ADIOLOGY AND NCOLOGY September 2007 Vol. 41 No. 3 Ljubljana ISSN 1318-2099 ;krajšan povzetek glavnih znacilnosti zdravila emzar200mgprašekzaraztopinonzainfundiranje,Gemzar1 gprašeknza raztopinozainfundiranje e.avanzdravila:200oz.1gngemcitabna,manitol,natrijevnacetat,klorovodikovanki>linain/alinnatrijevhidroksid(zanuravnavanjepH}. i .rapevtske indikacije: lokalno napredovali ali meta>tatski karcinom secnega mehurja, v kombinaciji z drugimi citostaticnimi zdra- iv i i ...:\.i ..:1.::\ :.:..;;....n.r.rb.š..c:\...::,r..ob:1.:...' 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Karcinom jajcnika j oiarb8fn°:a.e..n.......;:...ii.:ec;.r;.i...::.t.a....;..t:ij:.t.:.c.t:b..nptd. .:o k...p1!1...a ...Ž.m. 0n 1iie l.:e ...;::nki.td.;;.k..-i.:;.;.Jo..r.r: :1.ia:.'u:'h...;..:..:...,.!t..d:n.k.: iw:i...aj..C:v.t::: je aGe1 e k1.i.:...!..;:...k.-..n:!k:J..;..:..zd;a.[e.].:r.nb ..;i:J..:..klu::.r..ij.aj!.ni.;.g.d..:ni.ii:di!i::... 1vano toksicn ost. Odmerek lahko z vsakim c:niklusom ali med tekocinm ciklusom znnižamo glende na toksicnnost, izraženo pri bolniku. ·1j1 odi z GEMZARjem Kontraindik acije: Preobcutijvost za gemcitabin ali katero od pomožnih snovi. Bolnikom z zmerno do hudo okvarenim jetrnim de­lovanjem ali hudo okvarjenim ledvicnim delovanem Gemzara ne .memo dajati. Posebnanopozorilain previdnostni ukrepi:Podajl.ane casajinfuz1jein skrajsanjepriporocenegaintervala medodmerkipovecue­ lj jjj ta toksicnost. Genmcitabin moramo pri bolnikih z bnlago do zmerno okvanr enim ledvicnim delovanjem in pri bolnikih z blago okvar- j nimlvkinnr .dr:}:.J;. G.%....nx.....f;!.e..i.bi.! b..1im.;.t:s.ij...n....;e..P:ift:p.......ikih.:.o. !.fj.. r 2nkl ojaek vi;.n.;a ..:;:1:n.:..n...:vf):n;..:.!.!d..-...r..:dri.j..i:: i:.;:rj....d.:::ur:;.n..c..:i.r..a .!d:d!:: 1jpjjj1.i 1j jenjem in do 6 me.em po njem . Pred vsa.im odmerkom je treba preveriti k oncentracije trombocitov, lev k ocitov in granulocitov. Tvegan ezaneželeneucinke,povezanezdihali,evi$je pribolninkihsnkar cinomomnpljljljjucin pucnim imevki,nkotnpri drugihtipihtu- e es vaek tnni...;iJ.fn..;d...'.i.....1.a;f;.n;.:..nf1.:t.. .i.......ri....i.:;....;k.fe .r:barn;..:vi..J!\n.!%:...e:...li..i 1 Gemcitabin sonpriotnrocihnpreuncevalivom!jenihpre,kušanijhfaze 1 in2prirazlicnihtipihtumornjev.Te študijenisonpodalezado,ti podatkovzazagotovitevucinkovitostiin varnostigem citabinapriotrocih. .:..:..ij..\:r.C:i: .d..t..dit .t.env j.]h ..t;.h\: r...h ;.r.pred kemoterapijo ali po nej) gemcitabin deluje radio-i vani k.nj Neželeni ucinnk i: Ob.val na toksicnost in odnklic obsevana; Zel. pogosti: levkopenia, trombocitopenij jja, anemija, dispneja, slabo;!, lbaee0 .:.t..r:;;..0:i ...isi.;to.t ..!.'....i:.;;jj..j.;..1./t:a.J!. .t.!n:..:.:ii.i.....j; .:;;.;ii:: brilnanevtropenija,anoreksija,glavobol,mpanost,nespecno,t,diarea,zaprtje,stomatrtis,poviSGnne vrednostibilirubina,znn ojenje,sr ­bene, alopecija, mialgija, bolecine v hrbtu, mrzlica, edem obraza; Majnj pogosti: ucni edem, bronhospazem, inter;ticijski pnevmo­ jplj kasda ....1:o;.n..h.:.jv. :r..j..d 1:..:!h;:.....:t.c.Ts....; ];.; :r;..bJi'o..:.:fit.::n.r;:k3!: j klinicnizna.iperiferneg3vaskuliti.ain gangrene,hudenk oinenreakcije,vnkjucnoznlu$Cenjeminbuloznimivzbr stmi. l Imetnik dovojenja za promet: Eli Lilnly Hodings _Umited, King$Cnlere Road, Basing>toke, Hampshire, RG21 6XA Velika Britanija jljll Nacin in režimizdajezdravila:H-Zdravilosen1zdaale narecept,uporabapa>e samovnbolnišnicah. Datum revizije besedila: 14.10.2006 :li Lilly farmacevtska družba, d.o.o. )unajska 156, 1000 Ljubljana, Slovenija ·el.: (01) 5800 01 O, faks: (01) 5691 705 ADIOLOGY ANO NCOLOGY Editorial office Radiology and OncologtJ Institute of Oncology Zaloška 2 SI-1000 Ljubljana 5/ovenia Phone: +386 1 5879 369 Phone/Fax: +386 1 5879 434 E-mail: gsersa@onko-i.si Aims and scope September 2007 Vol. 41 No. 3 Pages 99-160 ISSN 1318-2099 UDC 616-006 CODEN: RONCEM Radiology and Oncology is a journal devoted to publication of original contributions in diagnostic and interventional radiology, computerized tomography, ultrasound, magnetic resonance, nuclear medicine, radiotherapy, clinical and experimental oncology, radiobiology, radiophysics and radia/ion protection. Editor-in-Chief GregorSerša Ljubljana, Slovenia Executive Editor Viljem Kovac Ljubljana, Slovenia Editorial Board Karl H. Bohuslavizki Hamburg, Germany Maja Cemažar Ljubljana, Slovenia Christian Dittrich Vienna, Austria Metka Filipic Ljubljana, Slovenia Tullio Giraldi Trieste, Italy Maria G6deny Budapest, Hungary Vassil Hadjidekov Sofia, Bulgaria Marko Hocevar Ljubljana, Slovenia Maksimilijan Kadivec Ljubljana, Slovenia Advisory Committee Deputy Editors AndrejCiir Ljubljana, Slovenia Igor Kocijancic Ljubljana, Slovenia Mikl6s Kasler Budapest, Hungary Michael Kirschfink Heidelberg, Germany Janko Kos Ljubljana, Slovenia Tamara Lah Turnšek Ljubljana, Slovenia Damijan Miklavcic Ljubljana, Slovenia Luka Milas Houston, USA Damir Miletic Rijeka, Croatia MajaOsmak Zagreb, Croatia Branko Palcic Vancouver, Canada Dušan Pavcnik Portland, USA Geoffrey J Pilkington Portsmouth, UK Ervin B. Podgoršak Montreal, Canada Uroš Smrdel Ljubljana, Slovenia Primož Strojan Ljubljana, Slovenia Borut Štabuc Ljubljana, Slovenia Ranka Štern-Padovan Zagreb, Croatia Justin Teissie Tolouse, France SandorT6th Oroshaza, Hungary Gillian M. Tozer Sheffield, UK Andrea Veronesi Aviano, Italy Branko Zakotnik Ljubljana, Slovenia Marija Auersperg Ljubljana, Slovenia; Tomaž Benulic Ljubljana, Slovenia; Jure Fettich Ljubljana; Valentin Fidler Ljubljana, Slovenia; Berta Jereb Ljubljana, Slovenia; Vladimir Jevtic Ljubljana, Slovenia; Stojan Plesnicar Ljubljana, Slovenia; Živa Zupancic Ljubljana, Slovenia Publisher Association of Radiologi; and Oncology Affiliated with 5/ovenian Medica/ Association -5/ovenian Association of Radiology, Nuclear Medicine Society, 5/ovenian Society far Radiotherapy and Oncology, and 5/ovenian Cancer Society Croatian Medica/ Association -Croatian Society of Radiology Societas Radiologoru111 Hungaroru111 Friuli-Venezia Giulia regional groups of S.I.R.M. (Italimz Society of Medica/ Radiologi;) Copyright © Radiology and Oncologij, Ali rights reserved. Reader for English Vida Kološa Key words Eva Klemencic Secretary Mira Klemencic Design Monika Fink-Serša Printed by Imprint d.o.o., Ljubljana, Slovenia Published qzzarterly in 600 copies Beneficiary na111e: DRUŠTVO RADIOLOGIJE IN ONKOLOGIJE Zaloška cesta 2, 1000 Ljubljana S/ovenia Beneficiary bank accozmt nu111ber: S156 02010-0090006751 !BAN: SI56020100090006751 Ozzr bank name: Nova Ljubljanska banka, d.d., Ljubljana, Trg republike 2, 1520 Ljubljana; Slovenia SWIFT: LJBASI2X Subscription fee far institutions EUR 100, individuals EUR 50 The pzzblication of 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 avai/able on the internet at: http://www.onko-i.sijradiolonco/ and http://www.versita.com ISSN 1581-3207 Ljubljana, Slovenia ISSN 1318-2099 September 2007 UDC 616-006 Vol. 41 No. 3 CODEN: RONCEM CONTENTS RADIOLOGY CT-guided percutaneous transthoracic needle biopsy of lung lesions ­ 99 2-year experience at the Institute of Radiology in Ljubljana Kocijancic I, Kocijancic K Adult obstructing ileocolic intussusception 107 Žolcalj I, Magaš Z, Pavcec Z, Saghir H, Pal A, Kolaric Z, Marotti M IMAGING IN CLINICAL MEDICINE Basal cell carcinoma in the inner canthus Jancar B 113 ONCOLOGY Adjuvant treatment of breast cancer patients with trastuzumab Matos E, Cufer T 115 Ionising radiation and trans-generational instability Vrhovac I, Nilcšic G 123 3D-conformal radiotherapy for inoperable non-small-cell lung cancer ­A single centre experience Fromm S, Rottenfusser A, Berger D, Pirlcer R, Potter R, Polcrajac B 133 Quality of life following thoracotomy for lung cancer Debevec L, Rozman I 144 Diagnostic and treatment problems with parosteal osteosarcoma. A clinical and a histological study of 7 cases and review of the literature Samardziski M, Zafiroski G, Tolevska C, Konstadinova-Kunovska S, Vasileva V 152 SLOVENIAN ABSTRACTS I NOTICES VIII Radiology and Oncology is covered in Biomedicina Slovenica, Chemical Abstracts, EMBASE / Excerpta Medica, Sci Base and Scopus CT-guided percutaneous transthoracic needle biopsy of lung lesions – 2-year experience at the Institute of Radiology in Ljubljana Igor Kocijancic and Ksenija Kocijancic Institute of Radiology, University Clinical Centre Ljubljana, Ljubljana, Slovenia Background. In 1883, Leyden described percutaneous lung biopsy, but it was not until 1970s that image guided fine needle chest biopsy gained widespread acceptance. Haaga and Alfidi reported CT-guided tho­racic biopsy in 1976. Currently, tissue sampling of a thoracic lesion is indicated when the diagnosis is not obtained by the endobronchial technique and when the cytological diagnosis will modify the stage of the disease or influence the therapeutic strategy. Cytology obtained by small-gauge needle aspiration biopsy confirms the nature of the lesion in 80 – 95% of cases and carry a low incidence of major complications according to the literature. The purpose of this retrospective analysis was to provide basic data about diagnostic accuracy and incidence of pneumothorax and chest tube insertion with respect to percutaneous transthoracic CT-guided needle biopsy of lung lesions. Methods. After positioning of the patient we performed a spiral CT of the thorax with the accordingly placed metal mark, which helped us to set the optimal cutaneous entry point. After that we re-checked the localisation of the lesion and marked the entry point with a pen and clean the surface to keep it sterile. After we applied local anaesthetic subcutaneously, we used coaxial 18G Gallini aspiration biopsy needles with cutting tip for CT-guided aspiration cytologic examination. The length of the needle was chosen according to the distance of the targeted lesion. Results. From January 2005 to January 2007 forty-three patients – 24 men and 19 women who were 26-79 years old (mean +/-SD, 59.8 +/-10 years) were referred to the Institute of Radiology to undergo the PTNB. One patient was referred twice. Consequently, the hospital records and images of 44 consecutive cases of percutaneous transthoracic fine needle aspiration biopsy procedure were retrospectively analysed. The overall diagnostic accuracy was 93.2%, the pneumothorax rate was 27.2% and the chest tube insertion rate with percutaneous transthoracic CT-guided needle biopsy was 4.5%. Conclusions. Based on these cases, our 2-year experience is indicating that percutaneous transthoracic CT-guided needle biopsy is an effective and safe procedure for evaluation of undetermined lung lesions. Key words: lung neoplasms – pathology, biopsy needle; pneumothorax Received 22 September 2007 Accepted 29 September 2007 Correspondence to: Assist. Prof. Igor Kocijancic, MD, PhD, Institute of Radiology, Clinical Center Ljubljana, Zaloška 2, SI -1000 Ljubljana, Slovenia; Phone: + 386 1 520 85 31; Fax: + 386 1 520 24 97; E-mail: igor.koc@kclj.si Introduction In 1883, Leyden first described percutane­ous lung biopsy, but it was not until the 1970s that image guided fine needle lung biopsy gained widespread acceptance. In this early years percutaneous lung biop­sies and advances in cytopathology were reported as well in our institution1,2. Haaga and Alfidi3 first reported the CT-guided bi­opsy in 1976. Since that many authors con­firmed the technique as safe and accurate in diagnosing benign and malignant lesion of the chest.4-8 Nowadays, tissue sampling of a thoracic lesion is indicated when the diagnosis is not obtained by endobronchial technique and when cytological diagnosis will modify the stage of the disease or influ­ence the therapeutic strategy. With the advent of lung cancer screen­ing using low-dose helical CT an increased incidence of smaller lung lesion and also small lung cancer has been reported in some countries.9,10 It is well known that the detection of lung cancer in early stage may improve the prognosis of such patients.11-13 In management of solitary pulmonary nodule we use a repeated CT examination with the evaluation of volume change of the small pulmonary nodule but when an increase in size is recognized on follow-up CT examination a verification of the lesion becomes mandatory. Beside this, main in­dications for percutaneous transthoracic needl e biopsy (PTNB) are: pulmonary nod­ule or nodules without specific diagnostic criteria on computed tomography (CT) as­certaining benignity; pulmonary nodule(s) or mass(es) suggestive of malignancy, pul­monary nodule in a patient with a history of extrapulmonary primary malignancy, a residual nonregressive lesion following ra­diotherapy and chemotherapy, a residual nonregressive infiltrate following specific antibiotic therapy, chronic diffuse pulmo­nary infiltrate in selected cases. The need for the preoperative diagnosis of a solitary pulmonary nodule depends on the pretest probability of diagnosing a lesion that would obviate an unnecessary thoracoscopy or thoracotomy.16 Concerning CT characteristics of pulmo­nary nodules, it is known that 43% of nod­ules smaller than 1 cm are benign as well as that 97% of nodules bigger than 3 cm are malignant. Thirty-three % of primary malignant nodules have regular contours and 46% of benign nodules are spiculated. Twenty-six % of benign nodules and 5% of malignant nodules are more or less calcified while 21% of benign and 40% of malignant nodules show air bronchogram. Overall, a correct diagnosis can be estab­lished by CT in 66-98% cases.17 The aim of this analysis was to provide basic data about the diagnostic accuracy and frequency of complications of lung bi­opsy procedures with CT guidance of nee­dle insertion over the last two years. Methods When the transthoracic needle biopsy was performed, the procedure itself, possible complications and its accuracy had been carefully explained to the patient. Upon this conversation the patient was requested to sign the Informed consent form. The clinicians obtained routine partial thromboplastine time (PTT), prothrombine time (PT) and platelets level in all patients. We performed CT guided PTNB, which enabled a precise localisation of the lesion. All procedures were conducted on a mul­tislice CT scanner (Somatom 16, Siemens, Erlangen, Germany) by two radiologists ex­perienced in thoracic radiology and image-guided biopsy techniques. The scanning parameters of the Somatom 16 were 120 kVp, 120-200 mA, 1.5 mm collimation; 3- to 5-mm slice thickness and a table speed of 30 mm/sec (pitch up-to 1.5). Biopsies were performed without injection of i.v. contrast media. Necrotic tissue and cystic lesions were identified during prior diagnostic con­trast enhanced CT. Unenhanced CT scans were reviewed with a lung window setting (window width 1600 HU, window level -600 HU) and with a mediastinal window setting (window width 350 HU, window level 35 HU). The position of the patient was then se­lected according to the desired needle path. It should be remembered that the position of the lesion can vary considerably when changing position from supine to prone or to oblique. The needle path should avoid transversing intercostals vessels so the needle entry was optimally defined at mid intercostals space whenever possible. In addition, it was necessary to try avoiding transgression of a pleural fissure, bullae or puncture of large vessel, bronchi and the oesophagus. We tried to insert the needle through the normal lung and to keep the length of the needle path to a minimum. We believed this reduced the risk for com­plication to a minimum. The patient was instructed to stop breathing after normal inspiration at func­tional residual capacity. The technique of breath-holding was explained to each pa­tient and was practiced shortly before the procedure. To evaluate the procedure we could use adjusted (narrow) spiral scans or thick col­limation (1 cm) sequence scans. The real time CT control should be avoided due to high doses for the patient and the staff. After positioning of the patient we per­formed a spiral CT of the thorax with the accordingly placed metal mark, which helped to set the optimal cutaneous entry point. After that we re-checked the localisa­tion of the lesion with regard to its anatomi­cal environment. Once having the patient positioned at the desired table position, we marked the entry point with a pen and cleaned the surface to keep it sterile. We ap­plied the local anaesthetic subcutaneously (2-5 ml 2% lidocain) and waited a few min-utes. We do not apply any sedo-analgesia on routine basis. For CT- guided aspiration cytologic ex­amination coaxial 18G Gallini aspiration biopsy needles with cutting tip were used. The length of the needle was chosen accord­ing to the distance of the targeted lesion. The cytologist was always present to check the quality of the material. If needed, additional percutaneous passes were per­formed to get the satisfactory tissue sam­ple. Finally, the patient underwent post-pro­cedural CT scan to check for possible com­plications (pneumothorax, haemorrhage, pleural effusion…). In case of large pneu­mothorax or moderately to severe dyspno­eic patient the placement of chest catheter or tube was considered. Others had the size of pneumothorax re-evaluated 7 days after the last follow-up examination if the patient was asymptomatic. In case of the increased pneumothorax (on follow-up chest radio-graphs) or the patient becoming sympto- Radiol Oncol 2007; 41(3): 99-106. matic or large pneumothorax was found, a chest tube was placed. Following the biopsy the patient was turned around to lie on the side which had been punctured for 15 to 30 minutes to pre­vent the possibility of pneumothorax evolu­tion or progress. Patients were generally observed, ad­vised to stay in a recumbent position and under the medical staff supervision for at least for 4 to 5 hours after biopsy, then an erect expiratory chest X-ray was obtained. If normal, the compliant patients were dis­charged home. In the event a patient be­came symptomatic, an immediate follow up erect expiratory posteroanterior chest ra­diograph was obtained and in case of large pneumothorax (>30%) a chest catheter or tube was considered. Results From January 2005 to January 2007 43 patients – 24 men and 19 women who were 26-79 years old (mean +/- SD, 59.8 +/- 10 years) were referred to the Institute of Radiology to undergo the PTNB. One patient was referred twice. Consequently, the hospital records and images of 44 consecutive cases of percu­taneous transthoracic fine needle aspira­tion biopsy procedure were retrospectively analysed. Diameter of pulmonary nodules/ masses was measured on lung window set­tings. They measured from 0.8 cm to 6 cm in diameter (mean 2.3 cm, SD+/- 1.3 cm). Cytological results were compared to the histological diagnosis after the surgery or to clinic and/or imaging follow up findings. To ascertain the benign nature of a lung no­dule we used the following criteria: a techni­cally successful biopsy, fair aspiration that is not normal lung, no signs of malignancy among aspirated cells and normal finding on bronchoscopy. In our study, aspiration specimens were cytologically diagnosed into three groups by an experienced cytologist and/or by a cytology counsel as follows: negative for malignant cells 14/44 (32%) specimens, insufficient component 2/44 (4.5%) speci­mens and malignant lesion 28/44 (63.5%) specimens. All malignant lesions were nod­ules: 8 adenocarcinoma, 8 non-small cell lung cancer, 1 small-cell lung cancer, 2 car-cinoids, 1 bronchiolo alveolar carcinoma, 1 lymphoma and 7 metastases. Unspecific/ inflammatory lesions (n=7) were most fre­quently benign lesions. The overall diagnostic accuracy, pneu­mothorax rate and chest tube insertion rate were determined. Positive results at PTNB were consid­ered to be true-positive when surgically confirmed, in case of biopsy of another site confirmed cancer with the same cytological characteristics, when the lesion increased in size or other proven metastases were found. According to the medical information all 28 cytologically positive cases turned out to be true positive. Negative results at PTNB were consid­ered to be true-negative when surgically confirmed, when the lesion disappeared or decreased in size on subsequent follow-up examinations or when it remains stable on the follow-up CT for 24 months. Thirteen of 14 cytologically negative cases turned out to be true negative. There was one false-negative case. This was a solitary mass in an elderly, smoking women, located in the apex of the left lung, surrounded by a few non-specific paren­chymal changes. Cytology revealed no ma­lignant cells but the lesion was surgically removed since it was asymptomatic and not seen on radiographs a few months ago. The histology examination of removed tissue showed adenocarcinoma. We considered true-positive and true-negative findings to be diagnosed cases while false-positive cases, false-negative cases and insufficient samples were consi­dered non-diagnosed cases. The overall diagnostic accuracy of PTNB (number of accurately diagnosed cases/to­tal number of PTNB) turned out to be 93.2% in our series. There were no major peri or post-proce­dural complications observed. During or af­ter the biopsy we diagnosed pneumothorax in 12/44 patients. In two of them the chest catheter or tube was inserted. That makes the pneumothorax rate to be 27.2% and the chest tube insertion rate to be 4.5%. In 5 patients minor, asymptomatic intraparen­chymal bleeding was observed. There was also one case of major parenchymal bleed­ing immediately after the needle position (prior to the first sample taking), accompa­nied by moderate hemoptysis. After a while symptoms decreased, the procedure was resumed and also successfully completed. In the post-procedural course the patient experienced a few minor events of haemop-tysis which spontaneously resolved within a week. In 36/44 (82%) cases of PTNB, the co-op­erating on-site cytologist evaluated the cy­tological sample from an initial puncture as being sufficient for the diagnosis. However, in the remaining 8 cases patients we had to repeat the puncture and sample taking up to maximum four times. Even then the final cytology report in two cases indicated the tissue sample as inadequate. Both lesions were small (less than 1.5 cm) and deep (needle path more than 10 cm long) - the so called “difficult thoracic lesions”. The retro­spective analysis of the procedures evalu­ated both to be inaccurately targeted. Discussion Haaga and Alfidi reported the first case of aspiration biopsy guided by CT in 1976.3 Ever since the technique have expanded and many papers confirmed it as safe and Radiol Oncol 2007; 41(3): 99-106. accurate in diagnosing benign and malig­nant lesions of the chest.4-8 According to the published data so far, the percutaneous needle aspiration biopsy is a safe and accurate technique to diagnose benignant and malignant pulmonary le­ sions.4-8,14-28 Only the puncture of vascular structure such as an aneurysm or pulmonary arterio-venous malformation represent is absolute­ly contraindicated. The correct diagnosis should be obtained with contrast enhanced cross section imaging modalities such as CT and magnetic resonance imaging (MRI). Relative contraindications are: puncture of both lungs within the same session, punc­ture of only one functional lung, chronic res­piratory insufficiency, pulmonary arterial hypertension, cardiac insufficiency, recent acute coronary event, severe emphysema and uncorrected coagulation defect. Cough, dyspnoea and reduced patient cooperation are further limiting factors. Mechanical ventilation is also a relative contraindica­tion of PTNB. The overall diagnostic accuracy (93.2%) was very high in our series and exceeds most of the ranges of results of CT-guided biopsy, reported in the literature, which include the data on pulmonary nodules of any size2-6,12-26 as well as that of fiberoptic bronchoscopy.29 The pneumothorax rate (27.2%) as well as the chest tube insertion rate (4.5%) in our series were within the ranges of results of CT-guided biopsy reported in the litera­ture.16,24-28 Two important factors that affect the diagnostic accuracy are lesion size and needle path length. Many investigators re­port that diagnostic accuracies of CT-gui­ded needle aspiration biopsies were influ­enced mainly by the lesion size4-7,17-20,25-28 but only one suggesting needle path length is a more important factor in the diagnostic accuracy of CT-guided transthoracic needle aspiration biopsy.16 It is also indicated that solitary pulmonary nodules of 10 mm or less should be followed up by repeated CT rather than biopsies because the diagnostic accuracy for these nodules is significantly lower than for larger solitary pulmonary nodules.16 The percentage of predicted FEV1 is a well known measure of the de­gree of chronic obstructive pulmonary dis­ease in patients22 while decreased FEV1 is suggested to be a factor influencing pneu­mothorax rate.5,21 Beside the percentage of predicted FEV1 of the patient also the needle path length and the number of needle passes were of­ten considered to be related to the pneu­mothorax rate as well as to the chest tube insertion one. Other factors like lesion size, needle-pleural angle, needle size, location of the nodule and needle approach some­times did but sometimes did not improve pneumothorax and chest tube insertion rates.5,6,16,18-21,27,26 Unfortunately, the number of our cases is too low to allow the reliable stepwise re­gression analysis to test the importance of these factors that may affect the diagnos­tic accuracy, pneumothorax rate and chest tube insertion rate. Knowing that the number of punctures can significantly affect pneumothorax and chest tube insertion rate, some investiga­tors recently applied a coaxial technique for CT-guided thoracic interventions19,20,30,31 in order to reduce both of them. In case of such technique the leading needle only once passes through the pleural space re­gardless to the numbers of tissue sampling and, consequently, the risk for pneumo-thorax has been reduced. In our study we did not adapt a coaxial technique since the great majority of our procedures ended up with a sufficient sample of tissue after only a single puncture. For such workflow it is necessary to cooperate with the on-site cy­tologist in order to repuncture and obtain another specimen in cases of insufficient material for the diagnosis from the initial attempt. We always considered the needle path length because a longer needle path tends to damage a larger part of lung parenchyma in between the pleura and the target lesion and may, consequently, increase the risk of pneumothorax. Hence, it is preferably to try an accurate single puncture of target le­sion and to plan the needle trajectory to be as short as possible. Other possible complications (e.g. intrapa­renchymal bleeding, pleural effusion, infec­tion) are not common. Air embolism, a rare but potentially fatal complication can happen during CT-guided PTNB of the lung.23 In conclusion, our results confirmed CT-guided transthoracic needle biopsy as a useful and safe diagnostic tool for the de­termination of different lung lesions. The overall diagnostic accuracy, pneumothorax rate and chest tube insertion rate are within ranges, reported by other authors. From our experience and according to the data in the literature an accurate single puncture with the shortest needle path should be applied in order to minimize the risk of complica­tion. If there is no on-site cytologist present, one should consider the coaxial technique of CT-guided biopsy, which probably has the potential to further reduce the chest tube insertion rate which is significantly in­creased if the operator risks an additional puncture. References 1. Jereb M, Us Krasovec M. Transthoracic needle bi­opsy of mediastinal and hilar lesions. Cancer 1977; 40: 1354-7. 