 F no RAr diatrizoate 370 50 0,15 no 1; 2; 3 18. VI 18 M no RAr diatrizoate 370 60 0.3 IVU 1; 2; 3 19. TG 38 F no RAr diatrizoate 370 40 0.03 no 1; 3 20. PP 58 M yes RAr diatrizoate 370 30 0.11 RA 1; 2; 3 21. AD29 M no RAr diatrizoate 370 36 0.15 no 1; 2; 3 22. VY 68 M no RAr iopromide 300 50 0.19 no 1; 2 1; 2 23. DZ 46 M yes RAr diatrizoate 370 50 no 1; 2; 3 24. SD44 F RAr diatrizoate 370 35 0.26 IVU 1; 2 25. ID21 M yes RAr diatrizoate 370 40 0.08 no 2; 3 26. ME 68 F RAr diatrizoate 370 14 Abdominal 1; 2 CT; IVU 27. GV 64 M RAr diatrizoate 370 45 1; 2 28. HP 52 M RAr diatrizoate 370 45 1; 2 29. TZ 34 M no RAr iopromide 300 50 0.03 no 1; 2 * CAr - Cerebral arteriography, RAr - Renal arteriography; **1 - before arteriography, 2 - after arteriography, 3 - 24 hours after arteriography Radiol Oncol 2005; 39(2): 153-8. Table 2. Frequency of chromosomal aberrations (CA) and micronuclei (MN) in the peripheral blood lymphocyte of the patients undergoing to arteriography Chromosomal aberrations, % No Case Sampling CA, No Cells Total MN, ? Cells Total time* scored with Chromosome Chromatide No of scored with No of cells CA, % Fragments Dicentrics Fragments CA, % cells MN, %o MN,% 1.GI 1. 200 2 1 0 1 2 2000 16.00 19.5 2. 250 2,8 2,4 0 0,4 2,8 2000 24.00 27.00 2.KG 1. 200 1 1 0 0 1 20008.008.00 2. 200 1 1 0 0 1 2000 13.0015.00 3. DG 1. 200 1 0,5 0 0,5 1 2000 14.50 17.00 2. 200 0,5 0,5 0 0 0,5 2000 14.00 15.50 4. RF 1. 200 0.5 0 0 0,5 0,5 2000 7.00 7.00 2. 200 1 1 0 0 1 20009.009.50 5.DS 1. 200 1 0 0 1 1 20007.007.00 2. 200 2 1,5 0 0,5 2 2000 5.50 6.00 6. SM 1. 200 1,5 1 0 0,5 1,5 2000 7.00 7.00 2. 200 1,5 1 0 0,5 1,5 2000 11.50 11.50 7. DK 1. 200 1 0,5 0 0,5 1 2000 5.00 5.00 2. 200 1,5 0,5 0,5 0,5 1,5 2000 8.00 10.00 8.ED1.2001 0 0 1 1 2. 2000,5 0 0 0,5 0,5 9. MP 1. 200 0,5 0 0 0,5 0,5 2000 7.00 7.00 2. 200 0,5 0,5 0 0 0,5 2000 10.00 11.5 10. PD1. 200 4.5 3 0.5 1 4.5 2.2003 1.5 0 1.5 3 3.1005 2 1 25 11.II 1. 2003 3 0 0.5 3.5 2. 400 6 4.25 0.25 1.75 6.25 3. 2004.5 6 0.5 0 6.5 12.EL 1. 2002 1 0 1 2 2.2003 1.5 0 1.5 3 3.1003 2 0 13 13.PX 1. 1001 0 0 1 1 2. 400 3.25 1.75 0 1.5 3.25 3. 2003.5 2.5 0 1 3.5 14.HI 1. 200 2.5 2 0 0.5 2.5 2.2003 2 0 13 3.2005 3.5 0 1.5 5 15.SV 1. 1001 1 0 0 1 2. 300 2.3 0.7 0 1.6 2.3 3.2004 1 0 34 16.HS 1. 200 1.5 1 0 0.5 1.5 2.4004 1.5 0.5 2 4 3. 2003.5 3 0 0.5 3.5 17.ML 1. 2001 1 0 0 1 2. 2005.5 4.5 0 1 5.5 3.2002 2 0 02 18.VI 1. 200 1.5 0.5 0 1 1.5 2.2002 1.5 0 0.5 2 3.2003 1.5 0.5 1 3 19.TG 1. 200 1.5 1 0 0.5 1.5 3.2002 1 0 12 20.PP 1. 2001 0.5 0 0.5 1 2. 2001.5 1 0 0.5 1.5 3. 2003.5 2.5 0 1 3.5 No Case Sampling CA, No Cells Total MN, ? Cells Total time* scored with Chromosome Chromatide No of scored with No of cells CA, % Fragments Dicentrics Fragments CA, % cells MN, %o MN,% 21. AD1. 200 0.5 0.5 0 0 0.5 2. 200 1 0.5 0 0.5 1 3. 200 0.5 0.5 0 0 0.5 22. VY 1. 200 1.5 1 0 0.5 1.5 2000 9.5 13.5 2. 400 3.75 3.25 0 2.5 5.75 2000 12.5 15.5 23. DZ 1. 100 0 0 0 0 0 2. 200 3.5 1.5 0 2 3.5 3. 100 3 2 0 1 3 24. SD1. 100 5 3 0 2 5 2. 100 4 2 0 2 4 25. ID2. 200 3.5 2 0 1.5 3.5 3. 200 6.5 3.5 1 2.5 7 26.ME 1. 2003 1.5 0.5 1 3 2. 300 4.7 2.7 0.3 1.7 4.7 27.GV 1. 2002 1 0 1 2 2.2002 1.5 0 0.5 2 28.HP 1. 2002 0.5 0 1.5 2 2. 2001.5 1 0 0.5 1.5 29. TZ 1. 2000 14 15 2. 2000 17.5 17.5 *1 – before arteriography, 2 – after arteriography, 3 - 24 hours after arteriography agnostic examination within the year before entering the study (Table 1). The mean frequency of cells carrying chro­mosomal aberrations in the group of 28 in­vestigated patients was 1.62% ± 0.18 before angiography, and 2.77% ± 0.21 immediately after diagnostic examination (Figure 1). The difference was statistically significant (t = 3.21; PZZZ0.01). The frequency of cells with aberrations was estimated 24 hours after the diagnostic exposure only in 14 subjects and was found to be 3.61 % ± 0.39. The frequency score for the same subjects immediately after angiography was 3.39 % ± 0.32 and did not differ significantly in the analysis after 24 hours (PVVV0.05). In the group of patients submitted to renal arteriography, the fre­quency of cells with chromosomal aberra­tions immediately before and after the expo­sure was 1.81% ± 0.22, and 3.22% ± 0.25, re­spectively (Table 2), (PZZZ0.01). No increase in the frequency of chromosomal aberrations was observed in the patients who has under­gone cerebral arteriography (PVVV0.05). The yield of micronuclei also increased sig­nificantly after angiography (Table 2). The frequency varied from 5‰to 16‰in subjects before, and from 5.5‰ to 24‰ in different subjects immediately after the examination. The mean values of micronuclei in peripheral lymphocytes of the investigated subjects was 9.5C ± 0.69 before, and 12.5 ± 0.80 after the examination (Figure2). The difference was statistically significant (. 