ADIOLOGY illll NCOLOGY March 2006 Vol. 40 No. 1 Ljubljana ISSN 1318-2099 Editorial office Radiologij and OncologrJ March 2006 Institute oj Oncology Vol. 40 No. 1 Zaloška 2 Pages 1-66 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 Radiology and Oncology is a journal devoted to publication oj original contributions in diagnostic and interventional radiologij, computerized tomography, ultrasound, magnetic resonance, nuclear medicine, radiotherapy, clinical and experimental oncology, 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 Be1aFornet Branko Palcic Zagreb, Croatia Budapest, Hungary Vancouver, Canada Karl H. Bohuslavizki Tullio Giraldi Jurica Papa Hamburg, Germany 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, Hungary Ljubljana, Slovenia Marjan Budihna Berta Jereb Ervin B. Podgoršak Ljubljana, Slovenia Ljubljana, Slovenia Montreal, Canada Malte Clausen Vladimir Jevtic Jan C. Roos Hamburg, Germany Ljubljana, Slovenia Amsterdam, Netherlands Christoph Clemm H. Dieter Kogelnik Slavko Šimunic M11nchen, Germany Salzburg, Austria Zagreb. Croatia Mario Corsi Jurij Lindtner Lojze Smid Udine, Italy Ljubljana, Slovenia Ljublja1:a,Slovenia Ljubomir Diankov Ivan Lovasic BomtStabuc Sofia, Bulgaria Rijeka, Croatia Ljubljana, Slovenia Christian Dittric/1 Marijan Lovrencic Andrea Veronesi Vienna, Austria Zagreb, Croatia Aviano, Italy Ivan Drinkovic LukaMilas Živa Zupancic Zagreb, Croatia Houston, USA Ljubljana, Slovenia Gillian Duc/zesne Metka Milcinski Melbourne, Australia Ljubljana, Slovenia Publisher Association oj Radiology and Oncology Affilia ted with Slovenian Medica/ Association -Slovenian Association oj Radiology, Nuclear Medicine Societi;, Slovenian Society far Radiotherapy and Oncologij, and Slovenian Cancer Societi; Croatian Medica/ Association -Croatian Society oj Radiologi; Societas Radiologorum Hungarorum Friuli-Venezia Giulia regional groups oj S.I.R.M. (Italian Society oj Medica/ Radiology) Copyright © Radiologi; and OncologiJ. Ali rights reserved. Reader for English Vida Kološa Keywords Eva Klemencic Secretary Mira Klemencic Design Monika Fink-Serša Printed by Imprint d.o.o., Ljubljana, Slovenia Published quarterly in 700 copies Benefician; name: DRUŠTVO RADIOLOGIJE IN ONKOLOGIJE Zaloška cesta 2, 1000 Ljublj"ana Slovenia Benefician; 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 far institutions EUR 100 (20.000 SIT), individuals EUR 50 (5000 SIT) The publication oj this journal is subsidized by the Slovenian Research Agency. Indexed and abstracted by: BIOMEDICINA SLOVENICA CHEMICAL ABSTRACTS EMBASE / Excerpta Medica Sci Base Scopus This journal is printed on acid-free paper Radiology and Oncology is available on the internet at: http://www.onko-i.si/radioloncol ISSN 1581-3207 Ljubljana, Slovenia ISSN 1318-2099 March 2006 UDC 616-006 Vol. 40 No. 1 CODEN: RONCEM CONTENTS RADIOLOGY Imaging of small amounts of pleural fluid. Part two -physiologic pleural fluid Kocijancic I 1 The estimation of the value and mobility of Parks' angle in case-series of patients with defecatory disorders -prospective clinical exarnination supplemented with the defecographic exarnination Kotodziejczak M, Sudol-Szopinska I, Grochowicz M, Bochenek A, Swiattowska M 7 Lherrnitte-Duclos disease and pregnancy Franko A, Hoijar-Erlic I, Miletic D, Petrovic O 17 CLINICAL ONCOLOGY Locoregional control and survival after breast conserving therapy Rajer M, Majdic E 23 Neck extensor muscle weakness (Dropped head syndrome) following radiotherapy Bhatia S, Miller RC, Lachance DL 29 Ameloblastic fibroma Božic M, Ihan Hren N 35 Erlotinib in previously treated non-small-cell lung cancer Smrdel U, Kovac V, Zwitter M 39 EXPERIMENTAL ONCOLOGY Phytohaemagglutinin as a modulator of DNA repair measured by chromosome aberration analysis in micronucleus assay in ionizing radiation biodosimetry Durinec M, Žeiježic D in Garaj-Vrhovac V 43 The role of p38 MAP kinase in cancer cell apoptosis Lenassi M, Plemenitaš A 51 SLOVENIAN ABSTRACTS 57 NOTICES 63 Radiology and Oncology is covered in Biomedicina S/ovenica, Chemica/ Abstracts, EMBASE / Excerpta Medica, Sci Base and Scopus review Imaging of small amounts of pleural fluid. Part two - physiologic pleural fluid Igor Kocijancic Department of Radiology, Institute of Oncology, Ljubljana, Slovenia Background. There are only a few articles reporting the possibility of radiographic and sonographic detec­tion of physiologic pleural fluid in healthy individuals. In the last decade the advent of sonographic equip­ments enables the detection of small amounts of physiologic pleural fluid in about 20% of healthy individ­uals. In certain physiologic conditions (i.e. pregnancy) the physiologic pleural fluid could be detected more frequently by chest ultrasonography. Conclusions. A positive result, if detected, should not be taken as a sign of the occult thoracic disease. Key words: pleura; pleural effusion; radiography, thoracic Introduction The pleural space is the extremely thin, well-defined liquid space which facilitates the slid­ing of lung within the chest cavity. A small amount of fluid in the pleural space acts as an efficient lubricating layer which minimizes energy losses during the respiration and max­imizes the transmission of forces from the chest wall to the lung.1 Limited studies in healthy human volun­teers indicate that the volume of fluid is gen­erally no more than 5 ml, but may be as much as 15 to 20 ml.2 In a recent report Noppen et al.3 showed that the amount of pleural fluid in Received 22 September 2005 Accepted 29 September 2005 Correspondence to: Assist. Prof. Igor Kocijancic, MD, PhD, Department of Radiology, Institute of Oncology, Zaloška 2, SI - 1000 Ljubljana; Slovenia. a single pleural space is 4 to 13 ml. They ac­cessed the pleural cavity in 34 otherwise healthy subjects treated with thoracoscopic sympaticolysis for the severe essential hyper-hidrosis. In the literature there are only few articles reporting the possibility of imaging of physi­ologic pleural fluid. There are only two arti-cles,4,5 both over 50 years old, reporting on the use of lateral decubitus radiography for demonstrating normal pleural fluid in healthy individuals. With the advent of sonography it was shown that very small amounts of pleu­ral fluid can be demonstrated this way. If the amount of pleural fluid is small, it is mostly adherent to the pleural surface and for that reason it is essentially invisible by imag­ing methods. When the amount of pleural flu­id approaches towards 15 ml, it becomes free within the pleural cavity, particularly at costophrenic recesses, around the hilar and lobar margins6 and it then becomes potential­ly visible by imaging methods. There is no clear border between the amount of pleural fluid in phsyiologic and pathologic (i.e. effu­sion as a sign of pleural disease) conditions. Lateral decubitus chest radiograpy Lateral decubitus chest radiographs were used for many years for the diagnosis of small pleural effusions, but there are only two arti-cles,4,5 both over 50 years old, reporting on the use of lateral decubitus radiography for demonstrating normal pleural fluid in healthy individuals. Hessen4 improved the technique with the central beam aimed at the lateral chest wall, together with the elevation of the patient’s hip. He found physiologic pleural fluid layer of 3 mm or more in 12 cases of 300 healthy volunteers. The exposure in expira­tion is mentioned in the work of Müller and Löfstedt,5 but apparently without gaining wider acceptance. They examined 120 healthy persons by their method and ob­served fluid in 11 cases. They also performed thoracocentesis and found that the amount of fluid was 3- 15 ml. Both techniques (patient’s position during examination and exposure in suspended expi­ration) were applied in the study of Kocijancic et al.7,8 in 106 healthy volunteers, but they found only one case of pleural fluid layer in the lateral decubitus position (Figure 1). So our conclusion is that physiologic pleural fluid visible on lateral chest radiography is an extreme­ly rare condition. In every such case the pleural disease or pleural involvement should be con­sidered. Hessen4 also examined 92 women 6 to 10 days after delivery with lateral chest radiog­raphy and found pleural fluid layer in 21 cas­es. This “physiologic” condition is nowadays well known as “benign postpartum pleural ef­fusion”.9,10 Chest ultrasonography In the last decades ultrasonography (US) of pleural space becomes a leading real-time method for demonstrating small pleural effu­sions.11-15 Kocijancic et al.7 in a preliminary study of 106 healthy volunteers showed that physio­logic pleural fluid layer of 2 mm or more could be detected in experimental conditions in 25% of persons. They performed chest US of the lower pleural space throughout a 15 by 20 cm opening in the special examination table after 5 minutes leaning in the lateral de­cubitus position, the same position as in lat­eral decubitus chest radiography. In decubi- Figure 1. Left lateral decubitus expiratory radiograph showing 3 mm thick density with horizontal level (arrow­head over phrenicocostal sinus), consisting with criterion defining pleural fluid. Medial margin of the scapula should not be missinterpreted as pleural fluid accumulation (arrowhwead at the level of 4th rib). Radiol Oncol 2006; 40(1): 1-5. tus position the pleural space was interrogat­ed several times searching for the fluid accu­mulation (Figure 2). They repeated the exam­ination of lower pleural space with the sub­ject leaning on the elbow, still in the lateral decubitus position. In this so called “elbow position” (Figure 3) there were no instances in which fluid was only detected whilst in the lateral decubitus position. In the follow up study they repeated chest US on each subject after two to four months.16 They suggest that there are indi­viduals with US permanently less (“dry pleu­ral space”) or more (“wet pleural space”) physiological pleural fluid (Figure 4). In these reports they determined US crite­ria for phsiologic pleural fluid: at least 2 mm thick (but not exceeding 5 mm) anechogenic zone between the parietal and the visceral pleura and/or changing of fluid layer thickness between expiration and inspiration as well as changing with different positions of the patient.7,16 In the majority of cases (75%), physiologic pleural fluid has wedge-shaped appearance on chest US (Figures 3, 4), while in the re­maining cases anechoic fluid was visible be­tween two parallel pleural lines. As the US examination is a real time method it is very important that all sonographic measurements with the probe perpendicular to the thoracic wall should be done. Results of a pilot study of pleural space US in 47 healthy pregnants by Kocijancic et al.17 confirmed physiologic pleural fluid in 60% of perfectly health pregnants. Such a positive re­sult, if isolated, should not be taken as a sign of occult thoracic disease (Figure 5). Conclusions The physiologic pleural fluid could evidently be an important source of error in the diag­nosis of pleural effusion by imaging methods, at first by chest US. In the cases of the so called “wet pleural space” chest US showed the fluid layer more accurately than radiography does. The possi- Radiol Oncol 2006; 40(1): 1-5. ble reasons are: flexibility of US perpendicu­lar approach compared to chest radiography in which the beam is tangential, clear US con­trast of pleural fluid compared to adjacent structures (radiographically the density of the fluid and the bone are very near) and techni­cally improved ultrasound scanners. Chest US should be introduced for pa­tients with diseases frequently affecting pleu­ra, such as systemic connective tissue dis­eases and certain neoplasms. The aim of such examination would be to establish the base­line status of pleural space (e.g. if visible pleural fluid is present before the treatment). The subsequent examination in the case of disease progression would thus enable us to identify small pleural effusion as an early sign of pleural involvement. References 1. Lai-Fook SJ. Mechanics of the pleural space: fun­damental concepts. Lung 1987; 165: 249-67. 2. Black LF. The pleural space and pleural fluid. Mayo Clin Proc 1972; 47: 493-506. 3. Noppen M, De Waele M, Li R, Gucht KV, D’Haese J, Gerlo E, Vincken W. Volume and cellular con­tent of normal pleural fluid in humans examinat-ed by pleural lavage. Am J Crit Care Med 2000; 162: 1023-6. Radiol Oncol 2006; 40(1): 1-5. 4. Hessen I. Roentgen examination of pleural fluid. A study of the localisation of free effusions, the potentialities of diagnosing minimal quantities of fluid and its existence under physiological condi­tions. Acta Radiol 1951; 86(Suppl): 1-80. 5. Müller R, Löfstedt S. Reaction of pleura in primary tuberculosis of the lungs. Acta Med Scand 1945; 122: 105-33. 6. Henschke CI, Davis SD, Romano PM, Yankelevitz DF. The pathogenesis, radiologic evaluation, and therapy of pleural effusions. Radiol Clin North America 1989; 27: 1241-54. 7. Kocijancic I, Kocijancic K, Cufer T. Imaging of pleural fluid in healthy individuals. Clin Radiol 2004; 59: 826-9. 8. Kocijancic I. Imaging of small amounts of pleural fluid. Part one - small pleural effusions. Radiol Oncol 2005; 39: 237-42. 9. Heffner JE, Sahn SA. Pleural disease in pregnancy. Clinics in Chest Medicine 1992; 13: 667-78. 10. Gourgoulianis KI, Karantanas AH, Diminikou G, Molyvdas PA. Benign postpartum pleural effu­sion. Eur Respir J 1995; 8: 1748-50. 11. Mathis G. Thoraxsonography - part I.: Chest wall and pleura. Ultrasound Med Biol 1997; 23: 1131-9. 12. Kocijancic I. The accuracy of chest sonography in the diagnosis of small pleural effusion. Radiol Oncol 2003; 37: 13-6. 13. Eibenberger KL, Dock W, Metz V, Weinstabl C, Haslinger B. Grabenwöger F. Ranking of Supine Chest Radiographs for Diagnosis and Quanti­fication of Pleural Effusions-Checking via Sono­graphy. Fortschr Rontgenstr 1991; 155: 323-6. 14. Marks WM, Filly RA, Callen PW. Real - time eval­uation of pleural lesions: New observations re­garding the probability of obtaining free fluid. Radiology 1982; 142: 163-4. 15. Kocijancic I, Vidmar K, Ivanovi-Herceg Z. Chest sonography versus lateral decubitus radiography in the diagnosis of small pleural effusions. J Clin Ultrasound 2003; 31: 69-74. 16. Kocijancic K, Kocijancic I, Vidmar G. Sonography of pleural space in healthy individuals. J Clin Ultrasound 2005; 33: 386-9. 17. Kocijancic I, Pušenjak S, Kocijancic K, Vidmar G. Sonographic detection of phsiologic pleural fluid in normal pregnant women. J Clin Ultrasound 2005; 33: 63-6. Radiol Oncol 2006; 40(1): 1-5. The estimation of the value and mobility of Parks’ angle in case-series of patients with defecatory disorders - prospective clinical examination supplemented with the defecographic examination Malgorzata Kolodziejczak1, Iwona Sudol-Szopinska2, Maciej Grochowicz1, Anna Bochenek3, Magdalena Swiatlowska3 1Proctology, Sub-Department of General Surgery, Hospital at Solec, Warsaw; 2Department of Diagnostic Imaging, Medical Academy Warsaw and Central Institute for Labour Protection-National Research Institute, Warsaw; 3Department of Radiology, Hospital at Solec, Warsaw, Poland Background. Defecography is used by a majority of colorectal surgeons for it is the only method for anatomic and dynamic studies of the act of defecation. The method provides information on different aspects of anorec­tal and pelvic floor function and offers the possibility of visualizing the development of anatomic abnormalities. Methods. We analyzed the defecography findings carried out at 56 patients (50 female and 6 male) from 24 to 83 years of age (the average age 58.3 years) with proctologic ailments such as: faecal incontinence, sensation of obstruction in the rectum, constipations, rectal prolapse, solitary ulceration of rectum. The values of Parks’ an­gle (ARA - the anorectal angle) were measured at rest, at strain and during defecation. Other parameters meas­ured included: duration of sphincter relaxation, overall duration of defecation, mobility of the pelvic diaphragm. Results. Abnormal values of Parks’ angle at rest and at strain were found in patients with the following prob­lems: faecal incontinence, sensation of obstruction in rectum and constipation. However, they did not turn out to be characteristic for patients with rectal prolapse. Defecography has helped to detect concomitant rectocele in pa­tients suffering from constipation and sensation of obstruction in the rectum. Defecography has also proved to be effective in the evaluation of patients who suffered from solitary ulceration of rectum. During the examination of these patients it has been observed that Parks’ angle in various phases of defecation has flattened. The duration of sphincter relaxation in the studied group was changeable and did not depend on the kind of pathology. Conclusions. Defecography is one of the examinations which can be helpful in the evaluation of patient’s motor functions both before and after the operation. Key words: constipation; foecal incontinence; defecography Received 31 August 2005 Accepted 20 September 2005 Correspondence to: Assist. Prof. Iwona Sudol-Szopinska, MD, PhD, CIOP-PIB, ul. Czerniakowska 16, 00-701 Warsaw, Poland; Fax +48 2232 65991; E-mail: iwsud@ciop.pl Introduction Methods The complex mechanism of defecation is con­trolled by both the central nervous system and the medullar centres. One of the steps of defecation reflex is the relaxation of sphincter muscles (puborectal and external anal sphincter) and the widening of the anorectal angle (ARA) of Parks’, caused by the activat­ed sensation of tenesmus of the central nerv­ous system. There are several factors which affect the defecation activity: volume and consistency of faeces, capacity of the rectal ampulla and susceptibility of the rectum wall, continence of sphincter muscles, sensory mechanism, mechanical factors such as: pelvis floor mus­cles, and value of the ARA of Parks’. Recognized as the necessary condition for normal human continence, Parks’ angle is formed between the longitudinal axis of the rectum and the axis of the anal canal and cre­ated by applying traction on the rectum by stretched puborectal muscle.1 Today, defecography is used by a majority of colorectal surgeons for it is the only method for anatomic and dynamic studies of the act of defecation.2 The method provides information on different aspects of anorectal and pelvic floor function and offers the possi­bility of visualizing the development of anatomic abnormalities.2 Although the number of investigations has questioned the significance of the ARA in the maintenance of faecal incontinence, the con-figurational changes of the ARA with volun­tary contraction or relaxation of the pelvic floor may be important.3 Furthermore, many clinicians continue to place credence in the ARA, and routine measurements are often taken.3 In this paper we present the applica­tion of defecography in the measurement of the ARA and the findings in defecography in patients with disturbed defecation. A group of 56 consecutive patients (50 fe­males and 6 males) from 24 to 83 years of age (the average age 58.3 years old) who suffered from defecation activity disorders in the form of: - constipation, - sensation of obstruction or incomplete defecation, - faecal incontinence, - rectal prolapse, - solitary ulcer of rectum were examined. Each patient was qualified for defecogra­ phy by the surgeon. Prior to the examination the medical history of these patients was tak­en including information about past diseases, injuries and child-birth, in the case of the fe­male patients. The patients’ continence for gas and faeces was evaluated with the Wexner scale. They also underwent the usual proctologic investigation and rectoscopy. Finally, the defecographic examination was performed be an experienced radiologist. Whole diagnostics were performed by one team of doctors. Informed consent was obtained after the nature of the procedures had been fully ex­plained to the patients, and the study was ap­proved by the Medical Academy authorities. The technique of defecographic examination The patients were prepared in a similar way as for the enema examination. The day before the investigation they took X-Prep or Fortrans. The contrast medium used for the examination was barium sulphate suspension concentrated with starch (solution of boiled potato flour) in order to obtain the thick con­sistency similar to the consistency of stool. The contrast medium was administered per rectum through Foley’s catheter in the amount enough to fill the splenic flexure of the colon. The examination was carried out in Radiol Oncol 2006; 40(1): 7-15. two stages. During the first stage, after the application of the contrast medium in the re­cumbent position, the patient was seated on a plastic bucket and then the catheter was withdrawn. The patient was asked to bear down as if to defecate. The examination was recorded on a mag­netic tape and the durations of the sphincter relaxation and the overall defecation were measured. The duration of sphincter relax­ation is the time measured between the be­ginning and the end of widening of the anal canal. The overall duration of defecation is the time needed for passing stools.4 The recording was made in video technique with PANASONIC UCR/TV camera and XD PRO SUPER UMS 180 tape. During the second stage three x-ray films were taken: at rest, during the defecation and in the phase of maximum contraction. The x-ray films taken in 35 x 35 mm format were later used for measuring precisely the anorectal angle and evaluating the pelvis floor mobility. The films also allowed for the evaluation of the size of rectocele. During defecography the following param­eters were estimated: ARA and its dynam­ics,3,5 duration of sphincter relaxation and Table 1. Patients with faecal incontinence overall duration of defecation. ARA was formed at intersection of the line running along the axis of the anal canal and the tan­gent line to the posterior wall of the rectum. The proper value of this triangle at rest is 95 ­105°. During the defecation the angle should increase (up to about 150°) and during the contraction it should decrease up to about 80°. The mobility of pelvic diaphragm was es­timated on the basis of lowering of the anorectal junction in relation to the ischiadic tubers. The accepted standard was the lower­ing of anorectal junction not exceeding 3.5 cm during tenesmus.6 In addition, the dis­tance of the rectal posterior wall from the sacral bone was measured. The recording of the defecographic examination on the video tape allowed estimating individual stages of the defecation. Results Tables 1-6 show the results for six separate groups of patients depending on the ailment and the course of the disease. Thirteen patients with symptoms of gas and faecal incontinence were examined No. Age Sex No of Parks’ Parks’ Parks’ Rectocele Wexner Pelvic floor Total births angle at angle at angle at scale mobility defecation rest contraction defecation (cm) time/s/ 177 M-110 90 115 -3 <1 10 266 F2 110 110 145 -12 >1 10 3 51 F 2 150 100 120 Big 14 <5 8 473 F2 115 110 120 -14 <5 20 549 M-100 95 125 -3 <5 17 669 F485 80 90 -4<3 7 755 F1 115 105 125 -17 <7 10 835 F1 120 110 118 -14 <1 35 956 F1 110 110 120 -8 <1 10 1073F -117 108 123 Big 4 <5 30 1157 F -118 112 125 Small 10 1 32 1272F2 120 120 135 -17 4 5 1351F 1 115 98 132 