vol.44 no.4 december 2010 pemetreksed Pravi Izbor Pravi Bolnik Pravi Cas Edina histološko usmerjena citostaticna terapija ALIMTA/cisplatin: Zdravljenje prvega reda pri bolnikih z nedrobnocelicnim pljucnim karcinomom, ki nimajo pretežno luskaste histologije Edina kombinirana terapija s signifikantno izboljšanim preživetjem: 12,6 meseca pri bolnikih z adenokarcinomom pljuc1 SKRAJŠAN POVZETEK GLAVNIH ZNACILNOSTI ZDRAVILA Ime zdravila ALIMTA 100 mg prašek za koncentrat za raztopino za infundiranje in ALIMTA 500 mg prašek za koncentrat za raztopino za infundiranje Kakovostna in kolicinska sestava ALIMTA 100 mg: vsaka viala vsebuje 100 mg pemetrekseda (v obliki dinatrijevega pemetrekseda). Po pripravi vsebuje vsaka viala 25 mg/ml pemetrekseda. Pomožne snovi: Vsaka viala vsebuje približno 11 mg natrija. Manitol, klorovodikova kislina, natrijev hidroksid. ALIMTA 500 mg: vsaka viala vsebuje 500 mg pemetrekseda (v obliki dinatrijevega pemetrekseda). Po pripravi vsebuje vsaka viala 25 mg/ml pemetrekseda. Pomožne snovi: Vsaka viala vsebuje približno 54 mg natrija. Manitol, klorovodikova kislina, natrijev hidroksid. Terapevtske indikacije: ALIMTA je v kombinaciji s cisplatinom indicirana za zdravljenje bolnikov z neresektabilnim malignim plevralnim mezoteliomom, ki jih še nismo zdravili s kemoterapijo. ALIMTA je v kombinaciji s cisplatinom indicirana kot zdravljenje prvega izbora za bolnike z lokalno napredovalim ali metastatskim nedrobnocelicnim pljucnim karcinomom, ki nima pretežno luskaste celicne histologije. ALIMTA je indicirana kot monoterapija za zdravljenje lokalno napredovalega ali metastatskega nedrobnocelicnega pljucnega karcinoma, ki nima pretežno luskaste celicne histologije pri bolnikih, pri katerih bolezen ni napredovala neposredno po ke­moterapiji na osnovi platine. Zdravljenje prvega izbora naj bo platinasta dubleta z gemcitabinom, paklitakselom ali docetakselom. ALIMTA je indicirana kot monoterapija za zdravljenje drugega izbora bolnikov z lokalno napredovalim ali metastatskim nedrobnocelicnim pljucnim karcinomom, ki nima pretežno luskaste celicne histologije. Odmerjanje in nacin uporabe: ALIMTO smemo dajati le pod nadzorom zdravnika, usposobljenega za uporabo kemoterapije za zdravljenje raka. ALIMTA v kombinaciji s cisplatinom Priporoceni odmerek ALIMTE je 500 mg/m2 telesne površine (TP), dan kot intravenska infuzija v 10 minutah prvi dan vsakega 21-dnevnega ciklusa. Priporoceni odmerek cisplatina je 75 mg/m2 TP, infundiran v dveh urah približno 30 minut po zakljucku infuzije pemetrekseda prvi dan vsakega 21 dnevnega ciklusa. Priporoceni odmerek cisplatina je 75 mg/m2 TP, infundiran v dveh urah približno 30 minut po zakljucku infuzije pemetrekseda prvi dan vsakega 21 dnevnega ciklusa. Bolniki morajo prejeti zadostno antiemeticno zdravljenje, pred in/ali po prejemanju cisplatina jih moramo tudi ustrezno hidrirati. ALIMTA kot samostojno zdravilo Priporoceni odmerek ALIMTE je 500 mg/m2 TP, dan kot intravenska infuzija v 10 minutah prvi dan vsakega 21 dnevnega ciklusa. Režim premedikacije Da zmanjšamo incidenco in resnost kožnih reakcij, dajemo kortikosteroid dan pred dajan­jem pemetrekseda, na dan dajanja pemetrekseda in naslednji dan. Kortikosteroid naj ustreza 4 mg deksametazona, danega peroralno dvakrat dnevno. Za zmanjšanje