2 = 7.85; PZZZ0.01). Discussion In this study, we found a higher frequency of chromosomal aberrations and micronuclei in the group of patients exposed to the diagnos­tic x-ray with the application of contrast me­dia during angiography compared to their control values before the exposure. The dif­ference was statistically significant for both cytogenetic biomarkers used: chromosomal aberrations (PZZZ0.01) and micronuclei for­mation (PZZZ0.01). Micronuclei arose in the cytoplasm of binucleated cells as a result of CA induction7 and they were proved to be a sensitive bioindicator of genotoxic exposure. The use of contrast agent in radiodiagnostic arteriography aimed to increase the absorp­tion of X-rays in blood vessels. This was due to the iodine atom included and resulting ef­fect of high photoelectric absorption. As a consequence, the cells in the vicinity of the contrast agent might have absorbed larger ra­diation dose and might have been exposed to greater cytotoxic effects.4 This could explain the observed significant genotoxic damage in the peripheral blood lymphocytes of the in­vestigated patients in our study. Previous in vitro studies found that some contrast agents might possess genotoxic properties by themselves1 and might have a potential to increase the genotoxicity of X-rays as well.2,4 Previous studies also proved that certain contrast media could also pene­trate the epithelial cells through a transcellu­lar mechanism.8,9 In conclusion, there is a significant in­crease in the frequency of chromosome dam­age in the peripheral blood lymphocytes of the subjects undergoing diagnostic arteriography. These results suggest the need for studying the radiosensitizing property of the contrast media to reduce the patient dose without com­promising the image quality. Further in vitro studies are needed to elucidate the mecha­nism of the combined genotoxic effects of io­dinated contrast agents and radiation. References 1. Parvez Z, Kormano M, Satokari K, Moncada R, Eklund R. Induction of mitotic micronuclei by X-ray contrast media in human peripheral lympho­cytes. Mutation Res 1987; 188: 233-9. 2. Hadjidekova V, Bulanova M, Hadjidekov V. Cytogenetic effects of uropoline and diagnostic dose radiation on human lymphocytes. Studia Bioph 1991; 140: 51-6. 3. Cohran ST, Norman A. Induction of micronuclei in lymphocytes of patients undergoing excretory urog­raphy with ioversol. Invest Radiol 1994; 29: 210-2. 4. Norman A, Cochran S, Sayre J. Meta-analysis of increases in micronuclei in peripheral blood lym­phocytes after angiography or excretory urogra­phy. Radiation Res 2001; 155: 740-3. 5. Hagmar L, Bonassi S, Stromberg U, Brogger A, Knudsen L, Norppa H, et al and the European Study Group on Cytogenetic Biomarkers and Health. Chromosomal aberrations in lymphocytes predict human cancer: a report from the European Study Group on cytogenetic biomarkers and health. Cancer Res 1998; 58: 4117-21. 6. Evans HJ. Cytological methods for detecting chemical mutagenes. In: Hollaender A, editor. Chemical mutagenes, principles and methods for their detection. New York: Plenum; 1976. p.1-29. 7. Fenech M, Moorley A. The effect of donor age on spontaneous and induced micronuclei. Mutation Res 1985; 148: 99-105. 8. Andersen R, Tvedt K, Nordby A, Laerum F. Contrast medium concentration in epithelial mu-cosal cells after colonic instillation of Iodixanol. Academic Radiol 2002; 9: 379-85. 