Big 12 4 17 Radiol Oncol 2006; 40(1): 7-15. Table 2. The patients who felt sensation of obstruction or incomplete defecation No. Age Sex No of Parks’ Parks’ Parks’ Rectocele Wexner Pelvic floor Total births angle at angle at angle at scale mobility defecation rest contraction defecation (cm) time/s/ 1 55 F 2 110 80 120 little 0 =1cm 20 2 59 F 3 115 95 125 - 0 =2cm 110 3 55 F 1 95 95 105 little 0 =10cm 10 4 46 F - 120 110 112 - 1 =1,5cm 125 5 45 F 2 115 110 135 big 0 =2cm 12 6 30 M 95 85 115 - 3 =4cm 150 7 59 F 4 105 95 125 little 2 =5cm 240 8 63 F - 105 95 110 - 1 =5cm 45 9 73 F 2 95 86 115 big 2 =4cm 25 10 69 F 1 133 120 130 little 0 =3cm 32 11 65 F 2 90 80 180 14 =1cm 3 12 35 M 115 105 122 0 =3,5cm 41 13 60 F 1 95 90 115 little 8 =4cm 6 (Table 1). In 1 case a small rectocele was de­tected which had not been discovered initial­ly by means of the proctologic examination. In 3 other cases a big rectocele was detected. Other 11 patients were characterized by too obtuse Park’s angle at rest and did not de­crease during contractions. Two patients had the right angle. In 9 out of 13 cases Parks’ an­gle did not decrease during the contraction. The lowering of pelvis floor mobility was de­tected in 7 cases. The overall duration of defe­cation did not turn out to be characteristic. The value of ARA in these cases was mostly incorrect. Thirteen patients, who felt sensation of ob­struction or incomplete defecation, were ex­amined (Table 2). In 8 cases ARA at rest was abnormally obtuse but in 9 cases it was prop­erly acute during contractions. Rectocele, not diagnosed initially during palpation, was de­tected at 6 patients; in 2 of them it was big. Table 3. Patients with solitary rectal ulcer The overall duration of defecation length­ened; in 1 case it amounted to 2.5 minutes. Most of the patients in this group had abnor­mally obtuse Parks’ angle at rest and the over­all duration of defecation was lengthened. Another group consisted of 2 female pa­tients with solitary ulcer of rectum (Table 3). These patients were characterized by “flatten­ing” of the value of Parks’ angle during vari­ous stages of defecation. In both cases ARA did not decrease during the contraction and the overall duration of defecation lengthened. The pelvis floor mobility was in both cases normal. Defecography turned out to be useful at examining patients with this rare disease. Values of Parks’ angle in various stages of the defecographic examination got flattened (the lack of dynamics of ARA during defecation) and the overall duration of defecation length­ened. There were 10 patients with rectal pro- No. Age Sex No of Parks’ Parks’ Parks’ Rectocele Wexner Pelvic floor Total births angle at angle at angle at scale mobility defecation rest contraction defecation (cm) time/s/ 1 37 F -108 110 118 -0 1,5cm 40 2 66 F 1 155 125 155 -0 1,5cm 14 Radiol Oncol 2006; 40(1): 7-15. Table 4. Patients with rectal prolapse No. Age Sex No of Parks’ Parks’ Parks’ Rectocele Wexner Pelvic floor Total births angle at angle at angle at scale mobility defecation rest contraction defecation (cm) time/s/ 1 81 F 4 * * * - 13 * * 2 80 F - * * * - 14 * * 3 47 F 4 * * * - 16 * * 4 24 M - 95 80 115 - 0 4 7 5 72 F 3 95 120 140 Big 7-8 cm 2 7 10 6 50 M - 110 80 180 - 0 1 20 7 70 F 2 128 127 140 4cm 0 4 25 8 61 F 1 ?? ?? ? - 8 4 15 9 74 F 1 120 107 140 - 16 * * 10 65 F 1 85 87 140 - 16 * 47 *Due to technical difficulties not all the parameters hale been measured. lapse (Table 4). Three of them could not un­dergo the examination due to technical rea­sons, i.e. the complete incontinence of con­trast medium. In 2 cases the examination helped to detect rectocele (1 was big). The overall duration of defecation was lengthened in 4 cases. The pelvis floor was abnormally lowered in 2 cases. In 3 cases abnormally ob­tuse ARA was detected. Values of ARA did not turn out to be characteristic for the group of patients with rectal prolapse. The group, who is characterized by symp­toms of constipation, consisted of 12 patients Table 5. The patients with obstruction (Table 5). The overall duration of defecation was lengthened in 4 cases and in the remain­ing 8 cases it was within the normal range. Rectocele was found in 9 patients: a small one in 2 cases, a medium one in 6 cases, and a big one in 1 case. In 5 cases ARA during contrac­tion did not decrease which was abnormal. In six cases abnormally obtuse ARA was detect­ed at rest. The last group consists of 2 female pa­tients who could not be assigned to any other group of proctologic ailments (Table 6). One of them had undergone rectopexy and the No. Age Sex No of Parks’ Parks’ Parks’ Rectocele Wexner Pelvic floor Total births angle at angle at angle at scale mobility defecation rest contraction defecation (cm) time/s/ 179 F2135 95 135 -0 =4 10 269 F3120 90 135 -0 =2 15 377 F-143 135 155 -0 =12 8 4 55 F -103 95 118 little 6 =2 22 5 66 F 1 123 129 148 middle 0 =6,8 19 6 53 F 1 105 80 100 middle 0 =3 10 7 47 F -70 80 100 middle 0 =2,4 20 831 F-97 84 132 big 0 =2 10 9 44 F 2 115 115 120 middle 2 =4 10 1026 F -127 120 143 middle 0 =2 18 1157F -72 66 70 middle 0 =5 15 12 72 F -105 105 150 llittle 0 =3 15 Radiol Oncol 2006; 40(1): 7-15. Table 6. Others disorders No. Age Sex No of births Kind of disorder Parks’ Parks’ Parks’ Rectocele Wexner Pelvic floor Total angle at angle at angle at scale mobility defecation rest contraction defecation (cm) time 1 48 F 1 Following rectopexy 100 100 135 5 4 10 2 48 F 2 Following burgery on recto-vaginal fistula 95 92 100 0 5 30 other post partum plastic operation of recto-vaginal fistula protected with transversosto-my. The former was characterized by low dy­namics of ARA during defecation and the lack of decreasing the angle during contrac­tions. Unfortunately no examination was car­ried out due to the complete incontinence of contrast medium caused by the full wall rec­tal prolapse. The examination could not be comparative in relation to the pre-operative condition of the patient. In the case of the patient with post partum plastic operation of rectovaginal fistula pro­tected with transversostomy the fistula was not detected. ARA during defecation got flat­tened; there were very small differences be­tween the various stages of defecation. The overall duration of defecation lengthened more than twice. These disorders might have been caused with the temporary exclusion of the last segment of alimentary tract. Additionally to the above presented groups of patients, four underwent the exam­ination simultaneously in two groups. There were two patients with symptoms of rectal prolapse and faecal incontinence and another two patients with constipation and sensation of the obstruction. In each group the duration of sphincter relaxation was individually vari­able and did not depend on the pathology. Discussion Defecation activity disorders may occur on a different level and their causes are not always easy to diagnose. In order to evaluate the causes affecting the defecation a number of methods is used, such as: anorectal manome-try, transrectal ultrasound, electromyogra­phy, magnetic resonance and others. The sig­nificance of defecography and especially its value in measurements of the ARA is, howev­er, questioned by many authors. The main drawback of the method is inability to differ­entiate the effect of pelvic floor laxity from the incontinence on the basis of ARA result.3 Many clinicians continue, however, to place credence in the ARA, and routine meas­urements are often taken.3 This examination, apart from estimating ARA, allows physi­cians to evaluate the efficiency of rectal sphincters, pelvis floor muscles and suscepti­bility of the rectal ampulla. It is at this time probably the only objective means of meas­urement of anorectal anatomy and function because the sitting position for examination is not easily attainable with other methods.7 Defecography was first described in 1952 by Walden.8 In 1953 Ekengren and Snellman9 published an article in which they presented the application of defecography in diagnos­tics of constipation. In 1968 Broden and Snellman10 characterized and named the de­fecographic technique as well as indications for its application. In 1980s Mahieu el al.11,12 described the application of defecography as a new diagnostic procedure. Their work con­sisted of two parts and included an evalua­tion of anorectal functions using defecogra­phy. The investigation was carried out on healthy patients and patients suffering from proctologic diseases. We present results of defecography per- Radiol Oncol 2006; 40(1): 7-15. formed in several groups of patients with fol­lowing disorders: - constipation, - sensation of obstruction or incomplete defecation, - suspicion of rectocele, - faecal incontinence, - rectal prolapse. Defecography turned out to be a useful ex­amination and allowed for a very precise di­agnosis. In a group of patients with the sen­sation of incomplete defecation and sensa­tion of obstruction, for example, six out of thirteen were diagnosed with rectocele. It was also possible to measure ARA fairly precisely and in this way to evaluate the function of the pelvic diaphragm what is impossible using other diagnostic methods. Abnormal values of ARA were detected in the group of patients characterized by constipations, faecal inconti­nence and the sensation of obstruction in the rectum. It could be related to defective func­tion of pelvic diaphragm and in some cases with the low contractility of puborectal mus­cle. Signs of nonrelaxing puborectalis muscle Agachan et al.13 found in 28.8% of the patients with defecatory disorders. He used manome-try, electromyography, and defecography. The latter in his opinion was probably the best for this purpose. This opinion is sup­ported by Karasics et al.,14 who claims that the value of the ARA is directly dependent on the puborectal muscle activity. Not effective con­traction of the puborectalis causes abnormal values of the ARA in each phases of defeca­tion. He adds that many patients have not ev­ident functional diseases of the rectum which may be diagnosed by means of defecography. Also Jorge et al.,3 who compared defecogra­phy with proctography, found defecography reliable and superior, mostly because it is the only diagnostic test which provides anatomic details. In the majority of our patients suffering from incontinency value of the ARA was ab­normal. Almost half of them had the exces­sive lowering of the pelvis floor, which might have led to incontinency. The latter factor is underlined by many authors.3 ARA did not turn out to be characteristic for patients with rectal prolapse. Although the defecographic examination was difficult to carry out in this group of patients, it showed the mechanism of rectal prolapse and was useful in choosing the right surgery tech­nique. Defecography is particularly useful in the diagnostics of early stages of the rectal prolapse when the upper part of the rectum becomes intussuscepted. In one case we ob­served acute ARA during the maximal sphincters contraction following the rectocele surgery because of the rectal prolapse, which was typical for the functional results of sur­gery of that type. Defecography has also proved to be effec­tive in the evaluation of patients who suffered from solitary ulcer of rectum. During the ex­amination of these patients it has been ob­served that ARA in various phases of defeca­tion has flattened. The duration of sphincter relaxation in the studied group was change­able and did not depend on the kind of pathology. Despite improvements in imaging tech­nique and better understanding of anorectal disorders, the exact role of defecography in defining anorectal disorders and its impact on therapy remains controversial.7,14 In spite of its undoubted diagnostic value we conclude that this examination should be an additional one to the clinical examination. The defecog­raphy is enable to visualise the peritoneal out­line and its pouches, and may be of limited value in case of enterocele or rectal intusses­ception16 (although in the latter, defecography is necessary to sort out cases of intussescep­tion that might be clinical relevant whereas the clinical diagnosis of intussusception is re­lated only to long intussusception).17 The problem may also result from e.g. multifac­toral aetiology of obstructed defecation which makes it difficult to determine whether de- Radiol Oncol 2006; 40(1): 7-15. fecographic findings are the cause or result of excessive straining in patients with the ob­structed defecation.7 Additionally, there are scientific works which describe healthy vol­unteers who underwent this examination. Although they had not suffered from any proctological ailments, the defecographic ex­amination detected some disorders. Besides, not all the parameters which were used in our study appeared reliable for other researchers. Klauser18 tested reproducibility and agreement among three clinicians (a ra­diologist, a gastroenterologist, and a colorec­tal surgeon), all experienced in defecography, in evaluating defecographies, and did not in­clude in his study the measurement of the ARA. In his opinion, it has no clinical rele­vance. Dvorkin et al.19 compared magnetic resonance defecography and evacuation proctography. They confirmed the primary role of proctography for the diagnosis of in-tussusception, and the complementary role of magnetic resonance defecography by giving information on movements of the whole pelvic floor. Whereas Beer-Gabel et al.20 found no differences between dynamic transperineal ultrasound and defecating proctography for the measurement of the ARA, anorectal junction position at rest and during straining. Although defecography cannot be the only grounds for treating the patient,7 contempo­rary surgery of large intestine should be sup­plemented with a detailed evaluation of rec­tum functional functions. Our results in sev­eral case-series presented did not allow for any definitive data because of the hetero­geneity of the included group. They are pre­liminary, and some cases, e.g. solitaire rectal ulcer and rectal prolapse, were presented due to their rareness. The whole work will conti­nue but at this stage we are convinced that defecography is one of the examinations which can be helpful in the evaluation of pa­tient’s motor functions both before and after the operation. Conclusions 1. Abnormal values of Parks’ angle at rest and during constipation were detected at pa­tients who suffered from: faecal inconti­nence, sensation of obstruction in rectum and with constipation. 2. Values of Parks’ angle did not turn out to be characteristic for the examined group of patients with rectal prolapse. 3. Duration of sphincter relaxation was in­dividually variable and did not depend on the pathology. 4. Defecography enabled to detect con­comitant rectocele at patients with constipa­tions and the sensation of obstruction in rec­tum 5. Defecography was helpful at the evalua­tion of patients with solitary ulcer of rectum. In these cases ARA at various stages of defe­cation becomes “more flat”. References 1. Parks AG. Anorectal incontinence. J R Soc Med 1975; 68: 681-90. 2. Mellgren A, Bremmer S, Johansson C, Dolk A, Uden R, Ahlback SO, et al. Defecography. Results of investigations in 2,816 patients. Dis Colon Rectum 1994; 37: 1133-41. 3. Jorge JMN, Wexner SD, Marchetti F, Rosato GO, Sullivan ML, Jagelman DG. How reliable are cur­rently available methods of measuring the anorec­tal angle? Dis Colon Rectum 1992; 35: 332-8. 4. Selvaggi F, Pesce G, Scotto E, Carlo D, Mattefone V, Cannonio S. Evaluation of normal subject by defecographic technique. Dis Colon Rectum 1990; 33: 698-702. 5. Yoshioka K, Pinho M, Ortiz J, Oya M, Hyland G, Keyghley MRB. How reliable is measurement of the anorectal angle by videoproctography? Dis Colon Rectum 1991; 34: 1010-3. 6. Selvaggi F, Pesce G, Scotto Di Carlo E, Maffettone V, Canonico S. Evaluation of normal subject by de­fecographic technique. Dis Colon Rectum 1990; 33: 698-702. Radiol Oncol 2006; 40(1): 7-15. 7. Dam JH, Ginai AZ, Gosselink MJ, Huisman WM, Bojer HJ, Hop WCJ, et al. Role of defecography in predicting clinical outcome of rectocele repair. Dis Colon Rectum 1997; 40: 201-7. 8. Walden L. Defecation block in cases of deep rec-togenital pouch. Acta Chir Scand 1952; 165(Suppl): 1-121. 9. Ekengren K, Snellman B. Roentgen appearances in mechanical rectal constipation. Acta Radiol 1953; 40: 447-56. 10. Broden B, Snellman B. Procidientia of the rectum studied with cineradiography: a contribution to the discussion of causative mechanism. Dis Colon Rectum 1968; 11: 330-47. 11. Mahieu P, Pringot J, Bodart P. Defecography I. Description of a new procedure and results in nor­mal patients Gastrointest Radiol 1984; 9: 247-51. 12. Mahieu P, Pringot J Bodart P. Defecography II. Contribution to the diagnosis of defecation disor­ders. Gastrointest Radiol 1984; 9: 253-61. 13. Agachan F, Pfeifer J, Wexner SD. Defecography and proctography. Results of 744 patients. Dis Colon Rectum 1996; 39: 899-905. 14. Karasick S, Karasick D, Karasick SR. Functional disorders of the anus and rectum: findings on de­fecography. AJR Am J Roentgenol;1993; 160: 777-82. 15. Savoye-Collet C, Savoye G, Koning E, Leroi AM, Dacher JN. Defecography in symptomatic older women living at home. Age Ageing 2003; 32: 347-50. 16. Bremmer S, Ahlback SO, Uden R, Mellgren A. Simultaneous defecography and peritoneography in defecation disorders. Dis Colon Rectum 1995; 38: 969-73. 17. Karlbom U, Graf W, Nilsson S, Pahlman L. The ac­curacy of clinical examination in the diagnosis of recital intussusception. Dis Colon Rectum 2004; 47: 1533-38. 18. Kluser AG, Ting KH, Mangel E, Eibl-Eibesfeldt B, Muller-Lissner SA. Interobserver agreement in de­fecography. Dis Colon Rectum 1994; 37: 1310-16. 19. Dvorkin LS, Hetzer F, Scott SM, Williams NS, Gedroyc W, Lunniss PJ. Open-magnet MR de­fecography compared with evacuation proctogra­phy in the diagnosis and management of patients with rectal intussusception. Colorectal Dis 2004; 6: 45-53. 20. Beer-Gabel M, Teshler M, Schechtman E, Zbar AP. Dynamic transperineal ultrasound vs. defectogra­phy in patients with evacuatory difficulty: a pilot study. Int J Colorectal Dis 2004; 19: 60-7. Radiol Oncol 2006; 40(1): 7-15. case report Lhermitte-Duclos disease and pregnancy Artur Franko1, Izidora Holjar-Erlic1, Damir Miletic1, Oleg Petrovic2 1Department of Radiology and 2Clinic of Gynaecology and Obstetrics, Clinical Hospital Rijeka, Croatia Background. Lhermitte-Duclos disease or dysplastic gangliocytoma of the cerebellum is a rare disorder that can cause progressive mass effects to the structures occupying posterior fossa. Magnetic resonance imaging is a diagnostic modality of choice demonstrating characteristic non-enhancing gyriform pattern with the en­largement of cerebellar folia, hypointense on T1 and hyperintense on T2 weighted magnetic resonance im­ages. Case report. The authors present a case of 37-year old woman with previously unknown Lhermitte-Duclos disease in the third trimester of pregnancy from the first signs of the disease to the first six months after de­livery. Conclusions. More experience will be needed with this disease in pregnancy and post delivery period to recommend pregnancy for women with such condition. However, this case shows that a pregnant woman with Lhermitte-Duclos disease could reach full-term pregnancy and deliver a healthy child, without life-threatening risk. Key words: cerebellar neoplasms; ganglioneuroma Introduction Dysplastic cerebellar gangliocytoma (Lher­mitte-Duclos disease) is a rare disorder, char­acterized by a slowly progressive unilateral neoplastic mass of the cerebellar cortex. The histopathological findings of Lhermitte-Duclos disease (LDD) include the widening of Received 5 January 2006 Accepted 15 February 2006 Correspondence to: Izidora Holjar-Erlic, MD, Department of Radiology, Clinical Hospital Rijeka, Krešimirova 42, 51000 Rijeka, Croatia, Tel/Fax: +385(51)651-386; E-mail: izidora.holjar@ri.htnet.hr the molecular layer, which is occupied by ab­normal ganglion cells, absence of the Purkinje cell layer and hypertrophy of the granulan cell layer. Magnetic resonance imag­ing (MRI) is a diagnostic modality of choice and reveals a characteristic non-enhancing gyriform pattern with the enlargement of cerebellar folia. The lesion is hypointense on T1- and hyperintense on T2-weighted mag­netic resonance images.1 In patients with a posterior fossa tumour suggestive of a dys-plastic gangliocytoma on neuroimaging stu­dies, a pathologic confirmation is necessary.2 Dysplastic cerebellar gangliocytoma is commonly associated with the progressive mass effect in the posterior fossa and is typi­cally presented with headaches, cerebellar dysfunction, occlusive hydrocephalus and cranial nerve palsies. The disease usually manifests in young adults, but the age at pres­entation ranges from birth to the sixth decade. There is no sex predilection. The therapy consists of decompression of the pos­terior fossa by a total surgical removal of the tumour mass.3 A problem of surgical removal of these tumours is to miss the borderline be­tween tumour and healthy cerebellum tissue so that the incomplete removal of the tumour is not rare.4 To our knowledge there were no reports of LDD in pregnancy. In our case report we in­tend to present the potential influence of LDD on pregnancy and delivery. Case report A 37-year-old woman was admitted at the Clinic of Gynaecology and Obstetrics in the 27th week of her first pregnancy for monitor­ing and programming the childbirth. Hospitalisation and programmed delivery by caesarean section has been recommended from her neurosurgeon before the control MRI was preformed, because she had a histo­ry of partial cerebellar tumour resection. Namely, 19 years ago, CT was performed due to the cerebellar dysfunction and the in­creased intracranial pressure (intensive headaches, nausea, dizziness and optical nerve oedema). CT had shown a large mass of the right cerebellar hemisphere suspicious of gliomal tumour and she underwent the neu­rosurgical extirpation. Only a partial resec­tion was preformed with the implantation of ventriculoatrial shunt. The histopatological findings included a widening of cerebellar cortex due to hypercellular granular layer without a clear border with thin molecular layer and presence of large Purkinje cells. The presence of true neoplastic tissue was not found and regular CT controls were recom-mended. She constantly suffered from headache and dizziness in exertion when she had the opportunity to do MRI eight years ago. After this first MRI which described tu­mourous mass in the pontocerebellar angle and the right cerebellar hemisphere, a new re­section with drainage was recommended when she was 29-years old, but our patient did not accept surgery. The symptoms were stable during pregnancy when in the third trimester became more frequent and aggra­vated. The neurosurgeon recommended MRI before making decision for the route of child delivery. MRI was performed in the 29th week of pregnancy showing the expansive lesion of the right cerebellar hemisphere with charac­teristic features (Figures 1 and 2). Nineteen years from her first symptoms our radiologist, based on typical MRI findings and history, concluded that it must have been Lhermitte-Duclos disease. The neurosurgeon recommended delivery by caesarean section and our patient delivered