toksicnosti morajo bolniki dnevno jemati tudi peroralno folno kislino ali multivitaminski pripravek, ki jo vsebuje (350 do 1000 mikrogramov). V sedmih dneh pred prvim odmerkom pemetrek­seda morajo vzeti vsaj pet odmerkov folne kisline, odmerjanje pa morajo nadaljevati ves cas zdravljenja in še 21 dni po zadnjem odmerku pemetrekseda. Bolniki morajo prejeti tudi intramuskularno injekcijo vitamina B12 (1000 mikrogramov) v tednu pred prvim odmerkom pemetrekseda in enkrat vsake tri cikluse zatem. Kasnejše injekcije vitamina B12 lahko dajemo isti dan kot pemetreksed. Kontraindikacije: Preobcutljivost za zdravilno ucinkovino ali katerokoli pomožno snov. Dojenje. Socasno cepljenje proti rumeni mrzlici. Posebna opozorila in previdnostni ukrepi: Pemetreksed lahko zavre delovanje kostnega mozga, kar se kaže kot nevtropenija, trombocitopenija in anemija (ali pancitopenija). Pri bolnikih, ki pred zdravljenjem niso prejemali kortikosteroidov, so porocali o kožnih reakcijah. Uporabe pemetrekseda pri bolnikih z ocistkom kreatinina < 45 ml/min ne priporocamo. Bolniki z blagim do zmernim popušcanjem delovanja ledvic naj se izogibajo jemanju nesteroidnih protivnetnih zdravil (NSAID), denimo, ibuprofena in acetilsalicilne kisline 2 dni pred dajanjem pemetrekseda, na dan dajanja in še 2 dni po dajanju pemetrekseda. Vsi bolniki, ki jih lahko zdravimo s pemetreksedom, naj se izogibajo jemanju NSAID-ov z dolgimi razpolovnimi casi izlocanja vsaj 5 dni pred dajanjem pemetrekseda, na dan dajanja in še vsaj 2 dni po dajanju pemetrekseda. Porocali so o resnih ledvicnih primerih, vkljucno z akutno ledvicno odpovedjo, s pemetreksedom samim ali v povezavi z drugimi kemoterapevtiki. Pri bolnikih s klinicno pomembno tekocino tretjega prostora moramo razmisliti o drenaži izliva pred dajanjem pemetrekseda. Kot posledico toksicnosti pemetrekseda v kombinaciji s cisplatinom za prebavila so opažali hudo dehidracijo, zato moramo bolnike pred prejemanjem terapije in/ali po njej ustrezno hidrirati, prejeti morajo zadostno antiemeticno zdravljenje. Obcasno so v klinicnih študijah pemetrekseda, obicajno ob socasnem dajanju z drugo citotoksicno ucinkovino, porocali o resnih srcnožilnih dogodkih, vkljucno z miokardnim infarktom in možganskožilnimi dogodki. Odsvetujemo uporabo živih oslabljenih cepiv. Spolno zrelim moškim odsvetujemo zaploditev otroka v casu zdravljenja in še 6 mesecev zatem. Priporocamo ukrepe prosti zanositvi ali vzdržnost. Zaradi možnosti, da zdravljenje s pemetreksedom povzroci trajno neplodnost, naj se moški pred zacetkom zdravljenja posvetujejo o shranjevanju semena. Ženske v rodni dobi morajo v casu zdravljenja s pemetreksedom uporabljati ucinkovito kontracepcijo. Porocali so o primerih radiacijske pljucnice pri bolnikih, ki so jih zdravili z radiacijo pred, med ali po zdravljenju s pemetreksedom. Porocali so o radiacijskem izpušcaju pri bolnikih, ki so se zdravili z radioterapijo pred tedni ali leti. Zdravilo Alimta 500 mg vsebuje približno 54 mg natrija na vi-alo. Pomembno za bolnike, ki so na dieti z nadzorovanim vnosom natrija. Medsebojno delovanje z drugimi zdravili in druge oblike interakcij: Socasno dajanje nefrotoksicnih zdravil (denimo, aminoglikozidov, diuretikov zanke, spojin platine, ciklosporina) lahko potencialno povzroci zakasnjeni ocistek