9. Rencken I, Sola A, Al-Ali F. Necrotizing enterocol­itis: diagnosis with CT examination of urine after enteral administration of iodinated water-soluble contrast material. Radiology 1997; 205: 87-90. Radio/ Oncol 2005; 39(2): 91-4. Kronicno neishemicno uvihanje tankega crevesa samega vase in v debelo crevo Roic G, Vrtar Z, Posaric V, Boric I, Cigit I Izhodišca. Kronicno uvihanje (intususcepcija) dela crevesa samega vase ali v sosednjo crevesno vijugo traja 14 ali vec dni. V clanku prikazujemo takšen redek primer pri bolnici z neakutno bolecino v trebuhu. Prikaz primera. Opisujemo 14-letno bolnico, ki je imela en mesec krcevite bolecine v presledkih v spodnjem delu trebuha in so bile odvisne od hranjenja. Naredili smo rentgensko slikanje tre­buha, nato pa še ultrazvocno in CT preiskavo trebuha, ki sta nam omogocili diagnozo. Bolnico smo operirali. Ob laparatomiji smo ugotovili uvihanje tankega crevesa samega vase in v debelo crevo. Uvihanje je bilo dolgo 70 cm, prevladovalo je uvihanje Meckelovega divertikla. Zakljucki. Neznacilna klinicna slika kronicnega uvihanja crevesa veckrat onemogoca takojšnjo tocno diagnozo in zato tudi zakasnelo ali neustrezno ukrepanje. Ultrazvok in CT trebuha sta se ponovno pokazali kot najucinkovitejši in najkoristnejši predoperativni preiskavi. Ker je lahko ob uvihanju crevesa prisotna tudi druga lezija, je pri odraslih in pri mladostnikih vedno potrebna operacija. Radio/ Oncol 2005; 39(2): 95-9. Osteosarkom maksile Sayin B, Yildirim N, Vural M, Dede D Izhodišca. Maksilofacialni sarkomi so redki tumorji, še redkejši pa so osteosarkomi celjusti. V nasprotju z osteosarkomi dolgih kosti se maksilofacialni pojavljajo predvsem v 3. in 4. desetletju življenja. Prikaz primera. Opisujemo 18-letno bolnico, ki smo ji histološko potrdili osteoblasticni os­teosarkom maksile po predhodni preiskavi z racunalniško tomografijo (CT). Ceprav smo bolni­co radikalno operirali in nato adjuvantno zdravili s kemoradioterapijo, smo cez dve leti na obrazu ugotovili obsežno lokalno ponovitev bolezni. Zakljucki. Radiografska ocena osteosarkoma maksile je pomembna preiskava -zlasti CT -saj omogoca ob diagnozi nacrtovanje radikalne operacije. Radio/ Oncol 2005; 39(2): 159-66. Slovenian abstracts Radio/ Oncol 2005; 39(2): 101-14. Vecrezna racunalniška tomografija pljucne embolije Bešlic Š, Dalagija F, Durovic V Izhodišca. Namen raziskave je bil ugotoviti, kakšen je prispevek veclistne racunalniške tomo­grafije (MSCT) pri diagnosticiranju pljucne embolije (PE) in kakšne spremembe smo našli pri naših bolnikih. Metode. V obdobju enega in pol leta smo PE ugotovili pri 25 bolnikih (15 moških in 10 žensk). Povprecna starost bolnikov je bila 54,4 let (25 -74). Preiskave smo naredili s »Somatom Volume Zoom« Siemensovo CT napravo, ki je imela 4 detektorje, kolimator 4 x 2,5 mm in s katero smo naredili retrospektivni EKG ter rekonstruirali reze na razdaljo 0,8 mm. Aplicirali smo 130 ml kontrastnega sredstva v raztopini s hitrostjo 3,5 ml/s in z zakasnitvenim casom 22 sekund. Rezultati. Med preiskavo smo ugotovili embolizme v glavnih vejah pulmonarne arterije pri 14 (56%) bolnikih, v desni veji pri 10 (40%) in v levi veji pri 4 (16%), bilateralne pulmonarne em­bolisme pa smo videli pri 11 (44%) bolnikih. Subsegmentalne pljucne embolizme smo diagnos­ticirali pri pri 8 (32%). Pljucni infarkt smo ugotovili pri 12 (48%) bolnikih in je v 11 (44%) primer­ih povzrocil razširitev istostranske pljucne arterije, redistribucijo cirkulacije in razširitev vej pulmonarne arterije pa smo v infarktnem podrocju pa smo opazili pri 9 (36%) bolnikih. Ojacanje pljucnega parenhima s kontrastom smo opazili pri 10 (40%), bolnikih, podrocja oslabljenja pa pri 15 (60%). Krvavitve smo opazili pri 21 (84%) bolnikih, mrežasto pljucno risbo pri 11 (44%), moza­icno pa pri 3 (12%). Trombe v levem in desnem atriju smo videli samo pri 2 (8%) primerih, perikardialno krvavitev pri 1 (4%), mediastinalne bezgavke pri 1(4%), nenadno prekinitev per­iferne veje z infarktom apeksa pri pri 1 (4%) ter hemoptize pri 1 (4%) primeru. Ob globoki vens­ki trombozi smo ugotavljali kot vzrok embolizmov še okvaro delovanja srca pri 7 (28%) bolnikih in maligno obolenje pri 3 (12%). Zakljucki. MSCT je odlicna neinvazivna metoda za prikazovanje trombov v pulmonalni arteriji. Pri naših bolnikih smo najpogosteje našli embolizme v desni veji pulmonalne arterije. Razlicne spremembe ob pljucnih embolizmih lahko vidimo samo z MSCT, tako to preiskavo vedno pogosteje izvajamo ob sumu na pljucno embolijo. Radio/ Oncol 2005; 39(2): 115-21. Slovenske izkušnje pri obravnavi bolnikov s pljucnim rakom, njihove znacilnosti in preživetje Debevec L, Debeljak A, Eržen J , Kovac V, Kern I