a healthy male child after 40 weeks of pregnancy. After delivery she reported the aggravation of symptoms: headache, dizziness, disturbance of balance Radiol Oncol 2006; 40(1): 17-21. and paresthesia in both arms. She suffered from this discomforts for six months when she went on control MRI. Control MRI was unchanged, but she accepted the operation at that time. Patohistological findings con­firmed our radiological diagnosis. Discussion Tumours of ganglion cells are very rare. They include: gangliocytoma, ganglioneurinoma, Lhermitte-Duclos disease and dysembry­oplastic neuroepithelial tumour. Some con­sidered them to be dysplasias rather than true neoplasm; others refer to them as malforma­tions.5 Lhermitte-Duclos disease is a rare cerebellar lesion with features of both malfor­mation and benign neoplasm. MR imaging usually distinguishes the LDD by its charac­teristic “tiger-striped” appearance (Figure 3).6 In recent years several cases involving the association between LDD and Cowden’s syn­drome (CS), an autosomal dominant condi­tion characterized by multiple hamartomas and neoplastic lesions in the skin and inter­nal organs were reported. These included mu-cocutaneous lesions, acral keratosis, thyroid adenoma, fibrocystic disease ovarian cyst, in­testinal polyposis, and arteriovenous malfor­mation. Patients with LDD should receive a complete dermatological and systemic screening, because some of the lesions can develop into malignant tumors.7 The associa­tion between Lhermitte-Duclos disease and Cowden disease has been under-recognized and under-reported. The recognition of this association has a direct clinical relevance be­cause a diligent long-term follow up monitor­ing of individuals with Lhermitte-Duclos dis­ease and Cowden disease may lead to the ear­ly detection of malignancy.8 In approximately 40% of documented cases of LDD, CS can be diagnosed, and in 60% of cases LDD appears to occur sporadically.9 Patients diagnosed with Lhermitte-Duclos disease must be ade­quately evaluated for Cowden’s syndrome.10 We presented a 37-year-old pregnant woman who had an isolated form of LDD be­ginning in her teenage period (16 years). During pregnancy she was under the perma­nent supervision of her obstetrician and no Radiol Oncol 2006; 40(1): 17-21. obstetric complications were obtained. Pregnancy is an aggravating factor for brain tu­mours acting by three mechanisms: accelera­tion of tumour growth, increase of peritumoral oedema and development of immunotolerance to foreign tissue agents. There may be a rela­tion between pregnancy hormones. According to Depret-Mosser et al.11 induced therapeutic abortion and caesarean section are no longer routinely performed, and now being replaced by vaginal delivery with a systematic instru­mental extraction. The presence of an intracra­nial neoplasm during pregnancy has a serious implication for the anaesthetic management of labour and delivery. The physiological changes of pregnancy and labour are potentially haz­ardous to women with intracranial neoplasm, but the provision of adequate pain relief dur­ing labour reduces the risk for the mother.12 The other group of authors recommended cae­sarean delivery with the patient under general anaesthesia, followed by the immediate neuro-surgical decompression in neurologically un­stable patients to minimize temporal lobe or cerebellar herniation.13 The delivery should be advocated in the early third trimester after documentation of foetal pulmonary maturity. In our case we had a neurologically stabile pa­tient who reached the full term pregnancy. The obstetrician took into consideration her age (37 years), reported deterioration of symptoms in exertion and recommended neurosurgical examination before making his decision for elective caesarean delivery. The way of delivery is still a question and should be solved between the obstetrician and the neurosurgeon for each patient indi­vidually. More experience with LDD in preg­nancy is necessary for making a solid attitude about a way of delivery in neurologically sta-bile patients. The management of brain tu­mours should be tailored to the individual pa­tient. There may be a relation between preg­nancy hormones and the rate of brain tumour growth mediated through specific intracellu­lar receptors.14 More experience will be needed with this disease in pregnancy and post delivery period to recommend pregnancy for women with this condition. However, this case shows that a pregnant woman with LDD could reach full-term pregnancy and deliver a healthy child, without serious risk for her life. References 1. Nowak DA, Trost HA. Lhermitte-Duclos disease (dysplastic cerebellar gangliocytoma): a malforma­tion, hamartoma or neoplasm? Acta Neurol Scand 2002; 105: 137-45. 2. Chen KS, Hung PC, Wang HS, Jung SM, Ng SH. Medulloblastoma or cerebellar dysplastic ganglio-cytoma(Lhermitte-Duclos disease). Pediatr Neurol 2002; 27: 404-6. 3. Nowak DA, Trost HA, Porr A, Stolzle A, Lumenta CB. Lhermitte-Duclos disease (Dysplastic ganglio­cytoma of the cerebellum). Clin Neurol Neurosur 2001; 103: 105-10. 4. Buhl R, Barth H, Hugo HH, Straube T, Mehdorn HM. Dysplastic gangliocytoma of the cerebel-lum:Rare differential diagnosis in space occupying lesions of the posterior fossa. Acta Neurochirurgica 2003; 145: 509-12. 5. de Arriba-Villamor C, Martinez-Mata A, Espinosa-Mogro H, Rubio-Viguera V. Tumors of the gan­glion cells. Rev Neuroradiol 1998; 27: 1008-11. 6. Klish J, Juengling F, Spreer J, Koch D, Thiel T, Buchert M, et al. Lhermitte-Duclos disease: Assessment with MR imaging, positron emission tomography, single-photon emission CT and MR spectroscopy. Am J Neuroradiol 2001; 22: 824-30. 7. Vantomme N, Van Calenbergh F, Goffin J, Sciot R, Demaerel P, Plets C. Lhermitte-Duclos disease is a clinical manifestation of Cowden`s syndrome. Surg Neurol 2001; 56: 201-4. 8. Robinson S, Cohen AR. Cowden disease and Lhermitte-Duclos disease: Characterization of a new phakomatosis. Neurosurgery 2000; 46: 371-83. 9. Murata J, Tada M, Sawamura Y, Mitsumory K, Abe H, Nagashima K. Dysplastic gangliocytoma (Lhermitte-Duclos disease) associated with Cowden disease: report of a case and review of the literature for the genetic relationship between the two disease. J Neuro-Oncol 1999; 41: 129-36. Radiol Oncol 2006; 40(1): 17-21. 10. Cummings TJ, Ebert RH, Provenzale J, McLendon RE. A 16 year old female with a cerebellar mass. Brain Pathol 2001; 11: 391-3. 11. Depret-Mosser S, Jomin M, Monnier JC, Vinatier D, Bouthors-Ducloy AS, Christiaens JL, et all.Cerebral tumors and pregnancy. Apropos of 8 cases. J Gyneacol Obstet Biol Reprod 1993; 22: 71-80. 12. Finfer SR. Management of labour and delivery in patients with intracranial neoplasms. Brit J Anaesth 1991; 67: 784-7. 13. Tewari KS, Cappuccini F, Asrat T, Flamm BL, Carpenter SE, DiSaia PJ, et al. Obstetric emergien­ces precipitated by malignant brain tumors. Am J Obstet Gynecol 2000; 185: 1215-21. 14. Isla A, Alvarez F, Gonzalez A, GraciaGrande A, PerezAlvarez M, GarciaBlazquez N. Brain tumor and pregnancy. Obstret Gynecol 1997; 89(1): 19-23. Radiol Oncol 2006; 40(1): 17-21. Locoregional control and survival after breast conserving therapy Mirjana Rajer, Elga Majdic Department of Radiotherapy, Institute of Oncology Ljubljana, Slovenia, Background. The purpose of our study was to present a 5-year survival and locoregional control rates in breast cancer patients and to establish eventual impact of the treatment and patient characteristics on lo-coregional control and survival. Methods. From January 1998 to December 1999 564 stage 1 and 2 breast cancer patients were treated with breast conserving therapy. We evaluated the following characteristics: age, histological diagnosis, grade, size, number of metastatic lymph nodes, hormonal receptor status, extensive intraductal component (EIDC), vas­cular invasion, pathologic tumour margins, type of surgery and use of adjuvant therapy. Results. The mean age of our patients was 54.2 years. Invasive ductal carcinoma was the most common di­agnosis (82.4%), followed by invasive lobular carcinoma (10.6%). Most of the tumours were grade 2. Seventy-two % of patients had T1 tumours, 24% T2 and 3% Tis tumours. Metastatic lymph nodes were pres­ent in 44% of patients. All patients were treated with breast conserving surgery followed by radiotherapy (RT). Fifty % of patients received adjuvant chemotherapy and/ or hormonal therapy. The 5-year survival rate was 88.5%. Tumour size, number of metastatic lymph nodes, grade, hormonal receptors and vascular invasion proved to be statistically significant prognostic factors for the survival, while age and histological diagnosis were not. Local recurrence developed in 4.3% of our patients, while in 3.4% regional recurrence developed. Conclusions. Breast conserving surgery followed by RT was associated with good rates of locoregional con­trol and survival, comparable to those reported in the literature. Key words: breast neoplasms – surgery; survival analysis Received 20 February 2006 Accepted 28 February 2006 Correspondence to: Mirjana Rajer, MD, Department of Radiotherapy, Institute of Oncology Ljubljana, Zaloška 2, 1000 Ljubljana, Slovenia; Phone: + 386 41 26 99 46; Fax.: + 386 1 587 9 400; E-mail: mrajer@onko-i.si Introduction Breast conserving therapy has been used since the 1960s and is now considered best practice in the treatment of early breast can­cer. Retrospective and prospective random­ized trials demonstrated that breast conserv­ing therapy (BCT) produces rates of survival and locoregional control similar to those of mastectomy.1 Breast conserving surgery re­moves a detectable disease in the breast and/or regional lymph nodes, but has no ef­fect on possible undetected disease in the re­maining breast, chest wall, regional lymph nodes or distant sites.2 By combining surgery, radiotherapy and adjuvant systemic therapy we can lower the risk of locoregional and dis­tant recurrence. In spite of this combined therapy there are still patients who develop recurrences. Local recurrence rates of 5-20% have been reported in different studies after BCT.1-3 Although the impact of local recurrence on overall survival is not well established, it has a detrimental psychological effect on the patient.1,4,5 By identifying those patients who have higher risk of developing a locoregional and/or dis­tant recurrence, we can determine the right treatment to minimize the risk.1 The purpose of this retrospective study was twofold. First of all, to present a 5-year sur­vival and locoregional control rates in patients treated at Institute of Oncology in Ljubljana and, secondly, to establish the eventual im­pact of treatment and patient characteristics on locoregional control and survival. Methods From January 1998 to December 1999 564 breast cancer patients stage I and II were treated at the Institute of Oncology Ljubljana with breast conserving therapy. The patient data were obtained by medical records. We evaluated the following patient and tumour characteristics: age, histological diagnosis, grade, size, number of metastatic lymph nodes, hormonal receptor status, extensive intraductal component (EIDC), vascular inva­sion, pathologic tumour margins, type of sur­gery and use of adjuvant therapy. We record­ed eventual locoregional and/or distant recur­rence by the retrospective analysis. Statistical univariate analyses were done using the SPSS program. A statistical signifi­cance was assessed with Log-rank, Breslow and Tarone-Ware tests. Results Patient and tumour characteristics The patient’s age ranged from 28 to 77 years. The mean age was 54.2 years. The age distribu­tion is presented on the histogram (Figure 1). Most of the tumours were present in the upper outer quadrant (45%), followed by the outer lower quadrant (11%). Invasive ductal carcinoma (IDC) was by far the most common histological diagnosis (82.4% of tumours), fol­lowed by invasive lobular carcinoma (ILC) (10.6%) and ductal carcinoma in situ (DCIS) (2.6%). Other histological types of tumours were rare. The grade was more evenly distrib­uted. The most common was Grade 2 with 44%, followed by Grade 3 with 33% and Grade 1 with close to 26%. Most of the tumours were T1 (72%) and T2 (42%). Tis was present in 3% of cases. Sixty-six % of patients had negative axillary lymph nodes, 25.7% had one to three metastatic lymph nodes and 7.6% had more than three metastatic nodes. Positive estrogen receptors were detected in 66.4% of tumours and positive proges- Radiol Oncol 2006; 40(1): 23-8. Figure 2. Overall survival of patients. terone receptors in 51.1%. Vascular invasion was present in 2.6% of tumours and 15% of tumours had an EIDC. Treatment All patients were treated with breast conserv­ing operation, either tumorectomy or quad-rantectomy. All patients received postopera­tive radiotherapy with two tangential fields. The total dose was 50 Gy followed by a boost with electrons to the tumour bed of 10 to 16 Gy. In patients with more than three metasta­tic axillary lymph nodes, 50 Gy was given to the supraclavicular fossa. No patient received radiotherapy to the axilla. About half of pa­tients received adjuvant chemotherapy (54%) and hormonal therapy (50.4%). Survival The 5-year overall survival rate was 88.5% (Figure 2). Prognostic factors for survival In the context of our analysis, age and his­tology proved statistically non significant, while the influence of tumour size, nodes, grade, estrogen and progesterone receptors, vascular invasion and local and regional fail­ure was significant. Figure 3. Impact of the tumour size on survival (p = 0.000). As expected, a larger tumour leads to a lower survival probability (Figure 3). In this case as well as in other presented graphs, that will follow, the difference was statistically significant. Comparing the overall survival rate (88.5%), in patients with Grade 3 tumours it was well below 80%, while for the patients with Grade 1 tumours it was close to 100% (Figure 4). The patients who had tumours with posi­tive estrogen and progesterone receptors had higher survival probability (Figures 5, 6). The patients with a local recurrence had lower survival probability (Figure 7). The same holds for regional recurrence (Figure 8). For these patients the 5-year survival was just above 20%. Vascular invasion proved to be a statistical­ly significant prognostic factor. For patients with tumours with vascular invasion, the 5­year survival was just above 20%. We have to mention the problem of missing data for this particular prognostic factor, so we should be careful when interpreting the results. Prognostic factors for local recurrence The local recurrence occurred in 4.3 % of patients. Since the number of cases with local recurrence was small we used a simple cross-tabulation analysis (Table 1). Radiol Oncol 2006; 40(1): 23-8. Tumour grade, number of metastatic lymph nodes, surgical margins and hormonal receptors were prognostic factors for devel­opment of local recurrence. Prognostic factors for regional recurrence The regional recurrence occurred in 3.4% of patients. The total number of recurrences was 19. The total number of patients with metastatic axillary lymph nodes was 188. One recurrence was in the axilla, one in the parasternal region and 17 in the supraclavic­ular region (Table 2). The small number of events is a problem for statistical analysis. However, the number of metastatic lymph nodes in the axilla is a risk factor for supraclavicular recurrence in our patients. Table 1. Prognostic factors for local recurrence Discussion In the study we tried to evaluate the 5-year survival and locoregional control in our pa­tients after BCT and to establish eventual prognostic factors. The overall 5-year sur­vival was 88.5%. This result is similar to oth­er studies.1 Prognostic factors that had an impact on the survival were tumour size, nodes, grade, estrogen and progesterone re­ceptors, vascular invasion and local and re­gional failure. As expected, larger tumours led to lower survival probability. There was a marked dif­ference between tumours with diameter less than 2 cm compared to those with more than 2 cm (90% versus 70% 5-year survival). There was also a marked difference re­garding the tumour grade with lesser survival Prognostic factor % of Local recurrence Grade 1 – 1.8% Grade Grade 2 – 3.6% Grade 3 – 7.8% 0 – 2.7% Number of metastatic axillary lymph nodes <3 – 5.5% >3 – 14% Margins Free margins – 2.7% Involved – 12.5% Estrogen, progesterone Negative receptors . higher chance of local relapse Radiol Oncol 2006; 40(1): 23-8. probability in patients with less differentiated tumours. The number of metastatic axillary lymph nodes is a well established prognostic factor2 which was also confirmed in our study. Patients with negative lymph nodes had 90% 5-year survival probability, while those with more than three metastatic nodes had only 40%. The presence or absence of hormone re­ceptors had also an impact on the survival. Those patients who had positive receptors had higher survival probability. The same is true for patients who had tumours without vascular invasion. We have to mention that a lot of data was missing for this variable, so we Table 2. Number of metastatic lymph nodes and percentage of regional recurrence No of metastatic % of regional lymph nodes recurrence 0 1.6 1-3 6.3 >3 9 can not be conclusive regarding this prognos­tic factor. Local and regional failure influenced the survival. A recent meta-analysis confirmed the impact of local recurrence after BCT on survival which is similar to the impact of a re­currence after modified radical mastectomy. It is estimated that for 4 local relapses avoid­ed 1 life will be saved.1,2,6 Interestingly, age was not a significant prognostic factor for the survival. The local recurrence occurred in 4.3% of patients. This is comparable to other studies, where the local failure ranges from 1.2­ 20%.1,7-9 We tried to identify the prognostic factors for local recurrence, but the small number of patients with local recurrences made the analysis difficult. We found some impact of grade (higher grade, more recurrences), num­ber of metastatic lymph nodes (more metasta­tic lymph nodes, more relapses), surgical re­section (patients with involved margins had Radiol Oncol 2006; 40(1): 23-8. more local recurrences) and the receptor sta­tus (positive receptors, better prognosis). The regional recurrence was less common, with 3.4% of patients. Most of the regional re­currences developed in the supraclavicular fossa and only one in the axilla. Therefore we conclude that there is no need to irradiate the axilla after an axillary dissection even if metastatic lymph nodes were found at the operation. Conclusions Survival and locoregional control rates in our patients are comparable to those reported in the literature. Axillary recurrence is rare after an axillary dissection even in patients with >3 metastatic lymph nodes without RT to the ax-illa. References 1. Mirza NQ, Vlastos G, Meric F, Bucholz TA, Esnaola N, Singletary E, et.al. Predictors of locore­gional recurrence among patients with early stage breast cancer treated with breast conserving ther­apy. Ann Sur Oncol 2002; 9: 256-65. 2. Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans E, et al; Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the ran-domised trials. Lancet 2005; 366: 2087-106. 3. Majdic E. Can axillary treatment in selected breast cancer patients be avoided? Radiol Oncol 2000; 34: 255. 4. Van der Hage JA, Putter H, Bonnema J, Bartelink H, Therasse P, Van der Velde CHJ. Impact on lo-coregional treatment on the early stage breast can­cer patients: a retrospective analysis. Eur J Cancer 2003; 39: 2192-99. 5. Dinshaw KA, Budrukkar AN, Chinoy RF, Sarin R, Badwe R, Hawaldar B, et al. Profile of prognostic factors in 1022 indian women with early stage breast cancer treated with breast conserving ther­apy. Int J Radiat Oncol Biol Phys 2005; 36: 1132-41. 6. Whelan T, Clark R, Roberts R, Levine M, Foster G. Ipsilateral breast tumor recurrence post lumpecto­my is predictive of subsequent mortality: results from a randomized trial. Int J Radiat Oncol Biol Phys 1994; 30: 11-6. 7. Straus K, Lichter A, Lippman M, Danforth D, Swain S, Cowan K, et al. Results of the national cancer institute early breast cancer trial. J Natl Cancer Inst Monogr 1992; 11: 27-32. 8. Cabioglu N, Hunt KK, Buchholz TA, Mirza N, Singletary SE, Kuerer HM, et.al. Improving local control with breast conserving therapy: a 27 year single institute experience. Cancer 2005; 104: 20-9. 