pemetrekseda. Socasno dajanje snovi, ki se tudi izlocajo s tubulno sekrecijo (denimo, probenecid, penicilin), lahko potencialno povzroci zakasnjeni ocistek pemetrekseda. Pri bolnikih z normalnim delovanjem ledvic lahko visoki odmerki nesteroidnih protivnetnih zdravil (NSAID-i, denimo, ibuprofen) in acetilsalicilna kislina v visokih odmerkih zmanjšajo eliminacijo pemetrekseda in tako lahko povecajo pojavnost neželenih ucinkov pemetrekseda. Pri bolnikih z blagim do zmernim popušcanjem delovanja ledvic se moramo izogibati socasnemu dajanju pemetrekseda z NSAID-i (denimo, ibuprofenom) ali acetilsalicilne kisline v visokih odmerkih 2 dni pred dajanjem pemetrekseda, na dan dajanja in še 2 dni po dajanju pemetrekseda. Socasnemu dajanju NSAID-ov z daljšimi razpolovnimi casi s pemetreksedom se moramo izogibati vsaj 5 dni pred dajanjem pemetrekseda, na dan dajanja in še vsaj 2 dni po dajanju pemetrekseda.Velika razlicnost med posamezniki v koagulacijskem statusu v casu bolezni ter možnost medsebojnega delovanja med peroralnimi antikoagulacijskimi ucinkovinami ter kemoter­apijo proti raku zahtevata povecano pogostnost spremljanja INR. Kontraindicirana socasna uporaba: Cepivo proti rumeni mrzlici: tveganje za smrtno generalizirano bolezen po cepljenju. Odsvetovana socasna uporaba: Živa oslabljena cepiva (razen proti rumeni mrzlici): tveganje za sistemsko, potencialno smrtno bolezen. Neželeni ucinki Klinicne študije malignega plevralnega mezotelioma Zelo pogosto: znižani nevtrofilci/granulociti, znižani levkociti, znižan hemoglobin, znižani trombociti, nevropatija-senzoricna, diareja, bruhanje, stomatitis/faringitis, slabost, anoreksija, zaprtje, izpušcaj, alopecija, povišan kreatinin, znižan ocistek kreatinina, utrujenost. Pogosti: dehidracija, motnje okusa, konjuktivitis, dispepsija. Klinicne študije nedrobnocelicnega pljucnega karcinoma -ALIMTA monoterapija, zdravljenje 2. izbora: Zelo pogosti: znižan nevtrofilci/granulociti, znižani levkocitit, znižan hemoglobin, diareja, bruhanje, stomatitis/faringitis, slabost, anoreksija, izpušcaj/lušcenje, utrujenost. Pogosti: znižani trombociti, zaprtje, povišanje SGPT (ALT), povišanje SGOT (AST), srbenje, alopecija, povišana telesna temperatura. Klinicne študije nedrobnocelicnega pljucnega karcinoma -ALIMTA v kombinaciji s cisplatinom, zdravljenje 1. izbora: Zelo pogosti: znižan hemoglobin, znižani nevtrofilci/granulociti, znižani levkocitit, znižani trombociti, slabost, bruhanje, anoreksija, zaprtje, stomatitis/faringitis, diareja brez kolostomije, alopecija, izpušcaj/lušcenje, povišan kreatinin. Pogosti: nevropatija-senzoricna, motnje okusa, dispepsija/zgaga. Klinicne študije nedrobnocelicnega pljucnega karcinoma -ALIMTA monoterapija, vzdrževalno zdravljenje: Zelo pogosti: znižan hemoglobin, slabost, anoreksija, utrujenost, izpušcaj/lušcenje, utrujenost. Pogosti: infekcija, znižani levkociti, znižani nevtrofilci, nevropatija-senzoricna, bruhanje, mukozitis/stomatitis, diareja, povišanje ALT (SGPT), povišanje AST (SGOT). Obcasno so v klinicnih študijah pemetrekseda porocali o primerih resnih srcnožilnih in možganskožilnih dogodkov, vkljucno z miokardnim infarktom, angino pektoris, cerebrovaskularnim insultom in prehodnimi ishemicnimi atakami; primerih kolitisa ter o primerih intersticijske pljucnice z respiratorno