2. Jereb M. The usefulness of needle biopsy in chest lesions of different sizes and locations. Radiology 1980; 134: 13-5. 3. Haaga JR, Alfidi RJ. Precise biopsy localisation by computer tomography. Radiology 1976; 118: 603-7. 4. Westcott JL. Direct percutaneous needle aspira­tion of localized lesions: results in 422 patients. Radiology 1980; 137: 31-5. 5. Kazerooni EA, Lim FT, Mikhail A, Martinez FJ. Risk of pneumothorax in CT-guided transthoracic aspiration needle biopsy of the lung. Radiology 1996; 198: 371-5. 6. Li H, Boiselle PM, Shepard JO, Trotman-Dickenson B, McLoud TC. Diagnostic accuracy and safety of CT-guided percutaneous needle aspiration biopsy of the lung: comparison of small and large pul­monary nodules. AJR Am J Roentgenol 1996; 167: 105-9. 7. Khouri NF, Stitik FP, Erozan YS. Transthoracic needle aspiration biopsy of benign and malignant lung lesion. AJR Am J Roentgenol 1985; 144: 281-8. 8. Stanley JH, Fish GD, Andriole JG. Lung lesions: cy­tologic diagnosis by fine-needle biopsy. Radiology 1987; 162: 389-91. 9. Barsky SH, Cameron R, Osann KE, Tomita D, Holmes EC. Rising incidence of bronchioloal­veolar lung carcinoma and its unique clinicopatho-logic features. Cancer 1994; 73: 1163-70. 10. Travis WD, Travis LB, Devesa SS. Lung cancer. Cancer 1995; 75(S1): 191-202. 11. Sone S, Takashima S, Li F, Honda T, Maruyama Y, Hasegawa M, et al. Mass screening for lung cancer with mobile spiral computed tomography scanner. Lancet 1998; 351: 1242-5. 12. Marshall D, Simpson KN, Earle CC, Chu C. Potential cost-effectiveness of one-time screening for lung cancer (LC) in a high-risk cohort. Lung Cancer 2001; 32: 227-36. 13. Henschke Cl, Naidich DP, Yankelevitz DF, McGuinness G, McCauley DI, Smith, et al. Early Lung Cancer Action Project: initial findings on repeat screenings. Cancer 2001; 92: 153-9. 14. Klein JS, Zarka MA. Transthoracic needle biopsy: An Overview. J Thorac Imaging 1997; 12: 232-49. 15. Minami M, Kawauchi N, Oka H, Itai Y, Sasaki Y: High resolution CT of small lung nodules: Malignancy versus Benignancy. Radiology 1992; 185: 357-60. 16. Ohno Y, Hatabu H, Taneka D, Higashino T, Watanabe H, Ohbayashi C, et al. CT-guided tran­sthoracic needle aspiration biopsy of small solitary pulmonary nodules. AJR Am J Roentgenol 2003; 180: 1665-9. Radiol Oncol 2007; 41(3): 99-106. 17. Laurent F, Latrabe V, Vergier B, Michel P. Percutaneous CT-guided biopsy of the lung: com­parison between aspiration and automated cutting needles using a coaxial technique. Cardiovascular Intervent Radiol 2000; 23: 266-72. 18. Garcia-Rio F, Pino JM, Casadevall J, Gómez L, Atienza JM, Díaz-Lobato S, et al. Use of spirom­etry to predict risk of pneumothorax in CT-guided transthoracic needle aspiration biopsy of the lung. J Comput Assist Tomogr 1996; 20: 20-3. 19. Laurent F, Michel P, Latrabe V, Tunon de Lara M, Marthan R. Pneumothoraces and chest tube insertion after CT-guided transthoracic lung bi­opsy using a coaxial technique: incidence and risk factors. AJR Am J Roentgenol 1999; 172: 1049-53. 20. vanSonnenberg E, Casola G, Ho M, Neff CC, Varney RR, Wittich GR, et al. Difficult thoracic lesions: CT-guided biopsy experience in 150 cases. Radiology 1988; 167: 457-61. 21. Ko JP, Shepard JO, Drucker EA, Aquino SL, Sharma A, Sabloff B, et al. Factors influencing pneumothorax rate at lung biopsy: are dwell time and angle of pleural puncture contributing fac­tors? Radiology 2001; 218: 491-6. 22. American Thoracic Society. Lung function testing: selection of reference values and interpretative strategies. Am Rev Respire Dis 1991; 144: 1202-18. 23. Hirasawa S, Hirasawa H, Taketomi-Takahashi A, Morita H, Tsushima Y, Amanuma M, et al. Air embolism detected during computed tomography fluoroscopically guided transthoracic needle bi­opsy. Cardiovasc Intervet Radiol 2007 (in press). 24. Kinoshita F, Kato T, Sugiura K, Nishimura M, Kinshita T, Hashimoto M, et al. CT-guided tran­sthoracic needle biopsy using a puncture site-down positioning technique. AJR Am J Roentgenol 2006; 187: 926-32. 25. Heck SL, Blom P, Berstad A. Accuracy and com­plications in computed tomography fluoroscopy-guided needle biopsies of lung masses. Eur Radiol 2006; 16: 1387-92. 26. Lourenco R, Camacho R, Barata MJ, Canario D, Gaspar A, Cyrne C. CT-guided percutaneous transthoracic biopsy in the evaluation of undeter­mined pulmonary lesions. Rev Port Pneumol 2006; 12: 503-24. 27. Andreson JM, Murchison J, Patel D. CT-guided lung biopsy; factors influencing diagnostic yield and complication rate. Clin Radiol 2003; 58: 791-7. 28. Gupta S, Krishnamurthy S, Broemeling LD, Morello FA, Wallace MJ, Ahrar K, et al. Small subpleural pulmonary lesions: short- versus long-needle path CT-guided biopsy. Comparison of di­agnostic yields and complications. Radiology 2005; 234: 631-7. 29. Baaklini WA, Reinoso MA, Gorin AB, Sharafkaneh A, Manian P. Diagnostic yield of fiberoptic bron­choscopy in evaluating solitary pulmonary nod­ules. Chest 2000; 117: 1049-54. 30. Charig MJ, Phillips AJ. CT-guided cutting-needle biopsy of lung lesion-safety and efficacy of an out­patient service. Clin Radiol 2000; 55: 964-9. 31. Geraghty PR, Kee ST, McFarlane G, Razavi MK, Sze DY, Dake MD. CT-guided needle aspiration biopsy of pulmonary nodules: needle size and pneumothorax rate. Radiology 2003; 229: 475-81. case report Adult obstructing ileocolic intussusception Ivan Žokalj1, Zvonimir Magaš2, Zlatko Pavcec1, Hussein Saghir1, Andrej Pal1, Zvonimir Kolaric3 , Miljenko Marotti4 1Department of Radiology and Ultrasound, County Hospital Cakovec, Croatia; 2Department of Surgery, County Hospital Cakovec, Croatia; 3Department of Internal Medicine, County Hospital Cakovec, Croatia; 4Department of Diagnostic and Interventional Radiology, University Hospital “Sisters of Mercy”, Zagreb, Croatia Background. We report a case of the adult obstructing ileocecal intussusception caused by carcinoma of the coecum. Case report. A 44-year-old male patient has been admitted to the hospital with strong pain in the upper abdomen, vomiting and high amylase level in the blood serum 154 U/L (norm. 23-91 U/L at 37şC) and in the urine 792 U/L (0-400 U/L at 37şC). Sudden worsening of the patient’s general condition on the 9th day after the admission associated with clinical and radiological signs of bowel obstruction were the reasons to perform emergency computerized tomography (CT) after days of clinical observation and follow-up with abdominal X-rays and ultrasound (US). CT revealed multiple concentric rings with centrally placed soft-tissue structure with higher attenuation on post-contrast scans, “target mass”. Right haemicolectomy with terminolateral ileotransversoanastomosis without preoperative reduction was performed. Intraoperatively aboral loops of the ileum were found prolapsed into the coecum and ascendant colon with carcinoma of the coecum (Dukes B, Astler-Coller B2) acting as a neoplastic lead point for intussusception. Conclusions. The adult intussusception may be a rare cause of abdominal pain but it must be on the dif­ferential diagnosis list in the case of intermittent abdominal pain, especially with clinical and radiologi­cal signs of the bowel obstruction. The reported case supports the opinion that CT is the imaging method of choice for the adult intussusception. Key words: intestinal obstruction; intussusception; adult; ileocecal valve Introduction Intussusception is a prolapse of a bowel loop with its mesenteric fold (intussuscep- Received 18 September 2007 Accepted 30 September 2007 Correspondence to: Ivan Žokalj, MD, Department of Radiology and Ultrasound, County Hospital Cakovec, Croatia; E-mail: ivan.zokalj@ck.htnet.hr tum) into the lumen of a contiguous seg­ment (intussuscipiens).1 Intussusception in adults is rare, it counts for 5-16% of all cases of all intussusceptions This condi­tion is often at the end of the differential diagnosis list.2,3 The clinical presentation of intussusception in adults is variable in appearance. The signs and symptoms of the bowel obstruction predominate in 82% of cases.4 Patients usually complain on chronic intermittent abdominal pain or prolonged abdominal pain, nausea, vomit­ing and constipation.3,4 The most common reason for the operative intervention is the acute bowel obstruction. Unfortunately, the preoperative diagnosis of intussusception in adults is relatively rarely established.4 In most of the adult intussusception cases, in over 90%, there is a pathological lead point.5 Malignant tumour is the lead point in approximately two thirds of colonic in-tussusceptions, but only in one quarter of enteric intussusceptions in adults.4 Abdominal computerized tomography (CT) is the most useful imaging diagnostic method for the diagnosis of intussuscep­tion. Ultrasound (US) is the second most effective imaging tool.6,7 Adult intussuscep­tions are usually treated surgically, espe­cially colonic variants. Resection without reduction was suggested as the best meth­od. Opinions differ among surgeons what is the best modality of the treatment of adult intussusceptions today. The role of preo­perative reduction of adult intussusception is in the focus of the debate.7,8 Case report A 44-year-old male patient had medical history of uretherolithiasis and chronic gastritis which has been treated with H2 antagonists. Two days before the admission he complained on upper abdominal pain and vomiting, which relieved spontane­ously. On the day of admission, he com­plained again on upper abdominal pain. During the physical examination painless palpable mass which extended from epi­gastrum to the umbilicus with dimensions of 10 x 5 cm, has been found. First labora­tory tests showed higher amylase level in the blood serum 154U/L (norm. 23-91 U/L at 37°C) and the urine 792 U/L (0-400 U/L at 37şC) and normal results of WBC 9.1 x 109, erythrocytes 4.8 x 1012 , erythrocyte sedimentation rate 4/10, C-reactive protein (CRP) 1.1 mg/L. Abdominal X-rays depicted bowel me-teorism without distension in the ileocecal region and lienal flexure. The endoscopic evaluation of the upper gastrointestinal tract performed on the 4th day after the ad­mission revealed small oesophageal varices placed in the aboral third of the oesopha­gus just beneath cardia and a mild form of antral gastritis. The first abdominal US performed on the 5th day after the admis­sion did not show any abnormalities. The control abdominal US on the 7th day after the admission depicted expansive forma­tion in the epigastrium with concentrically placed hypoechoic and hyperechoic layers with a maximal diameter of 10 cm (“target mass”). The working diagnosis was acute pancreatitis with suspected pseudocyst of the pancreas. In the following days the patient devel­oped clinical signs of bowel obstruction. On the 9th day after the admission the pa­tient had severe and much stronger pain in the upper abdomen in comparison with the first day of this episode. Control abdomi­nal X-rays showed the distension of enteric loops without earlier depicted colonic me-teorism. The follow-up abdominal US, per­formed on the same day, revealed earlier de­picted “target mass” in the upper abdomen with bigger maximal diameter of 12 cm and more clearly delineated contours from the surrounding structures. The patient under­went abdominal CT which revealed multiple concentric rings on the place of sonographi­cally depicted “target mass” with centrally placed soft-tissue structure which had higher attenuation on post-contrast scans. Control laboratory tests revealed again nor­mal levels of WBC, erythrocytes, CRP and decreased amylase blood serum (111 U/L) and urine level (1041 U/L). Due to a worsen clinical condition of the patient the emergency right haemicolecto-my with terminolateral ileotransversoanas­tomosis was performed. Ileocolic invagi-nation with terminal ileum invaginated in transverse colon was found. The polypoid Figure 3. CT of the abdomen – post-contrast axial scan - horizontal plane. Mass consisted of multiple concentric rings placed in the middle upper abdomen with external hyperdensity ring (returning intussusceptum and intussuscipiens – white right arrow ), hypodensity ring , internal hiperdensity ring (canal and wall of intussusception – white notched right arrow) and soft tissue density structure in a central position – a malignant lead point (white arrowhead). Dilatation of small bowel loops. form of coecal carcinoma served as a lead point in this case of the adult intussuscep­tion. The result of the patohystologic analy­sis was adenocarcinoma of the coecum, classified as Dukes B stage, Astler-Coller B2 and T3NOMX. The patient was discharged Radiol Oncol 2007; 41(3): 107-12. from the intensive care unit on the second day after the surgical intervention. The pa­tient’s general condition was improved and he was discharged from the hospital after the total stay of 21 days. Discussion The case presented in this article repre­sents difficulties in establishing the aetio­logy of the prolonged upper abdominal pain connected with non-specific clinical signs and laboratory test results. The diagnosis of the intussusception in adults is rarely established preoperatively. The diagnosis is usually established during the surgery per­formed because of the bowel obstruction. The adult intussusception is the cause of bowel obstruction in only 1% of patients.7 Cross-sectional imaging tools like US and CT, especially modern fast scanners with possibilities of volumetric scanning, make the preoperative diagnosis of the adult in-tussusception more possible. Intussusceptions are usually divided according to the location. Dean, Ellis and Sauer have classified intusussceptions into four groups: 1 Enteric-small bowel invagination into small bowel 2 Ileocecal-the ileocecal valve being the leading point of the intususception 3 Ileocolic-ileum protruding through the il­ eocecal valve with the coecum remaining stationary 4 Colocolic-colon invaginating into colon.4 Organic lesions are the underlying pathologic cause in 10-20% of the patients. Aetiology of intussusception in adults is demonstrated in 70% to 90%. Large bowel intussusceptions are usually caused by ma­lignant tumours. In small bowel intussus­ceptions a lead points are predominantly non-malignant tumours, like lipomas and polyps. Enteroenteric intussusceptions, in the transient non-obstructing form, can be found in patients with coeliac disease and Crohn’s disease where a pathologically changed bowel wall with altered peristalsis can form a leading edge for the intususce­ ptum.1,3,4,9,10 In the study published in 1999, conduct­ed by Warshauer and Lee, less than 1/3 of adult intussusceptions depicted with CT or MR had a neoplastic lead point. Non-neo­plastic intussusceptions were mostly ente­roenteric, significantly shorter and smaller in diameter.3 The bowel obstruction is uncommon in adult non-neoplastic intussusceptions.3 Non-neoplastic adult intussusceptions can be transient and may not demand aggres­sive work-up.1,3 Diagnostic studies in evaluation of the suspected intusussception are plain abdo­minal film (abdominal X-rays), US, barium enema (irigography), CT, magnetic reso­nance (MR) and colonoscopy.3,4,6 CT is the diagnostic method of choice because of its non-invasiveness and short scanning time on modern scanners. CT can also depict changes which are responsible in development of intussusception (the leading edge). CT appearance of intussusception has a few different forms: 1 Target pattern - multiple concentric rings 2 Reniform pattern – renal like or bilobed mass with peripheral high attenuation values 3 Sausage-shaped pattern – sausage-shaped mass with alternating areas of low and high attenuation.1,11 On axial CT scans a target lesion is often depicted (multiple concentric rings) with al­ternating circumferential areas of high and low attenuation. The external ring on axial scans (or outer cylinder) usually consists of returning intussusceptum and intussus­cipiens. The crescent of the mesenteric fat forms the middle ring (middle cylinder) and the internal ring (central cylinder) contains the wall of intussusception and canal.1 Using the alternative cross-sectional methods, like US and MR, the intussusce­ption will also be depicted as a lesion with the target appearance (multiple concentric rings). In the early phase the intussuception is usually a “target mass” associated with the bowel obstruction. The progression of the disease causes the bowel wall thicken­ing and layering on the images. Finally, if the patient is not treated, the bowel wall necrosis appears as an amorphous mass on the images.1,11 In this case we had a target pattern of an ileocolic intussusception on US and CT images. Non-specific clinical signs and symp­toms were the main reasons why CT was not used earlier for the evaluation of this patient. Abdominal CT has been originally planned because the treating physician as­sumed that the main cause of the upper abdominal pain in this case is the acute pancreatitis complicated with pseudocyst of the pancreas. Sudden worsening of the patient’s general condition connected with clinical and radiological signs of the bowel obstruction were the reasons to perform emergency CT which depicted the ileocecal intussusception with a characteristic target pattern. In this case, CT results gave the key reason to surgeons for their decision to per­form an emergency surgical treatment. The form of the surgical treatment de­pends on the patient’s medical history and intraoperative findings. Opinions about the treatment of different variants of adult intussusception differ today, especially colonic intussception should be reduced before the resection.6,7,8 The treatment in the adults for colonic variants of intusscep­tion is always operative and the resection without reduction is recommended accord­ing to Azar and Berger.7 Sarr in his invited commentary to article of Omori et al. pub­lished in 2003 proposed the preoperative reduction in selective cases of intussuscep­tions to allow an elective procedure.8 The preoperative reduction of the colonic intus­susception may help to reduce the extent of the surgical procedure, for example, to treat the ileocolonic intussusception with a small bowel resection instead of a right hemicolectomy, according to Sarr.8 Benign enteric lesions without adhesions and be­nign colonic lesions are usually treated with the resection to prevent a recurrent intussusception.7 Conclusions In this case we report about a patient with non-specific clinical symptoms character­ized with the intermittent abdominal pain and with the slowly progressive bowel obstruction. After nine days of clinical observations and a follow-up with abdomi­nal X-rays and US the upper abdomen le­sion with target appearance was detected. Because of the worsened general condition the patient underwent the CT examina­tion which demonstrated typical findings of the intussusception. CT findings and a worsened clinical picture were the reasons for an urgent surgical intervention. The right haemicolectomy without a preopera­tive reduction of the intussusception has been done. The adult intussusception may be a rare cause of the abdominal pain but it must be on the differential diagnosis list in the case of the intermittent abdominal pain, especially with clinical signs of the bowel obstruction. The reported case also supports the opinion that CT is the imaging method of choice for the adult intussusce­ption. Radiol Oncol 2007; 41(3): 107-12. References 1. Catalano O. Transient small bowel intussception: CT findings in adults. Br J Radiol 1997; 70: 805-8. 2. Agha FP. Intussusception in adults. AJR Am J Roentgenol 1986; 146: 527-31. 3. Warshauer DM, Lee JKT. Adult intussusception detected at CT or MR imaging:Clinical-imaging correlation. Radiology 1999; 212: 853-60. 4. Stubenbord WT, Thorbjarnarson B. Intussusception in adults. Ann Surg 1970; 172: 306-10. 5. Garner JP, Haldipur, Ravi K, Amarnath TS, Gupta R. Colonic intussusceptions in adults: three cases and review of the literature. Indian J Surg 2006; 68: 322-4. 6. Omori H, Asahi H, Inoue Y, Irinoda T, Takahashi M, Saito K. Intussusception in adults: a 21-year experience in the University-affiliated Emergency Center and indication for nonoperative reduction. Dig Surg 2003; 20: 433-9. 7. Azar T, Berger DL. Adult intussusception. Ann Surg 1997; 226: 134-8. 8. Sarr M. Commentary on Intussusception in adults: a 21-year experience in the University-affiliated Emergency Center and indication for nonoperative reduction. Dig Surg 2003; 20: 438-9. 9. Merine DS, Fishman EK, Jones B, Siegelman SS. Enteroenteric intussusception: CT findings in nine patients. AJR Am J Roentgenol 1987; 148: 1129-32. 10. Knowles MC, Fishman EK, Kuhlman JE, Bayless TM. Transient intussusception in Crohn disease: CT evaluation. Radiology 1989; 170: 814. 11. Eisen LK, Cunningham JD, Aufses AH Jr. Intussusception in adults: institutional review. J Am Coll Surg 1999; 188: 390-5. images in clinical medicine Basal cell carcinoma in the inner canthus Boris Jancar Department of Radiation Oncology, Institute of Oncology, Ljubljana, Slovenia Figure 3. One year after irradiation. Received 12 April 2007 Accepted 19 April 2007 Correspondence to: Prim. Boris Jancar, MD, MSc, Department of Radiation Oncology, Institute of Oncology Ljubljana, Zaloška 2, Ljubljana, Slovenia; Phone; + 386 1 5879 295; Fax: + 386 1 5879 295; E-mail: bojancar@onko-i.si Figure 4. One year after irradiation. In January 2003, a 66-year-old patient vis­ited the outpatient clinic at our Institute for the follow-up examination of the tumour in the inner canthus of the right eye. Biopsy of the tumour was made in November 2002 at the Department of Otorhinolaryngology and Cervicofacial Surgery of the University Medical Centre Ljubljana. Histology of the excised sample confirmed basal cell carci­noma. The patient also told that, 10 years earlier, i.e. in 1993, he was operated on for a “lump” that developed on the same site. The patient was told that “lump” was sebaceous glad. But in a year, the “lump” reappeared and was removed again. In 1994, the patient was operated on for squamous cell carcinoma of the ethmoidal sinus on the right, which was infiltrating into the right orbit. Ethmoidectomy was per­formed on the right side, with the exentera­tion of the right orbit. Postoperatively, the patient was treated also with telecobalt ther­apy and received a tumour dose (TD) 56 Gy. On the follow-up examination in 2003, an indurated 2.5 cm long scar was still seen in the canthus of the right eye. The left cheek and orbit were covered with epithesis mate­rial (Figures 1, 2). The patient was irradiated by an orthovolt unit (Pantak), with the bulb of the irradiated eye protected; he received a TD 40 Gy. The tumour regressed com­pletely (Figures 3, 4). These photos (Figures 3, 4) were taken on 14 January 2004. On the last follow-up control in May 2006, no evidence of the disease recurrence was observed either in the area of ethmoid sinus or in the inner canthus of the right eye. review Adjuvant treatment of breast cancer patients with trastuzumab Erika Matos, Tanja Cufer Institute of Oncology Ljubljana, Department of Medical Oncology, Ljubljana, Slovenia Background. Trastuzumab is a monoclone antibody directed against HER2 receptors that are overexpressed in approximately 20% of breast cancer patients. The present paper presents five clinical trials in which tras­tuzumab was applied in breast cancer patients in adjuvant setting. The results of all the trials consistently demonstrate a high efficacy of this target drug in the patients with HER2 positive tumours. So far, no formal guidelines for using trastuzumab in adjuvant setting for breast cancer have been approved. The reasons are many: (i) mean observation time in the studies done so far was considerably short; (ii) the drug was used according to different schedules, (iii) the overall time of treatment with trastuzumab was different in each trial, (iv) late side effects of treatment with trastuzumab are inadequately investigated, and (v) nobody can so far say for sure for which HER2 status patients therapy with trastuzumab is really beneficial. Conclusions. Trastuzumab is definitely very helpful in the treatment of the HER2-positive breast cancer patients that are hormone-independent and of anatomically larger tumours; but, what the absolute ben­efit of trastuzumab therapy in the treatment of small hormone-dependent tumours is remains a mystery. Incidentally, it must be borne in mind that cardiotoxicity, the well known side effect, may put particularly elderly patients at risk of death, thus beating any treatment advantages down. It has also not been yet re­solved at what time it would be most appropriate to start with the therapy with trastuzumab, what would be the optimal duration of the therapy and whether trastuzumab is to be administered concurrently with chemotherapy or immediately after it? What is the optimal treatment duration, one or two years or only a few months? In addition there is still a question of optimal HER2 status determination and which HER2 status predicts for trastuzumab benefit. These questions will hopefully be answered after a longer observa­tion time of the patients included in five clinical trials that are discussed in the article. Key words: breast neoplasms- therapy; receptor, ERB-2 – antagonists and inhibitors; antibodies, mono­clonal Received 12 July 2007 Accepted 26 July 2007 Correspondence to: Erika Matos, M.D., Institute of Oncology Ljubljana, Zaloška 2, SI-1000 Ljubljana, Slovenia; Phone: +386 1 5879 284; Fax: +386 1 5879 400; E-mail: ematos@onko-i.si Introduction Breast cancer is the most frequent malig­nant disease in women. Given the clinical course, this disease is very diverse. It has now been known for some time that breast cancer may be hormone-dependent or in­dependent and that this characteristic is one of the crucial in the course of the dis­ease and its treatment. After recognizing new molecular characteristics of tumour cells, the diversity appears to be even greater. Tumour cell membranes as well as the inside of cells are populated with dif­ferent proteins that are incorporated in the signal paths controlling the cell growth and reproduction. One of these proteins is HER2, a receptor for human epidermal growth factor. The tumours with overex-pressed receptor HER2 are referred to as HER 2 positive tumours, which represent approximately 20% of all breast cancers. These tumours are biologically more ag­gressive. At the time of disease detection, they are usually larger than HER2 negative