Izhodišca. Namen raziskave je bil ugotoviti znacilnosti bolnikov s pljucnim rakom, ki so bili di­agnosticirani na Klinicnem oddelku za pljucne bolezni in alergijo Golnik v letu 1996. Prav tako smo želeli ugotoviti, kolikšna je bila razlika med izbranim in dejanskim zdravljenjem ter kakšno je bilo preživetje bolnikov. Metode. Retrospektivno smo analizirali dokumentacijo 345 bolnikov, starih od 37 do 90 let (me­diana 65), 285 moških in 60 žensk. Telesna zmogljivost (Karnofsky): VVV 80 pri 171 bolnikih, 60-80 pri 130 in ZZZ60 pri 44 bolnikih. Tumor smo mikroskopsko potrdili pri 97% bolnikov, z bronhoskopijo pri 281, s transtorakalno igelno biopsijo pri 23, z biopsijo perifernih bezgavk pri 12, s citološko preiskavo sputuma pri 7, s citološko preiskavo plevralnega izliva pri 4, z biopsijo oddaljenih zasevkov pri 2, z mediastinoskopijo pri 1 in z obdukcijo pri 4 bolnikih. Histološko in/ali citološko smo dokazali: pri 131 bolnikih epidermoidni, pri 86 žlezni, pri 63 velikocelicni, pri 51 drobnocelicni, pri 1 nedrobnocelicni in pri 2 bolnikih neopredeljeni karcinom. Klinicni stadij pri nedrobnocelicnem raku je bil v 63 primerih stadij I, v 32 stadij II, v 48 stadij IIIA, v 59 stadij IIIB, v 77 stadij IV, v 2 primerih pa stadija ni bilo mogoce dolociti. Pri bolnikih z drobno­celicnim rakom smo ugotovili v 24 primerih omejeno obliko bolezni, v 27 pa razširjeno bolezen. Rezultati. Dejansko onkološko zdravljenje je bilo drugacno kot izbrano zdravljenje pri 11 % bol­nikov. Primarno smo z obsevanjem zdravili 102 (30%) bolnika, z operacijo 77 (23%), s kemoter­apijo 47 (14%) ter s podpornim zdravljenjem 111 (33%) bolnikov. Pri operiranih bolnikih je bil klinicni stadij pravilno dolocen pri 46% bolnikov, prenizko ocenjen pri 44% ter previsoko ocen­jen pri 10% bolnikov. Petletno preživetje vseh bolnikov je bilo 7,8% (mediana 6,2 meseca), petletno preživetje operativno zdravljenih bolnikov pa 41,9% (mediana 33 mesecev). Srednje preživetje obsevanih bolnikov je bilo 5,7 meseca, bolnikov zdravljenih samo podporno pa 2,5 mesecev. Preživetje je bilo statisticno znacilno odvisno od telesne zmogljivosti in stadija bolezni. Sklep. Izbrano onkološko zdravljenje smo dejansko izvedli pri 89% bolnikov. S kemoterapijo smo zdravili majhen odstotek bolnikov z nedrobnocelicnim rakom. Pet let je preživelo samo 26 bolnikov zdravljenih z operacijo in eden, ki je bil zdravljen le podporno, kar potrjuje, da je kirurška odstranitev najuspešnejši nacin zdravljenja pljucnega raka. Radio/ Oncol 2005; 39(2): 123-31. Kirurško zdravljenje malignega plevralnega mezotelioma. Izkušnje interdisciplinarne obravnave v Sloveniji Eržen J, Vidmar S, Sok M, Debeljak A, Kecelj P, Kovac V, Stanovnik M, Rott T, Kern I Izhodišca. Namen raziskave je bil ugotoviti operacijske zaplete, pooperacijsko smrtnost, vrsto in nacine dopolnilnega zdravljenja, potek bolezni in preživetje pri bolnikih, pri katerih je bila nare­jena ekstraplevralna pnevmonektomija (EPP) ali plevrektomija zaradi malignega plevralnega mezotelioma (MPM). Metode. V letih od 2000 do 2003 je bilo 18 bolnikov z MPM napotenih na Klincni oddelek za torakalno kirurgijo Klinicnega centra v Ljubljani. Operirali smo 17 bolnikov in pri pri dveh naredili samo eksplorativno torakotomijo, preostalih 15 pa smo operirali z namenom ozdravitve. Pri 5 ženskah in 9 moških (starih od 52 do 68 let) smo naredili EPP, pri enem pa plevrektomijo. Osem bolnikov je po operaciji dobivalo cisplatin 100 mg/m2 + mitomicin C 6-10 mg/m2 (5 bol­nikov) ali gemcitabin 1000 mg/m2(3 bolniki) in imelo obsevanje hemitoraksa od 24 Gy do 58 Gy (KT+RT); 3 niso bili dodatno zdravljeni; 3 so prejeli le citostatike brez obsevanja (KT) od tega sta 2 bolnika dobila cisplatin 100 mg/m2 + mitomicin C 6-10 mg/m2 , eden pa cisplatin 100 mg/m2 in gemcitabin v podaljšani infuziji (250 mg/m2 1. in 8. dan); en bolnik je bil le obsevan (54 Gy). Rezultati. V zgodnjem pooperacijskem obdobju ni nihce umrl, popoperativnih zapletov pa je bi­lo 42%. V srednjem opazovalnem obdobju 40 mesecev (28-64) smo pri 9 od 15 (60%) bolnikih ugotovili ponovitev bolezni, 8 od 15 (53,3%) bolnikov je umrlo, vsi zaradi lokalne ponovitve tu­morja. Med tremi bolniki, ki niso bili dodatno onkološko zdravljeni, je eden (s stadijem TlbN0M0) živ brez znakov bolezni 46 mesecev po operaciji, pri drugi