insuficience, primerih edema in o ezofagitisu/radiacijskem ezofagitisu. Redkeje pa o primerih potencialno resnega hepatitisa in pancitopenije. Po uvedbi zdravila na trg so porocali o primerih akutne odpovedi ledvic s pemetreksedom samim ali v povezavi z drugimi kemoterapevtiki, primerih radiacijske pljucnice pri bolnikih, ki so jih zdravili z radiacijo pred, med ali po njihovem zdravljenju s pemetreksedom, primerih radiacijskega izpušcaja pri bolnikih, ki so se v preteklosti zdravili z radioterapijo in o primerih periferne ishemije, ki je vcasih vodila v nekrozo okoncin. Imetnik dovoljenja za promet Eli Lilly Nederland B.V., Grootslag 1 5, NL 3991 RA, Houten, Nizozemska. Datum zadnje revizije besedila 24.10.2009. Nacin in režim izdajanja zdravila: H Podrobnejše informacije o zdravilu Alimta, so na voljo na lokalnem predstavništvu SIALM00018 Eli Lilly Farmacevtska družba, d.o.o. Brnciceva 41G, 1231 Ljubljana - Crnuce, Slovenija Telefon: +386 (0)1 5800 010 Faks: +386 (0)1 5691 705 Publisher Association of Radiology and Oncology Affiliated with Slovenian Medical Association – Slovenian Association of Radiology, Nuclear Medicine Society,Slovenian Society for Radiotherapy and Oncology, and Slovenian Cancer Society Croatian Medical Association – Croatian Society of RadiologySocietas Radiologorum HungarorumFriuli-Venezia Giulia regional groups of S.I.R.M. Italian Society of Medical Radiology Aims and scope Radiology and Oncology is a journal devoted to publication of original contributions in diagnostic and interventionalradiology, computerized tomography, ultrasound, magnetic resonance, nuclear medicine, radiotherapy, clinical andexperimental oncology, radiobiology, radiophysics and radiation protection. Editor-in-Chief Gregor SeršaLjubljana, Slovenia Executive Editor Viljem KovacLjubljana, Slovenia Deputy Editors Andrej Cör Izola, Slovenia Igor KocijancicLjubljana, Slovenia Editorial Board Advisory Committee Karl H. Bohuslavizki Hamburg, Germany Damir Miletic Rijeka, Croatia Marija Auersperg Ljubljana, Slovenia Maja Cemažar Ljubljana, Slovenia Maja Osmak Zagreb, Croatia Tomaž Benulic Ljubljana, Slovenia Christian Dittrich Vienna, Austria Branko Palcic Vancouver, Canada Jure Fettich Ljubljana, Slovenia Metka Filipic Ljubljana, Slovenia Dušan Pavcnik Portland, USA Valentin Fidler Ljubljana, Slovenia Tullio Giraldi Trieste, Italy Geoffrey J. Pilkington Portsmouth, UK Berta Jereb Ljubljana, Slovenia Maria Godény Budapest, Hungary Ervin B. Podgoršak Montreal, Canada Vladimir Jevtic Ljubljana, Slovenia Vassil Hadjidekov Sofia, Bulgaria Uroš Smrdel Ljubljana, Slovenia Stojan Plesnicar Ljubljana, Slovenia Marko Hocevar Ljubljana, Slovenia Maksimilijan Kadivec Ljubljana, Slovenia Miklós Kásler Budapest, Hungary Primož Strojan Ljubljana, SloveniaBorut Štabuc Ljubljana, SloveniaRanka Štern-Padovan Zagreb, Croatia Mirjana Rajer Ljubljana, SloveniaŽiva Zupancic Ljubljana, Slovenia Michael Kirschfink Heidelberg, Germany Justin Teissié Toulouse, France Janko Kos Ljubljana, Slovenia Sándor Tóth Orosháza, Hungary Tamara Lah Turnšek Ljubljana, Slovenia Gillian M. Tozer Sheffield, UK Damijan Miklavcic Ljubljana, Slovenia Andrea Veronesi Aviano, Italy Luka Milas Houston, USA Branko Zakotnik Ljubljana, Slovenia Radiol Oncol 2010; 44(4): A. Editorial office