tumours, very often axillary lymph nodes are already involved, and in non-treated patients, the time interval to the disease recurrence is usually shorter.1 According to recent results, these tumours are highly sensitive to anthracylines, whereas their sensitivity to hormonal therapy is less explicit. Approximately 50% of HER2 positive tumours are hormone-depen­dent; however, it seems that the hormonal therapy is less efficient in patients with these tumors.1-3 HER2 status can be determined by immu­nohistochemistry (ICH) or by fluorescence in situ hybridization (FISH). The former de­termines the quantity of HER2 protein in a cell membrane, and the latter, the HER2 gene amplification.1 The prognosis of the HER2-positive breast cancer patients improved significantly with the introduction of HER2-targeted agent, namely trastuzumab, in the treatment. Trastuzumab is a recombinant monoclonal antibody directed against HER2 receptor. Trastuzumab first proved to be effective in the treatment of patients with advanced breast cancer and overexpression of HER2 receptors.4,5 The binding of trastuzumab to HER2 re­ceptor inhibits the signal pathways inside a tumour cell, which are essential for a cell growth, reproduction and distant metasta­tic spread. Trastuzumab, applied as mono-therapy or in combination with cytostatics, significantly increases the survival of pa­tients with HER2 positive metastatic breast cancer and improves disease control.4,5 Unfortunately, metastatic breast cancer is still incurable disease. Trastuzumab was found to be effective in patients with over-expressed HER2 receptor, determined posi­tive either immunohistochemicaly (IHC 3+) or by FISH. If IHC score is 2+, FISH test should be performed in order to determine HER2 status.6 In addition to trastuzumab, targeting se­lectively HER2 receptor, some new target drugs are already in pre-clinical and clini­cal trials; according to the results of clini­cal trials, some have already proven to be effective in the treatment of HER2 positive breast cancer patients. One of these drugs is lapatinib, a small molecule inhibiting not only HER2 but also HER1 receptor.1 The role of trastuzumab in adjuvant therapy High efficiency of trastuzumab in the treat­ment of metastatic breast cancer motivated researchers to further investigate the drug and use it in adjuvant setting. So far, five big prospective clinical trials in which trastuzumab was applied as adju­vant therapy have been performed. Over 13,000 patients were included in these tri­als, all investigated trastuzumab applied in combination with cytostatics. The tri­als were carried out according to different treatment schedules (Table 1). In the HERA trial patients were administered trastuzum-ab only after completed adjuvant cytostatic treatment. This was the three arm trial: (i) ę ę ę Ă ę ę ę ę ę ę ę ę ę ę ę ę ę ę the treatment arm without trastuzumab – the comparison arm, (ii) the treatment arm with one-year trastuzumab therapy, and (iii) the treatment arm with two-year trastuzu­mab therapy. So far, only the results of the second arm are available, i.e. of one-year therapy with trastuzumab, while the results of the two-year therapy are awaited and will hopefully be available next year.7 In both American trials (NSABP-B31 in NCCTG N9831), the patients first received chemo­therapy according to AC schedule (adriab­lastin, cyclophosphamide), and continued with a weekly or three-weekly paclitaxel. Trastuzumab was added to paclitaxel, and after completing cytostatic therapy, the pa­tients were receiving it as monotherapy for one year.8,9 In the BCIRB 006 clinical trial, the patients were first treated with 4 cycles of chemotherapy according to AC schedule, followed by docetaxel with or without the addition of trastuzumab, which they were receiving for one year. The third treatment arm in BCIRG 006 was non-anthracycline one; the patients in this arm were treated with a combination of docetaxel and carbo­platin to which trastuzumab was added at the very start of the therapy. The patients from this treatment arm were treated with trastuzumab for one year as well. In con­trast to the two American trials in which the patients were receiving trastuzumab in weekly doses, the patients of the BCIRG 006 trial started the therapy with weekly doses of trastuzumab and were receiving it in these doses as long as they were receiv­ing also docetaxel; after completing chemo­therapy with docetaxel, they were recei­ving it in 3-weekly schedule.10 The Finnish trial FinHER was slightly different from all the others. The patients received only nine weekly infusions of trastuzumab in combi­nation with taxanes or vinorelbine, and af­ter that the treatment with anthracyclines was following.11 Patients’ selection The treatment schedules in the above trials were different, but the inclusion criteria were very similar. The criterion that was common to all trials was the requirement that the patients had the HER2 positive tumour surgically removed. Another in- Radiol Oncol 2007; 41(3): 115-22. clusion criterion was normal LVEF (left ventricular ejection fraction) and absence of any serious cardiologic morbidity. The trials were conducted on the patients with positive as well as those with negative axil­lary lymph nodes. The lowest percentage of node-positive patients (57%) was included in the HERA trial and the highest (89%) in the FinHER trial. The patients with node negative disease were also included in the trials provided that they had at least one additional unfavourable prognostic factor. This additional prognostic factor was the size of the tumour that, in HERA trial, had to be larger than 1 cm 7, whereas in the American trials, it had to be larger than 2 cm and/or 1 cm provided that the tumour was hormone-independent.8 For the inclu­sion in the BCIRG 006 trial, the size of the tumour had to be larger than 2 cm; if it was smaller, it had to be hormone-independ­ent or purely differentiated or diagnosed in a patient aged less than 35 years.10 The Finnish trial included patients with tu­mours larger than 2 cm or if smaller those with negative progesterone receptors.11 The patients with hormone-dependent as well as those with hormone-independent tu­mours were included in the above trials. The lowest percentage of patients with hor-mone-independent tumours was included in the Finnish trial (47%) and the highest in the BICRG 006 trial (54%). Results – efficacy of trastuzumab applied in adjuvant setting Despite different treatment schedules, the results of these trials were remarkably consistent. They definitely proved that the addition of trastuzumab to the cytostatics remarkable increases the likelihood of cure of the patients with operable HER2-positve breast cancer. After a mean observation time of more than three years, it was noted that the use Table 2. Efficacy of trastuzumab in adjuvant setting 1.) NSABP B31/NCCTG 9831 (MFU 3 years) DFS HR = 0.49 p = 0.001 OS HR = 0.63 p < 0.004 2.) HERA (MFU 2 years) DFS HR = 0.64 p < 0.0001 OS HR = 0.66 p < 0.0115 3.) BCIRG 006 (MFU 3 years) AC . TH DFS HR = 0.61 p < 0.0001 OS HR = 0.67 p < 0.004 TCH DFS HR = 0.59 p = 0.0003 OS HR = 0.66 p = 0.017 4.) Fin-HER (MFU 3 years) RFS HR = 0.42 p = 0.01 OS HR = 0.41 p = 0.07 DFS - disease-free survival OS- overall survival RFS - relapse-free survival MFU - median follow up of trastuzumab decreased the risk of re­currence by approximately 50% (HR range 0.42 – 0.64) and the risk of death by ap­proximately 40% (HR range 041 – 0.66). The differences in the disease-free survivals and overall survivals were highly statistically significant in all trials (Table 2). The addi­tion of trastuzumab has a favourable effect regardless of the concomitantly applied cy­tostatic therapy. A statistically significantly improved disease-free survival and overall survival were reported also in the patients who were treated with non-anthracycline adjuvant therapy.10 And, to our surprise in Finnish trial merely a nine-week therapy with trastuzumab improved significantly both the disease-free survival and overall survival at same extend as one year therapy in other trials.11 Table 3. Relative and absolute benefit of adjuvant trastuzumab according to hormonal status of tumor and anatomical spread of the disease Relative risk for relapse * – HERA trial (oral Estimation of absolute benefit ** presentation: Gelber; SABCS 2005) (12) ER in PR neg. ER in/ali PR poz. ER in PR neg. ER in/ali PR poz. N=4 33% 33% 16% 16% N1-3 25% 12% 12% 6% N0 18% 10% 9% 5% * median observation time of 1 year ** 50%-reduced risk of relapse was estimated from the results of the above trials (8,9,10,11) with a mean observation time ranging 1-3 years. The analysis of the results showed a 40-50% relative risk reduction. Patients’ subgroup particularly benefiting from the treatment with trastuzumab According to the results presented, tras­tuzumab is effective for all HER2 positive breast cancer patients, irrespective of ana­tomical stage (tumour size, nodal status) and of hormonal receptor status.7,8 Today, it is generally accepted treatment for HER2 positive early breast cancer pa­tients. The data analysis of the HERA tri­al presented by Gelber at SABCS in 2005 showed that the absolute benefit was var­ied.12 The patients with hormone-independ­ent tumours or anatomically amply spread disease are benefiting more from the treat­ment with trastuzumab. And what is also very important that the significance of hor-mone-dependency diminishes with the in­creasing spread of the disease (Table 3). HER2 status determined by IHC or FISH seems to be a reliable parameter for select­ing metastatic breast patients who may benefit from trastuzumab therapy. But it is not known if HER2 status determined by these two methods defines well a group of patients who may benefit from adjuvant trastuzumab. A study presented at last ASCO meeting showed that a significant proportion of patients with HER2 negative tumours benefited from adjuvant trastuzu­mab. At the time being we are still not sure if HER2 status as it is defined now is a good predictor of benefit from adjuvant trastuzu­mab.13 Significance of early start of treatment with trastuzumab At present, it is believed that the patients with HER2-positive tumours should start the adjuvant therapy with trastuzumab as early as possible. The above suggestion was confirmed also by the analysis of 1682 patients included in the clinical trial N9831 that compared the survival of the patients who received trastuzumab after the com­pleted treatment with cytostatics and the survival of patients who started the therapy with trastuzumab concomitantly with pa-clitaxel. The latter patients who received trastuzumab earlier, i.e. concomitantly with paclitaxel, had significantly better survival (HR 0.63).8 Safety of treatment with trastuzumab In all trials performed on trastuzumab, car-diotoxicity appears to be to the most severe side effect. From the studies on the patients with disseminated disease, it could be as­sumed that the combination of anthracy­clines and trastuzumab, though considered to be a highly effective combination, was Radiol Oncol 2007; 41(3): 115-22. Table 4. The risk of heart failure in patients treated with adjuvant trastuzumab: depends upon the age of a patients, heart function and previous anthracycline-based chemotherapy Age (years) <50 =50 50-54 3/48 (6.3%) 9/47 (19.1%) LVEF (%) 55-64 5/229 (2.2%) 10/194 (5.2%) after AC (7) 65+ 1/160 (0.6%) 2/159 (1.3%) p (age) = 0.04, p (LVEF) < 0.0001 severely cardiotoxic. A concomitant ap­plication of both agents is therefore unac­ceptable in routine clinical practice. An independent analysis of cardiotoxic effects was made on 837 patients included in the trial NSABP-B31 and, from the analysis of results it was concluded that the risk for cardiotoxicity correlated with the age of patients at first administration of trastuzu­mab and with the functional performance of the heart assessed before treatment by the LVEF. Undesired treatment effects may be expected to be more frequent in the pa­tients aged over 50 years and in those with lower starting LVEF. Patients with heart failure or poor functional performance of the heart were not included in the analysis (Table 4). However, it remains unclear to what extent cardiotoxicity is due to tras­tuzumab and to what extent to an earlier therapy with anthracyclines. An interesting conclusion drawn from the results of the trial BCIRG 006, which studied cardiotoxic side effects, was that cardiotoxicity signifi­cantly increased if trastuzumab was used after the anthracycline based chemothera­py; but, it did not appear after non-anthra­cyclne based chemotherapy.14 Other side effects of treatment, often mentioned in the studies, are also hyper­sensitive reactions. Severe allergic reac­tions e.g. drop of blood pressure or bron­chospasm, are very rare. The pyrogene reac­tions unique associated with the first drug administration are more frequent. They usually appear in app. 30% of patients. Pneumonitis is also a possible, but rather rare undesired effect with the incidence of approximately 0.2% (4). So far, no firm data is available about possible late side effects of treatment with trastuzumab. Conclusions Trastuzumab, an inhibitor of HER2 recep­tor, is definitely a very effective drug for the treatment of a selected group of pa­tients with HER2 positive breast cancer. Five large clinical trials including more than 13.000 patients uniformly confirmed the beneficial role of trastuzumab in terms of disease free survival and overall survival in all HER2 positive patients. However, the role of trastuzumab in the adjuvant therapy has not been precisely determined and the guidelines for its use have not been gener­ally approved yet. A number of questions remain unanswered, e.g.: What would be the optimal treatment duration? When should it be optimal to start the therapy with trastu­zumab? In which combination with cytostat­ics would it be optimal? When should the combination with anthracycline be applied? Which patients would be likely to benefit optimally from the treatment with trastuzu­mab? How to prevent undesired cardiotoxic effects of the drug? What are late side ef­fects of treatment with trastuzumab? We be­lieve that these questions will be answered after a longer observation time and tho­rough follow-up of the patients treated with trastuzumab and included in the described clinical trials performed to prove the effi­ciency of trastuzumab in adjuvant setting. Only a careful observation and follow-up of patients treated with trastuzumab by expe­rienced therapists will present benefits of such treatment for each patient individually and thereby also to other potential patients. Undoubtedly, trastuzumab is a very promi­sing drug for a selected group of HER2 positive breast cancer patients. In addition, there are new target drugs in development. Among the drugs for treating HER2-positive breast tumours, the most promising seems to be lapatinib, a dual inhibitor of both HER1 and HER2 receptors. What will be the optimal role of trastuzumab as well as of a few dozens of other target drugs that are being tested is not yet known; but, the drug trastuzumab was the first that proved (i) that the targeted therapy is far more efficient than the empiric treatment with cytostatics, in particular when it is applied in an early stage of the disease, that means in adjuvant setting, and (ii) that the targeted therapy, if properly chosen and managed, will improve overall survival and disease control rates in breast cancer patients. References 1. Winer EP, Piccart-Gebhart MJ, Rugo HS, Sledge GW. Management of HER2-positive breast cancer. In: Perry MC, editor. ASCO 2006 Educational book. Alexandria, VA: ASCO; 2006. p. 3-14. 2. Gennari A, Sormani MP, Puntoni M, Bruzzi P. A pooled analysis on the interaction between HER-2 expression and responsiveness of breast cancer to adjuvant chemotherapy. [Abstract 41]. Breast Cancer Res Treat 2006; 100(Suppl 1):s9. 3. Lipton A, Ali SM, Leitzel K, Chinchilli V, Engle L, Harvey HA, et al. Elevated serum Her2/neu level predicts decreased response to hormone therapy in metastatic breast cancer. J Clin Oncol 2002; 20: 1467-72. 4. Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubiana-Hulin M, et al. Randomized phase II trial of the efficacy and safety of trastuzu­mab combined with docetaxel in patients with hu­man epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: The M77001 study group. J Clin Oncol 2005; 23: 4265-74. 5. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344: 783-92. 6. Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, et al. American Society of Clinical Oncology; College of American Pathologists. American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer. J Clin Oncol 2007; 25: 118-45. 7. Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, et al. HERA study team. 2-year follow-up of trastuzumab after adju­vant chemotherapy in HER2-positive breast can­cer: a randomized controlled trial. Lancet 2007; 369: 29-36. 8. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE, Davidson NE, et al. Trastuzumab plus adju­vant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353: 1673-84. 9. Perez ES, Romond EH, Suman VJ, Jeong J, Davidson NE, Geyer CE, et al. Updated results of the combined analysis of NCCTG N9831 and NSABP B-31 adjuvant chemotherapy with/without trastuzumab in patients with HER2-positive breast cancer.[Abstract 512]. 2007 ASCO Annual Meeting Proceedings. J Clin Oncol 2007; 25(Suppl I): 6s. 10. Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Pawlicki M, et al. Phase III randomized trial comparing doxorubicin and cyclophospha­mide followed by docetaxel (ACT) with doxo­rubicin and cyclophosphamide followed by do-cetaxel and trastuzumab (ACTH) with docetaxel, carboplatin and trastuzumab (TCH) in her2 posi­tive early breast cancer patients: BCIRG 006 study. Breast Cancer Res and Treat 2005; 94(Suppl 1): s5. 11. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Bono P, Alanko T, Kataja V, et al; FinHer Study Investigators. Adjuvant docetaxel or vinorelbin with or without trastuzumab for breast cancer. N Engl J Med 2005; 354: 789-90. 12. Gelber RD. HERA trial (oral presentation); SABCS 2005. Radiol Oncol 2007; 41(3): 115-22. 13. Paik S, Kim C, Joeng J, Geyer CE, Romond EH, Mejia-Mejia O, et al. Benefit from adjuvant tras­tuzumab may not be confined to patients with 3+ and/or FISH-positive tumors: Central testing results from NSABP B-31. [Abstract 511]. 2007 ASCO Annual Meeting Proceedings. J Clin Oncol 2007; 25(Suppl I): 5s. 14. Tan-Chiu E, Yothers G, Romond E, Geyer CE, Ewer M, Keefe D, et al. Assessment of cardiac dysfunc­tion in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol 2005; 23: 7811-9. review Ionising radiation and trans-generational instability Ivana Vrhovac, Goran Nikšic Faculty of Science University of Zagreb, Croatia Background. Indirect monitoring of the impact posed by ionising radiation to the genome instability of the descendants, consequent to the irradiation of one of their parents, boils down to the investigation of changes occurring exclusively in the mini-satellite loci of the cells constituting the gametal developmental line. The resultant mini-satellite mutations are expressed in their percentages, and equal to the ratio of the number of mutated alleles in that particular generation over the total number of alleles present. The impact of ionising radiation to the irradiated parent’s offspring was first noticed on haematopoietic mouse stem-cells. Even though an irradiated cell of a female parent lacks any mutations whatsoever, daughter cells present with the increased mutation rates. The observed phenomenon of the so called trans-generational instability has been defined as the occurrence of mutations in the genome of individuals originating from the irradiated ances­tors. Due to the aforementioned, one can conclude that these mutations need not be present in the irradiated parental cells, and do not necessarily vanish in the next few generations, but may result in the increase in mutation rates observed in the latter. Conclusions. The results of the investigations performed on the animal model, as well as of those carried out in human population, point to the occurrence of significant changes to be found on mini-satellite loci of the descending generation, while the mechanism underlying those changes hasn’t been completely clarified yet, and, therefore, calls for the further investigation. Key words: radiation ionizing; radiation effects; microsatellite repeats Introduction It has been well-recognised that ionising radiation is capable of inducing structural changes of biologically essential macro­molecules, resulting in the development Received 28 August 2007 Accepted 10 September 2007 Correspondence to: Ivana Vrhovac and Goran Nikšic, Faculty of Science University of Zagreb, Rooseveltov trg 6, 10 000 Zagreb, Croatia; Phone +385 1 48 77 700; E-mail: ivanavrhovac@yahoo.com E-mail: marsonia2258@yahoo.com of malignancy within a human organism.1 Therefore, the development and perfecting of biomonitoring methods which enable the follow-up of early indicators of cellular alterations caused by irradiation (i.e. the in­dicators of the reactions exhibited by irradi­ated cells), dependent on the radiation type and dose delivered, are critical. Last years have witnessed a significant advancement in the detection of effects of parental irra­diation, apparent in their offspring, i.e. the indirect effect of irradiation expressed as the genome instability of their descendents.2-6 Monitoring of the irradiation impact car­ried throughout a few generations subse­quent to the irradiation of one of the par­ents, actually boils down to the investigation of changes encountered in the mini-satellite loci of the referent population, the latter be­ing narrowed exclusively to the cells consti­tuting the gametal developmental line.7-10 The parameter employed in the follow-up of their frequency, the so called mutation rate, is calculated as the number of mutated alle­les present in the referent generation, over the total number of alleles hosted therein, and expressed either in form of ratio, or percentage of the mutations encountered. The impact of ionising radiation on the offspring of the first parental (F1), or the next few generations stemming from the irradiated individual, was first noticed on stem haematopoietic mouse cells. Although an irradiated cell of the female parent lacked any mutations whatsoever, the increase in the mutation rate of the daughter cells had been noticed. The phenomenon was termed the trans-generational instability, and defined as an uncommon and frequent occurrence of mutations to be found in the genome of individuals stemming from ir­radiated ancestors (parents, grandparents). Nevertheless, those mutations need not be present in the irradiated ancestors’ cells, and do not necessarily vanish in the next generation, however, may lead to the in­crease in mutation rate observed in some of the descendants embraced by the next few generations.11 The results of experimental studies con­ducted on mice, and the results of the in­vestigation carried out in persons irradiated in Chernobyl, have pointed to significant changes of mini-satellites hosted by the de­scendants, even though, as communicated by Dubrova affiliated with the Genetic Department of the Leicester University (United Kingdom), many issues haven’t been resolved yet.12-14 DNA satellites DNA satellites (micro- and mini-) are con­sidered to be frequently-repeated segments of the cellular genome. Within this frame, micro-satellites represent shorter repeats, measuring about 500 pb in their total length, with the basic repeat of 1-4 pb. Mini-satellites encountered in the human genome, are spots where frequent homolo­gous recombination takes place, located adjacent to the telomere sequences that do not undergo transcription. However, there exist also mini-satellites present in non-coded inter-genetic genome sequences, i.e. the sequences that, following transcription, represent parts of the intron. Mini-satel­lites are more complex, and are constituted of repeats measuring 10-100 pb in size, and 0.1-20 kb in length. Most of the repeats host the GGGCAGGAXG pattern, within which an X can be any nucleotide whatsoever. The most frequently encountered mini-satellites are polyA and polyT, as well as CT/AG and CA/TG sequences, greatly resembling the chi sequence of E. coli, which represents a recombinant signal. Mini-satellites encoun­tered in human genome are spots where homologous recombination takes place more frequently (the recombinant “hot spots”). However, as stated already, there exist also mini-satellites present in non-coded inter-genomic sequences, as well as the ones prone to exprimation, such as the MUCI locus, which contains the gene for the hyper-variable glycoprotein recovered from body fluids and some tissues, consti­tuted of frequently-repeated mini-satellite sequences.14 Satellite DNAs are prone to mutations. Mutations of mini-satellites encountered in humans, comprise complex intra-allele rearrangements and alterations of the se­quence length (mostly expansion). Mini-satellite mutations encountered in human populations, may arise spontaneously only in cells constituting the gametal develop­mental line, and are characterised by the high, 0.5-13%-mutation frequency per ga­mete, while mutations encountered in mi-cro-satellite sequences may be found in so­matic cells as well. Most of the mini-satellite loci (90%), are situated in the sub-telomere chromosomal regions, and had been considered irrel­evant for quite a long time. They were be­lieved to be the parts of the genome usually called “the junk DNA”, although nowadays an issue of their potential influence on the alternative splicing, genome imprinting sig­nal and regulation of gene expression, es­tablished on the transcriptional level, has been raised.8, 15-17 Differences in length of satellite sequen­ces can be easily detected with gel elec­trophoresis subsequent to the polymerase chain reaction (PCR). The starters (probes) employed with the polymerase chain re­action, are complementary to the parts of the genome surrounding the repeats. Their hyper-variability within population, and easiness of their detection, were the exact reasons for their forensic implementation. Based on the comparison of length of a cer­tain number of standard satellite loci, re­covered from samples taken from a number of persons, positive identification can be made.18,19 The exact determination of the loci and their mutations is accomplished by the hybridising Southern blotting me­thod.20 Trans-generational instability observed with irradiated mice The first experimental model utilised in the investigation of trans-generational in­stability, which made use of mini-satel­lite monitoring, was represented by the mice ESTR loci. Namely, the mini-satellites present in mice markedly differ from those present in humans, and are divided into two groups: real mini-satellites, measuring 0.5-10 kb in length, and having 14-17 bp long repeated patterns, and simple tan­dem repeated sequences, called the ESTR (expanded simple tandem