bolnici (stadij T2N0M0) se je bolezen ponovila v abdomnu ter je bila zdravljena s KT in operacijo in je živa 31 mesecev po prvi operaciji, tretji bolnik (stadij TlbN0M0) pa je umrl 2 meseca po operaciji zaradi lokalnega napredovanja bolezni. Iz skupine KT+RT je umrlo 6 od 8 bolnikov; bolnika s stadijem TlaN0M0 in TlbN0M0 9 mesecev po operaciji, 2 bolnika s stadijem T2N0M0 4 in 23 mesecev po operaci­ji, bolnik s stadijem T3N0M0 11 mesecev in bolnik s stadijem T3N2M0 7 mesecev po operaciji. Dva bolnika sta še živa (s stadijem TlbN0M0 in T2N0M0) 43 in 28 mesecev po operaciji. V KT skupini je eden od treh bolnikov (stadij T2N0M0) umrl 6 mesecev po operaciji, dva (s stadijem T2N0M0 in T3N0M0) pa sta še živa 43 in 20 mesecev po operaciji. Bolnica, ki je bila samo obse­vana, je živa 50 mesecev po operaciji. Srednje preživetje vseh operiranih bolnikov je bilo 20 mesecev, enoletno preživetje je bilo 53,3% in dvoletno 46,7%. Zakljucki. Radikalna kirurška odstranitev tumorske mase pri MPM je indicirana pri izbranih bolnikih. Operacijo je mogoce narediti varno z majhno pooperacijsko smrtnostjo in brez hudih zapletov. Število naših bolnikov je bilo premajhno in dopolnilno zdravljenje je bilo zelo razlicno, da bi lahko sklepali o prednosti dolocenega nacina zdravljenja. Potrebne bodo nadaljnje ran­domizirane študije in uvedba smernic za izbiro optimalnega zdravljenja pri posameznem bol­niku. Radio/ Oncol 2005; 39(2): 133-40. Zdravljenje anemije z epoetinom alfa pri bolnikih z rakom danke Velenik V, Oblak I, Kodre V Izhodišca. Anemija, ki povzroca zmanjšanje funkcionalne zmogljivosti in kakovosti bolnikove­ ga življenja, je pogosto spremljevalka raka. V klinicni raziskavi smo želeli ugotoviti, ali lahko z epoetinom alfa preprecimo padec in vzdržujemo zadovoljive vrednosti hemoglobina (Hb) pri bolnikih s karcinomom danke, ki jih po operaciji zdravimo z radiokemoterapijo (RT-KT). Sledili smo tudi bolnikove potrebe po transfuziji in varnost epoetina alfa. Metode. V raziskavo smo vkljucili 60 bolnikov po radikalni operaciji raka danke. V skupini A je bilo 39 bolnikov s koncentracijo Hb AAA 13 gldl ob pricetku pooperativne RT-KT, v skupini B pa 17 bolnikov s koncentracijo Hb VVV 13 g/dl ob pricetku pooperativnega zdravljenja in pri ka­terih je koncentracija Hb padla pod 12 gldl v casu KT-RT. Bolniki so prejemali epoetin alfa v odmerku 10.000 IE subkutano trikrat na teden. Ocenjevali smo naslednje parametre: (1) znacil­nost gibanja Hb med terapijo z epoetinom alfa in KT-RT, (2) delež bolnikov, ki so potrebovali transfuzijo in (3) delež bolnikov, pri katerih smo opazili neželene ucinke zdravljenja z epoetinom alfa. Rezultati. Statisticno smo obdelali 56/60 (93%) protokolov. Pri vseh bolnikih v skupini A je bilo opaziti statisticno pomemben porast (pZZZ0.001) Hb že po štirih tednih zdravljenja z epoetinom alfa (povprecen dvig Hb 1,97 I 0,91 gldl). Kljub nihanju koncentracije Hb je bila ta ves cas sta­tisticno pomembno višja kot ob zacetku raziskave (p=0,0017). V skupini B je bilo opaziti v prvih tednih spremljanja postopen padec koncentracije Hb, ki je dosegla v tretjem tednu statisticno pomembno nižjo vrednost kot ob vkljucitvi v raziskavo (p=0,006). Po uvedbi epoetina alfa je bi­lo tudi v tej skupini bolnikov opaziti normalizacijo vrednosti Hb in ustalitev med 12-13 gldl. Nihce od bolnikov v raziskavi ni prejel transfuzije. Nobeden od devetih opisanih neželenih ucinkov pri 6 bolnikih ni bil povezan z epoetinom alfa. Zakljucki: Epoetin alfa je ucinkovit v preprecevanju padca in vzdrževanju normalne vrednosti Hb pri bolnikih z rakom danke, ki so bili pooperativno zdravljeni s KT-RT. Hkrati je ucinkovit pri zmanjševanju bolnikovih potreb po transfuziji. Naša raziskava je pokazala, da je epoetin al­fa varno zdravilo, saj nismo zabeležili z njim povezanih neželenih ucinkov. Radio/ Oncol 2005; 39(2): 141-6. Prikaz bolnice z metastatskim timomom: solitarna metastaza je povzrocala asimptomatsko utesnitev hrbtenjace Gold DG, Miller RC Izhodišca. Ceprav so timomi histološko benigni tumorji, je lokalno njihova rašca lahko zelo agre­sivna, redko pa tudi metastazirajo. Prikaz primera. Opisujemo primer 47-letne bolnice, ki je bila pred 21 leti radikalno operirana zaradi timoma in nato postoperativno obsevana. K nam je bila napotena zaradi solitarne