Radiology and Oncology Institute of Oncology Zaloška 2SI-1000 Ljubljana Slovenia Phone: +386 1 5879 369Phone/Fax: +386 1 5879 434E-mail: gsersa@onko-i.si Copyright © Radiology and Oncology. All rights reserved. Reader for English Vida Kološa Secretary Mira KlemencicZvezdana Vukmirovic Design Monika Fink-Serša, Samo Rovan, Ivana Ljubanovic Layout Matjaž Lužar Printed byTiskarna Ozimek,Slovenia Published quarterly in 600 copies Beneficiary name: DRUŠTVO RADIOLOGIJE IN ONKOLOGIJEZaloška cesta 2,1000 LjubljanaSlovenia Beneficiary bank account number: SI56 02010-0090006751IBAN: SI56 0201 0009 0006 751Our bank name: Nova Ljubljanska banka, d.d., Ljubljana, Trg republike 2,1520 Ljubljana; SloveniaSWIFT: LJBASI2X Subscription fee for institutions EUR 100, individuals EUR 50 The publication of this journal is subsidized by the Slovenian Book Agency. Indexed and abstracted by: Science Citation Index Expanded (SciSearch®)Journal Citation Reports/Science EditionScopusEMBASE/Excerpta MedicaOpen J-gateChemical AbstractsBiomedicina Slovenica This journal is printed on acid- free paper On the web: ISSN 1581-3207 http://versita.com/science/medicine/ro/http://www.onko-i.si/radioloncol/ Radiol Oncol 2010; 44(4): B. contents contents reviews 207 Urine and bladder washing cytology for detection of urothelial carcinoma: standard test with new possibilities Margareta Strojan Fležar radiology 215 Imaging findings in bisphosphonate-induced osteonecrosis of the jaws Katarina Surlan Popovic, Miha Kocar 220 MRI in evaluation of perianal fistulae Amela Sofic, Serif Beslic, Nedzad Sehovic, Jasmin Caluk, Damir Sofic 228 Mammographycally occult high grade ductal carcinoma in situ (DCIS) as second primary breast cancer, detected with MRI: a case report Marta Zebic-Sinkovec, Maksimiljan Kadivec, Gasper Podobnik, Erik Skof, Marko Snoj clinical oncology 232 Effect of response quality and line of treatment with rituximab on overall and disease-free survival of patients with B-cell lymphoma Mateja Horvat, Barbara Jezersek Novakovic 239 Second primary cancers in patients with gastric cancer Oktay Buyukasik, Ahmet Oguz Hasdemir, Yusuf Gulnerman, Cavit Col, Ozgur Ikiz 244 Lymphedema following cancer therapy in Slovenia: a frequently overlooked condition? Tanja Planinsek Rucigaj, Nada Kecelj Leskovec, Vesna Tlaker Zunter Radiol Oncol 2010; 44(4): C. contents 249 Evaluation of clinical interventions made by pharmacists in chemotherapy preparation Lea Knez, Raisa Laaksonen, Catherine Duggan 257 Digital ischemic events related to gemcitabine: Report of two cases and a systematic review Cvetka Grasic Kuhar, Tanja Mesti, Branko Zakotnik 262 Ureteral metastasis as the first and sole manifestation of gastric cancer dissemination Vesna Bisof, Antonio Juretic, Josip Pasini, Marijana Coric, Mislav Grgic, Marija Gamulin,Zoran Rakusic, Zdenko Krajina, Martina Basic-Koretic, Ana Misir, Ranka Štern-Padovan letter to the editor 265 Management of cetuximab-induced skin toxicity with the prophylactic use of topical vitamin K1 cream Janja Ocvirk I slovenian abstracts VII notices VIII authors index 2010 subject index 2010 Radiology and oncology is covered in Science Citation Index Expanded (SciSearch®),Journal Citation Reports/Science Edition, Scopus, EMBASE/Excerpta Medica, Open J-gate, Chemical