9. Vinh-Hung V, Verschraegen C. Breast-conserving surgery with or without radiotherapy: pooled-analysis for risks of ipsilateral breast tumor recur­rence and mortality. J Natl Cancer Inst 2004; 96: 115-21. Radiol Oncol 2006; 40(1): 23-8. case report Neck extensor muscle weakness (Dropped head syndrome) following radiotherapy Sumita Bhatia, Robert C. Miller, Daniel L. Lachance Department of Radiation Oncology (S.B., R.C.M) and Department of Neurology (D.L.L.), Mayo Clinic, Rochester, Minnesota, 55905, USA Background. Dropped head syndrome is an unusual condition in which the head cannot be held upright in its normal anatomic position secondary to pronounced, isolated, neck extensor muscle weakness. Case report. A case of dropped head syndrome in a female with a history of radiotherapy for Hodgkin’s lymphoma and a clinical history consistent with multiple sclerosis is presented, and potential etiologies are discussed. Conclusions. Muscular atrophy and lower motor neuron injury secondary to isolated anterior horn cell in­jury from radiotherapy emerge as the most likely etiology. Key words: Hodgkin disease - radiotherapy; muscular athrophy; muscle weakness; head Introduction Case report Dropped head syndrome, a result of neck ex­tensor weakness, is a rare but striking clinical entity. Patients with this condition experience significant neck muscle weakness that leads to an inability to elevate the head from the chest. Our report presents a case of a woman with a clinical history of probable multiple sclerosis (MS) who developed dropped head syndrome after sequential courses of thoracic and cervical spine irradiation ten years apart. Received 30 January 2006 Accepted 9 February 2006 Correspondence to: Assist. Prof. Robert C. Miller, MD, Division of Radiation Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; Phone: +1 507 284-2949; Fax: +1 (507) 284-0079. In 1972 a 46 year old female presented with mild, intermittent symptoms of diploplia, dysarthria, fatigue, ataxia, and incoordinan­tion and was subsequently diagnosed with probable multiple sclerosis on clinical grounds by an experienced neurologist at our institution. She had mild neurological deficits from approximately 1972 to 1995, correspon­ding to an Eastern Cooperative Oncology Group/Zubrod performance status of 1, with minimal relapses and no history to suggest transformation to secondary progressive MS. Her past medical history was otherwise unre­markable, although she had received four fractions of radiation therapy to the left wrist for a possible fracture of the pisiform bone in the 1940’s. In 1975, the patient presented with in­guinal adenopathy and a biopsy revealed mixed cellularity Hodgkin’s lymphoma (MCHL). Her clinical stage was IIA, with in­volvement of inguinal and external iliac adenopathy. She received treatment to the pelvis and para-aortic lymph nodes with ra­diotherapy using an “inverted Y-technique.” Approximately one year later, a chest x-ray revealed right hilar adenopathy. Salvage ra­diotherapy was instituted. She was treated with radiotherapy alone to a modified mantle radiotherapy field that also included the en­tire volume of both lungs to a dose of approx­imately 18 Gy followed by treatment to a tra­ditional mantle field to a total central axis dose of 33 Gy. The dose delivered to the cer­vical spinal cord from the C3 to C7 vertebral bodies was approximately 31.1 Gy in 16 frac­tions. The patient developed a pathologically con­firmed recurrence of MCHL ten years later, in 1986, in the right parotid gland. Treatment was once more in the form of radiotherapy alone, to dose of 36 to 44 Gy. Opposed lateral 6 MV photon beams were used to treat a field encompassing the neck and Waldeyer’s Ring, with 9 MeV electron beams being employed over the spinal cord to limit the maximum spinal cord dose in the cervical region to 9 Gy in 20 fractions. Assuming no unintended overlap of the matched radiotherapy fields, the total cervical spinal cord dose for all ra­diotherapy was approximately 41 Gy. She re­ceived no other therapy. There was no evidence of MS exacerbation or any other change in neurological function during or immediately after either course of radiotherapy. In 1995, the patient developed progressive neck extensor weakness result­ing in an inability to hold her head upright. A detailed exam by her neurologist demonstrat­ed new symmetrical, isolated neck extensor weakness with accompanying muscle atrophy. The neurological exam otherwise showed no changes in her chronic deficits consisting of a mild mixed spastic ataxic gait and mild dysarthria, which were presumed secondary to MS. A provisional diagnosis of “dropped head” or “floppy neck” syndrome was made. At presentation, the neck weakness was mild, but became progressively more severe, resulting in an inability to hold her head up­right without assistance over the next year. A Tensilon test was negative for myasthenia gravis. She never developed evidence of myelopathy over ten years of observation. However, over the last few years she has de­veloped progressive dysphagia seemingly re­lated to a combination of her baseline deficits, the severely flexed position of her head, and progressive bulbar weakness, eventually requiring initiation of gastrostomy tube feedings. We wondered if perhaps this weakness was in part related to the same process affecting her cervical segments given the likely exposure of her brainstem to radio­therapy when the localized parotid recurrence was treated. Unfortunately, the patient never had an EMG (electromyography) or magnetic resonance imaging (MRI) of her spinal axis to better define her condition. However, clinical­ly, she has not developed signs of more wide­spread motor neuron disease, paraneoplastic syndrome, or more widespread central nerv­ous system demyelination. The patient currently remains alive, free of recurrence of Hodgkin’s lymphoma (HL), but debilitated by age, multiple medical comor­bidities, and dropped head syndrome. Aggre­ssive interventions are being avoided and testing declined. Her neck extensor weakness has been managed with a soft cervical collar. Discussion Floppy head syndrome, also commonly re­ferred to as “dropped head syndrome”, is the result of isolated weakness of the neck exten­sor muscles, without evidence for a more widespread neuromuscular disorder. This syndrome is characterized by an inability of Radiol Oncol 2006; 40(1): 29-33. patients to elevate the chin from the chest, re­sulting in difficulty swallowing, speaking and breathing. Differential diagnosis for neck ex­tensor muscle weakness includes myasthenia gravis, a variety of primary myopathies, amy­otrophic lateral sclerosis, hypothyroidism, and disorders of the spine.1-3 It has been rarely been described as a late effect of exter­nal beam radiotherapy treatment, primarily following treatment of Hodgkin’s lym­phoma.4 In the current case, the etiological consid­erations are influenced by the occurence of multiple courses of radiotherapy, and a pre­existing neurological disorder which on the basis of history and examination in the pre MRI era was thought to be consistent with MS. Diagnostic considerations include 1) chronic progressive radiation myelopathy, 2) progression of the underlying chronic neuro­logical illness, 3) muscle atrophy secondary to radiotherapy, 4) selective cervical segment anterior horn cell injury specifically related to radiotherapy, or 5) neuromuscular disease unrelated to MS or radiotherapy but with predominant involvement of neck extensor muscles. This patient did not evolve the typical clin­ical findings of chronic, progressive, trans­verse radiation myelopathy. Reagen et al. de­scribed four manifestations of radiation in­duced myelopathy in 1969.5 The first syn­drome is that of a transient myelopathy, mostly manifesting Lhermitte’s symptom and other sensory disturbances. The second syn­drome manifests with rapidly evolving para­plegia or quadraplegia as a result of spinal cord infarction. The third syndrome of radia­tion myelopathy involves selective damage to anterior horn cells, resulting in limited distri­bution lower motor neuron disease. The fourth form manifests as a chronic progres­sive myelopathy. Typical symptoms of chron­ic progressive radiation myelopathy include pronounced sensory loss as well as weakness at all levels below the area of injured spinal cord. Patients experience sensory changes, particularly in the lower extremities, hyper-reflexia and other symptoms of spasticity, and bowel and bladder dysfunction. In our case, the patient exhibited only isolated neck extensor muscle weakness in the absence of sensory or reflex changes, making it unlikely that cord infarction or chronic progressive myelopathy were the etiology of her neuro­logical dysfunction. A second explanation for the patient’s dropped head syndrome would be progres­sion of her previously noted neurological ill­ness, provisionally MS, as offered by an ex­perienced Mayo Clinic neurologist before the era of MRI. An additional consideration in this regard would be the effect of irradiation on the spinal cord in a patient with MS. Although an increased risk of neurotoxicity in MS patients receiving spinal cord radio­therapy has not been reported in the medical literature, anecdotal cases of dramatic toxici­ty after brain irradiation have been pub­lished.6 Though demyelination in the spinal cord can be associated with significant lower motor neuron dysfunction in the segments af­fected, additional signs of myelopathy are al­most always apparent. It is noteworthy that this patient never developed any additional clinical evidence for more widespread central nervous system demyelination, including oth­er signs of progressive spinal cord dysfunc­tion. Whether or not the presence of an un­derlying demyelinating disorder played any role in the appearance of dropped head syn­drome in this patient could not be deter­mined. Gradual atrophy and lack of development of bone and muscle in children and adoles­cents following radiotherapy has been well documented.7 Adult survivors of HL also re­port neck and shoulder symptoms, although the effects of irradiation of adult muscles and bones shows markedly less effect than is typ­ically seen in children whose musculoskeletal systems are still not fully matured.8 Portlock Radiol Oncol 2006; 40(1): 29-33. et al. have reported a case of dropped head syndrome following Mantle irradiation for HL in which muscle biopsies confirmed the presence of non-inflammatory, nemaline my-opathy within the radiation treated area and its absence outside the treated region. Nemaline myopathy unrelated to radiothera­py has also been associated with dropped head syndrome.9 Though an isolated neck extensor myopa-thy due to radiotherapy cannot be excluded, we feel that the most likely explanation for this patient’s neck extensor weakness is low­er motor neuron dysfunction secondary to ra­diation toxicity in anterior horn cells of the cervical spinal cord. Sporadic case reports, beginning in 1948, have appeared in the med­ical literature describing a clinical picture of “isolated motor symptoms, amyotrophy, paresis, and fasciculations” resulting from ra­diation injury to anterior horn cells of the spinal and/or the most proximal segment of peripheral nerves.10 The majority of cases have followed treatment of testicular neo­plasms, resulting in lumbar lower motor neu­ron (LMN) disease, but some reports have de­scribed cervical LMN injury after irradiation of the cervical spine.11 Esik has provided a tabular review of 47 published cases of this syndrome and drawn parallels between this form of radiation injury and LMN injury fol­lowing viral infections. Although agreement does not exist in the medical literature re­garding the underlying mechanism of injury, LMN disease typically follows radiotherapy at doses lower than the typical threshold for chronic progressive radiation myelopathy, 45 Gy, and has been reported occurring in a number of cases below a dose of 30 Gy.12 Dropped head syndrome can be a poten­tially debilitating disease, resulting in dys­phagia, dyspnea, and traction injury of the spinal cord in severe cases, especially in an older individual with advanced cervical spondylosis. In evaluating patients with new­ly diagnosed, isolated neck extensor weak­ness, potentially treatable neuromuscular dis­orders should be first considered and exclud­ed. In the current case, differentiation be­tween the two most probable etiologies, a di­rect myopathic radiation injury versus muscle weakness secondary to LMN from anterior horn cell injury, was problematic as the pa­tient declined an aggressive investigative ap­proach. Cervical MRI, EMG, muscle biopsy and laboratory investigation might have pro­vided a more definitive diagnosis. In patients with neck extensor weakness, after elimination of potentially treatable dis­orders, care is primarily supportive. A collar or brace should be considered to provide sup­port for the head in a more anatomically nor­mal position to facilitate activities of daily liv­ing and to help prevent contractures of the neck in a fixed flexed posture. Investigational therapies for dropped head syndrome with immunoglobulin and surgery have been re­ported in case form.13,14 Isolated neck extensor weakness appears to be a rare complication of radiotherapy. This case highlights the selective vulnerabili­ty of muscle, motor neurons, or both to radi­ation, and the need to consider the potential relevance of concurrent neurological or neu­romuscular disease in the manifestation of this disabling condition. References 1. Gourie-Devi M, Nalini A, Sandhya S. Early or late appearance of “dropped head syndrome” in amy­otrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2003; 74: 683-6. 2. Suarez GA, Kelly JJ Jr. The dropped head syn­drome. Neurology 1992; 42: 1625-7. 3. Katz JS, Wolfe GI, Burns DK, Bryan WW, Fleckenstein JL, Barohn RJ. Isolated neck extensor myopathy: a common cause of dropped head syn­drome. Neurology 1996; 46: 917-21. 4. McFarlane VJ, Clein GP, Cole J, Cowley N, Illidge TM. Cervical neuropathy following mantle radio­therapy. Clin Oncol (R Coll Radiol) 2002; 14: 468-71. Radiol Oncol 2006; 40(1): 29-33. 5. Reagan TJ, Thomas JE, Colby MY Jr. Chronic pro­gressive radiation myelopathy. Its clinical aspects and differential diagnosis. JAMA 1968; 203: 106­10. 6. Peterson K, Rosenblum MK, Powers JM, Alvord E, Walker RW, Posner JB. Effect of brain irradiation on demyelinating lesions. Neurology 1993; 43: 2105-12. 7. Larson DL, Kroll S, Jaffe N, Serure A, Goepfert H. Long-term effects of radiotherapy in childhood and adolescence. Am J Surg 1990; 160(4): 348-51. 8. Johansson AS, Erlanson M, Lenner P, Lindh J, Osterman B. Late side effects are common after treatment of Hodgkin’s disease. Muscular atrophy following radiotherapy is a neglected risk. [Swedish]. Lakartidningen 1998; 95: 44-7. 9. Portlock CS, Boland P, Hays AP, Antonescu CR, Rosenblum MK. Nemaline myopathy: a possible late complication of Hodgkin’s disease therapy. Hum Pathol 2003; 34: 816-8. 10. Tallaksen CM, Jetne V, Fossa S. Postradiation low­er motor neuron syndrome - a case report and brief literature review. Acta Oncol 1997; 36: 345-7. 11. Tan SV, Pye IF. Postradiation motor neuron syn­drome of the upper cervical region-a manifestation of the combined effect of cranial irradiation and intrathecal chemotherapy? J Neurol Neurosurg Psychiatry. 1991; 54: 469-70. 12. Esik O, Vonoczky K, Lengyel Z, Safrany G, Tron L. Characteristics of radiogenic lower motor neurone disease, a possible link with a preceding viral in­fection. Spinal Cord 2004; 42: 99-105. 13. Dominick J, Sheean G, Schleimer J, Wixom C. Response of the dropped head/bent spine syn­drome to treatment with intravenous im­munoglobulin. Muscle Nerve 2006 18; [Epub ahead of print]. 14. Amin A, Casey AT, Etherington G. Is there a role for surgery in the management of dropped head syndrome? Br J Neurosurg 2004; 18(3): 289-93. Radiol Oncol 2006; 40(1): 29-33. case report Ameloblastic fibroma Marko Božic and Nataša Ihan Hren Clinical Department of Maxillofacial and Oral Surgery; University Clinical Centre, Ljubljana, Slovenia Background. Ameloblastic fibroma (AF) is a rare odontogenic tumour. It consists of odontogenic ectomes­enchyme resembling the dental papilla and epithelium resembling dental lamina and enamel organ without dental hard tissues. Case report. A case report of a large ameloblastic fibroma involving the body of mandible from the lower left second incisor (32) to the lower left second molar (37) is presented. To our knowledge this is the only case of ameloblastic fibroma reported from Slovenia. Conclusions. An aggressive surgical treatment is suggested because of the possibility of recurrence and the possibility of malignant transformation of an AF to an ameloblastic fibrosarcoma. Key words: fibroma; odontoma; mandibula neoplasms Introduction Despite Ameloblastic fibroma (AF) is a rare odontogenic tumour, it occurs predominantly in children and therefore remain an impor­tant diagnostic consideration.1 It usually aris­es from the mandibular dentition although it can arise in maxilla.2 AF consists of odontogenic ectomes­enchyme resembling the dental papilla and epithelium resembling dental lamina and Received 15 February 2006 Accepted 28 February 2006 Correspondence to: Marko Božic, M.D., Clinical Department of Maxillofacial and Oral Surgery, University Clinical Centre Ljubljana, Zaloška 2, 1000 Ljubljana, Slovenia; Phone: +386 40 579 112; Fax: +386 15222495; E-mail: marko.bozic@medscape.com enamel organ without dental hard tissues.3 Knowledge of the malignant potential in the mesenchymal spindle cells of AF should assist in determining the management of these be­nign tumours, and may prevent malignant transformation to ameloblastic fibrosarcoma.4 At the Clinical Department of Maxill­ofacial and Oral Surgery in Ljubljana this is the only case of this tumour and to our knowledge the only one in Slovenia. Table 1 presents the frequency of odontogenic tu­mours from June 1995 to June 2005. Case report A 23-years old Caucasian asymptomatic woman visited her dentist in March 2004. On dental panoramic tomogram (DPT) a radiolu-cent lesion formed from three separate com­ Table 1. Odontogenic tumours seen at the Clinical Department of Maxillofacial and Oral Surgery in Ljubljana, Slovenia from June 1995 to June 2005. Tumour Number of cases Relative frequency among odontogenic tumours (%) Ameloblastoma 20 35.1 Odontogenic myxoma 3 5.3 Ameloblastic fibroma 1 1.8 Adenomatoid odontogenic tumour 2 3.5 Ameloblastic Fibrodentinoma 1 1.8 Cementoma 1 1.8 Odontogenic Fibroma (peripheral) 4 7.0 Calcifying Odontogenic Cyst 4 7.0 Complex Odontoma 21 36.8 Total 57 100 partments from the region 32 to 36 was found (Figure 1A). In February 2005 another DPT showed the lesion had increased. The roots of the teeth 35 and 36 were resorbed. The lesion was presumed to be a cyst so she was not sent to a maxillofacial surgeon before May 2005. The patient’s family anamnesis was posi­tive for neoplasms, diabetes and coronary heart disease. Her brother has Down’s syn­drome. A large hard swelling under intact soft tis­sues was palpated in the lower left vestibu­lum, all teeth were vital. A pathohistologic examination showed strands of odontogenic epithelium. In the centre the cells were focally similar to the em­bryonic stellate reticulum. The epithelial is­lands were surrounded by a rich mesenchy­mal component reminiscent of the dental papilla cells. Rare mitoses were present and the nuclear polymorphism was minimally ex­pressed. The teeth 31, 32, 33 and 37 were endodon­tically filled before surgery (Figure 1B), and then the extirpation of the tumour and the surrounding bone with nerve preservation was done. The teeth 33, 35 and 36 were ex­tracted and the teeth 31, 32 and 37 were apiectomized (Figure 1C). The postoperative course was uneventful with good bone regeneration (Figure 1D). A long-term follow-up and an implant-prostho­dontic treatment is planned. Discussion The relative frequency of AF among odonto­genic tumours seen at the Clinical Department of Maxillofacial and Oral Surgery in Ljubljana (1.8%) is within the fre­quencies described in the literature,5 al­though in some other countries it is more fre­quent.6 The age of described patient is above the mean age at presentation being 14.8 years.3 Our AF was incidentally found as 17% of the cases in a survey of 24 cases of AF from the Armed Forces Institute of Pathology.7 An aggressive surgical treatment is sug­gested by some authors because of the possi­bility of malignant transformation of an AF to an ameloblastic fibrosarcoma.8,9 Muller et al.8 reported that since 1960 44% cases of ameloblastic fibrosarcoma (19/43) arose from AF. There is also the consideration that the majority, if not all, of AFs are true neoplasms with a potential to recur and/or of malignant transformation and that some, especially those occurring during childhood, could rep­resent the primitive stage of a developing odontoma.10 The recurrence rate of AF found by Trodahl et al.7 was 43.5%; on the other hand Radiol Oncol 2006; 40(1): 35-8. Figure 1. A - March 2004 when the lesion was discovered; B - preoperative dental panoramic tomogram (July 2005); C - postoperative dental panoramic tomogram; D - two months after the operation. by Zallen et al.11 it was 18.3% after reviewing the literature with 85 cases of AF. Lysell and Sund12 proposed the incomplete primary re­moval as a reason of recurrence in their cas­es. This was supported by Mosby et al.13 ex­plaining that after the complete removal of a tumour clinically, this cannot be stated at a cellular level. They suggest the conservative removal of AF and modified block resection of any recurrence. No matter what the reason of recurrence is, all authors agree that a long­term follow-up is necessary. References 1. Jones AV, Franklin CD. An analysis of oral and maxillofacial pathology found in children over a 30-year period. Int J Paediatr Dent 2006; 16: 19-30. 2. Pereira KD, Bennett KM, Elkins TP, Qu Z. Ameloblastic fibroma of the maxillary sinus. Int J Pediatr Otorhinolaryngol 2004; 68: 1473-7. 3. Slootweg PJ. Ameloblastic fibroma/fibrodentino-ma. In: Barnes L, Eveson JW, Reichart P, Sidransky D, editors. World Health Organisation classification of tumours. Pathology and genetics of head and neck tumours. Lyon: IARC Press; 2005. 4. Kobayashi K, Murakami R, Fujii T, Hirano A. Malignant transformation of ameloblastic fibroma to ameloblastic fibrosarcoma: case report and re­view of the literature. J Craniomaxillofac Surg 2005; 33: 352-5. 5. Adebayo ET, Ajike SO, Adekeye EO. A review of 318 odontogenic tumors in Kaduna, Nigeria. J Oral Maxillofac Surg 2005; 63: 811-9. 6. Tamme T, Soots M, Kulla A, Karu K, Hanstein SM, Sokk A, et al. Odontogenic tumours, a collabora­tive retrospective study of 75 cases covering more than 25 years from Estonia. J Craniomaxillofac Surg 2004; 32: 161-5. Radiol Oncol 2006; 40(1): 35-8. 7. Trodahl JN. Ameloblastic fibroma. A survey of cases from the Armed Forces Institute of Pathology. Oral Surg Oral Med Oral Pathol 1972; 33: 547-58. 8. Muller S, Parker DC, Kapadia SB, Budnick SD, Barnes EL. Ameloblastic fibrosarcoma of the jaws. A clinicopathologic and DNA analysis of five cas­es and review of the literature with discussion of its relationship to ameloblastic fibroma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995; 79: 469-77. 9. Takeda Y, Kaneko R, Suzuki A. Ameloblastic fi­brosarcoma in the maxilla, malignant transforma­tion of ameloblastic fibroma. Virchows Arch A Pathol Anat Histopathol 1984; 404: 253-63. 10. Chen Y, Li TJ, Gao Y, Yu SF. Ameloblastic fibroma and related lesions: a clinicopathologic study with reference to their nature and interrelationship. J Oral Pathol Med 2005; 34: 588-95. 11. Zallen RD, Preskar MH, McClary SA. Amelo­blastic fibroma. J Oral Maxillofac Surg 1982; 40: 513-7. 12. Lysell L, Sund G. Ameloblastic fibroma: report of two cases. Br J Oral Surg 1978; 16: 78-85. 