repeats), measur­ing 0.5-16 kb in length, and having 4-6 bp long repeats.12,13,15,21 Mice ESTR loci contain shorter repeated patterns, and their muta­tions occur both in somatic and gametal developmental line cells. Though in some features (length of the repeated sequence, high content of G/C base pairs, and locus length) resembling more those found in humans, mice mini-satellites do not exhibit mutations of a complex intra-allele-arrang­ing type, and do not present with a high mutation rate that can be run across in hu­man population.22-25 One of the most significant results in this research area is that of the experi­ment conducted in male mice of the CBA/ Figure 1. Model describing the inheritance of mutations in transgenic instability. Studied independent alleles are represented by the letters B and H, wild type is written in black and mutant types are written in various colours. Each colour represents a different kind of mutation. The genotype of the irradiated mouse is in the red box, of his direct offspring is in the pink boxes and in the black boxes is the genotype of non irradiated individuals. The picture shows that the mechanism of the inheritance doesn’t obey the rules of Mendelian inheritance and that mutations in minisatellite alleles that weren’t mutated in parents can occur. Epigenetic mechanism is the best explanation for this type of inheritance. Radiol Oncol 2007; 41(3): 123-32. H strain, irradiated with various radia­tion types (acute X-ray irradiation, chronic gamma-irradiation, and fission high-LET neutrons).12,13 At post-irradiation week 3, 6 and 10, irradiated males had copulated with non-irradiated females of the same strain. It has been held true that a time-period elapsed from the irradiation time-point, is of importance, since male germinative cells had stemmed from irradiated post-meiotic spermatozoids (at post-irradiation week 3), pre-meiotic spermatogonia (at post-irradi­ation week 6) and stem cells (at post-irradi­ation week 10) (Figure 1). Results obtained with all radiation types employed, had demonstrated statistically significant rise in the number of mutations emerging from the ESTR loci of F1 and F2 mice generation. The frequency of mutations was very simi­lar to that of parental samples, and failed to exhibit the tendency towards diminish-ment. Some of the research results point at the increase in mutation rates encountered among younger generations, while genome repeats point towards trans-generational instability exhibited following ionising radiation exposure of one of the parents. These research results have reflected in a significant decrease in number of mice re­quired for radiation experiments as com­pared to classical biomonitoring methods, capable of detecting genome changes solely in case a few thousands or even a few hun­dred thousands mice have been used. The detection of statistically significant number of mutations located on the ESTR loci, called for the employment of only 300-400 mice. In line with the foregoing, the investigation of mini-satellites proved better and more sensitive tool to be engaged in the monitor­ing of radiation impact, than classical cyto-logical techniques did.26 Promising results of the first experiments conducted in mice, motivated Dubrova and associates to continue their research in an attempt to disclose the mechanism under­lying the occurrence of mutations on the ESTR loci, the importance of gameto-gene­ric phase in which the irradiation took place, the importance of mice strain involved, and the importance of the type of irradiation employed. In light of the foregoing, aside from CBA/H, also other mice strains, such as C57BL/6 and BALB/c, have been used. The results of the research conducted in mice of parental generation, irradiated with low-LET X-rays and low-LET fission neutrons, were engaged for the purpose of disclosing the mechanism underlying the mutation occurrence. To this goal, changes on two independent loci of mice genome, Ms6-hm i Hm-2, have been observed. The re­sults revealed the origin of mutated alleles (either in a non-irradiated female, or in an irradiated male parent), to be detectable in most of the animals involved. A crucial part of the experiment was represented by the determination of mutations in gametes of the descendants whose genotype came as a result of coupling of sperms developed from irradiated post-meiotic spermatozoids (at post-irradiation week 3). As concerns the genotype of the offspring in question, the initial research results failed to reveal an increase in number of mutations, which led to the conclusion that the basic mechanism involved in trans-generational instability becomes active not sooner than the diploid gametal-generic stage. However, a further investigation yielded confusing results, since the rate of mutations found in the off­spring in reference, proved higher than that observed with the offspring of the control group, i.e. that originating from the non-irradiated male parent (the father). Under such terms, one is tempted to conclude that the source (the cause) of genetic instability encountered in the offspring, arises in fact either from diploid zygote following im­pregnation, or in the early embryo-generic stage, rather than during meiosis, as first assumed. The possibility that the source of instability lies within the very sperms was rejected based on substantial compactness and biochemical inactivity of their chroma­tin. Another surprising phenomenon en­countered during the course of the study, was the occurrence of mutations located on the allele inherited from non-irradiated mother, which means that genome instabi­lity induced by the irradiation of the male parent, affects the alleles inherited from an­other parent as well.27 There exist two theories on the mecha­nism underlying trans-generational insta­bility. According to one of them, mutation is a result of a direct damage inflicted to the DNA molecule in the area hosting one of the ESTR loci. If that is the case, in the offspring of an irradiated father (and their descendants), mutations located in the al­lele inherited from the father should be dominant. In oppose, mutations are equally encountered in both alleles of all descend­ants, ruling this possibility out. In addition, the number of changes encountered in 3-4 kb region, established in the population, is 100-fold greater than that statistically ex­pected in case of a mutation arising from a direct DNA damage.28 According to the second theory, mutations are included into a certain set of genes, such as those responsible for DNA repair. A mutation of the aforementioned kind might lead to the one engaging both alleles. If that is the case, in line with Mendel’s Laws of Inheritance, each generation would witness a decrease in mutation rate based on the crossover with non-irradiated females hosting wild gene types. However, in this particular case, the mutation rate is similar in individuals of all generations. Following the rejection of these theories, the cause of trans-genera­tional instability proposed in the literature, has been an epigenetic effect of a still non-clarified background. The experimental research has indicated that the frequency of mutations to be seen in the offspring of irradiated mice depends on the strain used in the experiments. Within this context, the BALB/c mice strain has been demonstrated to be the most sen­sitive one, while the C57BL/6 turned out to be the most stable one. The importance of utilisation of various mice strains lies within the corroboration of the fact that trans-generational instability is not a strain-specific phenomenon. Alike, the research into the genetic features of mice used for experimental purposes, contributes to the comprehension of mechanisms responsible for the mutations in reference. The results obtained in mice irradiated with doses of 0.4 Gy, 1 Gy and 2 Gy, are of significance in proving that both low- and high-LET ir­radiation may induce trans-generational instability, and that the rate of mutations encountered in the offspring is linearly dose-dependent. Alike human mini-satellites, mice ESTR sequences had been considered irrelevant and inert for a fairly long time. However, it has been proven that a number of changes encountered in the offspring of irradiated mice belonging to various strains (for in­stance, the increase in lung and skin tumour rate, the rate of blood cell malignancies and the decrease in ovarian cells’ impregnation rate), are inherited conformant to the trans-generational instability model.27 Specificity of hyper-mutable mini- satellites and the transgenic model The fact remains that, apart from human genome, there exists no other organism containing hyper-mutable mini-satellite loci in its genome. Therefore, the results of the investigation carried out on mice ESTR loci, could not, beyond reasonable doubt, be extrapolated to humans. Having in mind that mice mini-satellites follow the pattern similar to that in humans and resemble the Radiol Oncol 2007; 41(3): 123-32. latter in mutation rates, the potential solu­tion to the problem would be the introduc­tion of human mini-satellite loci into the mice genome. The transgenic individuals of such kind have been irradiated insofar; however, no such thing as the rise in rates of mutations encountered on these loci, nor the occurrence of trans-generational insta­bility, have been noted.17 Thetrans-generationalinstabilitywasfirst noticed in transgenic yeasts (Saccharomyces cerevisae), in which human mini-satellite loci had been introduced. In these models, even the protein that takes control over mini-sat­ellite expansion that occurs during meiosis (termed the Rad 1), had been discovered. However, the instability noted in yeasts markedly differ from that in humans; for instance, mini-satellite mutations are usu­ally boiled down to simple arrangements, lacking any trace of complex inter-and in-tra-allele rearrangements that can be found in people. In addition, in mutants in whom Rad 27 protein has been affected, complex post-mitotic mini-satellite mutations occur in somatic cells as well, while in people the latter are limited to the gametal develop­mental line. In some individuals, a sequence diminishment has been observed as well, as oppose to humans who presented with the preferred sequence expansions.17 Therefore, the sole manner of monitoring and investi­gating mini-satellite mutations in humans, are population studies. Population studies The results of the investigations indicating the presence of a post-irradiation risk im­posed on as many as three mice generations launched a debate on potential risks for the human population, too. It is of note that mutations occurring on human mini-satel­lites are exclusively narrowed down to the cells of the gametal developmental line, and are of a more complex nature, so that mice models can not be considered relevant. Although the investigation of mini-satel­lite mutations occurring in humans are far more difficult to explore, due to the need of having a correspondent control group, the samples had been collected among families exposed to Chernobyl catastrophe, as well as among persons included into radioac­tive testing conducted in the Kazakhstan region Semipalatinsk, and cancer patients receiving radiotherapy. Due to the fact that the research in question was conducted on a relatively small number of persons exposed to different radiation types, as well as due to the impossibility of determining the exact irradiation dose delivered to the exposed persons based on the timing of their irradiation within the set timeframe, this study yielded contradictory results. Owing to the short half-life of unstable radioisotopes to which the families victim-ised by the Chernobyl catastrophe have been exposed, doses measurable immedi­ately after the catastrophe were not relevant after all. Realistic doses were estimated based on the number of stable and unsta­ble chromosomal aberrations detected in the exposed persons.29 Blood samples had been collected from the families dwelling the Mogilev County of Belarus, affected by the Chernobyl catastrophe, while British families served as controls. The mini-sat­ellite analysis revealed the mutation rate registered in irradiated family members, to be 1.6-fold higher than that of controls. In addition, an elevated mutation rate was observed also with children coming from parents deemed as high dose recipients. However, due to the inadequacy of the controls, i.e. the fact that control families were of different nationality and observed a lifestyle different from that of the exposed group, the results of these investigations were given no credit. In view of solving this problem, an adequate control group was picked up, and compared to the members of the Ukrainian families (the areas un­der investigation were Zhitomir and Kiev Counties). For the aforementioned purpose, blood from children conceived prior and following the nuclear catastrophe had been sampled. In subjects conceived following the nuclear accident, a 60%-rise in muta­tion rate had been established. In addition, the exposed persons had been subjected to the genotype analyses of the cells constitut­ing the gametal developmental line, on the occasion of which only mutations in male cells (not in female ones) had been deter­mined, despite the fact that both genders were exposed to equal radiation doses.30 Similar research had also been conduct­ed among families dwelling Kazakhstan re­gion of Semipalatinsk who had resided in the vicinity of the nuclear facility nearby which, starting from 1949 up to 1989, as many as 470 nuclear tests had been per­formed. The families in reference lived nearby the area of atmospheric, as well as underground and surface explosions. Persons of similar nationality, parental age, professions, and smoking habits, originat­ing from the former Taldy Kurgan County of Kazakhstan, but not residing in the vici­nity of the aforementioned location, served as controls. Alike the previous two, this re­search yielded positive results in terms of mutation rate elevation, in this particular case by as much as 70% as compared to the controls. In all of the aforementioned stud­ies conducted in the territory of the former USSR, probes for the same mini-satellite al­leles had been used.26,29 However, there exist also studies which failed to confirm the aforementioned re­sults. For instance, the investigations con­ducted among children who managed to survive the most notorious event of an acute exposure to an enormous radiation dose, i.e. the Hiroshima bombing, failed to confirm the theory of trans-generational instability. Negative results of this study may serve as a proof that only certain types of radiation, or exposure (for instance, the Semipalatinsk families had been exposed to chronic, fairly uniform radiation, while the Hiroshima families had been exposed to an acute high-dose irradiation), are capa­ble of inducing such a phenomenon. As a limitation of the studies conducted among children who managed to survive the Hiroshima bombing, the fact that most of the children under investigation were born 10 years after the nuclear attack on their parents, has often been put forward. This fact is most often taken as the main reason for negativity of the results of the study in question, together with the possibility that there exists a time-period after which the epigenetic mechanism of mutation induc­tion "turns off". Negative results were also obtained with the analysis of sperm sam­pled from males diagnosed with seminoma both prior and following radiotherapy, who had been subjected to 0.4-0.8 Gy radiation, delivered in 15 fractions. The reason for the negativity of the results might be the fact that less-fractionated doses do not exhibit an additive effect. Additionally, negative results were obtained with the investiga­tions conducted among descendants of the workers who took part in cleansing of the Chernobyl facility following the nuclear ac­cident, and were exposed to daily radiation doses of 0.25 Gy. In confirmation of these results, the studies performed on mice managed to prove that a larger number of less fractionated doses lead to the same ef­fect as does the single one, equal to their sum.30,31 Mini-satellite diseases Mutations presented on mini-satellite loci are often put forward as causes of various diseases, for instance some tumours and Radiol Oncol 2007; 41(3): 123-32. certain types of diabetes mellitus, although their genetic background remains to be somewhat unclear. The investigations of this kind have focused on the mini-satellite locus HRAS1, the mutations of which are incriminated to cause or contribute to the development of various diseases, e.g. ovar­ian cancer, and hereditary breast and gall bladder cancer. One of the most prominent articles in the field, had been founded on the investigations of the HRAS1 locus, con­ducted in white females suffering from an ovarian cancer. Ovarian cancer is reported to be the fifth most common cause of death of US females, and the risk factors respon­sible for its more frequent onset are consid­ered to be white race, older age, nuliparity and oral contraception. The mini-satellite HRAS1 locus encountered within general population consists of 4 typical alleles and 12 atypical rare ones, the latter being trusted to emerge from the mutations of those 4 typical ones. Following the inves­tigation of the HRAS1 locus, performed in peripheral lymphocytes and tumour tissues of the sick women, as well as by virtue of comparison with the control samples taken from healthy white women of the similar age, a 50%-rise in share of rare alleles of the HRAS1 locus had been noted. Statistical analyses had revealed a 1.66-fold rise in risk of developing the disease, encountered in women hosting one rare allele, and as much as 2.86-fold rise in the referent risk posed to the women hosting two of such alleles. These results prove beyond doubt that HRAS1 locus plays a role in the onset of ovarian cancer, although the exact un­derlying mechanism remains to be unclear. It has been well-recognised that even as many as 4 nuclear transcript factors are bound to this allele, and that, under in vitro conditions, some of the alleles may pose as a transcription silencers or enhancers.31 The diseases that might arise as a conse­quence of trans-generational instability in­duced by ionising radiation are leukaemia and Hodgkin lymphoma. Such pathology had been observed in children born nearby the Sellafield Nuclear Plant of the United Kingdom. Namely, children dwelling this area were noted to have an extraordinar­ily high incidence of the diseases in ques­tion. The results of the study performed as early as in 1990, pointed to an extremely high risk of developing leukaemia and/or Hodgkin lymphoma, assessed in children whose parents had, prior to the conception, worked in the power plant in question, and had been exposed to substantial radiation doses.32 Further investigation The investigation conducted insofar, have demonstrated that ionising radiation is ca­pable of influencing the genome of non-ir­radiated descendants, more precisely their mini-satellite loci. Further investigations, which might disclose the mechanisms un­derlying the occurrence of mutations on mini-satellite loci and trans-generational instability, should aim at monitoring of mini-satellite mutations to be used as a bio-monitoring tool engaged in the assessment of risk of developing malignancies, present in the offspring. In addition, there exists the possibility of application of their re­sults to the goal of designing more efficient radiotherapeutic protocols and safety-at-work measures to be observed in persons dealing with ionising radiation sources.17 Significant improvement in understanding of the occurrence of micro-satellite muta­tions, is expected to be attained by the application of biophysical spectroscopic methods (for instance, NMR, circular dicro-ism), although the question why sequence expansions are preferred over deletions has been partially answered already, under the wing of the theory that this should be attributed to the difference in stability of alternative DNA molecular structures.33 References 1. 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 leukocites after .-radiation incident. Radiat Prot Dosim 2002; 98: 407-16. 2. Neel JV, Schull WJ, Awa AA, Satoh C, Kato H, Otake M, et al. The children of parents exposed to atomic bombs, estimates of the genetic doubling dose of radiation for humans. Am J Hum Genet 1990; 46: 1053-72. 3. Sankaranarayanan K. Ionizing radiation and ge­netic risks X. The potential “disease phenotypes” of radiation-induced genetic damage in humans, perspectives from human molecular biology and radiation genetics. Mutat Res 1999; 429: 45-83. 4. Kodaira M, Satoh C, Hiyama K, Toyama K. Lack of effects of atomic-bomb radiation on genetic in­stability of tandem-repetitive elements in human germ-cells. Am J Hum Genet 1995; 57: 1275-83. 5. Dubrova YE, Nesterov VN, Krouchinsky NG, Ostapenko VA, Neumann R, Neil DL, et al. Human minisatellite mutation rate after the Chernobyl ac­cident. Nature 1996; 380: 683-6. 6. Byrne J, Rasmussen SA, Steinhorn SC, Connelly RR, Myers MH, Lynch CF, et al. Genetic diseases in offspring of long-term survivors of childhood and adolescent cancer. Am J Hum Genet 1998; 62: 45-52. 7. Kelly R, Bulfield G, Collick A, Gibbs M, Jeffreys AJ. Characterization of a highly unstable mouse minisatellite locus: Evidence for somatic mutation during early development. Genomics 1989; 17: 121­8. 8. Dubrova YE, Jeffreys AJ, Malashenko AM. Mouse minisatellite mutations induced by ionizing radia­tion. Nature Genet 1993; 5: 92-4. 9. Sankaranarayanan K, Chakraborty R. Ionizing radiation and genetic risks XI. The doubling dose estimates from the mid- 1950s to present and the conceptual changes to the use of human data on spontaneous mutation rates and mouse data on induced mutation rates for doubling dose calcula­tions. Mutat Res 2000; 453: 107-27. 10. Vergnaud G, Denoeud F. Minisatellites, mutability and genome architecture. Genome Res 2000; 10: 899-907. 11. Little JB. Radiation carcinogenesis. Carcinogenesis 2000; 21: 397-404. 12. Dubrova YE, Plumb M, Brown J, Fennely J, Bois P, Goodhead D, et al. Stage specificity, dose response and doubling dose for mouse minisatellite germ-line mutation induced by acute radiation. Proc Natl Acad Sci 1998; 95: 6251-5. 13. Dubrova YE, Plumb M, Gutierrez B, Boulton E, Jeffreys AJ. Transgenerational mutation by radia­tion. Nature 2000; 405: 37. 14. Strachan T, Read A. Human Molecular Genetics 2. Oxford: BIOS Scientific Publishers Ltd; 1999. 15. Sadamoto S, Suzuki S, Kamiya K, Kominami R, Dohi K, Niwa O. Radiation induction of germline mutation at a hypervariable mouse minisatellite locus. Int J Radiat Biol 1994; 65: 549-57. 16. Bois P, Stead JHD, Bakshi S, Williamson J, Neumann R, Moghadaszadeh B, et al. Isolation and characterization of mouse minisatellites. Genomics 1998; 50: 317-30. 17. Bois PR. Hypermutable minisatellites, a human affair. Genomics 2003; 81: 349-55. 18. Armour JAL, Brinkworth MH, Kamischke A. Direct analysis by small-pool PCR of MS205 mini-satellite mutation rates in sperm after mutagenic therapies. Mutat Res 1999; 445: 73-80. 19. May CA, Tamaki K, Neumann R, Wilson G, Zagars G, Pollack A, et al. Minisatellite mutation frequen­cy in human sperm following radiotherapy. Mutat Res 2000; 453: 67-75. 20. Bruce A, Roberts K, Lewis J, Raff M, Walter P, Johnson A. Molecular biology of the cell (4th edition): New York: Garland Pub; 2002. 21. Fan YJ, Wang Z, Sadamoto S, Ninomiya Y, Kotomura N, Kamiya K, et al. Dose-response of radiation induction of a germline mutation at a hy­pervariable mouse minisatellite locus. Int J Radait Biol 1995; 68: 177-83. 22. Jeffreys AJ, Tamaki K, MacLeod A, Monckton DG, Neil DL, Armour JAL. Complex gene conversion events in germline mutation at human minisatel-lite. Nature Genet 1994; 6: 136-45. 23. Jeffreys AJ, Neumann R. Somatic mutation proc­ess at a human minisatellite. Hum Mol Genet 1997; 6: 129-36. Radiol Oncol 2007; 41(3): 123-32. 24. Tamaki K, May CA, Dubrova YE, Jeffreys AJ. Extremly complex repeat shuffling during germ-line mutation at human minisatellite B6.7. Hum Mol Genet 1999; 8: 879-88. 25. Buard J, Collick AJ, Brown J, Jeffreys AJ. Somatic versus germline mutataion process at minisatel-lite CEBI (D2S90) in human and transgenic mice. Genomics 2000; 65: 95-103. 26. Dubrova YE. Transgenerational germline insta­bility. 33th Annual Meeting of the European Environmental Mutagen Society” Aberdeen, Great Britain 2003, Abstract pp 18. 27. Barber R, Plumb MA, Boulton E, Roux I, Dubrova YE. Elevated mutation rates in the germ line of first- and second-generation offspring of irradiated male mice. Proc Natl Acad Sci USA 2002; 99: 6877­82. 28. Niwa O, Kominami R. Untargeted mutation of the maternally derived mouse hypervariable minisat­ellite allele in F1 mice born to irradiated spermato­zoa. Proc Natl Acad Sci USA 2002; 98: 1705-10. 29. Dubrova YE. Monitoring of radiation-induced germline mutation in human. Swiss Medical Weekly 2003; 133: 474-8. 30. Dubrova YE, Grant G, Chumal AA, Stezhka VA, Karakasian AN. Elevated minisatellite mutation rate in the post chernobyl families from Ukraine. Am J Hum Genet 2002; 71: 801-9. 31. Jeffreys N, Weitzel JN, Ding S, Larson GP, Nelson RA, Goodman A, et al. The HRASI minisatellite locus and risk of ovarian cancer. Cancer Res 2000; 60: 259-61. 32. Gardner MJ, Snee MP, Hall AJ, Powell CA, Downes S, Terrell JD. Results of case-control study of leu­kaemia and lymphoma among young people near Sellefield nuclear plant in West Cumbria. Br Med J 1990; 300: 423-9. 33. Wells RD, Dere R, Hebert ML, Napierala M, Son LS. Advance in mechanisms of genetic instability related to hereditary neurological diseases. Nucl Acids Res 2005; 33: 3785-798. 