in­traabdomimalne metastaze, ki je povzrocala asimptomatsko utesnitev hrbtenjace. Bolnico smo zdravili s preoperirativnim radikalnim obsevanjem, ki smo ga nacrtovali s pomocjo magnetne resonance in racunalniške tomografije, nato pa operirali. Operacija je bila narejena prav tako radikalno, brez zajetih robov. Po zdravljenju nismo opazili nevroloških motenj. Zakljucki. Za lokalno zdravljenje z obsevanjem in operacijo smo se odlocili, ker je poteklo kar 21 let od zdravljenja prvotnega tumorja in ker smo dopušcali možnost, da se je pocasi rastoci tu­mor širil limfogeno preko plevralnega prostora v retroperitonealni, podobno kot mezoteliom. Radio/ Oncol 2005; 39(2): 147-52. PCR in analiza talitvene krivulje kot metoda za odkrivanje najpogostejših dednih mutacij v BRCAl genu pri slovenskih bolnikih Novakovic S in Stegel V Odkrivanje dednih mutacij v genih, ki so povezani z nastankom raka, napove verjetnost nas­tanka raka pri nosilcih mutacij in pri njihovih potomcih. Najpogostejše oblike raka, ki so povezane s podedovanimi mutacijami, so crevesni rak (mutacije v APC genu pri bolnikih s fa­miliarno adenomatozno polipozo -FAP, mutacije genov za popravljanje neujemanja pri bolnikih z dednim nepolipoznim crevesnim rakom -HNPCC), maligni melanom (mutacije v CDKN2A in CDK4 genih) in rak dojke (mutacije v BRCA1 in BRCA2 genih). V clanku podajamo osnovne metodološke podatke za odkrivanje petih razlicnih mutacij v BRCA1 genu pri bolnikih s karci­nomom dojke in njihovih sorodnikih. Mutacije 1806C>T, 300T>G, 300T>A, 310G>A, 5382insC smo dolocali s pomocjo polimerazne verižne reakcije v realnem casu in analizo talitvene krivul­je. Primerjava z direktnim sekveniranjem je pokazala, da je uporabljena metoda dovolj obcutlji­va in hitra za dnevno rutinsko dolocanje mutacij v DNA izolirani iz periferne krvi. Radio/ Oncol 2005; 39(2): 153-8. Citogenetska analiza limfocitov v periferni krvi po kontrastni arteriografiji Popova L, Hadjidekova V, Karadjov G, Agova S, Traskov D, Hadjidekov V Izhodišca. Namen citogenetske raziskave je bil ugotoviti ucinek diagnosticne arteriografije na limfocite periferne krvi pri 29 bolnikih. Metode. Periferne vzorce krvi smo odvzeli 22 bolnikom, ki so bili napoteni na ledvicno arteri­ografijo in 7 bolnikom napotenim na možgansko arteriografijo (17 moškim in 12 ženskam, starim 13 -68 let). Citogenetska analiza limfocitov periferne krvi je bila narejena pred preiska­vo, neposredno po preiskavi in 24 ur kasneje. Vstopno kožno dozo sevanja med celotno rent­gensko preiskavo smo merili s termoluminescentnim dozimetrom in je bila 0,03-0,30 Gy. Uporabili smo kontrastno sredstva z nizko in visoko osmolarnostjo. Genotoksicnost smo ocen­jevali s pogostnostjo kromosomskih aberacij in mikronukleusov. Rezultati. Pogostnost kromosomskih aberacij in mikronukleusov v limfocitih periferne krvi je bila znacilno višja po arteriografiji, kot pa jih je bilo pred njo. Število kromosomskih aberacij se je skoraj podvojilo in je po 24 urah ostalo nespremenjeno. Zakljucki. Rentgenske preiskave z jodnim kontrastnim sredstvom, kot je arteriografija, lahko statisticno znacilno zvišajo število citogenetskih poškodb v limfocitih periferne krvi. Notices Notices submitted for publication should contain a mailing address, phone and/ or fax number and/ or e-mail oj a Contact person or deparhnent. Lung cancer July 3-6, 2005 The » 11 th W orld Conference on Lung Cancer« will be offered in Barcelona, Spain. Contact Heather Drew, Imedex, Inc., 70 Technology Drive, Alpharetta, GA 30005 USA; or call +1 770 751 7332, or fax +1 770 751 7334; or e-mail h.drew@ imedex.com, or see www.imedex.com/calenders/on­cology/htm Radiotherapy July 3-7, 2 J05 The FSTRO course »IMRT and Other Conformal Techniq .ies in Practice« will take place in Amsterdam, the Netherlands. Contact ESTRO office, Avenue E. Mounierlaan 83/12, B-1200 Brussels, Belgium; or call +32 2 775 93 40; or fax +32 2 779 54 94; or e-mail info@estro.be; or see http://www.estro.be Lung cancer August 15-17, 2005 The »4th IASLC Chinese International Conference on Lung Cncer« will take place in Harbin, China. Contact: Professor Li Houwen, MD China Medica! Unviersity; Fax : +86 24 23251962. Gynaecological malignancies August 25-27, 2005 The ESTRO course »Brachytherapy in Gynaecological Malignancies« will take place