13. Mosby EL, Russell D, Noren S, Barker BF. Ameloblastic fibroma in a 7-week-old infant: a case report and review of the literature. J Oral Maxillofac Surg 1998; 0368-72. Radiol Oncol 2006; 40(1): 35-8. case report Erlotinib in previously treated non-small-cell lung cancer Uroš Smrdel, Viljem Kovac Department of Radiotherapy, Institute of Oncology Ljubljana, Ljubljana, Slovenia Background. Erlotinib is a novel biological anti-tumour agent in the treatment of advanced non small cell lung cancer. It represents the molecularly-targeted therapy which has been studied extensively. Case report. We present a case of a patient who suffered from advanced non-small-cell lung cancer. After the progress of disease following a prior chemotherapy he was treated with erlotinib with remarkable effect which was shown at chest x ray and symptoms were quite reduced. Conclusions. In selected patients with advanced non-small-cell lung cancer Erlotinib improves survival and symptom control as it results in presented case. Key words: carcinoma, non-small-cell lung; antineoplastic agents Introduction In Europe lung cancer ranks first among all cancers and cancer related deaths in men and fourth in women. Similarly in Slovenia lung cancer ranks first in men with 787 new cases in year 2002 and fifth in women with 258 cas­es.1 Between 80 - 85% of cases are non small cell lung cancers. A majority of patients is presented in advanced or locally advanced stages, and therefore these patients are not candidates for potentially curative resection. In patients with advanced disease our current treatment of choice is platinum based Received 15 February 2006 Accepted 28 February 2006 Correspondence to: Uroš Smrdel, M.D., Department of Radiotherapy, Institute of Oncology; Zaloška 2, 1000 Ljubljana, Slovenia; Phone +386 1 5879 622; Fax +386 1 5879 400; E-mail: usmrdel@onko-i.si chemotherapy with the newer agents, mostly with gemcitabine in the initial setting.2,3 For patients who progress after achieving re­sponse to the primary treatment therapeutic option is the treatment with taxanes (e.g.doc­etaxel),4 pemetrexed5 or a novel antitumour agent in a clinical trial.6-8 Over the past few years, a number of new agents have become available for the treat­ment of metastatic non-small-cell lung can­cer, including the inhibitors of receptors of tyrosine kinase.9,10 Such a novel biological antitumor agent is erlotinib (Tarceva).11,12 Erlotinib is a small molecule inhibitor of HER1/EGFR tyrosine kinase; chemically it belongs to the quinazoline class and is orally available.13 It binds to an intracellular part of epidermal growth factor receptor and de­creases tumour proliferation, invasion, metastases formation angiogenesis and tu­mour cell adhesion, while it increases apopto-sis and probably also the sensitivity to chemotherapy. Among patients with non­small-cell lung cancer who receive erlotinib, the presence of an EGFR mutation may in­crease responsiveness to the agent, but it is not indicative of a survival benefit.14,15 In 2005 we enrolled in the study treatment with erlotinib through Tarceva EAP (extend­ed access protocol). In this report we would like to present a case of our first patient treat­ed with erlotinib. Case report Fifty-eight-year old male patient was present­ed for the first time in year 2003. He suffered from fatigue and dyspnoea on exercise. These symptoms lasted for two years. The patient was a former smoker who smoked for 30 years up to 20 cigarettes a day; seven years ago he stopped smoking. On chest X ray there was a left sided pleu­ral effusion and indurated right hilus. Bronhoscopy revealed stenosis of the mid­dle lobe bronchus and bronchus for the 6th left lobe, where mucosa was also granulated and bled at touch. Histologicaly invasive adenocarcinoma was confirmed in specimen taken at bron­hoscopy. Cytology of pleural effusion was twice negative at malignant cells. At the clinical examination we found a lymph node at the right supraclavicular re­gion. The initial stage at diagnosis was T4N3Mx; re-evaluation of native chest X rays showed metastatic lesions in both lungs, therefore the stage was T4N3M1. The patient was in good condition, Karnofsky performance status at the time of diagnosis was assessed at 80%. The patient received chemotherapy with cisplatinum and gemcitabine in the pro­longed infuse for 6 cycles, the maximal re­sponse was stagnation. The leading symptom was dyspnoea. Ten months after the completion of treat­ment chest X ray showed a progressing in lung, while the performance status deterio­rated gradually. In February 2005 the patient started the treatment with erlotinib. At the beginning of the treatment chest x ray showed the left sided pleural effusion, with patchy infiltrates centrally in both lungs, while in the periphery there were multiple small nodular lesions (Figure 1). After a month of the treatment with er-lotinib the patient’s general condition im­proved and his breathing improved too. Of the adverse effects he presented with GII rash. Radiol Oncol 2006; 40(1): 39-42. The improvement was seen also in chest X ray, with diminishing and rarefication of nodes shown in the periphery and also with the improvement of centrally located infil­trate. After two months of the treatment there was a further regression of all lesions seen on X ray (Figure 2). The patient resumed with his work as a public employee. Until January 2006 the patient was in a partial remission. He was employed; his only complaint was rash, which persisted. Upon progression the patient had more in­filtrates on X ray, his performance status was still excellent (Karnofsky 90). The patient continued treatment with chemotherapy with paclitaxel and carboplat­inum. Discussion In advanced non small cell lung cancer the aim of the treatment is to improve the sur­vival and the quality of life (ref. meta-analy-sis).3 The survival in advanced non small cell lung cancer is still not as good as in some oth­er types of advanced cancer (e. g. breast).16,17 The treatment with platinum based doublets had achieved some degree of the disease con­trol but the survival remains in range of 9 months to 1 year.16,18 This has been improved slightly by the introduction of the second line chemotherapy with docetaxel or pemetrexed, which have a moderate efficacy and is rea­sonably well tolerated.4,5,8 However, the mode of action of erlotinib differs from that of less specific agents - both, in terms of anti-tumour activity and side ef­fects.19 The use of erlotinib is not connected with any significant degree of nausea and vomiting, the main side effect remains rash, which is usually well manageable and does not interfere with everyday functioning.21 Care should be taken of diarrhoea, which can be potentially life threatening so it is vital to ensure the patient’s compliance with regimen and understanding of specific side effects.22 Oral medication is usually preferred over i. v. infusion. But one must bear in mind that spe­cific targeting of erlotinib means also that a significant proportion of patients receiving the drug will not benefit from it and that those would therefore benefit from early dis­continuation and change of the treatment strategy. We can, therefore, presume that in selected patients, erlotinib not only improves the sur­vival, but also improves the quality of life.8,15 According to the study by Sheppard et al., this beneficial effect is not restricted only to fe­male Asian non-smokers with lung adenocar­cinoma but also to other patients as our pa­tient witness.6 However, a careful monitoring of patient is needed and a discontinuation of the treat­ment at first signs of progressive disease and the reconsideration of other treatment op­tions is warranted. Our patient was not chemonaive, but re­ceived only the first line chemotherapy, so there is still a chance that he will respond to the second line chemotherapy. Furthermore, as his performance status improved, he is now probably a better candidate for the fur­ther treatment. Conclusions The patient we are presenting has clearly ben­efited from the treatment with erlotinib. However, even though he has progressed af­ter a year of the treatment he is still in a bet­ter clinical condition as before the treatment, likewise, despite his progression, radiologi­caly his tumour burden is still smaller than before the treatment. Radiol Oncol 2006; 40(1): 39-42. References 1. Cancer Registry of Slovenia. Cancer incidence in Slovenia 2000. Report No. 44. Ljubljana: Institute of Oncology Ljubljana; 2005. 2. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al, for the Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer: N Engl J Med 2002; 346: 92-8. 3. Kovac V, Smrdel U. Meta-analyses of clinical trials in patients with non-small cell lung cancer. Neoplasma 2004; 51: 334-40. 4. Barlesi F, Jacot W, Astoul P, Pujol JL. Second-line treatment for advanced non-small cell lung can­cer: a systematic review. Lung Cancer 2006; 51: 159-72. 5. Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previous­ly treated with chemotherapy. J Clin Oncol 2004; 22: 1589-97. 6. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al; National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353: 123-32. 7. Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: re­sults from a randomised, placebo-controlled, mul­ticentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005; 366: 1527-37. 8. de Marinis F, De Santis S, De Petris L. Second-line treatment options in non-small cell lung cancer: a comparison of cytotoxic agents and targeted ther­apies. Semin Oncol 2006; 33(1 Suppl 1): S17-24. 9. Giaccone G. Epidermal growth factor receptor in­hibitors in the treatment of non-small-cell lung cancer. J Clin Oncol 2005; 23: 3235-42. 10. Miller VA. Optimizing therapy in previously treat­ed non-small cell lung cancer. Semin Oncol 2006; 33(1 Suppl 1): S25-31. 11. Perez-Soler R. The role of erlotinib (Tarceva, OSI 774) in the treatment of non-small cell lung can­cer. Clin Cancer Res 2004; 10(12 Pt 2): 4238s-40s. 12. Tang PA, Tsao MS, Moore MJ. A review of er-lotinib and its clinical use. Expert Opin Pharmacother 2006; 7: 177-93. 13. Tamura K, Fukuoka M. Molecular target-based cancer therapy: tyrosine kinase inhibitors. Int J Clin Oncol 2003; 8: 207-11. 14. Johnson BE, Janne PA. Epidermal growth factor re­ceptor mutations in patients with non-small cell lung cancer. Cancer Res 2005; 65: 7525-9. 15. Tsao MS, Sakurada A, Cutz JC, Zhu CQ, Kamel-Reid S, Squire J, et al. Erlotinib in lung cancer ­molecular and clinical predictors of outcome. N Engl J Med 2005; 353: 133-44. 16. Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Brit Med J 1995; 311: 899-909. 17. Pompe-Kirn V, Zakotnik B, Zadnik V. Cancer pa­tients survival in Slovenia. Ljubljana: Istitute of Oncology Ljubljana; 2003. p. 30-4. 18. Le Chevalier T, Scagliotti G, Natale R, Danson S, Rosell R, Stahel R, et al. Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimens in advanced non­small-cell lung cancer: a meta-analysis of survival outcomes. Lung Cancer 2005; 47: 69-80. 19. Perez-Soler R, Chachoua A, Hammond LA, Rowinsky EK, Huberman M, Karp D, et al. Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung can­cer. J Clin Oncol 2004; 22: 3238-47. 20. Krause DS, Van Etten RA. Tyrosine kinases as tar­gets for cancer therapy. N Engl J Med 2005; 353: 172-87. 21. Ramalingam S, Belani CP. Molecularly-targeted therapies for non-small cell lung cancer. Expert Opin Pharmacother 2005; 6: 2667-79. 22. Blackhall FH, Rehman S, Thatcher N. Erlotinib in non-small cell lung cancer: a review. Expert Opin Pharmacother 2005; 6: 995-1002. Radiol Oncol 2006; 40(1): 39-42. Phytohaemagglutinin as a modulator of DNA repair measured by chromosome aberration analysis in micronucleus assay in ionizing radiation biodosimetry Martina Đurinec, Davor Želježic and Vera Garaj-Vrhovac Institute for Medical Research and Occupational Health, Mutagenesis Unit, Zagreb, Croatia Background. There are some correlations between cell’s ability to remove DNA damage and proliferative activity. The aim of this study was to examine the influence of phytohaemagglutinin (PHA) on DNA repair capacity in isolated human lymphocytes exposed to ionizing radiation. Methods. Lymphocytes were isolated from the whole blood using a Ficoll centrifugation. As the source of .-rays 60Co source Alcon, CGR-MeV was used. To achieve the absorbed dose of 2 Gy a total exposure to ra­diation lasted for 1.24 minutes at room temperature. Possible differences in DNA repair efficiency were monitored by chromosomal aberration analysis and micronucleus assay, 48 and 72 h after the PHA stimu­lation, respectively. Results. The number of dicentric chromosomes and acentric fragments were significantly increased in lym­phocytes stimulated by phytohaemagglutinin immediately after the irradiation compared to the cultures where the activator was added after 1, 2 and 4 h. The micronucleus assay did not show any significant dif­ferences in the number and distribution of micronuclei regardless of the time when the mitogen activator was added. Conclusions. The observed non-significant decreases in the total number of chromosomal aberration and micronuclei suggest that phytohaemagglutinin does not significantly contribute to the DNA repair. Key words: ionizing radiation; DNA damage; DNA repair; phytohaemagglutinins; chromosome aberra­tions; micronucleus test Received 10 January 2006 Accepted 9 February 2006 Correspondence to: Martina Đurinec, BSc, Institute for Medical Research and Occupational Health, Mutagenesis Unit, Ksaverska cesta 2, Zagreb, Croatia. Phone: +385 1 467 31 88; E-mail: djurinec@imi.hr Introduction During the last few decades ionizing radia­tion became unavoidably present in human lives. It is widely used in the variety of med­ical diagnostic procedures as electric energy source of nuclear power plants. It affects a human organism on daily basis in the form of cosmic radiation. Since air flights are becom­ing more common way of travelling, and it is known that cosmic radiation is significantly higher in upper layers of the atmospheres, the total dose population is expected to in­creases. It is known that ionizing radiation (IR) deposits its energy in cellular structures through discrete ionization events that are es­sentially randomly distributed in space. Unlike chemical agents, whose damaging po­tential is strongly dependent on diffusion processes and thus may be affected by sub-cellular structures, IR is highly penetrating: the physics and subsequent chemistry associ­ated with the photon absorption and the ion­izing events that occur along fast electron track are complete within a few microsec­onds.1 Ionizing radiation causes a wide spec­trum of chemically different types of lesions in DNA of which the so-called locally multi­ply damaged sites (LMDS) are assumed to be biologically most important.2,3 LMDS may consist of single-strand breaks (SSB) on op­posite strands that, if located close to each other, may give rise to double strand breaks (DSB).4 Thus, DSB induced by IR may arise as a direct consequence of one or more ionizing events or indirectly as a base or sugar damage on opposite strands. Ionizing radiation in physicochemical interaction with cellular DNA also produces a variety of primary le­sions, alkali-labile sites, DNA-DNA and DNA- protein crosslinks, and damage to purine and pyrimidine bases.5-8 DNA double strand breaks (DSB) are the most serious form of DNA damage. There are two path­ways for the repair of DSB.9 One is homolo­gous recombination (HR) which occurs dur­ing late S and G2 phase of the cell cycle and the other pathway is non homologous DNA end joining (NHEJ). It is predominant during G0, G1 and S phase of the cell cycle.10 If not repaired, DNA lesions could cause cell death. If misrepaired, DSBs contribute to chromoso­mal aberrations and genomic instability. Ionizing radiation produces chromosome aberrations (involving two chromatids) at the S phase and the chromatid aberrations at G2. To detect genetic alterations at the chromo­some level using chromosome aberration and micronucleus assay the cells should be in­duced to enter the G1 phase and undergo di­vision.11-14 Phytohaemagglutinin (PHA) selectively stimulates T lymphocytes to enter mitosis. The widespread popularity of peripheral blood culture as means of chromosome analysis has been largely dependent on that mitogen.15-23 There is some correlation be­tween cell’s ability to remove the DNA dam­age and its proliferative activity. It is well es­tablished that unstable aberrations like dicen­tric chromosomes, chromosome breaks and acentric fragments can be eliminated during the cell division. It was suggested that the regulation of DNA repair is dependent on cell cycle. It involves the expression of DNA re­pair enzymes within the defined program of gene control during the cell cycle. Some au­thors have shown that immediately after the irradiation mitogen-stimulated cells have a higher frequency of chromosome aberrations than the cells resting in G0 phase before the addition of mitogens.15 Our study aimed to examine the influence of PHA on DNA repair capacity of isolated human lymphocytes. Cell cultures were start­ed and PHA was added 0, 1, 2 and 4 h after the irradiation. Possible differences in the DNA repair efficiency was monitored by chromosomal aberration analysis and mi-cronucleus assay, 48 and 72 h after the PHA stimulation, respectively. Methods Isolation of lymphocytes The whole blood sample was taken from the cubital vein of a healthy adult male volunteer using heparinized vacutainer (Becton Dickinson, USA). There is no record that pri­or to the study the volunteer was exposed to any physical or chemical agent that might in- Radiol Oncol 2006; 40(1): 43-9. terfere with the results. Lymphocytes were isolated from the whole blood sample by a Ficoll centrifugation method.24 One milliliter of the whole blood was resuspended in 8 ml of Ham’s F-10 essential medium supplement­ed with L-glutamine, bovine serum (20%), penicillin (100 I.U./ml) and streptomycin (100 µg/ml). Irradiation of isolated lymphocyte As the source of .-rays 60Co source Alcyon, CGR-MeV was used. Vacutainer containing isolated lymphocytes was mounted in an acrylic phantom (dimensions: 20x20x15 cm3), in depth of 5.5 cm, transversally to the axis of the irradiation. The radiation field was 15 x 15 cm2, and the distance between the surface of phantom and the source of radiation was 80 cm. At total exposure to radiation lasted for 1.24 min at room temperature, thus the absorbed dose was 2 Gy. Cultivation of lymphocytes Phytohaemagglutinin (Murex Biotech Ltd.) (0,2ml) was added to lymphocyte cultures ei­ther immediately after the irradiation or after a certain recovery period (1, 2 or 4 h). Meanwhile cultures were held at 37°C.13 Since the analysis was done in duplicate, for each stimulation time, 4 different cultures were started: for the chromosomal aberration analysis and for the micronucleus assay. The analysis of structural chromosome aberrations The structural chromosome aberration analy­sis test was performed according to current IAEA guidelines.25 Simultaneously with cul­tures for the micronuclei assay, cultures for the chromosome aberration test were set up in the same manner. Duplicate cultures per sample were set up and incubated at 37°C for 48 h. After the PHA stimulation to arrest di­viding lymphocytes in metaphase, colchicine (Sigma) (0.004%) was added 2 h prior to the harvest. Cultures were centrifuged at 1000 rpm for 10 min, the supernatant was care­fully removed, and the cells were resuspend­ed in a hypotonic solution (0.075M KCl) at 37°C for 20 min. After the second centrifu­gation, the cells were fixed with a freshly prepared fixative of ice-cold methanol/gla­cial acetic acid (v/v 3:1). Fixation and cen­trifugation were repeated several times until the supernatants were clear. The cell sus­pension was dropped onto microscope slides and left to air-dry. Slides were stained with 5% Giemsa solution (Merck). For each stimulation analysis was done in duplicate, a total number of 200 methaphases was scored. Structural chromosome aberrations were classified based on the number of sis­ter chromatids and breakage events in­volved. Only metaphases containing 46 cen­tromeres were analyzed. A total number of each type of aberrations, as well as the per­centage of aberrant cells per subject were evaluated. Micronucleus assay The micronucleus assay was performed as described by Fenech and Morley with some modifications.26 After the irradiation lympho­cyte cultures were set up by adding 1 ml of isolated lymphocytes to 8 ml of F-10 medium (Sigma) supplemented with foetal calf serum (Sigma) and antibiotics penicillin (Pliva) and streptomycin (Krka). Following the stimula­tion with PHA, lymphocytes were incubated in vitro for 72 h at 37°C. Cytochalasin-B (Sigma) at the final concentration of 6 mg/ml was added to each culture at 44 h, and the cells were harvested after a further incubation of 28 h. After the treatment with physiological saline, cells were fixed with cold fixative, a mixture of methanol: acetic acid (v/v 3:1). The fixation step was repeated twice and cells were resuspended in a small volume of fixa­tive solution and dropped onto clean slides. Radiol Oncol 2006; 40(1): 43-9. Finally, they were stained with 5% aqueous solution of Giemsa dye (Merck) for 10 min­utes. For each stimulation the analysis was done in duplicate, thus a total of 500 binu­clear lymphocytes were scored. The data are expressed as the number of micronuclei per 500 binucleated cells as well as the frequency of binucleated cells containing one or more micronuclei. Statistical analysis The statistical significance of the results ob­tained was evaluated using the .2 - test. The level of statistical significance was set at 5%. Chi-Square test was used to compare the fre­quencies of chromosomal aberration and mi-cronuclei. Results Chromosomal aberration analysis The number of dicentric chromosomes and acentric fragments was found to be signifi­cantly increased in all irradiated lymphocytes regardless of the start point of the PHA stim­ulation compared to the control (p<5%). In ir­radiation exposed sample there were 97 acen­tric fragments and 12 dicentrics observed in PHA stimulated lymphocytes whereas in the control no dicentrics and 4 acentic fragments were found. The number of aberrations be­tween cultures stimulated 1, 2 and 4 hours af­ter the irradiation did not differ significantly (p< 5%). In cultures stimulated with PHA 1, 2 and 4 hours after the irradiation the number of acentric chromosomes and dicentric chromo­somes significantly decreased compared to the cultures where mitogen was added imme­diately after the irradiation. One hour after the irradiation the number of acentrics was 57, two hours after the irradiation the number of acentric chromosomes was 69 and four hours after the irradiation the number of acentrics was 48. The number of dicentric chromosomes decreased compared to the number of acentric chromosomes. Immedia­tely after the irradiation the number of dicen­tric chromosomes was 12, one hour after the stimulation the number of dicentrics was 1. Still, the difference in the number of di­centrics was not found to be significant (Table 1). Micronucleus assay Using micronucleus assay no significant dif­ferences in number of micronuclei were ob- Table 1. Total number and distribution of chromosome aberrations in isolated human lymphocytes stimulated to proliferate after the indicated post-irradiation periods. Two hundred cells were analyzed per each PHA stimula­tion point. Time after Total number Chromatid Chromosome Acentric Dicentric %of cells with irradiation of abberations breaks breaks fragments chromosomes abberations Isolated lymphocytes irradiated with 2 Gy 0 h 112a 3 / 97a 12a 38.0 1 h 58a,b / / 57a,b 1 21.5 2 h 76a,b 1 1 69a,b 5 29.0 4 h 53a,b / / 48b 5 23.0 Non-irradiated samples Lymphocytes 4 / / 4 / 2.0 Whole blood 2 / / 2 / 1.0 astatistically significant compared to the control P < 0.05 bstatistically significant compared to the 0h PHA stimulation point P < 0.05 Radiol Oncol 2006; 40(1): 43-9. Table 2. Frequencies of micronuclei in binucleated human lymphocytes stimulated to proliferate after the indicated post-irradiation periods. Five hundred cells were analyzed per each PHA stimulation point. Time after Cells Cells S MN / Distribution of micronuclei MN / irradiation without MN with MN 500 cells 1 MN 2 MN 3 MN 4 MN Cell Isolated lymphocytes irradiated with 2 Gy 0 h 396 104 116 94 8 2 / 0.23 1 h 411 89 104 74 15 / / 0.21 2 h 399 101 117 89 9 2 1 0.23 4 h 411 89 95 83 6 / / 0.19 Non-irradiated samples Lymphocytes 499 1 1 1 / / / 0.002 Whole blood 498 2 3 1 1 / / 0.006 MN = micronuclei served, regardless of the time mitogen activa­tor was added. In irradiated cultures the num­ber of micronuclei per cell ranged from 0.19­ 1.23 compared to the control where it was 0.002. Discussion This study presented the possible influence of phytohaemagglutinin on DNA-repair scor­ing the number of chromosome aberrations and micronuclei. To initiate DNA damage lymphocytes were irradiated with 2 Gy 22,23 using a .