3D-conformal radiotherapy for inoperable non-small-cell lung cancer – A single centre experience Sabine Fromm1, Andrea Rottenfusser1, Daniel Berger1, Robert Pirker2, Richard Pötter1, Boris Pokrajac1 1Department of Radiotherapy and Radiobiology, Medical University of Vienna, Austria 2Department of Internal Medicine, Division of Oncology, Medical University of Vienna, Austria Background. The purpose of this investigation was to evaluate feasibility, safety and efficacy of 3D­conformal radiotherapy (3D-RT) for inoperable non-small-cell lung cancer (NSCLC). Time to progression (TTP), including local recurrence and/or distant metastasis, local control rate (LCR), time to death (TTD) and side effects were evaluated. Patients and methods. From 1997 to 2002, a total of 84 patients with inoperable NSCLC were treated with 3D-RT according to a prospective protocol at our institution. Depending on performance status, lung function and dose-volume constraints, radiation doses of either 66-70 Gy or 50-60 Gy +/-platin-based chemotherapy were applied. Results. The treatment was well tolerated and the rate of side effects was low. Only one grade 4 pneumo­nitis was observed, the rate of grade 3 pneumonitis was 6% and 13% for grade 2. Two patients developed a grade 4 oesophagitis and no grade 3 oesophageal toxicity was observed. The analysis of dose-volume histograms (DVH) found a mean V20 (lung volume that receives 20 Gy) for the ipsilateral lung (IL) of 42%, a mean V20 for the contralateral lung (CL) of 14% and a mean lung dose IL of 25 Gy. The mean V20 IL in patients developing a pneumonitis grade 2-4 was 53.3%. The mean follow-up was 24 month. There was no difference in TTP (median 15 months) in the different treatment groups. Patients receiving higher radiation doses (66-70 Gy) had a benefit in an overall survival (OS) when the additional chemotherapy was applied (28 month vs. 16 month). Local control rates of mean 22% after 2 years were low. Conclusions. The application of radiation doses up to 70 Gy is feasible and safe, also in combination with chemotherapy. Still, the local control and OS is poor. Thus, further trials to investigate the possibility of dose escalation in the lung without increasing lung toxicity significantly, also in more advanced tumour stages, are mandatory. Key words: carcinoma, non – small – cell lung – radiotherapy; radiotherapy, conformal; radiotherapy planning; computer - assisted Received 26 September 2007 Accepted 30 September 2007 Correspondence to: Sabine Fromm, M.D., Department of Radiotherapy and Radiobiology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna; Austria; Phone: +43 1 40400 2689; Fax: +43 1 40400 2690; E-mail: sabine.fromm@akhwien.at Introduction In the European Union (EU) lung cancer is the most common cause of death from cancer. The estimated deaths in 1997 were 180 000, representing one-third of the total cancer mortality in the EU.1 In Austria, the mortality in men is declining since the 1980, whereas in women the incidence is rising in the last decades.2 For patients with oncological and/or functional inoperable non-small-cell lung cancer (NSCLC), 3D-conformal radiothera­py (3D-RT) has become an established treat­ment modality. The overall survival and distant failure rate can be improved with chemotherapy (ChT), applied sequential or concurrent to conformal radiotherapy.3-5 Therefore, combined chemo/radiotherapy is today the standard treatment for patients with advanced inoperable NSCLC in Stage IIIA/IIIB.6 Still, the most common pattern of fail­ure is local recurrence. For patients surviv­ing 6-12 months, local tumour control re­sults in the increased overall survival and is directly related to the applied radiation dose.7-9 With a radiation dose ranging from 64 to 80 Gy, local control rates of 70-92% can be achieved for stage T1-T3 tumours over a period of 12 months which decreases dose-dependently to 73-43% in the follow­ing years. Thus, attempts to decrease the rate of intrathoracic recurrence have been concentrated on dose escalation and differ­ent fractionation schedules throughout the last years.3,10-13 The purpose of this investigation was to evaluate feasibility, safety and efficacy of 3D- conformal radiotherapy with doses up to 70 Gy +/- platinum-based chemotherapy in patients with inoperable NSCLC treated within a prospective protocol in our institu­tion. Patients and methods This investigation includes 84 patients with oncological and/or functional inoperable, histologically proven NSCLC consecutively treated from 1997 to 2002 in the poten­tial curative intent at the Radiotherapy Department of the Medical University of Vienna. According to a prospective pro­tocol, 3D-RT with radiation doses up to 66-70 Gy was applied, depending on dose-volume-constraints for lung toxicity, per­formance status and lung function. All patients had a complete staging before the treatment including CT scan of the chest and upper abdomen, bronchoscopy, CT-guided biopsy or mediastinoscopy, pulmo­nary function test, bone scan and complete blood cell counts. Radiotherapy All 84 patients received 3D-conformal ra­diotherapy. The computed tomography (CT) for the planning was performed in inspiration while the patient was lying in a supine position with arms elevated above the head. During the treatment the patients were asked to hold the breath as maximal as possible. The planning CT scan of the entire thorax was done with a slice thick­ness of 8 mm. For optimal positioning, the breast-board was used. The CT images were transferred to the 3D planning system (HELAX®, MMS 6.1B). Organs at risk (lung, spinal cord, heart), gross tumour volume (GTV), clinical target volume (CTV) and planning target volume (PTV) were deline­ated. The GTV contoured the primary tu­mour plus involved pathological lymph nodes (= 10mm). Patients with supracla­vicular lymph node metastases were not included. The CTV was defined by adding 10mm around the GTV including also regional lymph nodes (mediastinum and ipsilateral hilus). For the PTV an additional margin of 5mm was placed around the CTV. The dose was prescribed to the ICRU point as de­scribed in the ICRU 50 recommendations.14 Dose volume histograms (DVH) have been calculated for both lungs and spinal cord. For the definition of the dose-volume con­straints we followed the recommendations of Graham et al.15 The maximum 20 Gy vol­ume (V20) was tolerated to be 50% for ipsi-lateral (IL), 30% for contralateral (CL) and 40% for both lungs. The mean lung dose for the ipsilateral lung had not to be more than 25 Gy. The dose to the spinal cord was maximum 50 Gy. The irradiation was delivered by multi­ple field arrangements using photons with an energy of 10-25 MV. A dose of 40 Gy was applied by AP/PA fields, followed by a field rearrangement (3-4 fields) to lower the dose to the spinal cord. For boost irradiation to the primary tumour, the shrinking field technique was used. The treatment was performed in conventional fractionation, 5 days a week, with a dose of 2 Gy per frac­tion. Chemotherapy A platinum-based chemotherapy in dou­blets was applied mainly sequential. Cisplatin was combined with taxotere, na­velbine, etiposide, gemcitabine or ifosfa­mide. The majority of patients (20) received 3 cycles before radiotherapy. A maximum of 6 cycles, 3 before and 3 after irradiation was given in 7 pts. Only 4 patients had con­comitant chemo/radiotherapy (Table 1). Side effects The diagnosis of pneumonitis was based on clinical symptoms of shortness of breath, cough, fever and in correlation with the radiographic findings on chest X-ray. Radiation pneumonitis and oeosphagitis were evaluated according to the RTOG/ EORTC radiation morbidity scoring cri­teria:16 grade 2 pneumonitis is defined as cough, requiring medication or mild dyspnea during exercise, grade 3 as clini­cal or on X-ray visible acute pneumonitis requiring steroids and maybe intermittent oxygen and grade 4 is severe respiratory in­sufficiency and continuous use of oxygen. Grade 2 oesophagitis is defined as mild dysphagia requiring medication, grade 3 as severe dysphagia with weight loss and de­hydration, grade 4 as complete obstruction, ulceration, perforation or fistula. Patients Depending on DVH constraints for V20 and mean lung dose, forced expiratory volume in 1 second (FEV1) and performance status, radiation doses of either 66-70 Gy or 50­60 Gy were chosen. The administration of chemotherapy depended on performance status and co-morbidity. Thus, for the ret­rospective analysis four different treatment groups were defined: Patients with a Karnofsky-index (KI) of 70-100%, FEV1 of = 1,3 l, treated with 3D-RT in combination with chemotherapy to a to­tal dose of 66-70 Gy were defined as group A and patients with the same KI and FEV1 but severe co-morbidity, treated with 66-70 Gy without chemotherapy as group C. A poorer performance status and/or a FEV1 = 1,3 l and high values at the DVH analysis resulted in 3D-RT of 50-60 Gy with chemo­therapy (group B) and in case of additional severe co-morbidity, 3D-RT (50-60 Gy) was performed without chemotherapy (group D). See details in Table 1. Follow-up After the treatment the patients were fol­lowed in a 3 months (mo) interval for the first 2 years (y). A thoracic CT-scan and a pulmonary function test were demanded in regularly intervals. If clinically indicated, a blood test and a CT-scan of the brain were performed. The recurrent disease was de­fined as appearance of new lesions on CT-scan 6 months after radiotherapy. Radiol Oncol 2007; 41(3): 133-43. Table 1. Patients characteristics A B C D Group (66-70 Gy+ChT) (50-60 Gy+ChT) (66-70 Gy) (50-60 Gy) Age (mean) 48y 61y 70y 70y Sex (n) Female 13 6 5 5 Male 16 10 21 8 Histology (n) Squamous cell carcinoma 12 7 18 8 Adenocarcinoma 16 6 6 4 Large cell carcinoma 1 3 2 1 Stage (n) IA 1 IB 5 2 IIB 1 1 6 2 IIA 5 2 8 5 IIIB 23 13 6 4 TNM (n) T1N0 1 T1N2 2 T1N3 1 1 T2N0 5 2 T2N1 1 T2N2 3 7 3 T2N3 2 1 T3N0 1 1 4 2 T3N2 1 3 2 2 T3N3 3 3 T4N0 8 2 4 3 T4N1 1 T4N2 7 5 T4N3 1 1 TXN3 1 RT dose (n; Gy) 50 7 7 60 9 6 66 15 12 70 14 15 ChT cycles (n) 6 7 2 5 1 0 4 3 2 3 13 8 2 1 3 1 0 1 ? 4 0 RT= radiotherapy; ChT= chemotherapy; n= number of patients Table 2. Dose volume histograms (DVH) analysis for all treatment groups (A-D), mean values and range ABCD Group (66-70 Gy+ChT) (50-60 Gy+ChT) (66-70 Gy) (50-60 Gy) V20IL (%) 39 (23-56) 47 (25-80) 39 (10-75) 47 (37-60) V20CL (%) 16 (2-40) 15 (0-35) 14 (1-33) 10 (1-30) Mean lung dose IL (Gy) 23 (16-32) 25 (9-41) 27 (10-36) 24 (15-33) Mean lung dose CL (Gy) 11 (4-25) 11 (4-24) 10 (3-18) 7 (3-12) IL= ipsilateral lung, CL= contralateral lung Statistical analysis Time to progression (TTP) was defined as an interval from the date of diagnosis to the development of local recurrence and/or distant metastasis or date of the last fol­low-up visit. Local control rates (LCR) of 1y and 2y were evaluated. Time to death (TTD), TTP and time to pneumonitis (grade 2-4) were estimated using the Kaplan-Meier product-limit method. To test the difference between survival curves, the log-rank test was used.17 Results Data have been analysed until November 2004. The evaluation included TTP, TTD, LCR, distant failure and side effects such as pneumonitis and oesophagitis. Additionally a DVH analysis was done. The mean follow up time was 24 mo (range 1-84), 2 patients were lost to the follow-up. Although DVH were calculated for all patients at the time of treatment, in 11 patients the calculated DVH could not be retrieved retrospectively from the planning system due to a technical defect on the hard disc. The DVH analysis showed a mean V20 IL of 42% with a range of 10 to 80%. The V20 CL was 14% (range 0-40%). The mean lung dose IL was 25 Gy (range 9-36) and CL 10 Gy (range 3-25). Although the mean values cor­respond to the dose volume constraints we used, in some patients it was due to the tu­mour volume not possible to refer to those parameters, what explains the large range of the different values. Thus, patients with higher values of V20 IL and mean lung dose IL and low FEV1 received only 50-60 Gy as already mentioned above (Table 2). Of all 84 patients, 1 patient (1%) devel­oped a grade 4 pneumonitis, 5 patients (6%) a grade 3 pneumonitis and 11 patients (13%) a grade 2 pneumonitis (Table 3). The medi­an time of the development of pneumonitis in patients who experienced a pneumonitis grade 2-4 was 2 mo, ranging from 1 to 11 mo. The statistic analysis for all patients showed that in a mean observation time of 24 mo (1-84) the median time of pneumoni-tis was not reached. The proportion of pa­tients developing a pneumonitis grade 2-4 was after 3 mo 15%, after 6 mo 18% and af­ter 11 mo 22%. Patients with a pneumonitis grade 2-4 had a mean V20 IL of 53.3% (33­ 85) and a mean lung dose IL of 30 Gy (17.2­ Radiol Oncol 2007; 41(3): 133-43. Table 3. Incidence of pneumontis and oesophagitis in the different treatment groups ABCD Group (66-70 Gy+ChT) (50-60 Gy+ChT) (66-70 Gy) (50-60 Gy) Pneumonitis Grade 2 4 (13%) 2 (11%) 3 (11%) Grade 3 2 (6%) 0 2 (7%) Grade 4 0 0 0 Oesophagitis Grade 2 5 (17%) 3 (17%) 2 (7%) Grade 3 0 0 0 Grade 4 1 (3%) 1 (6%) 0 3 (23%) 0 1 (8%) 1 (8%) 0 0 37.5). The additionally calculated sigmoid dose-response curve (Figure 1) showed a risk of 60% to develop a pulmonary toxicity (> grade 1) when the mean V20 IL was more than 50%. Looking at the detailed results of the dif­ferent treatment groups, we found in group A a median TTP of 13 mo, with a range of 4­85 mo and a median TTD was 28 mo, ranging from 7-85 mo. The median disease specific survival (DSS) was also 28 mo. The survival after 3 and 5y was 38% and 10% respective­ 1,0 ,9 ,8 ,7 ,6 ,5 ,4 ,3 ,2 ,1 0,0 Ĺ Figure 1. Sigmoid dose-response curve showing the correlation between V20 (%) IL and probability for pulmonary toxicity more than grade 1. . ly. The LCR was 48% after 1y and 24% after 2y. Eight patients (27%) had progressive dis­ease after radiotherapy, 12 (41%) developed distant metastases and 2 died of other, not cancer related causes. One patient with a stage IIIB tumour, located centrally, close to the oesophagus and the trachea developed a fistula (grade 4 complication) which was treated by a stent implantation. This patient died shortly after radiotherapy due to the local tumour progression. In group B, the median TTP was 15 mo ranging from 3-58 mo, the median TTD was 16 mo (3-27 mo), the LCR 38% after 1y and 25% after 2y. The three and 5y survival was 19% and 6% and the median DSS was 16 mo. The progressive disease after irradia­tion was seen in 5 patients (31%). A total of 5 patients (31%) developed distant metas­tases and 1 died of other causes. One 73y old patient with a T4N2 (stage IIIB) tumour developed an ulceration of the oesophageal mucosa (grade 4 complication) after irradia­tion, requiring hospitalisation, intravenous fluids and hyperalimentation. In group C the median TTP was 13 mo (range 5-65 mo), the median TTD 16 mo (range 5-78 mo), the median DSS was 15 mo, the LCR was 42% after 1y and 23% af­ter 2y. Nine patients (35%) had a tumour progression after radiotherapy, 6 (23%) had distant failure and 8 (31%) had not cancer Table 4. Median values for time to progression (TTP), time to death (TTD), disease specific survival (DSS) and local control rate (LCR) Group A (66-70 Gy+ChT) B (50-60 Gy+ChT) C (66-70 Gy) D (50-60 Gy) TTP (month) 13 15 13 13 TTD (month) 28 16 16 22 DSS (month) 28 16 15 16 LCR (%) 1-year 48 53 42 38 2-year 24 25 23 15 Ă 1,0 1,0 0,8 0,8 Ź Ź 0,6 0,6 0,4 0,2 0,0 0,00 20,00 40,00 60,00 80,00 100,00 . Figure 2. Kaplan-Meier overall survival curve for group A+C (66-70 Gy +/- ChT). related death. The three and 5y survival was 11% and 8%. No grade 3 or 4 oesopha­geal toxicity was found. Group D had a median TTP of 19 mo (range 3-22 mo), a median TTD of 22 mo (range 3-42 mo) and a median DSS was 16 mo. The LCR was 53% after 1y and 15% after 2y. Four patients (31%) had progres­sive disease after radiotherapy, no distant metastases were observed. Three patients died of other causes. The survival after 3 and 5y was 23% and 8%. No grade 3 or 4 oesophagitis was seen. One patient with a 0,4 0,2 0,0 0,00 10,00 20,00 30,00 40,00 50,00 60,00 70,00 . Figure 3. Kaplan-Meier overall survival curve for group B+D (50-60 Gy +/- ChT). T2N2 (stage IIIA) tumour developed a grade 4 pneumonitis, requiring continuous oxy­gen. The ipsilateral V20 for this patient was 60% and the ipsilateral mean lung dose was 32 Gy. Recurrent disease was found after 10 months and death occurred 42 mo after di­agnosis, without distant metastases. Long-time survivors For all treatment groups together a total of 14 patients survived more than 2 y with a median survival of 40 mo, ranging from 26 Radiol Oncol 2007; 41(3): 133-43. to 61 mo. Concerning long-time survival there was no significant difference between the different treatment groups (Figures 2, 3); however, patients receiving higher ra­diation doses (66-70 Gy) had a benefit in an overall survival (OS) when the additional chemotherapy was applied (28 month vs. 16 month). Discussion In the last decades, different treatment strategies were developed for locally ad­vanced non-small cell lung cancer. For inoperable stage III NSCLC, 3D-conformal radiotherapy in combination with chemo­therapy has lead to a better local control and longer survival.7 Nevertheless, the lo­cal control remains poor, although the first results in dose escalation trials are promis- ing.3,13,18 All patients included in this retrospec­tive analysis received a 3D-conformal radio­therapy within a prospective protocol with the aim to apply a maximum dose of 70 Gy. Depending on performance status, lung function and dose volume constraints such as calculated mean lung dose and 20 Gy lung volume (V20) different radiation doses ± chemotherapy have been applied on an individual basis resulting in four treatment groups. Our analysis showed that the appli­cation of radiation doses up to 70 Gy also in combination with sequential chemotherapy is feasible and safe. The treatment could be finished in all patients and no treatment re­lated death occurred. Four grade 3 pneumo­nitis (9%) were found in the “higher dose” (66-70 Gy) groups (A+C) and no grade 4 pneumonitis. The DVH analysis emphasised that the V20 IL in patients with grade 2-4 pneumoni-tis was mean 53.3%, with a mean lung dose IL of 30 Gy. Furthermore, the sigmoid dose-response curve shows that a V20 IL of more than 50% leads to a risk of 60% for pulmo­nary toxicity. This underlines the correla­tion of V20 IL with the incidence of radia­tion pneumonitis as reported by Graham et al.15 The authors showed that a mean V20 of the total lung (including both lungs minus PTV) of more than 32% was significantly correlating with high grade pneumonitis (= grade 3). The final toxicity results of a dose-escalation study of Kong et al. showed that the grade 2 and 3 lung toxicity was not directly associated with the prescribed tu­mour dose but correlated with dosimetric parameters. The risk of pneumonitis was significantly associated with a mean lung dose = 14 Gy (p = 0.002) and a V20 = 27% (p = 0,0008).19 For all 84 patients, no grade 3 oesophagi-tis was observed. Two grade 4 oesophageal toxicities were seen in patients with central, bulky tumours close to oesophagus and tra­chea. Our results also showed that in the group with higher radiation doses (66-70 Gy) the application of chemotherapy prolonged the survival compared to exclusive radiotherapy of 66-70 Gy (28 vs. 16 mo). Considering the DSS we found the same results (28 vs. 15 mo). Comparable results have been report­ed by Rengan et al.12 In this study a group of 35 patients with stage IIIB NSCLC received 64-84 Gy plus chemotherapy with a median overall survival (OS) of 20 mo for and local failure rate of 64%. Sim et al.5 reported for 152 patients with stage III NSCLC a median OS of 18 mo for the combined treatment compared to 11.7 mo for the radiotherapy alone group (p = 0,001). In the lower dose (50+60 Gy) groups (B+D) there has been no benefit in OS for patients receiving ChT as it was seen in the higher dose groups (A+C). The median survival time for the lower dose groups +/- ChT (16 vs. 22 mo) is also comparable with results in the literature. Different studies report a median OS of 13.8-16 mo for chemoradiotherapy and 9.7-16 mo for exclusive radiotherapy in stage III NSCLC with radiation doses between 50-63 Gy.12,20-22 The slightly better results for the group with exclusive radiotherapy (22 mo) for OS could not be confirmed for the DSS where no difference was found (median 16 mo for both groups). Concerning the development of distant metastases we could not obtain the same results as stated in several studies.6,20,23 In our analysis the rate of distant failure was not lower in patients with radio-/chemo­therapy as in patients receiving RT alone. The reason might be that especially in the higher dose groups, the majority of pa­tients receiving chemotherapy had stage IIIB whereas in the exclusive radiotherapy groups, also stages I and II were included. The LCR at 1y was in all 4 treatment groups nearly the same with mean 45% and no ad­vantage for higher radiation doses could be observed. Probably the number of patients was too small. The LCR at 2y was low in all four groups with the poorest result (15%) for the group receiving 50-60 Gy without chemotherapy. To improve the local control, different efforts have been made in the last years. Developments in 3D-planning and new techniques like self-gated radiotherapy at deep-inspiration breath hold (DIBH) en­able a better tumour targeting and sparing of normal tissue which allows an escalation of the radiation dose up to 100 Gy. Local control rates of 50-80% have been reported with radiation doses varying from 70.2 to 90 Gy.3,8,13,17,24,25 The limiting factor for dose escalation is the surrounding normal lung tissue. Radiation doses of = 90 Gy lead to severe pulmonary toxicity.3,13 Several studies showed that intensity modulated radiotherapy (IMRT), especially if guided by PET/CT imaging, has the ability to spare more normal lung tissue and allows 25-30% higher doses than with 3D-conformal radio­therapy.26,27 Advances in tumour staging could result in smaller treatment volumes, which would enable the application of higher radiation doses. Especially PET/CT improves the detection of lymphnode me­tastases and the differentiation between tu­mour tissue and atelectasis. De Ruysscher et al. showed in a planning study that the use of a combined PET/CT simulator re­duced the radiation dose to normal lung tissue and oesophagus and thus allowed a significant radiation dose escalation.28 Still, the risk of normal tissue toxicity should not be underestimated3,27 and new trials to evaluate a safe dose-escalation technique are obligatory. Conclusions The low incidence of severe side effects confirms that the application radiation doses up to 70 Gy with 3D-conformal radiotherapy is feasible and safe, taking into account 3D dose volume constraints. Our work suggests that the combination of chemotherapy and 3D-conformal radiother­apy of 66-70 Gy prolongs moderately the overall survival for patients with inoperable non-small-cell lung cancer with a low risk of severe pneumonitis. Nevertheless, local control rates remain low, especially after 2y. Thus the possibility of further dose escalation also in more ad­vanced tumour stages with a special regard to the long-term pulmonary and oesopha­geal toxicity should be investigated. Acknowledgements The authors would like to thank Martha Beranek for her technical support in cal­culating and retrieving dose-volume histo­grams and Brigitte Keringer and Waltraud Stepan for their secretarial assistance. Radiol Oncol 2007; 41(3): 133-43. References 1. Ferlay J, Bray F, Sankila R, Parkin DM. EUCAN: Cancer incidence, Mmortality and prevalence in the European Union 1997. Version 4.0. IARC Cancer Base No. 4. Lyon: IARC; 1999. 2. Bray F, Tycynski JE, Parkin DM. Going up or com­ing down? The changing phases of lung cancer epidemic from 1967 to 1999 in the 15 European Union countries. Eur J Cancer 2004; 40: 96-125. 3. Bradley J, Graham MV, Winter K, Purdy JA, Komaki R, Roa WH, et al. Toxicity and outcome results of RTOG 9311: a phase I-II dose-escalation study using three-dimensional conformal radio­therapy in patients with inoperable non-small cell lung carcinoma. Int J Radiat Oncol Biol Phys 2005; 61: 318-28. 4. Semrau S, Bier A, Thierbach U, Virchow C, Ketterer P, Klautke G, et al. R. 6-Year Experience of concurrent radiochemotherapy with vinorelbine plus a platinum compound in multimorbid or aged patients with inoperable Non-Small Cell Lung Cancer. Strahlenther Onkol 2007; 183: 30-5. 5. Sim S, Rosenzweig KE, Schindelheim R, Ng KK, Leibel SA. Induction chemotherapy plus three-di­mensional conformal radiation therapy in the de­finitive treatment of locally advanced non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2001; 51: 660-5. 6. Novello S, Le Chevalier T. Use of chemo-radiother­apy in locally advanced non-small cell lung cancer. Eur J Cancer 2002; 38: 292-9. 7. Ball D, Matthews J, Worotniuk V, Crennan E. Longer survival with higher doses of thoracic radiotherapy in patients with limited non-small cell lung cancer. Int J Radiat Oncol Phys 1993; 25: 599-604. 8. Thirion P, Holmberg O, Collins C, O’Shea C, Moriarty M, Pomeroy M, et al. Escalated dose for non-small lung cancer with accelerated hypofrac­tionated three-dimensional conformal radiation therapy. Radiother Oncol 2004; 71: 163-6. 9. Willner J, Baier K, Caragiani E, Tschammler A, Flentje M. Dose, volume and tumor control pre­dictions in primary radiotherapy of non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2002; 52: 382-9. 10. Baumann M, Herrmann T, Matthiessen, Koch R, Strelocke K, Paul U. CHARTWEL-Bronchus (ARO 97-1): a randomized multicenter trial to compare conventional fractionated radiotherapy with CHARTWEL radiotherapy in inoperable non­small-call bronchial carcinoma. Strahlenther Onkol 1997; 173: 663-7. 11. Catalano G, Jereczek-Fossa B, De Pas T, Leon ME, Cattani F, Spaggiari L, et al. Three-times daily ra­diotherapy with induction chemotherapy in locally advanced non-small cell lung cancer. Strahlenther Onkol 2005; 181: 363-71. 12. Rengan R, Rosenzweig KE, Venkatraman E et al. Improved local control with higher doses of radia­tion in large-volume stage III non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2004; 60(3): 741-747 13. Rosenzweig KE, Fox JL, Yorke E, Amols H, Jackson A, Rusch V, et al. Results of a phase I dose-esca­lation study using three-dimensional conformal radiotherapy in the treatment of inoperable nons-mall lung carcinoma. Cancer 2005; 103: 2118-27. 14. International Commission on Radiation Units and Measurements. Prescribing, recording and reporting photon beam therapy. ICRU Report 50. Bethesda: International Commission on Radiation Units and Measurements; 1993. 15. Graham MV, Purdy JA, Emami B, Harms W, Bosch W, Lockett MA, et al. Clinical dose-volume histogram analysis of pneumonitis after 3D treat­ment for non small cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 1999; 45: 323-9. 16. Cox JD, Stretz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organisation for Research and Treatment of cancer (EORTC). Int J Radiat Oncol Biol Phys 1995; 31: 1341-6. 17. Kaplan EL, Meier P. Non parametric estimation for incomplete observations. J Am Stat Ass 1958; 53: 457-81. 18. Belderbos J, Heemsbergen W, De Jaeger K, Baas P, Lebesque JV. Final results of a phase I/II dose escalation trial in non-small cell lung cancer using three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys 2006; 66: 126-34. 19. Kong FM, Hayman JA, Griffith KA, Kalemkerian GP, Arenberg D, Lyons S, et al. Final toxicity results of a radiation-dose escalation study on pa­tients with non-small-cell lung cancer (NSCLC): Predictors for radiation pneumonitis and fibrosis. Int J Radiat Oncol Biol Phys 2006; 65: 1075-86 20. Dillman RO, Seagren SL, Propert KJ, Guerra J, Eaton WL, Perry MC, et al. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med 1990; 323: 940-5. 21. Furuse K, Kubota K, Kawahara M, Kodama N, Ogawara M, Akira M, et al. Phase II study of concurrent radiotherapy and chemotherapy for unresectable stage III non small cell lung cancer. Southern Osaka Lung Cancer Study Group. J Clin Oncol 1995; 13: 869-75. 22. Kubota K, Furuse K, Kawahara M, Kodama N, Yamamoto M, Ogawara M, et al. Role of radio­therapy in combined modality treatment of locally advanced non-small-cell lung cancer. J Clin Oncol 1994; 12: 1547-52. 