in Paris, France. Contact ESTRO office, Avenue E. Mounierlaan 83/12, B-1200 Brussels, Belgium; or call +32 2 775 93 40; or fax +32 2 779 54 94; or e-mail info@estro.be; or see http://w.V\v.estro.be Radiotherapy August 28 -September 1, 2005 The ESTRO course »Physics for Clinical Radio­therapy« will take place in Como, Italy. Contact ESTRO office, Avenue E. Mounierlaan 83/12, B-1200 Brussels, Belgium; or call +32 2 775 93 40; or fax +32 2 779 54 94; or e-mail info@estro.be; or see http://www.estro.be Oncology September 5-9, 2005 The EORTC (European Organisation for Research and Treatment of Cancer) annual course »Cancer Clinical Trials: Methods and Practice« will take place in Brussels, Belgium. Contact Danielle Zimmermann, EORTC Education Office, Avenue E. Mounier 83, bte 11, B-1200 Brussels, Belgium; or call +32 2 774 16 02; or fax +32 2 772 62 33; or e-mail dzi@eortc.be; or see http://www.eortco.be/ Seminar/Educationpgm/Programs/prog2005.htm Radiotherapy September 24-29, 2004 The »Sth Biennial ESTRO Meeting on Physics and Radiation Technology for Clinical Radiotherapy« and »Pre-Meeting Workshop on Image-Guided Radio­therapy« will take place in Lisbon, Portugal. Contact ESTRO office, Avenue E. Mounier, 83/12, B-1200 Brussels, Belgium; or call +32 775 93 40; or fax +32 2 779 54 94; or e-mail info@estro.be; or see http://www.estro.be Radiation oncology September -October, 2005 The ISRO international teaching course on »Rational Developments from developing to devel­oped Countries« will take place in Lom bok, Indonesia. See http://www.isro.be 168 Notices Radiobiology October 2-6, 2005 The ESTRO course »Basic Clinical Radiobiology« will take place in Izmir, Turkey. Contact ESTRO office, Avenue E. Mounierlaan 83/12, B-1200 Brussels, Belgium; or call +32 2 775 93 40; or fax +32 2 779 54 94; or e-mail info@estro.be; or see http://www.estro.be Oncology October 7, 2005 The EORTC (European Organisation for Research and Treatment of Cancer) annual course »One-Day Introduction to EORTC Trials« will take place in Brussels, Belgium. Contact Danielle Zimmermann, EORTC Education Office, Avenue E. Mounier 83, bte 11, B-1200 Brussels, Belgium; or call +32 2 774 16 02; or fax +32 2 772 62 33; or e-mail dzi@eortc.be; or see http://www.eortco.be/ Seminar/Educationpgm/Programs/prog2005.htm Lung cancer October 16-20, 2005 The IASLC workshop »Biology and Prevention of Lung Cancer« will be offered in Woodstock, Vermont, USA. Contact Taryn Klocke at Envision Communications; call +1 770 763 5690; or see www.lungcancerpreven­tion.net Oncology October 30 -November 3, 2005 The ESTRO 24 / ECCO 13 Conference will take place in Paris, France. Contact FECS office, Av. E. Mounier, 83/4, B-1200 Brussels, Belgium; or call +32 7759340; or fax +32 2 7795494; or e-mail info@estro.be; or see http://www.fecs.be Radiation oncology November 13-18, 2005 The ESTRO course »Evidence-Based Radiation Oncology: Methodological Basis and Clinical Application« will take place in Dubrovnik, Croatia. Contact ESTRO office, Avenue E. Mounierlaan 83/12, B-1200 Brussels, Belgium; or call +32 2 775 93 40; or fax +32 2 779 54 94; or e-mail info@estro.be; or see http://www.estro.be Oncology November 21-25, 2005 The EORTC (European Organisation for Research and Treatment of Cancer) course »Organization and Implementation of Cancer Clinical Trials« will take place in Leuven, Belgium. Contact Danielle Zimmermann, EORTC Education Office, Avenue E. Mounier 83, bte 11, B-1200 Brussels, Belgium; or call +32 2 774 16 02; or fax +32 2 772 62 33; or e-mail dzi@eortc.be; or see http://www.eortco.be/ Seminar/Educationpgm/Programs/prog2005.htm Mesothelioma November 22-27, 2005 The »International Mesothelioma Symposium« will take place in Antalya, Turkey. Contact: Taryn Klocke; call +1 770-984-5113; Fax: +90 232 278 33 73. Lungcancer June 18, 2006 The »10th Central European Lung Cancer Confe­rence« will be offered in Prague, Czech Republic. Contact: +420-608-408-708; or e-mail info@confer­ence.cz; or see http://www.conference.cz Lungcancer April 19-26, 2006 »2nd The Latin American Conference on Lung Cancer« will be offered in Cancun, Mexico. E-mail: LungCancerLA@meet-ics.com: or see http:// www.LCLA2006.com Lungcancer September 28-30, 2006 »2nd The lnternational Workshop Early Invasive Lung