-ray 60Co source. The number of acentric fragments was significantly in­creased in lymphocytes stimulated by phyto­haemagglutinin immediately after the irradia­tion compared to the cultures where the acti­vator after 1, 2 and 4 h was added (Table 1). That finding could indicate that DSB repair mechanisms are efficient in G0 phase of the cycle and/or that the stimulation of lympho­cytes to undergo division without having time to eliminate the majority of the DNA lesions in G0 phase increases a misrepair rate result­ing in the increased number of chromosome type aberrations. These results support the finding that the formation of unstable aberra­tions is cell cycle dependent and that most of double strand breaks can be fixed in first 24 h after the irradiation.27 The same result but with different ap­proach was observed by Mayer et al. They showed that a higher level of the DNA repair events in stimulated cells does not necessarily reflect a higher DNA repair capacity. Additionally, they showed that all repair pro­teins needed for the repair of .-irradiation in­duced DNA-damage are already present in G0 cells at sufficient amounts and do not need to be induced once lymphocytes are stimulated to start cycling.28 Only specific DNA repair genes were found to be up-regulated after the PHA stimulation of which most have an addi­tional function in the DNA replication. The mitogen stimulation of lymphocytes may re­sult in an increased removal of only specific types of DNA lesions as it was reported by other authors.29,30 This observation might be explained by the cell cycle dependent regula­tion of specific DNA repair enzymes, that are more active in proliferating than in resting cells or by differences in the availability of de­oxyribonucleotides which are necessary for the DNA excision repair which is not involved in DSB repair.30,31 Mayer et al.28 identified on­ly 12 genes that responded with a more than 2-fold increase of transcripts to the mitogenic stimulus, with a maximum induction for each of the genes 72 h after the PHA treatment. A decrease in the number of chromosome type aberrations with the delay of PHA stimuli could indicate the gradual activation of addi- Radiol Oncol 2006; 40(1): 43-9. tional repair capacities, but still the decrease was not to found to be significant. That obser­vation is in the correlation with findings that more than 70% of all evaluated genes had con­stant expression levels within a twofold range compared to unstimulated.28 As shown in the Table 2. no significant dif­ferences were observed in the number of mi-cronuclei, regardless of the time point when the mitogen activator was added. Neverth­eless, the number of micronuclei for specific PHA stimulation point was significantly high­er than the number of chromosomal type of aberrations. It indicates that all micronuclei formed do not originate from acentrics only but also from entire chromosomes.32 Micro-tubules remain unsorted within the mitotic plane forming micronuclei.11 Obtained results could indicate that the repair of those lesions is not dependent on the time passed between the irradiation and the mitogen stimulation. Our results show the baseline level of fre­quency of micronuclei after 3 cell cycles which is the same as Ramirez et al. observed.32 The observed non-significant decreases in the total number of chromosomal aberration and micronuclei suggest that phytohaemagglu­tinin does not significantly contribute to the DNA repair. We could say that in order to maximize the sensitivity of the chromosomal aberration analysis phytohaemagglutinin has to be added immediately after the irradiation. References 1. Pfeiffer P, Goedecke W, Obe G. Mechanisms of DNA double-strand break repair and their poten­tial to induce chromosomal aberrations. Muta-genesis 2002; 15: 289-302. 2. Ward JF. DNA damage produced by ionizing radi­ation in mammalian cells: identities, mechanisms of formation and reparability. Prog Nucleic Acid Res Mol Biol 1998; 35: 95-125. 3. Ward JF. The yield of DNA double-strand breaks produced intracellularly by ionizing radiation: A review. Int J Radiat Biol 1990; 57: 1141-50. 4. Friedberg EC, Walker GC, Siede W. DNA Repair and Mutagenesis. In: Gerlach VL, Aravind L, edi­tors. Biological Responses to DNA Damage. Cold Harbor: Laboratory Press Inc., 2001. p. 8-18. 5. Garaj-Vrhovac V, Kopjar N. The alkaline Comet assay as biomarker in assessment of DNA damage in medical personnel occupationally exposed to ionizing radiation. Mutagenesis 2003; 18: 265-71. 6. Garaj-Vrhovac V, Kopjar N, Ražem D, Vekic B, Miljanic S, Ranogajec-Komor M. Application of the alkaline comet assay in biodosimetry: assess­ment of in vivo DNA damage in human peripher­al leukocytes after a . radiation incident. Radiat Prot Dos 2002; 98: 407-16. 7. Natarajan AT. Mechanisms of induction of muta­tions and chromosome alterations. Environ Health Perspect Suppl 1993; 101: 225-9. 8. Wilson VL, Taffe BG, Shields PG, Povery AC, Harris CC. Detection and quantification of 8 hy­droxydeoxyguanosine adducts in peripheral blood of people exposed to ionizing radiation. Environ Health Perspect 1993; 99: 261-3. 9. Liang F, Han M, Romanienko PJ, Jasn M. Homology-directed repair is a major double-strand break repair pathway in mammalian cells. Proc Natl Acad Sci 1998; 95: 5172-7. 10. Sonoda E, Sasaki MS, Buerstedde JM, Bezzubova O, Shinohara A, Ogawa H, et al. Rad 51-defined vertebrate cells accumulate chromosomal breaks prior to cell death. EMBO J 1998; 11: 598-608. 11. Maluf SW. Monitoring DNA damage following ra­diation exposure using cytokinesis-block micronu­cleus method and alkaline single-cell gel elec­trophoresis. Clin Chim Acta 2004; 347: 15-24. 12. Buckton KE, Hamilton GE, Paton L, Langlands AG. Chromosome aberrations in irradiated anky-losing spondylitis patients. In: Evans H, Lloyd DC, eds. Mutagen-induced chromosome damage in man. London: Edinburgh University Press Inc., 1978. p.142-5. 13. Natarajan AT, Obe G. Screening human popula­tions of mutations induced by environmental pol­lutants: use of human lymphocyte system. Ecotoxicol Environ Saf 1980; 4: 468-81. 14. Carrano AV, Natarajan AT. Considerations for population monitoring using cytogenetics tech­niques. ICPEMC publication 14. Mutat Res 1988; 204: 379-406. 15. Santos Mello R, Kway D, Norman A. Chromosome aberrations and T-cells survival in human lympho­cytes. Radiat Res 1974; 60: 482-8. Radiol Oncol 2006; 40(1): 43-9. 16. Arakaki D, Sparkes RS. Microtechnique for cul­turing lekocytes from whole blood. Cytogenetics 1963; 2: 57-60. 17. Li JG, Osgood EE. A method for the rapid separa­tion of leukocytes and nucleated erythrocytes from blood or marrow with a phytohaemagglu­tinin from red beans (Phaseolus vulgaris). Blood 1949; 4: 670-5. 18. Maluish AE, Strong DM. Lymphocyte prolifera­tion. In: Rose NR, de Macario EC, Folds JD, Lane HC, Nakamura RM, editors. Manual of clinical im­munology. Washington: DC Press Inc., 1986. p. 274-81. 19. Nowell PC. Phytohaemagglutinin: an initiator of mitosis in cultures of normal human leukocytes. Cancer Res 1960; 20: 462-6. 20. Waithe Wi, Hirschhorn K. Lymphocyte response to activators. In: Weir DM, editor. Handbook of ex­perimental immunology. Oxford: Blackwell Scien­tific Publications, 1979. pp. 26.1.-26.10. 21. Watt JL, Stephen GC. Lymphocyte culture for chromosome analysis. In: Rooney DE, Czepul­kowski BH, eds. Human cytogenetics- A practical ap­proach. Oxford, UK: IRL Press Inc., 1986. p.39-55. 22. Savoldi-Barbosa M, Sakamoto ET, Takahashi CS. Influence of novobiocin on g-Irradaited G0-lym­phocytes as analysed by cytogenetic endpoints. Gen Mol Biol 1999; 22: 217-23. 23. Boerrigter Meti, Vijg J. Single strand break disap­pearance in quiescent and phytohaemagglutinin-stimulated human peripheral blood lymphocytes exposed to a single low dose of .-irradiation. Int J Radiat Biol 1992; 61: 95-101. 24. Obe G, Beek B, Dudin G. The human leukocyte test system: V. DNA synthesis and mitoses in PHA stimulated 3-day cultures. Humangenetik 1975; 28: 295-302. 25. International Atomic Energy Agency -IAEA. Cytogenetic analysis for radiation dose assess­ment. Technical Reports Series. Vienna; 2001; No 405. 26. Fenech M, Chang WP, Kirsch-Volders M, Holland N, Bonassi S, Zeiger E. HUMN project: detailed description of the scoring criteria for the cytokine­sis-block micronucleus assay using isolated hu­man lymphocyte cultures. Mutat Res 2003; 534: 65­75. 27. Rothkamm K, Lobrich M. Misrepair of radiation ­induced DNA double-strand breaks and its rele­vance for tumorigenesis and cancer treatment. Int J Oncol 2002; 121: 433-40. 28. Mayer C, Popanda O, Zelezny O, von Brevern MC, Bach A, Bartsch H, et al. DNA repair capacity after gama irradiation and expression profiles of DNA repair genes in resting and proliferating human peripheral blood lymphocytes. DNA Repair (Amst) 2002; 1(3): 237-50. 29. Sirover M. Cell cycle regulation of DNA repair en­zymes and pathways. In: Transformation of human diploid fibroblasts. Boca Raton, Florida: CRC Press Inc, 1990. p. 29-54. 30. Boerrigter Meti, Mullaart E, Vilg J. Induction and disappearance of DNA strands breaks in human peripheral blood lymphocytes and fibroblasts treated with methyl methanesulfonate. Exp Cell Res 1991; 192: 61-6. 31. Green MHL, Waugh APW, Lowe JE, Harcourt SA, Cole J, Arlett CF. Effect of deoxyribonucleotides of human peripheral blood lymphocytes on the hy­persensitivity of human peripheral blood lympho­cytes to UV-B and UV-C irradiation. Mutat Res 1994; 315: 25-32. 32. Ramirez MJ, Surralles S, Puerto S, Creus A, Marcos R. Low persisrtance of radiation-induced centromere positive and negative micronuclei in cultured human cells. Mutat Res 1999; 440: 163-9. Radiol Oncol 2006; 40(1): 43-9. review The role of p38 MAP kinase in cancer cell apoptosis Metka Lenassi, Ana Plemenitaš Institute of Biochemistry, Medical Faculty, University of Ljubljana, Slovenia Background. Cellular behaviour in response to many extracellular stimuli is mediated through MAP kinase signalling pathways. p38 MAP kinase that is represented in mammals by four isoforms ( p38a, p38ß, p38. and p38d) is one of the four main subgroups of MAP kinases. Recent studies show that p38 activation is necessary for cancer cell death initiated by variety of anti-cancer agents. This finding connected cancer ther­apies previously considered to be mechanistically unrelated and raised the possibility of developing anti-can­cer agents that lack the side effects caused by events upstream of p38 MAPK. Many of the details of p38 induced apoptosis still need to be elucidated. Since most of the past studies rely only on the cell culture mod­els, all the results have to be verified using in vivo models. Also very little is known about the role of p38 mediated apoptosis on non-neoplastic cells in response to anti-cancer agents. Conclusion. Although p38 activation of cancer cell apoptosis is a very complex process, recent studies in­dicate a good starting point for new strategies that would increase the efficiency and decrease the toxicity of proven therapies. Key words: tumor cells, cultured; apoptosis; MAP kinase; antineoplastic agents Introduction Many extracellular stimuli are converted into specific cellular responses through the activa­tion of mitogen-activated protein kinase (MAPK) signalling pathways. MAPKs are ser­ine/threonine protein kinases that can phoshorylate both cytoplasmic and nuclear targets.1,2 Four distinct subgroups within the Received 28 February 2006 Accepted 8 March 2006 Correspondence to: Prof. Ana Plemenitaš, PhD, Institute of Biochemistry, Medical Faculty, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia; Phone: + 386 1 543 76 52; Fax: +386 1 543 76 41; E­mail: ana.plemenitas@mf.uni-lj.si MAP kinase superfamily have been de­scribed: extracellular signal-regulated kinases (ERKs), c-jun N-terminal or stress-activated protein kinases (JNK/SAPK), ERK/big MAP kinase 1 (BMK1), and the p38 group of pro­tein kinases.3 The p38 group is in mammals represented by four isoforms (p38a, p38ß, p38. and p38d) with overlapping but also dis­tinct physiological roles.4 Among them, p38a is the best characterized isoform. Recently, it was observed that retinoids, cisplantin and also other chemoterapeutic agents initiate cancer cell apoptosis through the activation of p38 MAP kinase. This finding connects cancer therapies previously considered to be mechanistically unrelated and raises the pos­sibility of developing anti-cancer agents that lack the side effects caused by events up­stream of p38 MAPK.5 The potential thera­peutic value of p38 and the availability of spe­cific chemical inhibitors made these protein kinases the subject of intensive studies dur­ing the past years.1 The focus of this review will be to highlight the characteristics and components of the p38 pathway, its role in cancer cell apoptosis and to indicate possible implications for can­cer therapy. The p38 MAP kinase signalling pathway p38 MAP cascade regulates a variety of cellu­lar responses to environmental stress, pro-in­flammatory cytokines, lipopolysaccharide (LPS) and other signals and was first de­scribed in 1994.6-8 The cascade consists of three conserved kinase modules that include MAPK kinase, which activates MAPK kinase that in turn activates MAPK, in our case p38 (Figure 1). p38 MAPK responds to the signal by becoming rapidly activated by dual phos­phorylation of the Thr-Gly-Tyr (TGY) motif.9 Four isoforms of the p38 family have been 10 identified in mammals: p38a (p38),6-8 p38ß, p38.11 and p38d,12 which differ in their tissue expression and affinity for upstream activa­tors and downstream effectors.4 Among them, p38a and p38ß show a relatively broad tissue expression in contrast to p38. and p38d that are differentially expressed de­pending on the tissue type.13 A major contri­bution to the studies of p38a and p38ß iso-forms is the availability of specific inhibitors, developed principally using 2,4,5-triaryl imi­dazoles as a template.14 There are two main MAPKKs that are known to activate p38, MKK315 and MKK6.16 While MKK6 is a common activator of all p38 isoforms, MKK3 is unable to activate p38ß de­spite 80% homology between these two MKKs. In specific cell types also MKK4, an upstream kinase of JNK, can aid in the activation of Figure 1. p38 MAP kinase signalling pathway (accord­ing to reference 3). p38a and p38d. In addition to activation with upstream kinases there is also a MAPKK-inde­pendent mechanism of p38 activation involv­ing TAB1, with no known biological context.3 The diverse range of MAPKKKs, upstream activators of MKKs, is responsible for suscep­tibility of p38 to such a wide range of extracel­lular stimuli. This MAP3K includes TAK1,17 ASK118 DLK/MUK/ZPK, MLK2 and MEKK4.19 The upstream of MAPKKs are also low molec­ular weight GTP-binding proteins from the Rho family and p21- activated kinases.3 The MAP kinase activation is often tran­sient under physiological conditions, being downregulated by dephosphorylation of vari­ous members of the MAP kinase pathway. The proteins responsible for that are different dual-specificity phosphatases, all grouped in the MAP kinase phosphatase (MKP) family.20 Activated p38 MAP kinase regulates the activity of a wide range of protein kinases (MAPKAPK2, MNK1, PRAK, MSK1), tran­scription factors (CHOP, p53, ATF-1/2/6, Sap1, MEF2, ELK1 and others) and some oth­er proteins, which then further regulate the activity of their targets. This complicated net­work of interacting proteins is in conse­quence responsible for different cell activi­ties, like apoptosis, cell-cycle arrest, cytokine production, cell differentiation, cell senes­cence and tumour suppression.3, 5 Radiol Oncol 2006; 40(1): 51-6. The role of p38 in apoptosis in cancer cells Apoptosis is an active form of cell death that plays an essential role in eliminating damaged cells or cells with defects in key-regulated processes such as growth.21 Once this highly regulated process is triggered, the apoptotic program involves activation of a series of bio­chemical events that end with the release of proteins from the mitochondria into the cyto­plasm and the nucleus.22 Not surprisingly, sev­eral tumours emerge with mutations in genes conferring apoptosis resistance, allowing them to continue uncontrolled growth under, for normal cells, pro-apoptotic conditions.23 There are some evidence for pro-apoptotic and anti-apoptotic role of p38 MAPKs, de­pending on the cell type and the stimuli. Overexpression of the active form of the p38 activator MKK6 protects cardiac myocytes from ß-adrenergic receptor-mediated apopto­sis.24 Similarly, the early activation of p38 is necessary and sufficient to protect Kym cells from tumour necrosis factor-a-mediated apoptosis,25 and expression of p38ß results in attenuated cell death induced by Fas ligand and UV light26. The activation of p38 may al­so protect through the down-regulation of the Fas receptor expression.27 Even more reports support the pro-apop­totic role of p38, for example, p38 is a media­tor of apoptosis in neurons28 and cardiac cells.29 In other cell types, p38 activates apop­tosis upon stimulation with tumour necrosis factor-a30, transforming growth factor-ß31 or in response to oxidative stress.32 The latter was also demonstrated in the case of TRAIL induced apoptosis mediated by reactive oxy­gen species (ROS)-activated p38 MAP kinase followed by the caspase activation in HeLa cells.33 Cells treated with betulinic acid, a se­lective inhibitor of human melanoma, also in­duce apoptosis through the ROS mediated p38 activation.34 The mechanisms by which p38 contributes to an enhanced pro-apoptotic response in­clude the phosphorylation and translocation of proteins from the Bcl-2 family, which leads to the release of cytochrome c from the mito­chondria,32, 35 the transforming growth fac­tor-ß-induced activation of caspase 836 as well as the regulation of membrane blebbing and nuclear condensation.37 At the transcription-al level, expression of monoamine oxidase28 or growth arrest and DNA damage (GADD)­inducible genes38 have been shown to medi­ate pro-apoptotic effects of p38. The impor­tance of p38 in apoptosis was also shown in the study of apoptotic response in different p38-deficient cells, like primary fibroblasts and immortalized cardiomyocytes and fibrob­lasts. All p38 deficient cells were more resist­ant to apoptosis induced by many different stimuli. The reduced apoptosis correlated with down-regulation of the proapoptotic proteins Fas and Bax as well as enhanced ac­tivity of the ERK survival pathway.39 This opposing effects on apoptosis ob­served for p38 probably reflect the multiple and complex activities of this signalling path­way, which acts on different targets at once and thus can yield distinct overall effects de­pending on the cellular context. Similar op­posing effects were also found for the other stress-activated protein kinase JNK.37 p38, a convergence point in cancer therapy? Recent studies show that the p38 MAP kinase activation is necessary for cancer cell death initiated by various anti-cancer agents. Retinoids like 13-cis retinoic acid or all-trans retionic acid (ATRA) initiate apoptosis in medulloblastoma cell lines by phosphorylat­ing p38 MAPK through the induction of bone morphogenetic protein 2 (BMP2).40 Another syntetic retinoid CD437 induces apoptosis in ovarian carcinoma cell culture also in p38 de­pendent way. The activated p38 phosphory­lates the transcription factor MEF-2, which has a proposed role in mitochondrial depolar- Radiol Oncol 2006; 40(1): 51-6. ization and apoptosis. In these cells ATRA does not induce p38 cascade, suggesting a distinct upstream mechanism from the one described for medulloblastoma.41 Four chemotherapeutic agents were shown to induce the p38 activation and mitotic cell-cycle arrest in HeLa human cervical carcino­ma cells by depolymerizing microtubules, (nocodazole, vincristine and vinblastine) or stabilizing them (taxol). The extent of apopto-sis in these cells is greater when induced by a direct activation of p38, because previously mentioned chemotherapeutics activate pro-apoptotic as well as pro-survival pathways in HeLa cells, which results in less apoptosis. The activated p38 induces cell death by stim­ulating translocation of Bax from the cytosol to the mitochondria. On the other hand, the p21-activated kinase (PAK) mediates cell sur­vival by phosphorylating Bad, thereby in­hibiting its pro-apoptotic function.42 The activation of p38 in several tumour cell lines was also observed after the treat­ment with cisplatin, an inorganic heavy met­al coordination complex, and doxorubicin, a DNA intercalating agent.43 Some anti-cancer agents utilize two dis­tinctive MAPK signalling pathways for killing cells. Phytosphingosine simultaneously downregulates the ERK survival pathway, which is critical for the death receptor inde­pendent activation of caspase-8, and activates p38 pathway, which is involved in the cell death pathway through the mitochondrial ac­tivation.35 Another example is 2-metho­xyestradiol (2-ME) apoptosis induction in prostate cancer cell line. A treatment with 2­ME leads to the p38 activation as well as JNK-mediated Bcl2 phosphorylation, which inacti­vates this anti-apoptotic protein.44 All these reports support the role of p38 MAPK as the key component for the cancer cell death after treating tumours with a vari­ety of anti-cancer agents. This finding con­nects cancer therapies previously considered to be mechanistically unrelated and raises the possibility of developing anti-cancer agents with the lack of the side effects caused by events upstream of p38 MAPK.5 Still many of the details of p38 induced apoptosis need to be elucidated. Since most of the past studies rely only on the cell culture models, all the results have to be verified us­ing in vivo models. Also very little is known about the role of p38 mediated apoptosis on non-neoplastic cells in response to anti-can­cer agents. The issue is also the drug resist­ance, therefore, more has to be learned about how tumours protect themselves from the pro-apoptotic activation of p38 MAPK. The study made on 20 liver cancer specimens shows that both MKK6 and p38 protein levels are lover in hepatocellular carcinoma tu­mours than adjacent non-neoplastic liver. This reduction of p38 levels could represent an anti-apoptotic mechanism that provides growth advantage to tumour cells.45 Conclusions Although the p38 activation of cancer cell apoptosis is a very complex process, recent studies indicate a good starting point for new strategies that would increase the efficiency and decrease the toxicity of proven therapies. 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Role of the p38 MAPK pathway in cisplatin-based therapy. Oncogene 2003; 22: 3998-4006. 44. Shimada K, Nakamura M, Ishida E, Kishi M, Konishi N. Roles of p38- and c-jun NH2-terminal kinase-mediated pathways in 2-methoxyestradiol-induced p53 induction and apoptosis. Carcino-genesis 2003; 24: 1067-75. 