23. Le Chevalier T, Arriagada R, Quoix E, Ruffie P, Martin M, Tarayre M, et al. Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a randomized trial in 353 patients. J Natl Cancer Inst 1991; 83: 417-23. 24. Barnes E, Murray B, Robinson D, Underwood LJ, Hanson J, Roa WH. Dosimetric evaluation of lung tumour immobilization using breath hold at deep inspiration. Int J Radiat Oncol Biol Phys 2001; 50: 1091-8. 25. Hof H, Herfarth KK, Munter M, Essig M, Wannenmacher M, Debus J. The use of the mul­tislice CT for the determination of respiratory lung tumor movement in stereotactic single-dose irradiation. Strahlenther Onkol 2003; 179: 542-7. 26. Grills IS, Yan D, Martinez AA, Vicini FA, Wong JW, Kestin LL. Potential for reduced toxicity and does escalation in the treatment of inoperable non-small-cell lung cancer: a comparison of inten­sity-modulated radiation therapy (IMRT), 3D con­formal radiation, and elective nodal irradiation. Int J Oncol Biol Phys 2003; 57: 875-90. 27. Holloway CL, Robinson D, Murray B, Amanie J, Butts C, Smylie M, et al. Results of a phase I study to dose escalate using intensity modulated radiotherapy guided by combined PET/CT imag­ing with induction chemotherapy for patients with non-small cell lung cancer. Radiother Oncol 2004; 73: 285-97. 28. De Ruysscher D, Wanders S, Minken A, Lumens A, Schiffelers J, Stultiens C, et al. Effects of radio­therapy planning with dedicated combined PET­CT simulator of patients with non-small cell lung cancer on dose limiting normal tissues and radia­tion dose-escalation: a planning study. Radiother Oncol 2005; 77: 5-10. Radiol Oncol 2007; 41(3): 133-43. Quality of life following thoracotomy for lung cancer Lucka Debevec, Irma Rozman University Clinic of Respiratory and Allergic Diseases Golnik, Golnik, Slovenia Background. The aim of the study was to assess the preoperative and postoperative quality of life (QoL) in lung cancer patients undergoing thoracotomy and to compare the impairment of QoL in resected and exploratory thoracotomized (ET) patients. Patients and methods. Forty-three patients age 31 to 82 (mean 61) thoracotomized (lobectomy 29, bilobec­tomy 1, pneumonectomy 8, ET 5) for non-small cell lung cancer were assessed using the EORTC QLQ-LC30 and QLQ-LC13 questionnaire preoperatively and a mean of 45±17 days after the thoracotomy and before eventual chemotherapy and radiation therapy. Results. After thoracotomy there were significantly impaired functional scales (physical functioning, role functioning, social functioning) and symptom scales (fatigue, constipation, appetite loss, dyspnoea, pain). The remaining symptoms (nausea/vomiting, insomnia, diarrhoea, coughing), global health status, functional scales (emotional functioning, cognitive functioning) and financial difficulties were impaired non-signifi­cantly. However, haemoptysis significantly improved and completely disappeared after thoracotomy. There were no significant differences between resected and ET patients. Conclusions. The study established significant impairment of QoL in the first two months after thora­cotomy, but no significant differences between resected and ET patients. Key words: lung neoplasms – surgery; thoracotomy; quality of life Introduction Surgery is the treatment of choice for technical and medical operable non-small cell lung cancer (NSCLC). However, thora­cotomy impairs quality of life (QoL) in the case of resection or exploration without resection. Exploratory thoracotomy (ET) Received 14 August 2007 Accepted 29 August 2007 Correspondence to: Assist. Lucka Debevec, MD, PhD, University Clinic of Respiratory and Allergic Diseases Golnik, SI-4204 Golnik, Slovenia; Phone: +386 4 2569 100; Fax: +386 4 2569 117; E-mail: lucka.debevec@ klinika-golnik.si as the only method for tumour verifica­tion is currently very rare. In the period 1990 to 1999 the ET rate was 9.1% among 1808 thoracotomized lung cancer patients at the Department of Thoracic Surgery, Clinical Centre Ljubljana, Slovenia.1 Of 131 evaluable ET patients, only one underwent surgery without preoperative verification. ET is mostly caused by unresectability. This was the case in 119/131 patients. Incidental ET (open and closed thoracotomy) could be a consequence of intraoperative complica­tions (1/131 patient) or necessity for pneu­monectomy in the case of poor pulmonary function (11/131 patients). In any case, one Table 1. Characteristics of the patients and tumours must take into account a certain percent of ET in every large group of thoracotomized Variable Value lung cancer patients. Number of patients 43 During the last ten years, QoL has be­come an important issue in the treatment of cancer. Especially in clinical trials it is considered an aspect as important or even more important than traditionally used endpoints such as remission rate, disease-free survival and time to progression.2 QoL assessment is a way to obtain objec­tive data in order to “measure” a patient’s condition and to evaluate the global impact of therapies administered to improve a pa­tient’s situation.3 QoL is multidimensional and according to the WHO is a definition of health composed of physical, mental and social function. To measure QoL, the symp­toms of a certain tumour are assessed in a semi-quantitative manner. For lung cancer patients the most popular questionnaire is the EORTC (European Organisation for Research and Treatment of Cancer) QLQ­C30 and its QLQ-LC13 module.4 Altogether it has 43 questions that are answered by pa­tients. For converting the answers into per-cent-values, a special scoring procedure is used5 and can be performed in connection with statistical analysis by common compu­ter programs. The aim of the present study was twofold: (1) to assess preoperative and postoperative QoL in lung cancer patients undergoing thoracotomy and (2) to compare the impair­ment of QoL in resected and ET patients. Patients and methods From February 2004 to July 2005, 78 pa­tients diagnosed at the University Clinic for Respiratory and Allergic Diseases Golnik, Slovenia, underwent surgery for NSCLC with intention to cure. These patients com­pleted the EORTC QLQ-C30 and QLQ­LC13 preoperatively. All ET patients (5 of 78 patients) and 38 resected patients com­pleted the questionnaire postoperatively again, at 45±17 days after thoracotomy, before eventual chemotherapy or radiation therapy. So 43 patients were eligible for the study. Age (years) - mean 61 (range 31-82) Male/Female 33/10 Histology squamous cell 21 adenocarcinoma 16 large cell 5 non-small cell 1 Forced expiratory volume in one second 81 ± 20 (FEV1 % ) -mean Carbon monoxide lung diffusion capacity 77 ± 19 (DLCO % ) - mean Clinical stage IA 12 IB 14 IIB 10 IIIA 7 Operation lobectomy 29 bilobectomy 1 pneumonectomy 8 ET 5 Postsurgical stage IA 13 IB 9 IIA 3 IIB 8 IIIA 5 IIIB 4 IV 1 The diagnostic procedure of lung tumour consisted in all patients of chest X-ray, CT Radiol Oncol 2007; 41(3): 144-51. p < 0.05 scan of the chest and upper abdomen, bron-100 choscopy, pulmonary function testing and BEFORE arterial blood gas analysis. Cervical media-80 AFTER stinoscopy was performed in 5 patients. 60 Tumour was microscopically confirmed be­fore surgery in all patients. 40 All patients had the ECOG performance status = 1. Other characteristics of the pa- Value (%) 20 tients and tumors are shown in Table 1. Thirty four patients underwent the ante­ 0 rolateral, 8 axillar, and 1 posterolateral tho-racotomy, with a partial rib resection in 12 Variable patients. Pain management postoperatively included epidural analgesia for 2 to 7 (mean Figure 1. Preoperative and postoperative quality of life 4) days. in 43 thoracotomized lung cancer patients – significant The resection was curative without a differences. residue of tumor (R0 stage) in 39 patients, stage R1 in 3, and stage R2 in 1 patient. As 100 postsurgical stage in Table 1 was designated pathological stage in resected patients and 80 surgical stage in ET patients. The causes of ET were as follows: pleu-60 ral carcinomatosis in 2, invasion of heart in 1, extensive invasion of mediastinal lymph 40 nodes in 1, and not permissible pneumon­ ectomy due to poor pulmonary function in 1 patient. Value (%) 20 0 Statistical analysis was carried out us­ing SPSS (Statistical Package for the Social Variable Sciences for Windows, Chicago, IL) ver­sion 13.0. The difference was confirmed by Figure 2. Preoperative and postoperative quality of paired-samples t test and independent-sam­ ples t test respectively. The level of signifi­ cance was p < 0.05. life in 43 thoracotomized lung cancer patients – non significant differences. level and location of pain, impairment was Results significant in unspecified pain (p = 0.030), pain interfering with daily activities (p = Preoperative and postoperative QoL is 0.000) and chest pain (p = 0.039). There was presented in Figure 1 and in Figure 2. no significance in the impairment of pain Functional scales (physical, role and social in the arm or shoulder (p = 1.000) or of pain functioning) and symptom scales (fatigue, in other parts (p = 0.133). constipation, appetite loss, dyspnoea and QoL was not significantly impaired ac-pain) significantly worsened (Table 2). In cording to the remaining symptoms (nau­thoracotomized patients it is very important sea/vomiting, insomnia, diarrhoea, cough-to define the pain. According to presence, ing), global health status, functional scales Radiol Oncol 2007; 41(3): 144-51. 2 Table 2. EORTC QLQ-C30 and QLQ-LC13 scores in 43 patients before and after thoracotomy Before thoracotomy After thoracotomy Variables Item numbers p-value Mean±SD Mean±SD Functional scales 1–7, 20–27 80.0±17.4 64.8±22.2 0.000 Physical functioning 1 – 5 80.9±20.8 59.8±33.2 0.000 Role functioning 6, 7 75.6±30.7 57.0±30.9 0.003 Emotional functioning 21–24 72.2±18.8 66,9±34.0 NS Cognitive functioning 20, 25 90.3±16.8 86.0±18.2 NS Social functioning 26, 27 83.3±24.1 59.3±40.0 0.001 Global QoL 29, 30 55.2±25.6 49.4±20.7 NS Symptom scales/items 8 –19, 28 18.1±15.3 30.0±16.3 0.000 Fatigue 10,12,18 26.4±25.1 44.4±21.8 0.000 Nausea/vomiting 14, 15 5.0±10.0 11.6±23.2 NS Insomnia 11 31.8±35.6 35.7±29.5 NS Constipation 16 9.3±25.5 21.7±25.5 0.041 Diarrhoea 17 3.9±16.6 4,7±13.8 NS Appetite loss 13 14.7±26.5 27.1±33.5 0.025 Financial difficulties 28 15.1±28.7 21.4±32.8 NS Dyspnoea 8, 33-35 1.6±0.6 1.9±0.6 0.001 Coughing 31 39.5±25.5 40.3±22.5 NS Haemoptysis 32 9.3±16.8 0.0±0.0 0.001 Pain 9,19,40-42 24.8±20.8 34.7±23.0 0.009 (emotional, cognitive) and financial diffi­culties. However haemoptysis significantly improved, and completely disappeared af­ter thoracotomy. In order to compare QoL in resected and ET patients, the differences (impair­ments or improvements) of single items before and after thoracotomy were com­puted. Afterwards the resected and ET group were compared according to these QoL differences. Table 3 shows that there were no significant differences between resected and ET patients except in haemo­ptysis, appearing only preoperatively in resected patients. Discussion Assessing QoL means measuring either the absolute value or relative alteration of quality, and in the case of expressive im­pairment items may attain a negative value. The goal of the study was the alteration of Radiol Oncol 2007; 41(3): 144-51. Table 3. The difference of quality of life alteration after thoracotomy in resected and exploratory thoracotomized (ET) patients Variables Item numbers ET pts Mean±SD Resected pts p-value Mean±SD Functional scales 1-7, 20-27 16.9±23.0 15.0±21.7 NS Physical functioning 1-5 36.0±62.6 19.1±28.0 NS Role functioning 6, 7 36.0±27.4 18.4±40.2 NS Emotional functioning 21-24 5.0±19.2 7.7±33.6 NS Cognitive functioning 20, 25 -3.3±7.5 5.3±19.0 NS Social functioning 26, 27 10.0±25.3 25.9±48.4 NS Global QoL 29, 30 6.7±18.0 5.7±24.2 NS Symptom scales/item 8-19, 28 -8.7±20.0 -12.3±19.0 NS Fatigue 10,12,18 -8.9±34.6 -19.3±29.2 NS Nausea/vomiting 14,15 -6.7±25.3 -6.6±26.1 NS Insomnia 11 -13.3±29.8 -2.6±35.8 NS Constipation 16 -26.7±43.5 -10.5±38.0 NS Diarrhoea 17 0.0±0.0 -0.9±23.9 NS Appetite loss 13 0.0±40.8 -14.0±34.3 NS Financial difficulties 28 -6.7±14.9 -6.3±30.3 NS Dyspnoea 8, 33-35 -5.0±16.2 -11.4±19.8 NS Coughing 31 0.0±23.6 -0.9±27.4 NS Haemoptysis 32 0.0±0.0 10.5±17.5 0.001 Chest pain 40 -13.3±38.0 -20.2±62.3 NS QoL due to establishing the value of items prior to and 1-2 month after a thoracotomy. Further change of QoL in ET patients is not clearly a consequence of surgery. This might be due to tumor progress or radia­tion and chemotherapy. As expected, thoracotomy significantly impaired physical, role, and social function­ing, and it increased dyspnoea and chest pain. Any thoracotomy results in a decline in vital capacity of approximately 25%, in­dependent of lung resection, which returns to normal after 6 to 8 weeks.6,7 The major effects result from changes in chest wall compliance and an increase in the work of breathing due to the surgical wound and postoperative pain.8 It was somewhat surprising that there was no significant change in emotional functioning and financial difficulties. These confirmed both patients’ optimism and the good social support in Slovenia. Postoperative constipation could be a con­sequence of poorer nutrition due to appe-tite loss or an effect of some medicines, es­pecially analgesics. In the literature there are not many arti­cles about the influence of thoracotomy on the QoL in lung cancer patients and we have found no published data on QoL in ET. Win et al.9 assessed the effect of thora­cotomy in 110 potentially curatable lung cancer patients using the EORTC QLQ-C30 and QLQ-LC13 before surgery and again at 1, 3 and 6 months postoperatively. Eight ET patients were excluded. Global QoL had deteriorated significantly 1 month after sur­gery but had returned to preoperative lev­els by 3 months. Symptoms had worsened significantly at 1 month after surgery but returned to baseline levels by 6 months. Low values of the preoperative QoL were not significantly associated with a poor surgical outcome. However, patients with low preoperative QoL functioning scales and high preoperative symptom scores were more likely to have poor postoperative (6 months) QoL. The only lung function measurement to show a marginally statisti­cally significant association with QoL at 6 months after surgery was the percentage of predicted carbon monoxide transfer factor (DLCO). Handy et al.10 measured QoL in 103 lung cancer patients with the Short-Form 36 Health Survey (SF-36) and Ferrans and Powers Quality-of-Life Index (QLI) preoper­atively and 6 months after surgery. Pain and impairment of functional health status per­sisted for 6 months after resection. DLCO, not forced expiratory volume in one sec­ond (FEV1), predicted postoperative QoL. Preoperative chemoradiation, the extent of resection, postoperative complications, and adjuvant therapy did not adversely affect functional health status or QoL 6 months after surgery. Dales et al.11 investigated QoL in 91 resect-ed lung cancer patients using the Clinical Dyspnea Index (CDI), Pneumoconiosis Research Unit Index (PRU), QL-Index (QLI) and Sickness Impact Profile (SIP). QoL was measured preoperatively and 1, 3, 6 and 9 months postoperatively. Dyspnoea signifi­cantly increased postoperatively at 1 and 3 months, but returned at 6 and 9 months. Similarly, activities of daily life were signifi­cantly impaired at 1 month, and returned to baseline at 6 and 9 months. Zieren et al.12 assessed QoL in 20 lung cancer patients 1 day before surgery, post­operatively on the day of discharge from hospital and at 3-month intervals thereafter until the end of the first postoperative year (6 times) using the EORTC QLQ-C30. The external evaluation was made by a psychol­ogist using the Spitzer Index. After surgery QoL was mainly affected by restrictions re­lated to physical activities, job and house­hold tasks, and disease symptoms, whereas limitations in emotional, social and finan­cial domains were found to be less frequent and less severe. Tumour recurrence was determined to have a significant and nega­tive influence on postoperative QoL. When compared to preoperative assessment, QoL had deteriorated on discharge from hos­pital but was restored within 3–6 months postoperatively in disease-free patients. Paull et al.13 measured QoL prior to re­section, at 0 to 3 months following resec­tion, and at more than 3 months after resec­tion in 37 patients with early-stage NSCLC using Functional Assessment of Cancer Therapy-Lung (FACT-L). Preoperative dysp­noea and postoperative chemotherapy were associated with worse postoperative QoL. Fiedler et al.14 measured QoL in 36 pa­tients 40 months (range 7–147) after pneu­monectomy for lung cancer using the EORTC QLQ-C30. Restricted QoL was mainly caused by reduction of lung func­tion due to the loss of parenchyma. Further adjuvant therapy at least 6 months after surgery did not reduce either impairment of lung function or the impairment of QoL. Radiol Oncol 2007; 41(3): 144-51. Balduyck et al.15 assessed QoL in 100 patients undergoing major pulmonary sur­gery for malignant disease preoperatively and 1, 3, 6 and 12 months postoperatively. Pneumonectomy was signficantly associ­ated with a less favorable QoL score evo­lution when compared with lobectomy. Comparing antero- and posterolateral tho-racotomy, significant differences in pain and dyspnea were seen in favor of the ante-rolateral technique. Pompeo et al.16 analyzed QoL in 16 pa­tients undergoing tailored combined sur­gery for stage I lung cancer and severe emphysema using the SF-36 questionnaire. Significant improvements occurred for up 36 months in the general health domain and for 24 months in physical functioning, role physical and general health SF-36 do­mains. They concluded that selected lung cancer patients with severe emphysema may benefit in terms of long-term QoL. Myrdal et al.17 compared QoL in 112 resected lung cancer patients and 121 pa­tients that underwent coronary bypass sur­gery using the SF-36 health questionnaire and Hospital Anxiety and Depression Scale (HADS). Lung cancer patients had poorer function because of reduced pulmonary function but showed no sign of increased anxiety or depression. Those that contin­ued to smoke after surgery had impaired mental health. Li et al.18 compared 24 patients resected at thoracotomy and 27 VATS (video–assist­ed thoracic surgery) resected lung cancer patients 6 months or more after surgery us­ing the EORTC QLQ-C30 and QLQ-LC13. Although VATS patients tended to score higher on the QoL and functioning scales and to report relatively fewer symptoms, there were no significant differences. Hoang et al.19 analyzed the importance of returning to work after thoracic surgery. Return to work is not a trivial component of global post-surgical QoL. Patients have in­dicated that they value being able to return to work as highly as their overall health. Following the statements above, the greatest impairment of QoL due to thora­cotomy was established immediately and in the first 3 months after surgery. QoL improved 6 to 9 months after surgery, but dyspnoea continued in the case of exten­sive resection and chest pain in some pa­tients. In the case of tumour recurrence or metastatic spread, QoL depends mainly on these. The results of this study agree with the studies cited. The non-significant difference in dyspnoea impairment in pne­monectomized and ET patients was prob­ably due to the small number of patients in each group. We are aware of shortcomings of the cur­rent study. Due to organizing difficulties it was not possible to assess the QoL in all patients at quite the same interval after tho-racotomy. The small number of ET patients and the heterogeneity of characteristics in the patients and tumours reduce the relia­bility of the results. Nevertheless the study is the first essay comparing the QoL fol­lowing the thoracotomy in ET and resected lung cancer patients. Conclusion This study established a significant impair­ment of QoL, of functional scales (physical, role and social functioning) and symptom scales (fatigue, constipation, appetite loss, dyspnoea, pain) 1-2 months after thoraco­tomy, but no significant differences be­tween resected and ET patients. References 1. Debevec L, Eržen J, Debeljak A, Crnjac A, Kovac V. Exploratory thoracotomy and its influence on the survival of patients with lung cancer. Wien Klin Wochenschr 2006; 118: 479-84. 2. Beitz J, Grecco C, Justice R. Quality-of-life and points in cancer clinical trials: the U.S. Food and Drug Administration perspective. J Natl Cancer Inst Monogr 1996; 30: 7-9. 3. Sculier JP, Mancini I, Paesmans M, Klastersky J. Quality of life and supportive care. In: Hansen HH, editor. IASLC Textbook of Lung Cancer. London: Martin Dunitz; 2000. p. 337-48. 4. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European Organisation for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in interna­tional clinical trials in oncology. J Natl Cancer Inst 1993; 85. 365-76. 5. Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A; on behalf of the EORTC Quality of Life Group. The EORTC QLQ-C30 Scoring Manual. 3rd Edition. Brussels: European Organisation for Research and Treatment of Cancer; 2001. 6. Bollinger CT, Perruchoud AP. Functional evaluation of the lung resection candidate. J Thorac Cardiovasc Surg 1998; 11: 198-212. 7. Ferguson MK, Reeder LB, Mick R. Optimizing selec­tion of patients for major lung resection. J Thorac Cardiovasc Surg 1995; 109: 275-81. 8. Lin J, Martinez FJ, Iannettoni MD. The medical eval­uation and management of the lung cancer patient pre-treatment. In: Pass HL, Carbone DP, Johnson DH, Minna JD, Turrisi AT, editors. Lung Cancer. Principles and Practice. Philadelphia: Lippincott Williams Wilkins; 2005. p. 400-25. 9. Win T, Sharples L, Wells FC, Ritchie AJ, Munday H, Laroche CM. Effect of lung cancer surgery on quality of life. Thorax 2005; 60: 234-38. 10. Handy JR, Skokan L, Brooks G, Ott GY. What hap­pens to patients undergoing lung cancer surgery? Outcomes and quality of life before and after sur­gery. Chest 2002; 122: 21-30. 11. Dales RE, Belanger R, Shamji FM, Leech J, Crepeau A, Sachs HJ. Quality-of-life following thoracotomy for lung cancer. J Clin Epidemiol 1994; l47: 1443-9 12. Zieren HU, Mueller JM, Hamberger U, Pichlmaier H. Quality of life after surgical therapy of bron­chogenic carcinoma. Eur J Cardio-thorac Surg 1996; 10: 233-7. 13. Paull DE, Thomas ML, Meade GE, Updyke GM, Arocho MA, Chin HW, et al. Determinants of qual­ity of life in patients following pulmonary resec­tion for lung cancer. Am J Surg 2006; 192: 565-71. 14. Fiedler R, Neef H, Hennig H, Rosendahl W, Lautenschlaeger C. Lebensqualitaet nach pneu­monektomie wegen bronchialkarzinom. Zentralbl Chir 1997; 122: 327-31. 15. Balduyck B, Hendriks J, Lauwers P, Van Schil P. Quality of life evolution after lung cancer surgery: A prospective study in 100 patients. Lung Cancer 2007; 56: 423-31. 16. Pompeo E, De Dominicis E, Ambrogi V, Mineo D, Elia S, Mineo TC. Quality of life after tailored combined surgery for stage I non-small-cell lung cancer and severe emphysema. Ann Thorac Surg 2003; 76: 1821-7. 17. Myrdal G, Valtysdottir S, Lambe M, Stahle E. Quality of life following lung cancer surgery. Thorax 2003; 58: 194-7. 18. Li WW, Lee TW, Lam SS, Ng CS, Sihoe AD, Wan IY, et al. Quality of life following lung cancer resection. Video-assisted thoracic surgery vs tho-racotomy. Chest 2002; 122: 584-9. 