Cancer: New Diagnostic Tools & Treatment Strategies« will be held in Turin, Italy. E-mail: a.crippa@congressiefiere.com or see http://www.congressifiere.com Notices 169 Lung and head & neck October 26-28, 2006 The »4th Lung & Head and Neck Conference« will be offered in Sheraton Hotel, Chicago, Illinois. Contact: Taryn Klocke; call +1 770-984-5113; or e­mail evokes@medicine. bsd. uchicago.edu Lung cancer September 2-6, 2007 The »12th World Conference on Lung Cancer« will be offered in Seoul, Korea. Contact Conference Secretariat; e-mail WCLC 2007@ncc.re.kr; or see http://vvww.iaslc.org!umages/ 12worldconfannounce. pdf As a service to our readers, notices of meetings ar courses will be inserted free o f charge. Please send information to the Editorial office, Radiology and OncologtJ, Zaloška 2, SI-1000 Ljubljana, Slovenia. Radio! Oncol 2005; 39(2): 167-9. FONDACIJA "DOCENT DR. J. CHOLEWA" JE NEPROFITNO, NEINSTITUCIONALNO IN NESTRANKARSKO ZDRUŽENJE POSAMEZNIKOV, USTANOV IN ORGANIZACIJ, KI ŽELIJO MATERIALNO SPODBUJATI IN POGLABLJATI RAZISKOVALNO DEJAVNOST V ONKOLOGIJI. MESESNELOVA 9 1000 LJUBLJANA TEL 0 1 51 9 1 2 77 FAKS 01 251 81 13 ŽR: 501 00-620-133-05-1 0331 15-214779 Activity of "Dr. J. Cholewa" Foundation for Cancer Research and Education -A Report for the Second Quarter of 2005 The Dr. J. Cholewa Foundation for Cancer Research and Education continues to support activities associated with cancer research and education in Slovenia with dif­ferent initiatives, as suggested by the members of the Foundation and all other inter­ested individuals in the country. Grant applications and other applications for various types of financial support are being dealt with immediately and thoroughly by the re­sponsible bodies formed by Foundation members with clinical and cancer research ex­perience and members with important experience in finance. The Foundation can claim severa! successful endeavours to its credit during the course of 2004 and already during the first quarter of 2005. The Dr. J. Cholewa Foundation for Cancer Research and Education continues to support the regular publication of "Radiology and Oncology" international scientific journal, which is edited, published and printed in Ljubljana, Slovenia, as it has done over the last couple of years and considering it one of its permanent commitments. Unfortunately, it has to be acknowledged that various public and privately owned enterprises find it ever more difficult to contribute financially to the Foundation. Severa! new suggestions are being considered at the moment. The Foundation ac­knowledges the importance of the commitment of various public companies and pri­vate individuals to its cause. Tomaž Benulic, MD Andrej Plesnicar, MD Borut Štabuc, MD, PhD kapsule raztopina za intravensko infundiranje Sestava 1 kapsula vsebuje 50 mg, 100 mg ali 150 mg flukonazola. 1 viala vsebuje 200 mg flukonazola. Indikacije Sistemske kandidoze, mukozne kandidoze, preprecevanje kandidoze, kriptokokoze, vaginalna kandidoza in dermatomikoze. Odmerjanje in nacin uporabe Velikost odmerka je odvisna od indikacije. Odraslim dajemo obicajno 50 do 800 mg flukonazola 1-krat na dan, otrokom pa 3 do 12 mg/kg telesne mase 1-krat na dan. Najvecji dnevni odmerek je 12 mg/kg telesne mase, za otroke, stare 5 do 13 let, pa 400 mg. Prvi dan zdrav1jenja priporocamo dvojni dnevni odmerek, ki je sicer predpisan za posamezno indikacijo. Trajanje zdravljena je odvisno od klinicne slike in mikološkega odziva. Bolniki z zmanjšanim delovanjem ledvic: Pri zdravtjenju z veckratnimi odmerki flukonazola dnevne odmerke prilagodimo vrednostim kreatininskega ocistka. Kontraindikacije Preobcutljivost za zdravilo, pomožne sestavine zdravila in za druge azole. Socasno jemanje flukonazola s terfenadinom ali cisapridom. Posebna opozorila In previdnostni ukrepi Pri bolnikih z motnjami v delovanju jeter je treba redno spremlJati aktivnost jetrnih encimov in bolnikovo stanje. Ob povecani aktivnosti Jetrnih encimov naj zdravnik presodi o koristnosti nadaljevanja zdravljenja in tveganju hujše Jetrne okvare. Nosecnost in dojenje Nosecnica zdravilo lahko jemlje le, ce je korist zdravljenja za mater vecja od tveganja za plod. Ker so koncentracije flukonazola v materinem mleku Podrobnejše informacije so na voljo pri proizvajalcu. Kr1