45. Iyoda K, Sasaki Y, Horimoto M, Toyama T, Yakushijin T, Sakakibara M, et al. Involvement of the p38 mitogen-activated protein kinase cascade in hepatocellular carcinoma. Cancer 2003; 97: 3017-26. Radiol Oncol 2006; 40(1): 51-6. Radio/ Oncol 2005; 40(1): 1-5. Majhna kolicina proste plevralne tekocine. Drugi del -fiziološka plevralna tekocina Kocijancic I Izhodišca. V literaturi je le nekaj clankov, ki porocajo o možnostih rentgenskega in ultra­zvocnega prikaza fiziološke plevralne tekocine pri zdravih. V zadnjem desetletju je napredek ul­trazvocne tehnologije omogocil prikaz majhnih kolicin fiziološke plevralne tekocine pri prib­ližno 20 % zdrave populacije. Ob dolocenih fizioloških stanjih, kot je na primer nosecnost, je prikaz fiziološke plevralne tekocine z ultrazvokom bolj pogost. Zakljucki. Pomembno je, da pozitivnega izvida brez spremljajocih klinicnih sprememb ne ocen­imo za znak bolezni. Radio/ Oncol 2006; 40(1): 7-15. Ocena Parksovega kota pri bolnikih z motnjami odvajanaja blata -prospektivna raziskava z defekografijo Kolodziejczak M, Sudol-Szopiriska I, Grochowicz M, Bochenek A, Swiatlowska M Izhodišca. Defekografijo uporablja veliko kolorektalnih kirurgov, ker lahko z njo anatomsko in dinamicno proucujejo odvajanje blata. S preiskavo ugotovimo anorektalno funkcijo in delovan­je medenicnega dna ter anatomske nepravilnosti. Metode. V prospektivni raziskavi smo z defekografijo proucili 58 bolnikov (50 žensk in 6 moških), ki so bili stari od 24 do 83 let (povprecno 58,3 leta) in so imeli proktološke težave. Bolniki so opisovali nezmožnost zadrževati blato, obcutek obstrukcije v rektumu, zaprtost, zdrs rektuma in rektalno razjedo. Velikost Parksovega kota smo merili pred odvajanjem blata, med napenjanjem in med odvajanjem blata. Merili smo tudi trajanje sfinkterske relaksacije, trajanje odvajanja blata in gibljivost medenicne prepone. Rezultati. Nenormalne vrednosti Parksovega kota smo ugotavljali pred odvajanjem blata in med napenjanjem pri bolnikih, ki niso uspeli zadrževati blato, ki so imeli obcutek obstrukcije v rek­tumu ali so bili zaprti. Pri zdrsu rektuma pa omenjene nenormalne vrednosti nismo zasledili. Defekografija nam je pomagala odkriti rektokelo pri bolnikih, ki so tožili zaradi zaprtosti in obcutka obstrukcije v rektumu. Koristna je bila tudi pri oceni bolnikov, ki so imeli rektalno raz­jedo. Parksov kot se je med odvajanja blata spreminjal, trajanje sfinkterske relaksacije pa je bilo spre­menljivo ne glede na vrsto bolezni. Zakljucki. Defekografija je koristna metoda pri motoricni oceni odvajanja blata pred in po kirurškem zdravljenju. Radio/ Oncol 2006; 40(1): 57-62. Radio/ Oncol 2005; 40(1): 17-21. Lhermitte-Duclosova bolezen in nosecnost Franko A, Holjar-Erloc I, Miletic D, Petrovic O Izhodišca. Lhermitte-Duclosova bolezen ali displaticni gangliocitom malih možganov je redka bolezen, ki lahko povzroca napredujoco tumorsko rast. Ugotovimo jo z magnetno resonanco, ki pokaže znacilne neobarvane girusne spremembe, razlicne intenzitete na T1 In T2 magnetnih slikah. Prikaz primera. Opisujemo 37-letno bolnico, ki smo ji dokazali Lhermitte-Duclosovo bolezen v tretjem tromesecju nosecnosti. Zakljucki. Prikazan primer kaže, da lahko nosecnica z Lhermitte-Duclosovo boleznijo brez živl­jenjskega tveganja donosi in rodi zdravega otroka. Potrebnih pa je vec izkušenj, da bi to opažan­je lahko posplošili. Radio! Oncol 2006; 40(1): 57-62. Radio/ Oncol 2006; 40(1): 23-8. S-letno preživetje ter pogostnost lokalne in regionalne ponovitve bolezni pri bolnicah z rakom dojk, ki smo jih zdravili z ohranitveno operacijo in obsevanjem Rajer M, Majdic E Izhodišca. Ohranitveno zdravljenje je del standardne terapije bolnic z zacetnim rakom dojk. V naši raziskavi smo skušali ugotoviti, kakšno je S-letno preživetje, pogostnost lokalne in region­ alne ponovitve bolezni ter ugotoviti morebitne dejavnike tveganja, ki na to vplivajo. Metode. Od januarja 1998 do decembra 1999 smo na Onkološkem inštitutu v Ljubljani zdravili 564 bolnic z rakom dojk v prvem in drugem stadiju bolezni. Pri vseh smo dolocili naslednje de­ javnike: starost, histološko diagnozo, stopnjo malignosti, velikost tumorja, število metastatskih pazdušnih bezgavk, prisotnost hormonskih receptorjev, ekstenzivno intraduktalno komponen­to, vaskularno invazijo, stanje resekcijskih robov, vrsto operacije in nacin dopolnilnega zdravl­jenja. Rezultati. Povprecna starost bolnic je bila 54,2 let. Najpogostejša histološka diagnoza je bila in­vazivni duktalni karcinom. Najvec tumorjev je bilo druge stopnje malignosti. Vecina tumorjev je bila T1 (72%), sledijo tumorji T2 (24%). Metastaze v pazdušnih bezgavkah je imelo 44% bolnic. Vse so bile zdravljene z ohranitveno operacijo in pooperativnim obsevanjem operirane dojke. Polovica bolnic je dobila dopolnilno kemoterapijo in hormonsko terapijo. Celokupno petletno preživetje je bilo 88,5%. Statisticno znacilni napovedni dejavniki so bili: velikost tumorja, število metastatskih pazdušnih bezgavk, stopnja malignosti, prisotnost hormonskih receptorjev in vaskularna invazija. Starost bolnic in histološki tip tumorja nista vplivala na preživetje. Lokalno ponovitev bolezni smo ugotovili pri 4,3% bolnic, regionalno pri 3,4%. Od 19 regionalnih ponovitev bolezni je bil ena v pazduhi, ena parasternalno in ostale v supraklavikularni loži. Zakljucki. Ugotovili smo, da sta celokupno S-letno preživetje ter pogostnost lokalne in region­alne ponovitve bolezni pri naših bolnicah primerljivi z rezultati v drugih raziskavah. Stopnja ma­lignosti, hormonski status in število pozitivnih bezgavk so napovedni dejavniki, ki napoveduje­jo tako celokupno preživetje kot lokoregionalno ponovitev bolezni, medtem ko se v naši raziskavi starost bolnic ni pokazala kot napovedni dejavnik. Radio/ Oncol 2006; 40(1): 57-62. Radio! Oncol 2006; 40(1): 29-33. Zmanjšana moc vratnih iztegovalnih mišic (sindrom padajoce glave) kot posledica obsevalnega zdravljenja Bhatia S, Miller RC, Lachance DL Izhodišca. Sindrom padajoce glave je redka bolezen, pri kateri bolnik ne more držati glave vzrav­nano v anatomski legi. Nastane zaradi zmanjšanja moci vratnih iztegovalnih mišic. Prikaz primera. Prikazujemo primer sindroma padajoce glave pri bolnici, ki je bila pred deseti­mi leti obsevana zaradi Hodgkinovega limfama, predhodno pa se je zdravila tudi zaradi multi­ple skleroze. Razpravljamo o možnih vzrokih nastanka bolezni. Zakljucki. Najbolj verjeten vzrok nastanka bolezni je bila poškodba prednjega roga hrbtenjace ob obsevanju, kar je povzrocilo poškodbo spodnjega motoricnega nevrona in mišicno atrofijo. Radio! Oncol 2005; 40(1): 35-8. Ameloblasticni fibrom Božic M, Ihan Hren N Izhodišca. Ameloblasticni fibrom je redek odontogeni tumor. Sestavljen je iz odontogenega ek­tomezenhima podobnega dentalni papili ter epitelija podobnega dentalni lamini in sklenini, je brez trdih zobnih tkiv. Prikaz primera. Opisujemo bolnico z velikim ameloblasticnim fibromom, ki se je razrašcal v spodnji celjustnici in je segal od spodnjega levega drugega sekalca (32) do spodnjega levega drugega kocnika (37). Po do sedaj zbranih podatkih je to prvi opisani primer ameloblasticnega fibroma v Sloveniji. Zakljucki. Zaradi možnosti ponovitve bolezni pa tudi spremembe ameloblasticnega fibroma v ameloblasticni sarkom svetujemo radikalno kirurško zdravljenje in daljše pooperativno sleden­je bolnikov. Radio/ Oncol 2006; 40(1): 57- 62. Radio/ Oncol 2006; 40(1): 39-42. Erlotinib pri zdravljenju nedrobnocelicnega raka pljuc Smrdel U, Kovac V Izhodišca. Erlotinib je novo biološko protitumorsko zdravilo, ki ga uporabljamo pri bolnikih z nedrobnocelicnim rakom pljuc. Predstavlja molekularno tarcno terapijo, ki so jo zelo intenzivno proucevali v klinicnih študijah. Prikaz primera. Predstavljamo bolnika, ki smo ga obravnavali zaradi razširjene oblike nedrob­nocelicnega raka pljuc. S kemoterapijo smo dosegli stagnacijo bolezni, ki je po desetih mesecih ponovno napredovala. Splošno stanje se je izrazito poslabšalo. Že po enem mesecu ponovnega sistemskega zdravljenja, tokrat z erlotinibom, so simptomi izzveneli in na rentgenski sliki prsnih organom vidimo znatno zmanjšanje bolezenskih sprememb (delno remisijo). Zakljucki. Pri izbranih bolnikih z nedrobnocelicnim rakom pljuc lahko erlotinib podaljša preživetje in znatno zmanjša simptome bolezni. Radio/ Oncol 2006; 40(1): 43-9. Fitohemaglutinin kot modulator DNK popravljalnih mehanizmov merjenih s številom kromosomskih aberacij in z mikronukleus testom po obsevanju z ionizirajocim sevanjem Durinec M, Želježic Din Garaj-Vrhovac V Izhodišca. Obstaja korelacija med sposobnostjo popravila poškodb DNK in sposobnostjo delitve celic. Zato je bil namen študije ugotoviti vpliv fitohemaglutinina (PHA) na sposobnost popravi­la DNK poškodb pri izoliranih humanih limfocitih, obsevanih z ionizirajocim sevanjem. Metode. Limfociti so bili izolirani na Fikol gradientu. Za obsevanje celic smo uporabili 60Co izvor proizvajalca Alcon. Celice so bile obsevane 1,24 minut pri sobni temperaturi, tako smo dosegli absorbirano dozo 2 Gy. Razlike v sposobnosti popravila DNA poškodb smo merili s številom kromosomskih aberacij in z mikronukleus testom 48 in 72 ur po PHA stimulaciji. Rezultati. Število dicentricnih in acentricnih kromosomov je bilo signifikantno povecano pri cel­icah, ki so bile stimulirane s PHA takoj po obsevanju, ne p apri celicah, kjer smo dodali PHA 1, 2 ali 4 ur kasneje. Mikronukleus test ni pokazal signifikantnih razlik v distribuciji ne glede na cas dodanega fitohemeglutinina. Zakljucek. Rezultati nakazujejo, da fitohemaglutinin ne vpliva signifikantno na popravljalne mehanizme DNK Radio/ Oncol 2006; 40(1): 57-62. Radio/ Oncol 2006; 40(1): 000-00. Vloga p38 MAP kinaze pri apoptozi rakavih celic Lenassi M, Plemenitaš A Izhodišca. Odzivanje celic na številne zunajcelicne signale poteka preko aktivacije MAP ki­naznih signalnih poti. Ena od štirih glavnih podskupin MAP kinaz je p38 MAP kinaza, ki je pri sesalcih prisotna v štirih izooblikah: p38a, p38j3, p38y in p38b. Nedavne raziskave so pokazale, da je za aktivacijo apoptoze rakavih celic z razlicnimi kemoterapevtiki nujna aktivacija p38 ki­naze. To spoznanje je v eni tocki povezalo poti delovanja raznolikih kemoterapevtikov ter s tem nakazalo nove možnosti njihovega razvoja brez stranskih ucinkov, ki jih sedaj povzrocajo do­godki pred aktivacijo p38. Veliko podrobnosti o p38 posredovani apoptozi je potrebno še raz­jasniti. Dosedanja dognanja je potrebno preveriti v in vivo modelih, saj se ta sedaj nanašajo predvsem na celicne kulture. Malo je znanega tudi o vlogi p38 pri apoptozi nerakavih celic po aktivaciji s kemoterapevtiki. Zakljucki. Ceprav je p38 posredovana aktivacija apoptoze rakavih celic zelo kompleksen proces, novejše študije ponujajo dober zacetek za razvoj novih kemoterapevtikov s povecano ucinkovi­tostjo in zmanjšano toksicnostjo. Radio/ Oncol 2006; 40(1): 57-62. Notices Notices submitted far publication should contain a mailing address, phone and/ or fax number and/ or e-mail oj a Contact person or department. Lung cancer April 19-26, 2006 The "2nd Latin American Conference on Lung Cancer" will be offered in Cancun, Mexico. Contact E-mail: LungCancerLA@meet-ics.com: or see http:// ww,v.LCLA2006.com Molecular oncology April 30 -May 4, 2006 The ESTRO teaching course "Molecular Oncology for the Radiation Oncologist" will take place in Granada, Spain. 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 Radiotherapy May 7-11, 2006 The ESTRO teaching course "Dose Determination in Radiotherapy: Beam Characterisation, Dose Calculation and Dose Verification" 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 Radiology May 15-17, 2006 The UK radiological congress will be held in Birmingham, UK. Contact UKRC 2006 Organisers, PO Box 2895, London WlA SRS, UK; or call + 44(0) 207 307 1410/20; or fax +44(0) 207 307 1414; or e mail confer­ence@ukrc.org.uk / exhibition@ukrc.org.uk; or see http:// www.ukrc.org.uk Bioethics May 18-20, 2006 The ESO advanced course "Ethics in Oncology" will take place in Bled, Slovenia. Contact Ms. Rita De Martini, European School of Oncology, Via del Bollo, 4, 20123 Milan, Italy; or call +39 02 85 46 45 27; or fax +39 02 85 46 45 45; or e-mail rdemartini@esoncology.org; or see http://,vww.can­cerworld.org/eso Oncology June 2-5, 2006 The 6th international celi death symposium on "The Mechanisms of Celi Death" will take place in Angra dos Reis, Brazil. Contact International Celi Death Society, Victoria Matassov, Secretary, c/o Queens College, CUNY 65­30 Kissena Blvd. Flushing, NY 11367-1575; or call +1 718 997 3450; or fax +1 718 997 3429; or e-mail vmatasso@qcl.qc.edu; or see http://www.celldeath­apoptosis.org Clinical oncology June 2-6, 2006 The 42nd ASCO Meeting will be offered in Atlanta, USA. Contact E mail: enews@asco.org; or see http:// www/asco.org Radiotherapy June 11-15, 2006 The ESTRO teaching course "Imaging for Target Volume Determination in Radiotherapy" will take place in Athens, Greece. 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 Radio/ Oncol 2006; 40(1): 63-6. Cancer research June 17-23, 2006 The 8th intensive workshop for European junior clinical oncologists "Methods in Clinical Cancer Research" will take place in Flims, Switzerland. Contact Federation of European Cancer Societies (FECS), Avenue E. Mounier, 83, B-1200 Brussels, Belgium; or call +32 2 775 02 06; or fax +32 2 775 02 45; or e-mail workshop@fecs.be; or see http:// www.fecs.be Lung cancer ]une 18-21, 2006 The "l0th Central European Lung Cancer Conference" will be offered in Prague, Czech Republic. Contact: +420-608-408-708; or e-mail celcc@confer­ence.cz; or see http://www.conference.cz/celcc2006 Prostate cancer June 25-2 7, 2006 The ESTRO teaching course "Brachytherapy for Prostate Cancer" will take place in Barcelona, Spain. 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 Bronchology June 25-28, 2006 The 14th Word Congress of Bronchology and the 14th Word Congress of Bronchoesophagology will take place in Buenos Aires, Republic Argentina. Contact: General Secretariat, Ms. Maria Graziani & Asociados with phone +4394 7726 4393 3437; or Fax: +541 439 33436; or E-mail: mg@mariagraziani.com Radiotherapy June 25-29, 2006 The ESTRO teaching course "IMRT and Other Conformal Techniques in Practice" will take place in Copenhagen, Denmark. Contact ESTRO office, Avenue E. Mounierlaan 83/12, B-1200 Brussels, Belgium; or call +32 2 775 93 40; or fax +32 2 779 54 94; or e-mail info@estro.be; or see http://www.estro.be Clinical tria! statistics June 28-30, 2006 The EORTC (European Organisation for Research and Treatment of Cancer) course "Clinical Tria! Statistics for Non Statisticians" will take place in Brussels, Belgium. Contact Danielle Zimmermann, EORTC Education Office, Avenue E. Mounier 83 B. 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.eortc.be Lung cancer June 30 -July 2, 2006 Inaugural IASLC Australian Lung Cancer Conference on Multidisciplinary Care will be offered in Palm Cove, North Queensland, Australia. Contact E-mail fongk@health.qld.gov.au Cancer research July 1-4, 2006 The "19th Meeting of the European Association for Cancer Research EACR 19" will take place in Budapest, Hungary. Contact EACR-19 Secretariat, Federation of European Cancer Societies, Avenue E. Mounier, 83, B­1200 Brussels, Belgium; or call +32 2 775 02 01; or fax +32 2 775 02 00; or e-mail EACR19@fecs.be; or see http://www.fecs.be Gynaecological malignancies August 31 -September 1, 2006 The ESTRO teaching course "Brachytherapy for Gynaecological malignancies" will take place in Vienna, Austria. 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 Radiotherapy September 3-7, 2006 The ESTRO teaching course "Physics for Clinical Radiotherapy" will take place in Innsbruck, Austria. 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 Radio/ Oncol 2006; 40(1): 63-6. Notices 65 Oncology September 8, 2006 The EORTC (European Organisation for Research and Treatment of Cancer) course "One-Day Introduction to EORTC Trials" will take place in Brussels, Belgium. Contact Danielle Zimmermann, EORTC Education Office, Avenue E. Mounier 83 B 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.eortc.be Radiobiology September 17-21, 2006 The ESTRO teaching course "Basic Clinical Radiobiology" will take place in Lisbon, Portugal. 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:/ /WW1v.estro.be Lung cancer September 25-26, 2006 The "2nd International Workshop Early Invasive Lung Cancer: New Diagnostic Tools & Treatment Strategies" will be held in Turin, Italy. Contact E-mail: a.crippa@congressiefiere.com or see http://www.congressifiere.com Otorhinolaryngology September 27 -30, 2006 The 11 th Danube Symposium 2006 "International Otorhinolaryngological Congress" will take place in Bled, Slovenia. Contact Albatros Bled, Ribenska 2, 4260 Bled, Slovenia; or call +386 4 5780 350; or fax +386 4 5780 355; or e-mail info@albatros-bled.com; or see http://WW1v.albatros-bled.com Oncology October 8-12, 2006 The ESTRO 25 / ECCO 14 Conference will take place in Leipzig, Germany. Contact FECS office, Av. E. Mounierlaan, 83/4, B­1200 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.estroweb.org Radiation oncology October 22-27, 2006 The ESTRO teaching course "Evidence-Based Radiation Oncology: Methodological Basis and Clinical Application" will take place in Giardini Naxos, 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 Lung and head & neck October 26-28, 2006 The "4th Lung & Head and Neck Conference" will be offered in Chicago, Illinois. Contact: Taryn Klocke; call +1 770-984-5113; or e­mail evokes@medicine.bsd.uchicago.edu Oncology October 26-29, 2006 The "2nd Congress of the Polish Oncology" will take place in Poznan, Poland. See http://www.kongresonkologii.pl Lung cancer November 8-12, 2006 The "3rd IASLC/ ASCO/ESMO International Conference on Targeted Therapies in Lung Cancer" will be held in Taormina, Sicily, Italy. Contact E-mail: fred.hirsch@UCHSC.edu Head &neck November 16-18, 2006 The "5th European Workshop on Basic Biology of Head & Neck Cancer" will take place in Poznan, Poland. Seehttp://www.orl.amp.wdu.pl/5workshop Radiotherapy November 19-23, 2006 The ESTRO teaching course "IMRT and Other Conformal Techniques in Practice" will take place in Gliwice, Poland. 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 Radio/ Oncol 2006; 40(1): 63-6. Surgical oncology November 30 -December 2, 2006 The "13th Congress of the European Society of Surgical Oncology ESSO 2006" will take place in Venice, Italy. Contact Conference Secretariat, ESSO 2006, Federation of European Cancer Societies, Avenue E. Mounier, 83, B-1200 Brussels, Belgium; or call +32 2 775 02 01; or fax +32 2 775 02 00; or e-mail ES­S02006@fecs.be; or see http://www.fecs.be Radiotherapy December 3-7, 2006 The ESTRO teaching course "lmage-guided Radiotherapy (IGRT)" will take place in Brussels, Belgium. 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 Toxicology July 15-19, 2007 The "1 lth International Congress of Toxicology" will be offered in Montreal, Canada. Contact Congress Secretariat, e-mail: ict2007@nrc­cnrc.gc.ca; or see http://www.ict2007.org Lungcancer September 2-6, 2007 The "12th World Conference on Lung Cancer" will be offered in Seoul, Korea. Contact Conference Secretariat; e-mail WCLC2007 @ncc.re.kr; or see http://www.iaslc.org1umages/ 12worldconfannounce.pdf Oncology September 23-27, 2007 The "14th European Cancer Conference ECCO 14" will take place in Barcelona, Spain. Contact Conference Secretariat, ECCO 14, The European Cancer Conference, European Cancer Societies (FECS), Avenue E. Mounier, 83, B-1200 Brussels, Belgium; or call +32 2 775 02 01; or fax +32 2 775 02 00; or e-mail ECC014@fecs.be; or see http://www.fecs.be Lungcancer August 21-24, 2009 The "13th World Conference on Lung Cancer" will be offered in San Francisco, USA. Contact Conference Secretariat; e-mail WCLC2007 @ncc.re.kr; or see http://www.iaslc.org1umages/ 12worldconfannounce.pdf As a service to our readers, notices oj meetings or courses will be inserted jree oj charge. Please send injormation to the Editorial ojfice, Radiology and OncologtJ, Zaloška 2, SI-1000 Ljubljana, Slovenia. Radio/ Oncol 2006; 40(1): 63-6. 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 0 1 25 1 81 1 3 ŽR: 501 00-620-1 33-05-1 0331 1 5-2 1 4 779 Activity of "Dr. J. Cholewa" Foundation for Cancer Research and Education -a report for the first quarter of 2006 The Dr. J. Cholewa Foundation for Cancer Research and Education is a modem and dynamic institution, trying to respond to all the contemporary challenges that fall up­on it in its mission to support activities associated with cancer research and education in Slovenia. As it deals with bestowing different grants and other forms of financial support to persons interested in cancer research and education in Slovenia, all the re­quests are being dealt with responsibly by Foundation members with clinical and re­search experience in cancer and by members with important experience in finance. With this in mind, the Foundation will also continue to support the publication of the results from research it supported in respectable international scientific oncology journals and in more novel electronic forms of dissemination of scientific information. 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. This support is considered to be one of its more impor­tant commitments. The Foundation also remains active in promoting cancer education in general, especially in general population, and among younger scientists with a par­ticular interest in cancer research. It is worth mentioning that many study and re­search grants have been already bestowed to young researchers from various scientif­ic fields associated with oncology in Slovenia and that many of them were also given grants to attend scientific meetings, conferences and symposia dealing with oncology worldwide. The information and knowledge of cancer in general and problems asso­ciated with caner research have thus spread as a result of these activities and the Dr. J. Cholewa Foundation for Cancer Research and Education has a special reason to re­spectfully acknowledge the importance of the commitment of various public compa­nies and private individuals to its cause. It is the policy of the Dr. J. Cholewa Foundation for Cancer Research and Education to lend support to individuals and institutions that participate in cancer research and education Slovenia with the idea that cancer research should be further encouraged in all parts of the country where the interest for such research exists. Tomaž Benulic, MD Andrej Plesnicar, MD Borut Štabuc, MD, PhD SIEMENS SiemensMedical.com/oncology SEEK-FIND-ACT-FOLLOW -the Continuum of Oncology Care™ Siemens oncology portfoilo comprises comprehens1ve max1m1zed utilizat1on potent1al. and pat1ent-friendly design workflow solut1ons mtegrat1ng the tuli spectrum of care and features. from screen1ng/early detect1on and d1agnos1s through therapy and follow-up. Ali from one prov1der -w1th over Every day in the United States alone. 29.000 cancer 100 years history of 1nnovat1on 1n medica! technology. patients rece1ve rad1at1on therapy del1vered by Siemens l1near accelerators. As chn1cal protocols trans1t1on to Siemens proven ciln1cal methods can help you to ach1eve 1nclude IMRT and IGRT. Siemens seamlessly mtegrates more successful outcomes. How? Through 1ndustry­the d1agnost1c and treatment modaht1es. That's what we leading technology, 1ncreased product1v1ty measures tor call Best Practice Oncology Care. Siemens medica 1 Solutions that help Sanolabor Laaormeo ,· •., ZASTOPA PODJEDA: ..fMENTOR Prsni vsadki napolnjeni s silikonskim gelom, ekspanderji in drugi pripomocki pri rekonstrukciji dojk •.•:• kottermann • 1 Kottermann (Nemcija): laboratorijsko pohištvo, varnostne omare za kisline, luge, topila, pline in strupe, ventilacijska tehnika in digestorji Angelantoni scientifica (Italija): hladilna tehnika in aparati za laboratorije, transfuzijo, patologijo in sodno medicino CORNING Corning (Amerika): specialna laboratorijska plastika za aplikacijo v imunologiji, mikrobiologiji, virologiji, ipd., mehanske eno-in veckanalne pipete in nastavki '' B. l ·. Micronic (Nizozemska): sistemi za shranjevanje vzorcev, pipete, nastavki za pipete T-· ilhae's NoRcason to,qpaiiie w,ith .onciE)se 1 Implantech (Amerika): obrazni in glutealni vsadki Biomerica (Amerika): hitri testi za diagnostiko, EIA /RIA testi LABORMED d.o.o. Bežigrajski dvor • Ehret (Nemcija): Laminar flow tehnika, inkubatorji, sušilniki, suhi sterilizatorji in oprema za laboratorijsko vzrejo živali -kletke Dako (Danska): testi za aplikacijo v imunohistokemiji, patologiji, mikrobiologiji, virologiji, mano-in poliklonalna protitelesa Ea Sakura finetek (Evropa): aparati za pripravo histoloških preparatov: mikro­inkriotomi, zalivalci, tkivni procesorji, barvalci, pokrivalci ... BJO.