19. Hoang CD, Osborne MC, Maddaus MA. Return to work after thoracic surgery: an overlooked outcome measure in quality-of-life studies. Thorac Surg Clin 2004; 14: 409-16. Radiol Oncol 2007; 41(3): 144-51. Diagnostic and treatment problems with parosteal osteosarcoma. A clinical and a histological study of 7 cases and review of the literature Milan Samardziski1, George Zafiroski1, Cveta Tolevska2, Slavica Konstadinova-Kunovska3, Violeta Vasileva4 1University Clinic for Orthopedic Surgery-Skopje, 2Institute for Radiotherapy and Oncology-Skopje, 3Pathology Institute-Skopje, 4University Surgical Clinic ”St. Naum Ohridski” - Skopje Background. Parosteal osteosarcoma is a rare low-grade bone tumour. The operation material must undergo a careful patohistological analysis, because the extent of invasion of the medullar cavity and most pro­bably the extent of dedifferentiated areas determines the prognosis and occurrence of local recurrence and metastases. Patients and methods. In this retrospective clinical study, 7 cases of parosteal osteosarcoma of the bone have been analyzed. Six patients were with parosteal osteosarcoma and one with periosteal osteosarcoma. The study was performed at the Clinic for Orthopedic Surgery in Skopje, Macedonia, from 1995 to 2006. This tumour represents 1.5% of all 467 patients with primary bone tumours treated at the Clinic in the 12 year period. The age of 7 patients (3 female and 4 male) ranged from 8 to 39 years (median 27). The history analysis of the patients showed the misinterpreted diagnosis in 57% of the cases, with 71.4 % rate of local recurrence, 28.7% of metastases and 28.7% of mortality. The follow-up varied from 7 months to 9 years (median 37 months). Results. The clinical and histopathological findings of this study (same as those reviewed in the literature) confirmed the occurrence of two biologically different types of parosteal osteosarcoma: the predominant type is originally “benign” but has a definite malignant potential, causing metastases after the long symp­tom-free interval. The other type is highly malignant from the beginning. Conclusions. The compartmental, radical “en bloc” resection, followed by the regular review of the patients, is recommended for the low malignant type, however, the radical surgery, followed by chemotherapy, is recommended for the highly malignant tumours. Key words: osteosarcoma – diagnosis – therapy; periosteum Received 1 August 2007 Introduction Accepted 7 August 2007 Correspondence to: Milan Samardziski MD, MSc, Parosteal osteosarcoma is a rare low-grade University Clinic for Orthopaedic Surgery, University bone tumour. It was apparently described “St. Cyril and Methodius”, Vodnjanska 17, 1000 for the first time in 1951 by Geschickter and Skopje, Macedonia; Phone/Fax: + 389 23176 672; E-mail: milan_samardziski @ yahoo.com Copeland, regarding the initial confusion with the terminology.1,2 It occurs between the 2nd and 7th decade of life and it represents 1,6 to 2% of all malignant bone tumours.3 The most frequent location is the distal dorsal femur. Until clearly proven otherwise, a bone-forming tumour in this localisation must be regarded as parosteal osteosarcoma. To deter­mine the histopathological diagnosis could be “tricky”. The tumour is characterised by hya­linized fibrous stroma with low cell content without substantial nucleus polymorphism and variably dense bony trabeculae. The operation material must undergo a careful patohistological analysis, because the extent of invasion of the medullar cavity and most probably the extent of dedifferentiated areas determines the prognosis and occurrence of local recurrence and metastases.4,5 As most authors report, a wide margin of excision ensures the adequate surgical treat­ment of parosteal osteosarcoma in any surgi­cal grade or stage. No evidence for the devel­opment of primary tumour satellite nodules or of “skip” metastases were seen, so it would seem that truly radical or compartmental sur­gery is rarely indicated. The significant inci­dence of pulmonary metastasis among those patients with Grade III parosteal osteosarco-ma and involvement of the medullar cavity, suggests that, for them, adjuvant chemother­apy should be considered.3,4,6,7 The primary wide excision may be less effective for the lo­cal recurrence where there has been a previ­ous inadequate biopsy or surgical treatment, because of the contamination and spread of the tumour into the surrounding tissues.7 The tumour is most commonly misinter­preted as osteochondroma or heterotrophic ossification and even large institutions have limited experience of its diagnosis and man­agement.4 Parosteal osteosarcoma shows, like no other tumour, the necessity of close cooperation of all involved disciplines for diagnosis and therapy and should be trea­ted only in specialized institutions for bone tumour surgery. Patients and methods At the re-examination of the records at the Clinic for Orthopedic Surgery in Skopje, during the last 12 years (from 1995 to 2006), 7 cases of juxtracortical osteosar-coma were found. Five of them were pa­tients with parosteal osteosarcoma and one patient was with periosteal osteosarcoma. Parosteal osteosarcoma represented 1.5% of all 467 patients with malignant bone tu­mours treated in this time at the Clinic. Reviewing the records, bone scans with Technetium 99m, radiographs, arteriography, CT, MRI and histopathology findings showed 6 patients with the confirmed diagnosis of parosteal osteosarcoma and one was with a high grade chondroblastic type of periosteal osteosarcoma. Four of them were diagnosed and treated at the Clinic for Orthopedic Surgery in Skopje and 3 patients started their treatment elsewhere and were misdiagnosed for osteochondroma. Another three started their treatment as unspecified malignant tu­mour of distal femur and only one was prima­rily suspected to be parosteal osteosarcoma. Results The clinical details of all 7 patients are sum­marized in Table 1. Age and sex The age ranged from 8 to 39 years (median 27). There were 3 female and 4 male pa­tients. Site of the tumour In 4 cases the site of tumour was the pos­terior surface of the distal femur. In 1 case primary site of tumour was postero-medial surface of the proximal femur. In 1 case the site of tumour was proximal humerus and Radiol Oncol 2007; 41(3): 152-60. Table 1. Clinical details of the 7 cases Duration of Case / Sex Age Site of the tumor symptoms Symptoms initials (months) 1. VM 2. BT † 3. BS † 4. SV 5. ID 6. JM 7. RM F M M F M M F 28 27 8 39 24 17 32 Proximal tibia Distal femur Distal femur Distal femur Proximal femur Proximal humerus Distal femur 13 15 9 17 13 8 11 Painless tumour Blunt pain and tumour Blunt pain and tumour Painless tumour Painless tumour Severe pain tumour and reduction of movements Blunt pain and tumour median 27 median 13 Legend MSTSS - Musculoskeletal Tumor Society Score7; MMA - reconstruction of the defect with metilmet-acrilate (bone cement); Resection arthrodesis- reconstruction with intramedular nail and MMA; STE - special tumour endoprosthesis; † - lethal outcome. in 1 case the site of tumour was the poste-in 1 patient. The duration of the symptoms rior surface of the proximal tibia. varied from 8 to 17 months (median 13). Symptoms Radiological findings The most frequent sign on admission at In 4 cases the radiographs showed a densely the Clinic was localized painless swelling ossified and lobulated mass on the posterior present in 3 patients, progressively increas-mataphysial cortex of the distal femur (Figure ing blunt pain and swelling was present in 1a). Similar dense and lobulated tumours 3 patients and severe “night pain”, swelling were seen at the other sites. Tumours were and restriction of movements was present attached to the bone by broad base (Figure Local Follow-up Outcome Treatment Chemotherapy Metastases recurrence (months) (MSTSS) 1. radical resection +MMA 1. resection 2. reresection 3. amputation 1.resection arthrodesis 2. recurrence excision After Oper. After Oper. Neo- adjuvant After 6 months After 3 months After 3 months No Lungs after 23 months Lungs after 16 months 23 37 † 21 † 25 † 30 † 37 1. resection arthrodesis 2. STE. 1. resection and STE. 2. disarticulation after masive local recurrence 1. radical resection + nonvascular fibular graft After Oper. Neo- adjuvant No After 32 months After 61 months No No No No 71 67 109 39 31 33 1. “en bloc” resection 2. radical resection + STE Neo- adjuvant No No 7 38 median 6 19.5 37 33 1a, 1c). In one case, after the recurrence, two thirds of the circumference of the distal femo­ral metaphysis were involved (Figure 1b). This patient was considered to have medullar involvement on CT scans (Figure 3a). Pathological findings The tumours were ossified with occasional soft areas, all of them infiltrating the surrounding soft tissues. Most of them had typical histological appearance of a low grade parosteal osteosarcoma, with spindle cells and collagen fibers embed­ding osseous trabeculae. The spindle cell stroma was scarcely cellular, with low to moderate atypia of the cells, as well as low mitotic activity. The trabeculae were rather regularly arranged, but missing the osteoblastic rimming. Two of the cases also showed cartilaginous islands in the mainly fibroblastic tumour tissue (Figure 2a). Most of the cases had well (G1) to moderate (G2) degree of differentiation (Figure 2b). Only one presented a high grade chon­droblastic (G3) surface osteosarcoma. It was presented as a high grade sur­face chondroblastic osteosarcoma (case 3, Table 1), with scarce and hard to find foci of osteoid and wide areas of malig­nant cartilage. The tumour cells showed marked polymorphism and high mitotic index (Figure 2c). Recurrent lesions usu- Radiol Oncol 2007; 41(3): 152-60. ally showed less differentiation than the primary tumours. Medullar involvement In 7 patients managed, 1 had the initial histological medullar involvement and 2 patients had the medullar involvement after the local recurrence (Figure 3a). For two patients who were treated out of the Clinic for Orthopaedic Surgery in Skopje initially, it was not possible to tell due to the lack of evidence (Figure 3b, 3c). Only one patient didn’t have the medullar in­volvement at all (case 6). Discussion Parosteal osteosarcoma is a rare malignant bone tumour first described by Geschickter and Copeland in 1951.1,2,8, 9 Up to date, there are reports of parosteal osteosar-coma even in human pets.10 Larsson and Lorentcon found only 206 cases (includ­ing sixteen cases from their study) to be reported until 1980 in the world litera­ture.11 The annual incidence in Sweden, as they reported, corresponds to one case per 8 000 000 inhabitants and were accounted for about 2% of all primary malignant tumours of bone and 6.2% of all osteosar­comata. In comparison, Dahlin reported that parosteal osteosarcoma constituted only 3.7% of all osteosarcomata from Mayo Clinic.3,11,12 Most of the world studies documented difficulties in the diagnosis of parosteal os­teosarcoma. The inability to diagnose the lesion correctly often leads to inadequate initial operative procedures. The differen­tial diagnosis may include diverse entities such as: myositis ossificans, fracture callus, ossifying haematoma, osteochondroma, extraosseus osteosarcoma, parosteal chon­droma, desmoplastic fibroma and osteo­ ma.3,4,5,7,13 The clinical characteristic of patients who have a parosteal osteosarcoma is distinctly different from that of patients who have conventional osteosarcoma.2,13 The most common complain was “painless swelling”, the same as reviewed in the literature, pre­sented with 3 patients.3,4,7,8,12 Two of our patients had “blunt pain with swelling” and one had “night pain”. Most of our patients had the symptoms of prolonged duration more than one year before admitting at the Clinic. The site of the parosteal osteosarcoma in our study correlates with the reported sites of the literature. A predilection for anato­mic site was a characteristic feature of the patients in the study and showed that 50% of the patients in our study had the involved posterior part of distal metaphysis of the fe- mur.4,6,9,14, 15 The well described concept of dediffe­rentiated parosteal osteosarcoma with high­er incidence of development of metastases Radiol Oncol 2007; 41(3): 152-60. Figure 3a. frontal and lateral radiography of local recurrence of “high grade” chondroblastic type periosteal osteosarcoma (case 3). Figure 3b. CT of distal femur showing the extent of medullar involvement of the bone (case 3). is also applicable in our study.3,5,16,17 The dedifferentiation of the tumour showed the high incidence with pulmonary metastases in one of our patients. A long-term follow up is essential for assessing the real malig­nant potential of parosteal osteosarcoma since the recurrence can be considerably delayed.18 The results of various types of therapy are always difficult to evaluate in retro­spect. A review of the literature shows that the local excision of the tumours has almost invariably resulted in recurrence.3,6,9,13,17,18 The local recurrence was not related to the medullar involvement of the tumour but to the number or adequacy of biopsies and surgical margins of the resection of the tumour.14,19 Two of the patients had more than one, and one patient had three ina­dequate placed biopsies. Further more, three of the patients in our study had the intralesional or inadequate marginal resec­tion of the tumour during the primary sur­gical treatment. Over all results were poor to fair and varied from 25 to 39 points of MSTS score.20 Conclusions The findings of this study followed the the­ory that two distinct types of parosteal oste­osarcoma exist: one type, which is primarily highly malignant and the other one, which is originally benign but with the inherent malignant potential. Only two patients of our study had modern chemotherapy and this did not allow any definite conclusion. In most of the cases the histopathological diagnosis was a problem at the begin­ning of the treatment. For well delineated tumours with a well-differentiated histo­logical appearance, the radical (en block) resection of the tumour and surrounding soft tissue is strongly recommended. In patients with advanced tumours contain­ing pleomorphic areas and/or inadequate placed biopsies or prior inadequate surgical treatment, the amputation should be un­dertaken. Parosteal osteosarcoma shows, like no other tumour, the necessity of the close cooperation of all involved disciplines for the diagnosis and therapy and should be treated only in specialized institutions for bone tumour surgery. References 1. Geschickter CF, Copeland MM. Parosteal osteosa­rcoma of bone: a new entity. Ann Surg 1951; 133: 579-83. 2. Gross SW. The classic: sarcoma of the long bones: based upon a study of one hundred and sixty-five cases. 1879. Clin Orthop Relat Res 2005; 438: 9-14. 3. Lorentzon R, Larsson SE, Boquist L. Parosteal (juxtracortical) osteosarcoma. A clinical and his-topathological study of 11 cases and review of the literature. J Bone Joint Surg Br 1980; 62-B: 86-92. 4. Campanacci M, Picci P, Gherlinzoni F, Guerra A, Bertoni F, Neff JR. Parosteal Osteosarcoma. J Bone Joint Surg Br 1984; 66: 313-21. 5. Deling, D, Werner M. Pathomorphologie des parossalen osteosarcoms. Erfahrungen an 125 fällen des Hamburger Knochentumor-Registers. Orthopäde 2003; 32: 74-81. 6. Bacci G, Picci P, Ferrari S, Sangiorgi L, Mercuri M, Bertoni F, et al. Neoadjuvant chemotherapy for the treatment of osteosarcoma of the extremities: excellent response of the primary tumor to preoperative treatment with methotrexate, cisplatin, adriamycin, and ifosfamide. Preliminary results. [English, Italian]. Chir Organi Mov 1995; 80: 1-10. 7. Bertoni F, Boriani S, Campanacci M. Periosteal osteosarcoma and periosteal chondrosarcoma. Two distinct entities. J Bone Joint Surg Br 1982; 64: 370-6. 4th 8. Lichtenstein L. Bone tumors. edition. Saint Louis: CV Mosby Company; 1972. 9. Scaglietti O, Calandriello CB. Ossifying parosteal osteosarcoma. Parosteal osteoma or juxtacortical osteogenic sarcoma. J Bone Joint Surg Am 1962; 44­A: 635-47. Radiol Oncol 2007; 41(3): 152-60. 10. Thomas WB, Daniel GB, McGavin MD. Parosteal osteosarcoma of the cervical vertebra in a dog. Vet Radiol Ultrasound 1997; 38: 120-3. 11. Larsson SE, Lorentzon R. The geographic varia­tions of the incidence of malignant primary bone tumors in Sweden. J Bone Joint Surg Am 1974; 56-A: 592-600. 12. Pritchard DJ, Finkel MP, Reilly CA Jr. The eti­ology of osteosarcoma. A review of current considerations. Clin Orthop Relat Res 1975; (111): 14-22. 13. Okada K, Frassica FJ, Sim FH, Beabout JW, Bond JR, Unni KK. Parosteal osteosarcoma. A clinic-pathological study. J Bone Joint Surg Am 1994; 76: 366-78. 14. Kavanagh TG, Cannon SR, Pringle J, Stoker DJ, Kemp HB. Parosteal osteosarcoma. Treatment by wide resection and prosthetic replacement. J Bone Join Surg Br 1990; 72: 959-65. 15. Kumm DA.; Rütt J. Hakenbroch MH. Parosteal osteosarcoma of the tarsus. Arch Orthop Trauma Surg 1997; 116: 437-9. 16. Haeckel C, Ayala AG, Radig K, Raymond AK, Roessner A, Czerniak B. Protease expression in dedifferentiated parosteal osteosarcoma. Arch Pathol Lab Med 1999; 123: 213-21. 17. Ritschl P, Wurnig C, Lechner G, Roessner A. Parosteal osteosarcoma. 2-23-year follow-up of 33 patients. Acta Othop Scand 1991; 62: 195-200. 18. Lau TW, Wong JW, Yip DK, Chien EP, Shek TW, Wong LL. Local recurrence of parosteal osteosar-coma adjacent to a prosthesis after 20 years: a case report. J Orthop Surg 2004; 12: 263-6. 19. Lewis VO, Gebhardt MC, Springfield DS. Parosteal osteosarcoma of the posterior aspect of the distal part of the femur: oncological and functional re­sults following a new resection technique. J Bone Joint Surg Am 2000; 88-A: 1083-8. 20. Enneking WF, Dunham W, Gephardt MC, Malawar M, Prichard DJ. A system for functional evaluation of reconstructive procedures after surgical treat­ment of tumours of the musculoskeletal system, Clin Orthop 199; 286: 241-6. Radio/ Onco/ 2007; 41(3): 99-106. CT-perkutana transtorakalna tankoigelna biopsija pljucnih sprememb. Dvoletne izkušnje na Klinicnem inštitutu za radiologijo v Ljubljani Kocijancic I, Kocijancic K Izhodišca. Prvo perkutano pljucno biopsijo je leta 1883 opisal Layden, o prvem primeru pljucne biopsije pod nadzorom racunalniške tomografije (CT) pa sta leta 1976 porocala Haaga in Alfidi. Danes je odvzem tkiva iz sprememb v pljucih potreben, kadar z uporabo endobronhialnih tehnik sprememb ne moremo vzrocno opredeliti ter kadar citološki izvid lahko spremeni stadij bolezni ali vpliva na odlocitev o zdravljenju. Citološki pregled vzorca, odvzetega s tankoigelno biopsijo potrdi etiologijo sprememb v pljucih v 80 -95% primerov. Postopek odvzema je varen, saj so resni zapleti zelo redki. Z našo retrospektivno analizo smo želeli dolociti osnovne podatke o diagnosticni zanes­ljivosti te preiskave ter o pogostosti pnevmotoraksa pri naših bolnikih. Metode. Po namestitvi bolnika smo izvedli spiralno CT preiskavo prsnega koša z namešceno metalno znacko, ki nam je omogocila optimalni transkutani pristop. Po ponovni preverbi lokalizacije sprememb v pljucih in po subkutani anesteziji smo pri CT-vodeni tankoigelni aspiracijski biopsiji uporabili koaksialne 18G Gallini igle. Njihovo dolžino smo izbrali glede na globino tarcne spremembe. Rezultati. Od januarja 2005 do januarja 2007 smo pri 43 bolnikih (24 moških in 19 ženskah), ki so bili stari od 26 do 79 let, izvedli CT-perkutano transtorakalno tankoigelno biop­sijo pljucnih sprememb. Pri enem bolniku smo verificirali dve spremembi, vsako posebej. Retrospektivno smo tako pregledali bolnišnicno dokumentacijo 44 posegov pri 43 bolni­kih. Diagnosticna zanesljivost preiskave je bila 93,2%, pnevmotoraksov je bilo 27,2%, pri 4,5% bolnikov pa je bilo potrebno pnevmotoraks zdraviti z vstavitijo plevralnega drena. Zakljucki. Dvoletne izkušnje na Radiološkem inštitutu v Ljubljani potrjujejo, da je CI-vode­na perkutana transtorakalna tankoigelna biopsija zanesljiva in varna metoda za diagnostiko neopredeljenih sprememb v pljucih. Radio/ Oncol 2007; 41(3): I-VII. Slovenian abstracts Radio/ Onco/ 2007; 41(3): 107-12. Obstruktivna ileocekalna intususcepcija pri odraslem bolniku Žokalj I, Magaš Z, Pavcec Z, Saghir H, Pal A, Kolaric Z, Marotti M Izhodišca. Prikazujemo primer odraslega bolnika z obstruktivno ileocekalno intususcepcijo zaradi karcinoma cekuma. Prikaz primera. 44 letnega moškega smo sprejeli v bolnišnico s hudimi bolecinami v zgorn­jem delu trebuha, bruhanjem in povišano vrednostjo serumske amilaze (154 U/L, normala 23-91 U/L pri 37 ° C). Deveti dan po sprejemu se je bolnikovo stanje nenadoma mocno poslabšalo, prisotni so bili klinicni in radiološki znaki zapore crevesa. Naredili smo nujno CT preiskavo, predhodno pa smo bolnika opazovali ter njegovo stanje sledili s preglednim rentgenskim slikanjem trebuha ter UZ preiskavami trebuha. CT je pokazal mehkotkivno strukturo, obdano z vec koncentricnimi obroci, ki se je na pokontrastnih posnetkih dobro obarvala -videz tarce. Bolnika smo operirali, naredili smo desno hemikolektomijo s termi­nolateralno ileotransverzoanastomozo. Ob operaciji smo našli vec vijug tankega crevesa, zataknjenega v cekum in ascendentni kolon ter karcinom kolona (Dukes B, Astler-Coller B2), ki je predstavljal glavni vzrok intususcepcije. Zakljucki. Intususcepcija pri odraslih je redek vzrok trebušne bolecine, vendar pa je ena izmed diferencialno diagnosticnih možnosti, zlasti kadar je bolecina obcasna in so prisotni klinicni in radiološki znaki crevesne zapore. Opisan primer potrjuje CT preiskavo kot sli­kovno metodo izbora v primerih intususcepcije pri odraslem. Radio/ Oncol 2007; 41(3): 115-22. Dopolnilno zdravljenje bolnic z rakom dojke s transtuzumabom Matos E, Cufer T Izhodišca. Trastuzumab je monokolonsko protitelo, usmerjeno proti HER2 receptorejm, ki so prekomerno izraženi pri približno 20% bolnic z rakom dojke. Clanek predstavlja pet klinicnih raziskav, v katerih so trastuzumab uporabljali v okviru dopolnilnega zdravljenja raka dojke. Rezultati vseh opisanih raziskav kažejo na visoko ucinkovitost tega tarcnega zdravila pri bolnicah s HER2 pozitivnimi tumorji. Splošno sprejetih priporocil za uporabo trastuzumaba za dopolnilno zdravljenje raka dojke še ni. Vzrokov je vec: navedene klinicne raziskave imajo kratek srednji cas opazovanja, zdravilo je bilo uporabljeno v razlicnih she­mah, razlicen je bil skupni cas zdravljenja s trastuzumabom, pozni neželeni ucinki zdrav­ljenja so še slabo opredeljeni. Zakljucki. Še vedno ne vemo, katerim HER2 pozitivnim bolnicam zdravljenje s trastuzum­abom res koristi. Prav gotovo je korist velika pri pravih HER2 pozitivnih rakih dojk, ki so hormonsko neodvisni, in pri anatomsko vecjih rakih. Kakšna pa je absolutna dobrobit pri majhnih, hormonsko odvisnih rakih, ostaja odprto vprašanje. Vedeti moramo, da neželeni ucinek-kardiotoksicnost -lahko življenjsko ogrozi predvsem starejše bolnice in morebitno iznici dobrobit zdravljenja. Ne vemo še, kakšen je optimalen cas pricetka in trajanja zdrav­ljenja s trastuzumabom. Ali naj poteka zdravljenje s trastuzumabom socasno s kemoterapijo ali takoj za njo, ali naj zdravljenje traja eno leto, dve leti ali samo nekaj mesecev. Poleg tega ostaja še vedno odprto vprašanje optimalnega dolocanja HER2 statusa in kateri HER2 status napoveduje korist od zdravljenja s trastuzumabom. Na ta vprašanja nam bo dalo odgovor daljše opazovanje bolnic, vkljucenih v petih velikih prikazanih klinicnih raziskavah. Radio/ Oncol 2007; 41(3): I-VII. Radio/ Oncol 2007; 41(3): 123-32. Ionizirajoce sevanje in transgeneracijska nestabilnost Vrhovac I, Nikšic G Izhodišca. Posredno preucevanje vpliva ionizirajocega sevanja na nestabilnost genoma naslednikov kot posledice obsevanja njihovih staršev, lahko skrcimo na preiskovanje spre­memb, ki se pojavljajo samo na minisatelitnih lokusih celic, ki sestavljajo razvojno linijo gamet. Minisatelitne mutacije, ki so rezultat tega obsevanja, so izražene kot njihov odstotek in so enake razmerju števila mutiranih alelov v doloceni generaciji glede na celotno število prisotnih alelov. Vpliv ionizirajocega sevanja na potomce obsevanih staršev so prvic opazili na mišjih krvotvornih maticnih celicah. Kljub temu, da je obsevana celica matere brez mu­tacij, ima hcerinska celica povecan nivo mutacij. Ta fenomen, ki so ga poimenovali trans­generacijska nestabilnost je definiran kot mutacija v genomu posameznikov, ki so potomci obsevanih prednikov. Glede na zgoraj omenjeno, lahko zakljucimo, da te mutacije niso nujno prisotne v obsevanih starševskih celicah, niti ni nujno, da izginejo v nekaj naslednjih generacijah, temvec se lahko pokažejo kot povecano število mutacij pri potomcih. Zakljucki. Rezultati raziskav, ki so bile narejene na živalskem modelu, kot tudi raziskav na cloveški populaciji, kažejo na znacilne spremembe, ki jih najdemo na minisatelitnih lokusih v generacijah potomcev. Mehanizmt ki so odgovorni za te spremembe, še niso znani in so torej nove raziskave na tem podrocju potrebne. Radio! Oncol 2007; 41(3): 133-43. Radiotherapija s trodimenzionalnim planiranjem pri bolnikih z inoperabilnim nedrobnocelicnim rakom pljuc -izkušnje v posamicni ustanovi Fromm S, Rottenfusser A, Berger D, Pirker R, Potter R, Pokrajac B Izhodišca. Namen raziskave je bil ovrednotiti primernost, varnost in ucinkovitost radioterapi­ je s trodimenzionalnim planiranjem (3D-RT) pri bolnikih z inoperabilnim nedrobnocelicnim rakom pljuc (NSCLC). Zanimali so nas cas, ki je potekel do napredovanja obolenja (TTP), vkljucno s casom do lokalne ponovitve bolezni in/ali oddaljenih zasevkov, lokalna kontrola bolezni (LCR), cas do smrti (TTD) in stranski ucinki zdravljenja. Bolniki in metode. Od 1997 do 2002 smo s 3D-RT zdravili 84 bolnikov z inoperabilnim NSCLC. Upoštevali smo prospektivni protokol, ki smo ga naredili na Radioterapevtskem oddelku Klinicne bolnišnice na Dunaju. Glede na stanje splošne zmogljivosti, pljucno funk­cijo in glede na omejitev, ki ga je dolocalo razmerje med dozo in volumnom obsevanja, smo bolnike obsevali s 66-70 Gy ali 50-60 Gy, nekateri pa so bili zdravljeni tudi s sekvencno ali pa hkratno kemoterapijo, ki je vsebovala cisplatin. Rezultati. Bolniki so zdravljenje dobro prenašali, stranski ucinki zdravljenja pa so bili ma­jhni. Samo pri enem bolniku smo ugotovili pneumonitis stopnje 4, pri 6% bolnikov pneu­monitis stopnje 3 in pri 13% stopnje 2. Pri dveh bolnikih smo ugotovili esofagitis stopnje 4 in pri nobenem stopnje 3. Analiza histograma doza-volumen (DVH) je pokazala, da je 42% pljuc na strani, kjer je bil tumor, prejelo 20 Gy (V20), druga stran pljuc pa le 14% te doze. Srednja vrednost obsevalne doze pljuc na strani, kjer je bil tumor, je bila 25 Gy, srednja vrednost pri tistih bolnikih, kjer se je razvil pneumonitis stopnje 2-4, pa je bila 53,3%. Srednja vrednost sledenja bolnikov je bila 24 mesecev. Glede na razlicno obsevalno dozo nismo našli razlike v casu do napredovanja bolezni (srednja vrednost 15 mesecev). Tisti bol­niki, ki so ob višji obsevalni dozi (66-70 Gy) prejeli tudi kemoterapijo, pa so imeli statisticno znacilno daljše preživetje (28 mesecev vs. 16 mesecev). Po dveh letih smo le pri 22% boln­ikov dosegli lokalno kontrolo bolezni. Zakljucki. Zdravljenje z obsevalno dozo do 70 Gy je primerno, varno in ga lahko kom­biniramo tudi s kemoterapijo. Kljub temu sta stopnja lokalne kontrole bolezni in celokupno preživetje sorazmerno nizki. Predlagamo nadaljnje klinicne raziskave z višjo obsevalno do­zo, ki ne bo povzrocala povecane toksicnosti, tudi ne pri bolnikih z napredovalo boleznijo. Radio/ Oncol 2007; 41(3): I-VII. Slovenian abstracts Radio/ Oncol 2007; 41(3): 144-51. Kvaliteta življenja bolnikov s pljucnim rakom po torakotomiji Debevec L, Rozman I Izhodišca. Namen raziskave je bil oceniti kvaliteto življenja (KŽ) bolnikov s pljucnim rakom pred torakotomijo in po njej ter primerjati poslabšanje KŽ po resekciji in po eksplorativni torakotomiji. Bolniki in metode. Zaradi nedrobnocelicnega pljucnega raka je bilo torakotomiranih 43 bol­nikov, starih od 31 do 82 (povprecno 61) let in opravljenih 29 lobektomij, 1 bilobektomija, 8 pnevmonektomij in 5 eksplorativnih torakotomij. KŽ smo ocenjevali z vprašalnikom EORTC QLQ-LC30 in QLQ-LC13 pred operacijo in povprecno 45±17 dni po njej, še pred morebitno kemoterapijo in radioterapijo. Rezultati. Po torakotomiji so se znacilno poslabšali fukcionalna sposobnost (telesna zmo­gljivost, sposobnost za dnevna opravila in družbeno udejstvovanje) in simptomi: utrujenost, zaprtje, inapetenca, dispneja, bolecine. Neznacilno so bili slabši drugi simptomi (slabost oz. bruhanje, nespecnost, driska, kašelj), splošno zdravstveno stanje, funkcionalna sposobnost (razpoloženje, spoznavna sposobnost) in denarne težave. Hemoptize pa so se znacilno izboljšale in jih po torakotomiji ni bilo vec. Med bolniki, pri katerih je bil tumor reseciran, in bolniki, pri katerih je bila narejena samo eksplorativna torakotomija, ni bilo znacilnih razlik. Zakljucki. V raziskavi smo ugotovili znacilno poslabšanje KŽ v prvih dveh mesecih po torakotomiji, ni pa bilo znacilnih razlik med reseciranimi in eksplorativno torakotomiranimi bolniki. Radio/ Oncol 2007; 41(3): 152-60. Diagnosticiranje in zdravljenje parostealnega osteosarkoma. Klinicna in patohistološka raziskava 7 primerov ter pregled literature Samardziski M, Zafiroski G, Tolevska C, Konstadinova-Kunovska S, Vasileva V Izhodišca. Parosteal osteosarkom je redek nizkomaligni kostni tumor. Po kirurškem posegu je potreben skrben patohistološki pregled, ker stopnja tumorske invazije v kostni mozek in stopnja dediferenciranosti dolocata napoved poteka bolezni ter pogostnost lokalne pono­ vitve bolezni in metastaziranja. Bolniki in metode. V retrospektivni raziskavi smo analizirali 7 bolnikov s kostnim paro­stealnim osteosarkomom; 6 bolnikov je imelo parostealni in 1 periostealni osteosarkom. Obravnavali smo bolnike, ki so bili zdravljeni na Ortopedski kliniki v Skopju, Makedonija, od 1995 do 2006. V 12-letnem obdobju smo ugotovili med 467 bolniki s primarnimi kost­nimi tumorji 1,5% parostealnih osteosarkomov. Med 7 bolniki so bile 3 ženskega spola in 4 moškega, starosti od 8 do 39 let (srednja starost 27). Analiza je pokazala, da je kar 57% bolnikov imelo sprva napacno diagnozo, pri 71,4% se je pojavil lokalni recidiv, pri 28,7 % metastaze, smrtnost pa je bila 28,7%. Bolnike smo sledili od 7 mesecev do 9 let (srednja vrednost 37). Rezultati. Klinicni in histopatološki izsledki pricujoce raziskave so podobno kot podatki iz literature potrdili obstoj dveh biološko razlicnih tipov parostealnega osteosarkoma. Prevladuje tip, ki je sprva benigni, a ima vseeno maligni potencial in povzroca zasevke po daljšem prostem intervalu. Drugi tip je visokomaligni od zacetka. Zakljucki. Pri bolnikih, ki imajo prevladujoci nizkomaligni parostealni osteosarkom, priporocamo radikalno "en bloc" resekcijo tumorja s skrbnim sledenjem bolnika, pri vi­sokomalignem tipu osteosarkoma pa radikalno operacijo s kemoterapijo. Radio/ Oncol 2007; 41 (3 ): I-VII. Notices Notices submitted for publication should contain a mailing address, phone and/or fax number and/or e-mail of a Contact person or department. Radiotherapy October21-25, 2007 The ESTRO teaching course "Physics far Clinical ra­diotherapy" will take place in Limassol, Cyprus. 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 infa@estro.be; or see http://www.estro.be Prevention of tobacco November 2-4, 2007 The "6th Conference of the International Society far Prevention of Tobacco Induced Diseases" will take place in Little Rock, Arkansas; USA. E-mail Caro1yn.dresler@ksg03.harvard.edu Radiation oncology November 11-16, 2007 The ESTRO teaching course "Evidence Based Radiation Oncology: Methodological Basis & Clinical Application" 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 infa@estro.be; or see http://www.estro.be Prostate cancer November 15-17, 2007 The ESTRO multidisciplinary prostate cancer meeting will be offered. 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 infa@estro.be; or see http://www.estro.be Molecular markers in cancer November 15-17, 2007 The "EORTC-NCI-ASCO Annual Meetingon Molecular Markers in Cancer" will be held in Brussels. E-mail ENASC02007@eortc.be; or see http://www. eortc. be/ seminar/ENASCO2007 / Lungcancer December 5-7, 2008 The "3rd Asia Pacific Lung Cancer Congress" will be offered in India. E-mail: purvish@rediffmail.com Lungcancer December 7-8, 2007 The CELCC-ESMO workshop " Predictive Factors in Lung Cancer" will take place in Vienna, Austria. E-mail: robert.pirker@meduniwien.ac.at or see www. mondial-congress.com/celcc2007 Radiotherapy December 9-13, 2007 The ESTRO teaching course "Image-Guided Radiotherapy in Clinical Practice" 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 infa@estro.be; or see http://www.estro.be Oncology February 21-23, 2008 The "8th Targeted Therapy Meeting" will take place in Santa Monica, CA, USA-See http://www. iaslc.org Oncology March 5-9, 2008 The NCCN 13th Annual Conference "Clinical Practice Guidelines & Quality Cancer Care™" will be offered in Hollywood, Florida, USA See http://www.nccn.org Lung cancer April 23-26, 2008 The first Jung cancer conference in Europe will be held in Geneva, Switzerland. E-rnail pia.hirsch@uchsc.edu Lung cancer April 24-26, 2008 The "IASLC/ESMO Lung Cancer Conference" will be offered in Geneva, Switzerland. See http://www.iaslc.org Lung cancer June 12-14, 2008 The "11 th Central European Lung Cancer Conference" will be offered in Ljubljana, Slovenia. Contact Conference secretariat, Ms. Ksenia Potocnik, Department of Thoracic Surgery, Medica! Centre Ljubljana, Slovenia; or call +386 1 522 2485; or fax +386 1 522 3968; or e-rnail ksenia.potocnik @kclj.si; or see http://www.ce-lung2008.org/ Oncology October 9-10, 2008 The "3rd Latin American Cancer Conference" will take place in Vina del Mar, Chile. E mail nisehy@uol.com.br or rodrigo.arriagada@ki.se Oncology November 13-15, 2008 The Chicago/IASLC/ ASCO/ ASTRO symposiums "Malignancies of the Chest and Head and Neck" will be offered in Chicago. E-rnail: evokes@medicine. bsd. uchicago.edu Lung cancer 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.orgiurnages/ 12worldconfannounce. pdf Oncology September 4-8, 2009 The "34th ESMO Congress" will take place in Vienna, Austria. Contact ESMO Head Office, Congress Departrnent, Via La Santa 7, CH-6962 Viganello-Lugano, Switzerland; or +41 (0)91 973 19 19; or fax +41 (0)91 973 19 18; or e­mail congress@esmo.org; or see http://www.esrno.org As a service to our readers, notices of meetings or courses will be inserted free of charge. Please send information to the Editorial office, Radiology and Oncology, Zaloška 2, SI-1000 Ljubljana, Slovenia. Radio/ Oncol 2007; 41(3): VIII-IX. FUNDACIJA "DOCENT DR. J. CHOLEWA" JE NEPROFITNO, NEINSTITUCIONALNO IN NESTRANKARSKO ZDRUŽENJE POSAMEZNIKOV, USTANOV IN ORGANIZACIJ, KI ŽELIJO MATERIALNO SPODBUJATI IN POGLABLJATI RAZISKOVALNO DEJAVNOST V ONKOLOGIJI. DUNAJSKA 106 1000 LJUBLJANA ŽR: 02033-001 7879431 Activity of "Dr. J. Cholewa" Foundation for Cancer Research and Education -a report for the third quarter of 2007 The Dr. J. Cholewa Foundation for Cancer Research and Education continues to focus its activities and attention to cancer research and education in Slovenia and continues to deal carefully and with the requests and proposals for research grants and scholarships. The Foundation members with clinical and research experience in cancer and members with important experience in finance will continue to be instrumenta! in this activity. The Dr. J. Cholewa Foundation for Cancer Research and Education contin­ues to support the regular publication of "Radiology and Oncology" international medica! scientific journal in 2007. This journal is edited, published and printed in Ljubljana, Slovenia. This support emphasizes the spread of information and knowledge about advances in cancer among professionals and to many interested individuals in lay public and others in Slovenia and elsewhere. The Foundation also pays special attention to the support of the publication of the results from can­cer research in Slovenia in respectable international scientific journal worldwide. The Foundation salutes the start of usage of new premises of the Institute of Oncology in Ljubljana, Slovenia, a fine tribute to its coming 70th anniversary. Andrej Plesnicar, MD, MSc Borut Štabuc, MD, PhD Tomaž Benulic, MD Sanolabor 5th Conference on Experimental and Translational Oncology Kranjska gora, Slovenia, March, 26-30, 2008 Organized by: Janko Kos, Tamara Lah and Gregor Serša Topics: ¦ Carcinogenesis ¦ Mechanisms of Tumour Progression ¦ Stem Cells in Cancer ¦ Tumour Markers ¦ Delivery Systems in Cancer Therapy ¦ New Drugs and Therapeutic Markers Location: Hotel Kompas Kranjska gora, Slovenia http://www.hoteli-kompas.si Correspondence: Phone: +386 1 241 29 70 Fax: +386 1 241 29 80 Email: ceto@nib.si http://www.onko-i.si/ceto Organized under patronage of Association of Radiology and Oncology 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 •:te MICRONIC Micronic (Nizozemska): sistemi za shranjevanje vzorcev, pipete, nastavki za pipete T17npllan1tech: Tbuc's No Ruson to Opuate witb Anyon, Elsc 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, mono-in poliklonalna protitelesa Ea Sakura finetek (Evropa): aparati za pripravo histoloških preparatov: mikro­inkriotomi, zalivalci, tkivni procesorji, barvalci, pokrivalci IBS INTEGRA Wlf t11!1f f1 fl Integra Biosciens (Švica): laboratorijska oprema za mikrobiologijo, biologijo celic, molekularno biologijo in biotehnologijo SpectrumDesigns MEDICAL (Amerika): moški pektoralni vsadki Byron {Amerika): liposuktorji in kanile za liposukcijo Periceva 29, Ljubljana lnfo@labol'med.sl Tel.: (0)1 436 49 01 Fax: (0)1 436 49 05 www.labormed.s SIEMENS SiemensMed,cal.com oncology SEEK-FIND-ACT-FOLLOW -the Continuum of Oncology Care™ Siemens oncology portfolto compr,ses comprehens,ve max1m1zed utt11zat1on potent1al. and pat1ent-frtendly des,gn workflow solut,ons integrat,ng the full spectrum of care and features from screen,ng/early detect,on and d1agnos1s through therapy and follow-up Ali from one prov,der -w,th over Every day ,n the Un,ted States alone 29.000 cancer 100 years h,story of innovatton in med1cal technology pat,ents rece,ve rad,at,on therapy deltvered by S,emens ltnear accelerators As cl1n1cal protocols trans1t1on to Siemens proven clln,cal me hods can help you to ach,eve ,nclude IMRT and IGRT Siemens seamlessly integrates more successful outcomes How. Through ndustry­the d1agnost1c and treatment modal, ,es That's what we lead1ng technology, ,ncreased producttv1ty measures for call Best Practice Oncology Care Siemens med1cal Solutions thathelp ® rimidex anastrozol Kratka informacija o zdravilu Ime zdravila Arimidex 1 mgfilmsko obložene tablete Sestava Ena tableta vsebuje 1 mganastrozola. Indikacije Adjuvantno zdravljenje žensk po menopavzi, ki imajo zgodnji invazivni rak dojke s pozitivnimi estrogenskimi receptorji. Zdravljenje napredo­valega raka dojke pri ženskah po menopavzi. Ucinkovitost pri bolnicah z negativnimi estrogenskimi receptorji ni bila dokazana razen pri tistih, ki so imele predhodno pozitiven klinicni odgovor na tamoksifen. Odmerjanje in nacin uporabe 1 tableta po 1 mgperoralno, enkrat na dan. Pri zgodnjem raku je priporocljivo trajanje zdravljenja 5 let Kontraindikacije Arimidexje kontraindiciran pri: ženskah pred menopavzo, nosecnicah in dojecih materah, bolnicah s hujšo ledvicno odpovedjo (ocistek kreatinina manj kot 20 ml/min (oziroma 0,33 mljs)), bolnicah z zmernim do hudim jetrnim obolenjem, bolnicah, ki imajo mano preobcutljivost za anastrozol ali za katerokoli drugo sestavino zdravila. Posebna opozorila in previdnostni ukrepi 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 kakor20 mljmin (oziroma 0,33 mljs)). 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. Povzetek glavnih neželenih ucinkov Zelo pogosti (2: 10 %): navali vrocine, obicajno blagi do zmerni Pogosti (2: 1 % in < 10 %): astenija, bolecine / okorelost v sklepih, suhost vagine, razredcenje las, izpušcaji, slabost, diareja, glavobol (vsi obicajno blagi do zmerni) Arimidex znižuje nivo estrogena v obtoku, zato lahko povzroci zmanjšanje mineralne kostne gostote, kar pomeni za nekatere bolnike zvecano tveganje za zlome. Medsebojno delovanje z drugimi zdravili Zdravila, ki vsebujejo estrogen, ne smete dajati socasno z Arimidexom, ker bi se njegovo ne sme uporabljati skupaj z Arimidexom, ker lahko pride do zmanjšanja njegovega delovanja. Režim izdajanja zdravila Rp/Spec Datum priprave informacije Februar 2007 Pred predpisovanjem, prosimo, preberite celoten povzetek glavnih znacilnosti zdravila. Dodatne informacije in literatura so na voljo pri: AstraZeneca UK Limited Podružnica v Sloveniji Verovškova 55, Ljubljana in na spletnih straneh: www.breastcancersource.com www.arimldex.net AstraZeneca Za podrocja: • bioznanosti SYNGENE, INVITROGEN: DYNAL, ZYMED, MOLECULAR PROBES, CALTAG . diagnostike MINERVA, MEDAC, BIOTEK . gojenja celicnih kultur INVITROGEN-GIBCO, TPP, GREINER in SANYO merjenja absorbance, fluorescence in luminiscence BIOTEK . pipetiranja BIOHIT in BIOTEK . laboratorijske opreme SANYO . ciste vode za laboratorije ELGA LABWATER . HPLC in GC kolon, vial in filtrov PHENOMENEX in CHROMACOL/NATIONAL SCIENTIFIC SVETOVANJE, TRGOV! NA, TRŽENJE d.o.o. • Kališka 9 • P E: Stritarjeva S• 4000 KRANJ •Slovenija r: + 386 4 2 O 15 O 50 • F: + 386 4 2 O 15 O 55 • e-ma i 1: i nfo@kemomed.si • www.kemomed.si ,modal 20 mg; 100 mg, 250 mg. Sestava zdravila Vsaka kapsula zdravila Temodal vsebuje 20 mg, 100 mg ali 250 mg temozolamida.Terapevlske indikacije Temodal ,psule so indicirane za zdravljenje bolnikov z: -za zdravljenje novo diagnosticiranega glioblastoma multiforme, socasno z radioterapijo in kasneje kot monoterapija, -ialignim gliomom, na primer multiformnim glioblastomom ali anaplasticnim astrocitomom, ki se po standardnem zdravljenju ponovi ali napreduje. Odmerjanje in nacin porabe Temodal smejo predpisati le zdravniki, ki imajo izkušnje z zdravljenjem možganskih tumorjev. Odrasli bolniki z novo diagnosticiranim glioblastomom mulli­1rme Temodal se uporablja v kombinaciji z žarišcno radioterapijo (faza socasne terapije), temu pa sledi do 6 ciklov monoterapije z temozolomidom.Faza socasne tera­ije Zdravilo Temodal naj bolnik jemlje peroralno v odmerku 75 mg/m' na dan 42 dni, socasno z žarišcno radioterapijo (60 Gy, danih v 30 delnih odmerkih). Odmerka , boste zmanjševali, vendar se boste vsak teden odlocili o morebitni odložitvi jemanja temozolomida ali njegovi ukinitvi na podlagi kriterijev hematološke in ihematološke toksicnosti. Zdravilo Temodal lahko bolnik jemlje ves cas 42-dnevnega obdobja socasne terapije do 49 dni, ce so izpolnjeni vsi od naslednjih pogojev: isolutno število nevtrofilcev ? 1,5 x 109/1, število trombocitov ? 100 x 109/1, skupni kriteriji toksicnosti (SKT) za nehematološko toksicf!OS! :s 1. stopnje (z izjemo opecije, slabosti in bruhanja). Med zdravljenjem morate pri bolniku enkrat na teden pregledati celotno krvno sliko. Faza monoterapije Stiri tedne po zakljucku faze Jcasnega zdravljenja z zdravilom Temodal in radioterapijo naj bolnik jemlje zdravilo Temodal do 6 ciklov monoterapije. V 1. ciklu (monoterapija) je odmerek zdravila 150 g/m' enkrat na dan 5 dni, temu pa naj sledi 23 dni brez terapije. Na zacetku 2. cikla odinerek povecajte na 200 mg/m2 , ce je SKT za nehematološ˝o toksicnost za 1. cikel opnje :s 2 (z izjemo alopecije, slabosti in bruhanja), absolutno število nevtrofilcev (ASN) ? 1,5 x 109/1 in število trombocitov? 100 x 109/1. Ce odmerka niste pov­:ali v 2. ciklusu, ga v naslednjih ciklusih ne smete povecevati. Ko pa odmerek enkrat povecate, naj ostane na ravni 200 mg/m' na dan v prvih 5 dneh vsakega nasled­ega ciklusa, razen ce nastopi toksicnost. Med zdravljenjem morate pregledati celotno krvno sliko na 22. dan (21 dni po prvem odmerku zdravila Temodal). Ponavljajoci 1 ali napredujoci maligni gliom: Odrasli bolniki Posamezen ciklus zdravljenja traja 28 dni. Bolniki, ki še niso bili zdravljeni s kemoterapijo, naj jemljejo Temodal pero­lno v odmerku 200 mg/m2 enkrat na dan prvih 5 dni, temu pa naj sledi 23-dnevni premor (skupaj 28 dni). Pri bolnikih, ki so že bili zdravljeni s kemoterapijo, je .cetni odmerek 150 mg/m' enkrat na dan, v drugem ciklusu pa se poveca na 200 mg/m' enkrat na dan 5 dni, ce ni bilo hematoloških toksicnih ucinkov. Pediatricni 1lniki Pri bolnikih, starih 3 leta ali starejših, posamezen ciklus zdravljenja traja 28 dni. Temodal naj jemljejo peroralno v odmerku 200 mg/m' enkrat na dan prvih 5 dni, 1tem pa naj sledi 23-dnevni premor (skupaj 28 dni). Otroci, ki so že bili zdravljeni s kemoterapijo, naj prejmejo zacetni odmerek 150 mg/m2 enkrat na dan 5 dni, s 1vecanjem na 200 mg/m2 enkrat na dan 5 dni v naslednjem ciklusu, ce ni bilo hematoloških toksicnih ucinkov. Bolniki z motnjami v delovanju jeter ali ledvic Pri 1lnikih z blagimi ali zmernimi motnjami v delovanju jeter je farmakokinetika temozolomida podobna kot pri tistih z normalnim delovanjem jeter. Podatki o uporabi ravila Temodal pri bolnikih s hudimi motnjami v delovanju jeter (razred III po Child-u) ali motnjami v delovanju ledvic niso na voljo. Na podlagi farmakokineticnih last­isti temozolomida obstaja majhna verjetnost, da bo pri bolnikih s hudimi motnjami v delovanju jeter ali ledvic potrebno zmanjšanje odmerka zdravila. Kljub temu je ,trebna previdnost pri uporabi zdravila Temodal pri teh bolnikih. Starejši bolniki Analiza farmakokinetike je pokazala, da starost ne vpliva na ocistek temozolomida. Kljub 11u je potrebna posebna previdnost pri uporabi zdravila Temodal pri starejših bolnikih. Nacin uporabe Temodal mora bolnik jemati na tešce. Temodal kapsule mora ,lnik pogoltniti cele s kozarcem vode in jih ne sme odpirati ali žveciti. Predpisani odmerek mora vzeti v obliki najmanjšega možnega števila kapsul. Pred jemanjem ravila Temodal ali po njem lahko bolnik vzame antiemetik. ce po zaužitju odmerka bruha, ne sme še isti dan vzeti drugega odmerka. Kontraindikacije Temodal je ntraindiciran pri bolnikih, ki imajo v anamnezi preobcutljivostne reakcije na sestavine zdravila ali na dakarbazin (DTIC). Temodal je kontraindiciran tudi pri bolnikih s hudo elosupresijo. Temodal je kontraindiciran pri ženskah, ki so nosece ali dojijo. Posebna opozorila in previdnostni ukrepi Pilotno preskušanje podaljšane 42-dnevne sheme ravljenja je pokazalo, da imajo bolniki, ki so socasno prejemali zdravilo Temodal in radioterapijo, še posebej veliko tveganje za nastanek pljucnice zaradi okužbe s •eumocystis carinii (PCP). Profilaksa proti tovrstni pljucnici je torej pot.ebna pri vseh bolnikih, ki socasno prejemajo zdravilo Temodal in radioterapijo v okviru 42-dnevne eme zdravljenja (do najvec 49 dni), ne glede na število limfocitov. Ce nastopi limfopenija, mora bolnik nadaljevati s profilakso, dokler se limfopenija ne povrne na Jpnjo :s 1. Anliemelicna terapija: Z jemanjem zdravila Temodal sta zelo pogosto povezana slabost in bruhanje. Laboratorijske vrednosti Pred jemanjem zdravila Jrata biti izpolnjena naslednja pogoja za laboratorijske izvide: ANC mora biti ? 1,5 x 109/1 in število trombocitov ? 100 x 109/1. Na 22. dan (21 dni po prvem odmerku) v roku 48 ur od navedenega dne, morate pregledati celotno krvno sliko in jo nato spremljati vsak teden, dokler ni ANC nad 1,5 x 109/1 in število trombocitov nad 100 09/1. ce med katerimkoli ciklusom ANC pade na < 1,0 x 109/1 ali število trombocitov na < 50 x 109/1, morate odmerek zdravila v naslednjem ciklusu zmanjšati za eno • merno stopnjo. Odmerne stopnje so 100 mg/m2 , 150 mg/m2 in 200 mg/m2 • Najmanjši priporoceni odmerek je 100 mg/m2 Moški bolniki Temozolomid lahko deluje notoksicno, zato morate moškim, ki se zdravijo z temozolomidom svetovati, da naj ne zaplodijo otroka še šest mesecev po zdravljenju. Interakcije Socasna uporaba ·avila Temodal in ranitidina ni povzrocila spremembe obsega absorpcije temozolomida ali monometiltriazenoimidazol karboksamida (MTIC). Jemanje zdravila Temo dal 1rano je povzrocilo 33 % zmanjšanje Cmax in 9 % zmanjšanje površino pod krivuljo (AUC). Ker ne moremo izkljucili možnosti, da bi bila sprememba Cmax lahko 1icno pomembna, naj bolniki jemljejo zdravilo Temodal brez hrane. Analiza populacijske farmakokinetike v preskušanjih druge faze je pokazala, da socasna uporaba ,sametazona, proklorperazina, fenitoina, karbamazepina, ondansetrona, antagonistov receptorjev H2 ali fenobarbitala ne spremeni ocistka temozolomida. Socasno 1anje z valprojsko kislino je bilo povezano z majhnim, a statisticno znacilnim zmanjšanjem ocistka temozolomida. Uporaba zdravila Temodal v kombinaciji z drugimi ,losupresivnimi ucinkovinami lahko poveca verjetnost mielosupresije. Nosecnost študij na nosecih ženskah ni bilo. Predklinicne študije n.a podganah in kuncih z 11erkom 150 mg/m2 so pokazale teratogenost in/ali toksicnost za plod. Zato naj nosece ženske naceloma ne bi jemale zdravila Temodal. Ce pa je uporaba v casu ,ecnosti nujna, morate bolnico opozoriti na možne nevarnosti zdravila za plod. Zenskam v rodni dobi svetujte, naj med zdravljenjem z zdravilom Temodal preprecijo 10sitev. Dojenje Ni znano, ali se temozolomid izloca v materino mleko, zato ženske, ki dojijo, ne smejo jemati zdravila Temodal. Neželeni ucinki V klinicnih preskušanjih bili najpogostnejši neželeni ucinki, povezani z zdravljenjem, prebavne motnje, natancneje slabost (43 %) in bruhanje (36 %). Oba ucinka sta bila ponavadi 1. ali 2. pnje (od O do 5 epizod bruhanja v 24 urah) in sta prenehala sama ali pa ju je bilo mogoce hitro obvladati s standardnim antiemeticnim zdravljenjem. lncidenca hude sla­,ti in bruhanja je bila 4 %. Laboratorijski izvidi: Trombocitopenija in nevtropenija 3. in. 4. stopnje sta se pojavili pri 19 % in 17 % bolnikov, zdravljenih zaradi malignega ima. Zaradi njiju je bila potrebna hospitalizacija in/ali prekinitev zdravljenja z zdravilom Temodal pri 8 % in. 4 % bolnikov. Mielosupresija je bila predvidljiva (ponavadi je pojavila v prvih nekaj ciklusih in je bila najizrazitejša med 21. in 28. dnem), okrevanje pa je bilo hitro, ponavadi v 1 do 2 tednih. Opazili niso nobenih dokazov nulativne mielosupresije. Trombocitopenija lahko poveca tveganje za pojav krvavitev, nevtropenija ali levkopenija pa tveganje za okužbe.Imetnik dovoljenja za pro­t SP Europe 73, rue de Stalle 8-1180, Bruselj, Belgija. Nacin in režim izdaje Zdravilo se izdaja samo na recept, uporablja pa se pod posebnim nadzorom zdravnika 1cialista ali od njega pooblašcenega zdravnika. Datum priprave informacije september 2007 Podrobnejše informacije o zdravilu Temodal dobite na sedežu podjetja. Dunajska 22, 1000. Ljubljana lel: 0·1 300 1 O 70 fax: 01 30010 80 "'t temozolomid 0 Schering-Plough resnicni napredek Pri na novo odkritem glioblastomu multiforme in malignih gliomih, ki se ponovijo ali napredujejo. nove barve kapsul Temodal, omogocajo lažje odmerjanj Dunajska 22, 1000 Ljubljana lel: 01 300 10 70 lax: 01 300 1 O 80 Te111odal® c:p Schering-Plough temozolomid lete 5 f·1 1 msko obloženih ta @lek POVZETEK GLAVNIH ZNACILNOSTI ZDRAVILA Granisetron Lek 2 mg filmsko obložene tablete. SESTAVA: 1 filmsko obložena tableta vsebuje 2 mg granisetrona v obliki granisetronijevega klorida. TERAPEVT­SKE INDIKACIJE: Preprecevanje akutne slabosti in bruhanja, ki sta posledica zdravljenja s citostatiki (kemoterapije in radioterapije). Bolnik mora zdravilo vzeti na dan zdravljenja s citostatiki. ODMERJANJE IN NACIN UPORABE: Odrasli in otro­ci, stari vec kot 12 let in težki vec kot 50 kg: Odmerek zdravila je 1 mg dvakrat na dan ali 2 mg enkrat na dan, na dan zdravljenja s citostatiki. Odmerek (prvi) je treba vzeti eno uro pred zacetkom zdravljenja s citostatiki. Kombinacija s korti­kosteroidi: Ucinkovitost zdravila zvecamo z intravenskim dodatkom kortikoste­roida. Najvecji odmerek in trajanje zdravljenja: Najvecji odmerek, ki ga bolniki lahko vzamejo peroralno, je 9 mg granisetrona v enem dnevu. Starejši in bolniki z motenim ledvicnim in/ali jetrnim delovanjem: Odmerek je enak kot pri odraslih. KONTRAINDIKACIJE: Preobcutljivost za zdravilno ucinkovino granisetron, sorodne ucinkovine ali katerokoli pomožno snov. POSEBNA OPOZORILA IN PREVIDNOSTNI UKREPI: Zdravilo lahko zmanjša motiliteto crevesja, zato je treba bolnike, ki imajo znake subakutne crevesne zapore, med jemanjem zdravila Granisetron Lek skrbno nadzorovati. 5-HT3 antagonisti, kot je granisetron, so lahko vpleteni v nastanek aritmij ali nepravil­nosti EKG-ja. To je lahko klinicno pomembno pri bolnikih z že obstojecimi aritmijami ali motnjami konduktivnosti srca ali pri bolnikih, ki se zdravijo z antiaritmiki ali zaviralci adrenergicnih receptorjev beta. Zdravila Granisetron Lek ne smemo dajati bolnikom z redkimi dednimi boleznimi, kot so intoleranca za galaktozo, glukoza-galaktoza malab­sorpcijski sindrom, pomanjkanje Lapp laktaze. MEDSEBOJNO DELOVANJE Z DRUGI­Ml ZDRAVILI IN DRUGE OBLIKE INTERAKCIJ: Granisteron se presnavlja s pomocjo jetrnega citokroma P450; zaviralci ali spodbujevalci tega encima lahko spremenijo oc­ istek in posledicno razpolovni cas granisetrona. Pri ljudeh je indukcija jetrnih encimov s fenobarbitalom povzrocila zvecanje celotnega plazemskega ocistka granisetrona (za približno 25 %), danega intravensko. Do sedaj niso opazili znakov medsebojnega delo­vanja granisetrona in drugih pogosto predpisanih antiemetikov, kot so benzodiazepini, nevroleptiki in antiulkusni pripravki. Tudi med granisetronom in emetogenimi kemotera­ pevtiki ni bilo opaženih inlerakcij. VPLIV NA SPOSOBNOST VOŽNJE IN UPRAVLJA­ NJA S STROJI: Podatki, da bi Granisetron vplival na sposobnost vožnje, niso znani. NEŽELENI UCINKI: Zelo pogosti(> 1/10): glavobol, slabost, zaprtje. Pogosti(< 1/10, >1/100): zmanjšan apetit, driska, bruhanje, bolecine v trebuhu, astenija, bolecine, vroc­ ina. Redki(< 1/1.000, >1/10.000): aritmija, bolecine v prsih, patološko delovanje jeter, zvecanje jetrnih transaminaz. VRSTA OVOJNINE IN VSEBINA: Škatla s 5 filmsko ob­loženimi tabletami. NACIN IZDAJE ZDRAVILA: Na zdravniški recept. IMETNIK DO­VOLJENJA ZA PROMET: Lek farmacevtska družba d.d., Verovškova 57, Ljubljana, Slovenija. INFORMACIJA PRIPRAVLJENA: april 2007 @lek clan skupine Sandoz Lek farmacevtska družba d. d. Verovškova 57. 1526 Liubliana. Sloveniia • www.lP.k.ssi ® ERBITUX CETUKSIMAB Erbitux S mg/ml raztopina za infundiranje (skrajšana navodila za uporabo) Cetuksimab je monoklonsko lgG, protitelo, usmerjeno proti receptorju za epidermalni rastni faktor (EGFR). Terapevtske indikacije: Zdravilo Erbitux je v kombinirani terapiji z irinotekanom indici rano za zdravljenje bolnikov z metastatskim rakom debelega crevesa in danke in sicer po neuspešni citotoksicni terapiji, ki je vkljucevala tudi irinotekan. Zdravilo Erbituxje v kombinaciji z radioterapijo indicirano za zdravljenje bolnikov z lokalno napredovalim rakom skvamoznih celic glave in vratu. Odmerjanje in nacin uporabe: Zdravilo Erbitux pri vseh indikacijah infundirajte enkrat na teden. Zacetni odmerek je 400 mg cetuksimaba na m' telesne površine. Vsi naslednji tedenski odmerki so vsak po 250 mg/m'. Kontraindikacije: Zdravilo Erbituxje kontraindicirano pri bolnikih z znano hudo preobcutljivostno reakcijo (3. ali 4. stopnje) na cetuksimab. Posebna opozorila in previdnostni ukrepi: ce pri bolniku nastopi blaga ali zmerna reakcija, povezana z infundiranjem, lahko zmanjšate hitrost infundiranja. Priporocljivo je, da ostane hitrost infundiranja na nižji vrednosti tudi pri vseh naslednjih infuzijah. Ce se pri bolniku pojavi huda kožna reakcija (. 3. stopnje po kriterijih US Natianal Cancer Institute, Cammon Toxicity Criteria; NCI-CTC), morate prekiniti terapijo s cetuksimabom. Z zdravljenjem smete nadaljevati le, ce se je reakcija pomirila do 2. stopnje. Priporoca se dolocanje koncentracije elektrolitov v serumu pred zdravljenjem in periodicno med zdravljenjem s cetuksimabom. Po potrebi se priporoca nadomešcanje elektrolitov. Posebna previdnost je potrebna pri oslabljenih bolnikih in pri tistih z obstojeco srcno-pljucno boleznijo. Neželeni ucinki: Zelo pogosti(. 1/10): dispneja, blago do zmerno povecanje jetrnih encimov, kožne reakcije, blage ali zmerne reakcije povezane z infundiranjem, blag do zmeren mukozitis. Pogosti(. 1/100, < 1/10): konjunktivitis, hude reakcije povezane z infundiranjem. Pogostost ni znana: Opazili so progresivno zniževanje nivoja magnezija v serumu, ki pri nekaterih bolnikih povzroca hudo hipomagneziemijo. Glede na resnost so opazili tudi druge elektrolitske motnje, vecinoma hipokalciemijo ali hipokaliemijo. Posebna navodila za shranjevanje: Shranjujte v hladilniku (2 'C -8 '(). Ne zamrzujte. Vrsta ovojnine in vsebina: 1 viala po 20 ml ali 100 ml. Imetnik dovoljenja za promet: Merek KGaA, 64271 Darmstadt, Nemcija. Podrobne informacije o zdravilu so objavljene na spletni strani Evropske agencije za zdravila (EMEA) http://www.emea.europa.eu. 1 Dodatne informacije so vam na voljo pri: Merek, d.o.o., Dunajska cesta 119, 1000 Ljubljana, tel.: 01 560 3810, faks: 01 560 3831, el.pošta:info@merck.si II 1 ,MERCK www.oncology.merck.de 11SERONO 1 Tarceva is indicated far: • Treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy reg imen. • Tarceva in combination with gemcitabine is indicated far the treatment of patients with metastatic pancreatic cancer. For additional infarmation please consult your local Roche office. Reference: l. Shepherd FA, Rodrigues Pereira J, Ciuleanu Tet al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005 Jul l 4;353(2):123-32. 2. Moore MJ, Goldstein D, Hamm J et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Ciin Oncol. 2007 May 20;25(1 5) 1960-6. (/Tarceva· erlotinib HCI Roche farmacevtska družba d.o.o. Vodovodna cesta l 09 l 000 Ljubljana www.roche.si Radiology and Oncology Editorial policy Editorial policy of the journal Radiology and Oncology is to publish original scientific papers, professional papers, review arti­cles, case reports and varia (editorials, re­views, short communications, professional information, 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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