\. ,E N1.,ES Integra Biosciens (Švica): laboratorijska oprema za mikrobiologijo, biologijo celic, molekularno biologijo in biotehnologijo ·pect, um Des1gns ,"-\ r 1 > 1 < A 1 SpectrumDesigns MEDICAL (Amerika): moški pektoralni vsadki Byron (Amerika): liposuktorji in kanile za liposukcijo Periceva 29, Ljubljana info@labormed.si Tel.: (0)143649 01 Fax: (0)1 436 49 05 ERBITUX® CETUKSIMAB Zavira EGFR -odpira nove možnosti Ciljno usmerjeno zdravljenje metastatskega raka debelega crevesa in danke -( Visoko specificno monoklonsko lgG1 protitelo, ki kompetitivno inhibira receptorje za epidermalni rastni faktor (EGFR) -( Ucinkovitost je dokazana v kombinaciji z irinotekanom 1 Erbltux2 mg/ml raztopina za lnfundlranje (skrajšana navodila za uporabo) Cetukslmab je himemo monoklonsko lgGl protitelo, ki je usmerjeno proti receptorju za epidermalni rastni faktor (EGFR). Ter1pevtsk1 lndlkldje: Zdravilo Erbitux je v kombinirani terapiji z irinotekanom lndicirano za zdravljenje bolnikov z metastatsklm rakom debelega crevesa In danke z ekspresjo receptorjev za epidermalni rastni faktor (EGFR), In sicer po neuspešni citotokslcni terapiji, ki je vkljucevala tudi Jrinotekan. Odmerjanje In nacin uporabe: Zdravilo Erbitux infundlrajte i enkrat na teden z intravensko infuzijo prek linjskega filtra. Zacetni odmerek je 400 mg/m2 telesne površlne. Naslednji tedenski od me Od so vsak po 250 m&,'m2. Priporocljivo je, da z zdravljenjem s cetuksimabom nadajujete do napredovanja il osnovne bolezni. Kontraindikacije: Zdravilo 81Jituxje kontraindicirano pri bolnikih z znano hudo preobcutljivostno reakcijo (3. ali 4. stopnje) na cetuksimab. Posebna opozorila In pmldnostm ukrepi: Pojav hude preobcutljirostne reakcije (3. ali 4. stopnje) zahteva takojšnjo in stalno ukiniteveteraplje s cetukslmabom. Nefelenl ucinki: Pri pribllžno 5% bolnikov se lahko pojavijo preobcutljivostne reakcije. Pribllžno polovica teh reakcij je hudih. Pri približno 5% bolnikov lahko pricakujemo konjunktivitis. O dispneji so porocall pri 25% bolnikov z rakom debelega crevesa in danke v zadnjem stadju. Hude kožne reakcje se pojavijo v približno 15%, predvsem nastopijo v obliki aknam podobnega izpušcaja in/ali motenj nohtov. ce se pri ii bolniku pojavi huda kožna reakcija (stopnje 3), smete zdravljenje nadeljevati Je, ce se je reakcija pomirila do 2. stopnje. Paklran}e: 1 viala po 50 ml. Vsak ml raztopine vsebuje 2 mg cetuksimaba. Vse nadaljne infonnacje so vam na voljo pri: Merek, d.o.o., Dunajska cesta 119, 1000 Wubljana, tel.: 01560 3810, faks: 01 560 3831, el. pošta: info@merck.si i l) Cunningham D etal., Cetuximab Monotherapyand Cetuximab plus trinotecan in lrinotecan-Refractory MetastaticColorectal cancer. New ENGJ Med 2004; 351(4): 337-345 II 1 www.oncology.merck.de ,MERCK dopolnilno zdravljenje* rimidex vodilni zaviralec aromataze anastrozol Kratka informacija o zdravilu Arimidex 1 mg ,tava: Filmsko obložena tableta vsebuje ,g anastrozola. ikaclje: Adjuvantno zdravljenje žensk po nopavzi, ki imajo zgodnji invazivni rak ke s pozitivnimi estrogenskimi receptorji ;e ne morejo zdraviti s tamoksifenom adi povecanega tveganja za 11boembolizem ali nenormalnosti Jometrija. Zdravljenje napredovalega a dojke pri ženskah po menopavzi. nkovitost pri bolnicah z negativnimi rogenskimi receptorji ni bila dokazana en pri tistih, ki so imele predhodno :itiven klinicni odgovor na tamoksifen. merjanje In nacin uporabe: 1 tableta po ,g peroralno, enkrat na dan. Pri ,dnjem raku je priporocljivo trajanje avljenja 5 let. 1tralndlkaclje: Arimidex je 1traindiciran pri: ženskah pred nopavzo, nosecnicah in dojecih materah, nicah s hujšo ledvicno odpovedjo (ocistek atinina manj kot 20 ml/min (oziroma 3 ml/s)), bolnicah z zmernim do hudim nim obolenjem in bolnicah, ki imajo ,no preobcutljivost za anastrozol ali za erokoli drugo sestavino zdravila. Zdravila, sebujejo estrogen, ne smete dajati :asno z Arimidexom, ker bi se njegovo nakološko delovanje iznicilo.Tamoksifena ,e sme uporabljati skupaj z Arimidexom, ker lahko pride do zmanjšanja njegovega delovanja. Posebna opozorila in previdnostni ukrepi: Uporabe Arimidexa ne priporocamo pri otrocih, ker njegova varnost in ucinkovitost pri njih še nista raziskani. Menopavzo je potrebno biokemicno dolociti pri vseh bolnicah, kjer obstaja dvom o hormonskem statusu. Ni podatkov o varni uporabi Arimidexa pri bolnicah z zmerno ali hudo jetrno okvaro ali hujšo ledvicno odpovedjo (ocistek kreatinina manj kakor 20 ml/min (oziroma 0,33 ml/s)). Ni podatkov o uporabi anastrozola z analogi LHRH. Te kombinacije zdravil se ne sme uporabljati zunaj klinicnih preskušanj. Pri ženskah z osteoporozo ali pri ženskah s povecanim tveganjem za razvoj osteoporoze je treba dolociti njihovo mineralno gostoto kosti z denzitometrijo, na primer s slikanjem DEXA na zacetku zdravljenja, pozneje pa v rednih intervalih. Po potrebi je treba zaceti z zdravljenjem ali preprecevanjem osteoporoze in to skrbno nadzorovati. Ni verjetno, da bi Arimidex zmanjšal bolnicino sposobnost za vožnjo ali upravljanje s stroji. Ker pa so med uporabo Arimidexa porocali o splošni oslabelosti in zaspanosti, je potrebna previdnost pri vožnji in upravljanju strojev, dokler simptoma trajata. Nosecnost In dojenje: Arimidex je med nosecnostjo in dojenjem kontraindiciran. Neželeni ucinki: Najpogostejši neželeni ucinki so navali vrocine, suhost vagine in redcenje las. Ostali neželeni ucinki vkljucujejo gastrointestinalne motnje (anoreksija, slabost, bruhanje, diareja), astenijo, bolecine/okorelost v sklepih, zaspanost, glavobol in izpušcaje. Obcasna porocila navajajo krvavitev iz nožnice, ki se pretežno pojavlja pri bolnicah z napredovalim obolenjem raka na dojki v prvih tednih po prehodu z dotedanjega hormonskega zdravljenja na zdravljenje z Arimidexom. ce krvavitev traja dlje casa, so potrebne dodatne preiskave. Hiperholesterolemija, obicajno blaga do zmerna. O povišanih nivojih gama-GT in alkalne fosfataze so porocali le obcasno. Vzrocna povezanost omenjenih sprememb ni bila ugotovljena. Medsebojno delovanje z drugimi zdravili: Zdravila, ki vsebujejo estrogen, ne smete dajati socasno z Arimidexom, ker bi se njegovo farmakološko delovanje iznicilo. Tamoksifena se ne sme uporabljati skupaj z Arimidexom, ker lahko pride do zmanjšanja njegovega delovanja. Vrsta ovojnine In vsebina: Pretisni omoti iz PVC in aluminija, ki vsebujejo 28 tablet v škatlici. Režim izdaje zdravila: Rp/Spec Datum priprave informacije: oktober 2005 Pred predpisovanjem, prosimo, preberite celoten povzetek temeljnih znacilnosti zdravila. L{) datne informacije in literatura so na voljo pri: o traZeneca UK Limited, Podružnica v Sloveniji, Einspielerjeva 6, Ljubljana AstraZeneca . o.. rw.breastcancersource.com ,w ;:trimirl.v n,::i,t so Lepe rož i.ce i.n soncek PRVI IN EDINI ANTAGONIST NEVROKININ-1 (NK1 ) RECEPTORJEV1 EME'ND®t ( aprepitant) Preprecevanje akutne in zapoznele slabosti in bruhanja No\J. • Preprecevanje navzeje in bruhanja, povezanih z zmerno emetogeno kemoterapijo raka 1 \ndw„oc\ 0MSD Merek Sharp & llohme, inovativna zdravila d.o.o. Prosimo, da pred predpisovanjem preberete šmartinska cesta 140, 1000 Ljubljana, Slovenija priložen Povzetek glavnih znacilnosti zdravila. Tel.: 01/ 52 04 201, faks: 01/ 52 04 349, 52 04 350 Zdravilo se izdaja le na zdravniški recept (H/Rp). Literatura: 1. Arhiv MSD, Slovenija. tZašcitena blagovna znamka MERCK & Co., lnc., WMehouse Station, N. J., ZDA. uporaba EMEND-a in šentjanževke ni priporocljiva. povecal za približno S-krat, povprecni terminalni razpolovni cas Potrebna je previdnost pri socasni uporabi EMEND­aprepitanta pa se je povecal približno za 3-krat. a in zdravil, ki zavirajo aktivnost CYP3A4 (npr. Rifampicin: Pri enkratnem odmerku 375 mg EMEND-a 9. dan EMf.ND®t ritonavir, ketokonazol, klaritromicin, telitromicin), 14-dnevnega zdravljenja z rilampicinom (ki je mocan induktor ( C11Xepitant) ker kombinacija povzroci zvišanje plazemskih CYP3A4) 600 mg na dan, se jeAUC aprepitantaezmanjšal za 91 EMEND 80mg trde kapsule EMEND 125 mg trde kapsule EN-EMENHC/0527/11 11 SKR AJŠAN POVZETEK GL A VNIH ZNACILNOSTI ZDRAVILA Pred predpisovanjem, prosimo, preberite celoten Povzetek glavnih znacilnosti zdravila, ki ga dobite pri naših strokovnih sodelavcih! Sestava: EMEND 125 mg trde kapsule in EMEND 80 mg trde kapsule. Ena 125 mg kapsula vsebuje 125 mg aprepitanta. Ena 80 mg kapsula vsebuje 80 mg aprepitanta. Pomožne snovi: saharoza, mikrokristalna celuloza (E460), hidroksipropilceluloza (E463), natrijev lavrilsulfat, želatina, titanov dioksid (E171 )-125 mg kapsule pa še rdeci železov oksid (E172), rumeni železov oksid (E172), šelak, kalijev hidroksid, crni železov oksid (E172). Terapevtske indikacije: Preprecevanje akutne in zapoznele navzeje in bruhanja povezanih z zelo emetogeno kemoterapijo raka s cisplatinom. Preprecevanje navzeje in bruhanja, povezanih z zmerno emetogeno kemoterapijo raka. EMEND se daje v sklopu kombiniranega zdravljenja (glejte poglavje 4.2 v Povzetku glavnih znacilnosti zdravila). Odmerjanje in nacin uporabe: EMEND je na voljo v obliki 80 mg in 125 mg trdih kapsul. EMEND se daje 3 dni po shemi zdravljenja, ki vkljucuje kortikosteroid in antagonist 5-HT 3• Priporoceni odmerek zdravila EMEND je 125 mg peroralno prvi dan ter 80 mg enkrat na dan drugi in tretji dan. Podatkov o ucinkovitosti pri kombiniranju z drugimi kortikosteroidi in antagonisti 5-HT3 ni dovolj. EMEND se lahko jemlje s hrano ali brez. Trdo kapsulo je treba pogoltniti celo. Starejši bolniki: Pri starejših bolnikih odmerka ni treba prilagajati. Okvara ledvic: Pri bolnikih z okvaro ledvic in pri bolnikih s koncno ledvicno odpovedjo, ki se zdravijo s hemodializo, odmerka ni treba prilagoditi. Okvara jeter: Pri bolnikih z blago okvaro jeter odmerka ni treba prilagajati. Pri bolnikih z zmerno okvaro jeter so podatki omejeni, podatkov pri bolnikih s hudo okvaro jeter ni na voljo. Otroci in mladostniki: Varnost in ucinkovitost pri otrocih in mladostnikih nista znani. Uporabe pri bolnikih, ki so mlajši od 18 let, zato ne priporocamo. Kontraindikacije: Preobcutljivost za zdravilno ucinkovino ali katero koli pomožno snov. Zdravila EMEND se ne sme uporabljati socasno s pimozidom, terfenadinom, z astemizolom ali s cisapridom. Posebna opozorila in previdnostni ukrepi: Podatki o uporabi pri bolnikih z zmerno okvaro jeter so omejeni. Podatkov o uporabi pri bolnikih s hudo okvaro jeter ni na voljo. Pri teh bolnikih je treba aprepitant uporabljati previdno. EMEND je treba uporabljati previdno pri bolnikih, ki socasno jemljejo zdravila, ki se primarno presnavljajo s CYP3A4. Zato je treba previdno uporabljati kemoterapevtike, ki se presnavljajo s CYP3A4. še posebej je previdnost potrebna pri socasnem dajanju irinotekana, saj lahko kombinacija poveca toksicni ucinek. Pri socasni uporabi EMEND-a z alkaloidi rženega rožicka (ergot alkaloidi), ki so substrat za CYP3A4, se lahko zviša plazemska raven teh zdravil. Socasna uporaba EMEND-a z varfarinorn zmanjša protrombinski cas, izražen kot INR (lntemational Normalised Ratio). Pri bolnikih, ki se neprenehoma zdravijo z varfarinom, je treba INR skrbno spremljati med zdravljenjem z zdravilom EM ENO in 2 tedna po vsakem 3-dnevnem ciklusu zdravljenja z EMEND­om. Med jemanjem EMEND-a se lahko zmanjša ucinkovitost oralnih kontraceptivov. Med zdravljenjem z EMEND-om in dva meseca po zadnjem odmerku EMEND-a je treba uporabljati alternativna ali dodatna kontracepcijska sredstva. Socasnemu jemanju EMENO-a in zdravil, ki mocno inducirajo aktivnost CYP3A4 (npr. rifampicin, fenitoin, karbamazepin, fenobarbital), se je treba izogibati, ker kombinacija povzroci zmanjšanje plazemskih koncentracij aprepitanta. Socasna koncentracij aprepitanta. Bolniki z redkimi dednimi motnjami fruktozno intoleranco, malabsorpcijo glukoze in galaktoze ali insuficienco saharaze-izomaltaze ne smejo jemati tega zdravila. Medsebojno delovanje z drugimi zdravili in druge oblike interakcij: Aprepitant je substrat, zmerni zaviralec in induktor CYP3A4. Aprepitanteje tudi induktor CYP2C9. Kot zmerni zaviralec CYP3A4 lahko aprepitant zviša plazemske koncentracije socasno uporabljenih zdravil, ki se presnavljajo s CYP3A4. AUC peroralno vzetih substratov CYP3A4 se lahko poveca do približno 3-krat. Pri socasnem jemanju s substrati CYP3A4 svetujemo previdnost. EMEND-a se ne sme uporabljati skupaj s pimozidom, terfenadinom, z astemizolom ali s cisapridom. Aprepitant zavira CYP3A4, zaradi cesar bi se lahko zvišale plazemske koncentracije teh zdravil, kar bi lahko povzrocilo resne ali življenje ogrožajoce reakcije. Kot zmeren induktor CYP2C9 in blag induktor CYP3A4 in glukuronidacije, lahko aprepitant zniža plazemske koncentracije substratov, ki se izlocajo po teh poteh. Ta ucinek se lahko pokaže šele po koncu zdravljenja z EMEND-om. Indukcija substratov CYP2C9 in CYP3A4 je prehodna, maksimalen ucinek pa je dosežen v 3-5 dneh po koncu 3 dnevnega zdravljenja z zdravilom EMEND. V tem obdobju svetujemo previdnost pri dajanju peroralnih zdravil, ki se presnavljajo s CYP3A4. Pokazano je bilo, da aprepitant inducira presnavljanje S() varfarina in tolbutamida, ki se presnavljata s CYP2C9. Socasno dajanje EMEND­ a in teh ali drugih zdravil, ki se presnavljajo s CYP2C9, denimo fenitoina, lahko zniža plazemske koncentracije teh zdravil, zato svetujemo previdnost. EMEND nima medsebojnega vpliva z digoksinom, zato ve.etno ne intereagira s P-glikoproteinskim prenašalcem. Kortikosteroidi: Deksametazon: Pri socasnem jemanju z EMEND-0m je treba obicajni peroralni odmerek zmanjšati za približno 50 %. MeU/prednizolon: Pri socasni uporabi z EMEND-om je treba obicajni intravenski odmerek metilprednizolona zmanjšati za približno 25 %, obicajni peroralni odmerek metilprednizolona pa za približno 50 %. Kemoterapevtiki: V klinicnih raziskavah so EMEND uporabljali skupaj z naslednjimi kemoterapevtiki, ki se predvsem ali delno presnavljajo s CYP3A4: etopozid, vinorelbin, docetaksel in paklitaksel. Odmer1<0v teh zdravil niso prilagajali glede na morebitno medsebojno delovanje zdravil. Svetujemo previdnost; pri bolnikih, ki dobivajo taka zdravila, je lahko potreben dodaten nadzor. Midazolam: Pri socasni uporabi z EMEND-0m je treba upoštevati možne ucinke zvšanih plazemskih koncentracij midazolama in drugih benzodiazepinov, ki se presnavljajo predvsem s CYP3A4 (alprazolam, triazolam). EMEND poveca AUC midazolama, ki je obcutljiv substrat za CYP3A4. Varfarin: Pri bolnikih, ki se dolgotrajno zdravijo z varfarinom, je treba protrombinski cas (INR) sklbno nadzorovati med zdravljenjem z zdravilom EMEND in 2 tedna po vsakem . dnevnem ciklusu zdravljenja z EMEND-om. Tolbutamid: EMEND je pri jemanju po shemi 125 mg plVi dan ter 80 mg/dan drugi in tretji dan zmanjšal AUC tolbutamKla (ki je substrat za CYP2C9), ki so ga bolniki prejemali v enkratnem odmerku 500 mg per os pred zacetkom 3-1/100, <1/10): anoreksija, glavobol, omotica, kolcanje, zaprtje, driska, dispepsija, eruktacija, oslabelosUutrujenost, zvišanje ALT, zvišanje aspartat­ aminotransferaze (AST). Obcasne{>1/1.000, <11100): kandidiaza, okužbe s stafik>koki, anemija, febrilna nevtropenija, pridobivanje telesne teže, polidipsija, dezorientacija, evforija, anksioznost, nenonnalne sanje, motnje mišljenja, konjunktivitis, tinitus, bradikardija, navali vrocine, laringitis, kihanje, kašej, zatekanje izcedka iz l nosu v žrelo, draženje žrela, na\/Zeja*, bruhanje*, refluks kisline, motnje okusa, neugodje v epigastriju, zaprtje, gastroezofagalna refluksna bolezen, predrtje razjede dvanajstnika, bolecine v trebuhu, suha usta, enterokolitis, vetrovi, stomatitis, izpušcaji, akne, fotosenzitivnost, prekomerno potenje, mastna koža, srbenje, lezije kože, mišicni krci, bolecine v mišicah, poliurija, dizurija, polakisurija, bolecine v trebuhu, otekanje, zardevanje, nelagodje v prsnem košu, leta'l)ija, žeja, zvšanje alkalne fostataze, hiperglikemija, mikrohematurija, hiponatremja, znižanje telesne teže. i •Navzeja in bruhanje sta bila parametra u.nkovitosti prvih 5 dni po kemoterapiji; o njih so kot o neželenih ucinkih porocali šele poitem casu. Profil neželenih ucinkov je bil v podaljšku raziskave z vec ciklusi zdravljenja (do 5 dodatnih ciklusov kemoterapije) na splošno podoben tistemu po prvem ciklusu. Pri enem bolniku, ki je dobival aprepitant ob kemoterapiji zaradi raka, so porocali o Stevens-Johnsonovem sindromu kot o resnem neželenem ucinku. Pri enem bolniku, ki je prejemal aprepitant, vendar ne v raziskavi CINV (Cisplatin-lnduced Nausea and Vomiting), so porocali o angioedemu in koprivnici kot o resnem neželenem ucinku. Aprepitanta ni mogoce odstraniti s hemodializo. Vrsta ovojnine in vsebine: Na voljo so razlicna pakiranja, ki vsebujejo razlicne jakosti zdravila. Aluminijast pretisni omot, . vsebuje eno 125 mg kapsulo in dve 80 mg kapsuli. Na trgu ni vseh navedenih pakiranj. Imetnik dovoljenja za promet: MerckSharp& DohmeLtd. Hertford Road, Hoddesdon Hertfordshire EN 119BU Velika Brilanija Nacin in režim izdaje zdravila: Izdaja zdravila }e le na recept! Datum zadnje revizije besedila: november 2005. EMD-ABl-003 t Zašcitena blagovna znamka MERCK & CO., INC., Whitehouse Station, N.J., ZDA. 0MSD Merek Sharp & Dohme, inovativna zdravila d.o.o. Šmartinska cesta 140, 1000 Ljubljana, Slovenija Tel.: 01/ 52 04 201, faks: 01/ 52 04 349, 52 04 350 Tiskano v Sloveniji, marec 2006. 03-07-EMD-06e-SL0-009-J Tarceva is indicated for the treatment of patients with locally advanced or (f'Tarceva® metastatic Non-Small Cell Lung Cancer (NSCLC) after failure of at least one prior erlotinib HCI chemotherapy regimen. For additional information please consult your local Roche office. Reference: l-Tarceva (erlotinib) summary of product characteristics, F.Hoffmann-La Roche LTD., 2005. CROATIAN SENOLOGIC SOCIETY CROATIAN RADIOLOGY SOCIETY CROATIAN SOCIETY FOR RADIOTHERAPY AND ONCOLOGY CROATIAN SOCIETY FOR ULTRASOUND IN MEDICINE AND BIOLOGY CROATIAN SOCIETY FOR CLINICAL CYTOLOGY CROATIAN SOCIETY OF PATHOLOGY EU ROPA DON NA CROATIA XIV S.I.S. WORLD CONGRESS ON BREAST DISEASES III CROATIAN SENOLOGIC CONGRESS SENOLOGY 2006 18. -21. -May 2006 -Zagreb -Croatia Epidemiology Imaging Basic research Genetics Pathology Prevention Screening programmes Surgery Radiotherapy Hormone and Antiblastic therapy Women's anti-cancer meetings www.senology2006.com C. Announcement 2nd CENTRAL EUROPEAN COURSE (CEC 2006) METHODOLOGY OF CLINICAL TRIALS IN ONCOLOGY VIENNA, AUSTRIA; AUGUST 24th -26th , 2006 Host lnstitutions: CESAR Central European Society tor Anticancer Drug Research -EWIV Applied Cancer Research -lnstitution tor Translational Research Vienna (ACR-ITR VIEnna) Ludwig Boltzmann-Institute tor Applied Cancer Research (LBI-ACR VIEnna) Objective: To provide participants with the specific knowledge on the planning and performing of clinical studies of the phase 1-11-111 Contents: Bio-statistical issues Preclinical data as prerequisite tor the conception of clinical trials Clinical pharmacological and toxicological issues Planning and performing of clinical trials of the phase 1-11-111 Study design tor targeted therapies Study organization/-administration Data assessment and management Limitations and pitfalls of clinical trials Course Format: Lectures, presentation of case reports, systematic discussion and exchange of experiences among the participants and the faculty Workshop: phase 11-study protocol development lntormation: ACR-ITR VIEnna; c/o Bernardgasse 24/2, A-1070 Vienna, Austria Phone: + 43 1 523 35 94 Fax: + 43 1 523 35 944 Email: ch.dittrich@chello.at http://www.cesar.or.at 1 wish to obtain further informations on the course. Title Last Name: _______ ______ _ _ ____________First Name:. __ Address: ___________________________ _ Fax: _____ _ Email: ___ ____________ _ CLINIPORATOR NEW TECHNOLOGY FOR LOCAL TUMOUR CONTROL BY ELECTROCHEMOTHERAPY CLINIPORATOR™ and ELECTROCHEMOTHERAPY Electrochemotherapy is an innovative therapeutic technique for local tumour control. It combines the administration of reduced dose of drugs with high voltage pulsed electric fields: Electroporation. Electroporation, applied to the celi membrane, increases its permeability and allows highly cytotoxic drugs, non-permeant or poorly permeant, to enter the celi and exert their anti-tumour activity. Electrochemotherapy clinical indications = Primary cutaneous tumours: basal and squamous celi carcinoma. = Melanoma metastasis and in transit melanoma metastasis. = Cutaneous and subcutaneous metastasis of tumours independently of histology. Cliniporator complies with 93/42/EEC directive far medical device: CE 0051 CLINIPORATOR TECHNOLOGY Dosimetry of the Electrochemotherapy treatment. CLINIPORATOR allows the visualization and real tirne measurement of the characteristics of the applied electric pulses and of the current flown into tu moral tissue. Plate, hexagonal needle and row needle electrodes are available for clinicians to treat any kind of skin tumours. Pulse frequency. Cliniporator has been developed to allow pulse delivery at 1 Hz and 5kHz. This feature reduces muscle contraction associated with the electrical stimulus and makes the treatment well accepted. Data management. The software allows clinicians to store and manage patient's data. ESOPE clinical study (5th Framework Research Programme) AII above technologies have been implemented and used in the European Study ESOPE which aimed to validate the Standard Operating Procedures for Electrochemotherapy. Electrochemotherapy treatment was effective in 850/o of tumours treated. Gf \ IGEA s.r.1. Via Parmenide, 10/A-41012 Carpi (MO) -ltaly Phone: +39059699600-Fax +39059695778-e-mail: info@igeamedical.com He-alth Resources International 1.9ecru1tment company Our dients are d:eading healthcare providers running treatment and diagnostic centres all over the Uhited K:ihgdom. Along with the dynamic development of the companies we are looking for Radiologtsts· and Radiographers on the field of CT /MR diagnostics for newly opening diagnostic/imaging centres. The positions require: • at least 2 years experience with CT /MR diagnostic • good, workable knowledge of English What we offer: • attractive salary • long and short term contracts • help with GMC/HPC registration • help with acct>mmodation Starting date: Oct 2006 Ifyou are interested please, send your CV to info@healthresourcesinternational.co.uk Find out more about our company and contact us www.healthresoafcesinternational.co.uk Radiology and Oncology Instructions f or authors Editorial policy of the journal Radiologij and Oncology is to publish original scientific pa­pers, professional papers, review articles, case reports and varia (editorials, reviews, short communications, professional infarmation, book reviews, letters, etc.) pertinent to diag­nostic and interventional radiology, comput­erized tomography, magnetic resonance, ul­trasound, nuclear medicine, radiotherapy, clinical and experimental oncology, radiobiol­ogy, radiophysics and radiation protection. 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