Abstracts, Biomedicina Slovenica Radiol Oncol 2010; 44(4): D. 207 review Urine and bladder washing cytology for detection of urothelial carcinoma: standard test with new possibilities Margareta Strojan Flezar Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia Received 22 July 2010 Accepted 18 August 2010 Correspondence to: Prof. Margareta Strojan Fležar, MD, PhD; Institute of Pathology, Faculty of Medicine University of Ljubljana; Korytkova 2; SI-1000 Ljubljana, Slovenia. Phone: +386 1 543 7105; Fax: +386 543 7101; E-mail: margareta.strojan-flezar@mf.uni-lj.si Disclosure: No potential conflicts of interest were disclosed. Background. Light microscopic evaluation of cell morphology in preparations from urine or bladder washing contain­ing exfoliated cells is a standard and primary method for the detection of bladder cancer and also malignancy from other parts of the urinary tract. The cytopathologic examination is a valuable method to detect an early recurrence of malignancy or new primary carcinoma during the follow-up of patients after the treatment of bladder cancer. Conclusions. Characteristic cellular and nuclear signs of malignancy indicate invasive or in situ urothelial carcinoma or high-grade papillary urothelial carcinoma. However, low sensitivity of the method reflects the unreliable cytopatho-logic diagnosis of low-grade urothelial neoplasms as cellular and nuclear signs of malignancy in these neoplasms are poorly manifested. Many different markers were developed to improve the diagnosis of bladder carcinoma on urinary samples. UroVysion™ test is among the newest and most promising tests. By the method of in situ hybridization one can detect specific cytogenetic changes of urothelial carcinoma. Key words: cytology; urine; bladder washing; urothelial carcinoma Introduction The examination of urine is one of the oldest medi­cal procedures dating back to the Old Egypt.1,2First microscopical examination of the cells in the uri­nary sediment was reported by the Czech doctor Lambl back in 1856.2 At present the cytopathological examination of urine or other fluid samples from the urinary tract is a routine noninvasive diagnostic procedure to detect cancer of the urinary tract, foremost bladder cancer especially in patients with painless haema­turia.3,4It is also used during the follow-up proce­dures of the patients previously treated for blad­der cancer in order to early detect recurrence or new primary.4Exceptionally, the cytopathological examination of urine is used for the screening for urothelial carcinoma in the high risk population. The cytopathological examination is a highly specific method for the diagnosis of invasive and in situurothelial carcinoma and high-grade pap­illary carcinoma, however it is notorious of being unreliable for the detection of low-grade papillary neoplasms.5,6 Preparation of fluid samples from the urinary tract for cytopathological examination A most common sample from the urinary tract is spontaneous – voided urine. Bladder washing samples are also very frequent samples sent to the cytology laboratory. Other samples such as cath­eterized urine or urine obtained by the retrograde catheterization of urethers or renal pelvis are sent for the cytopathological examination only occa­sionally. The second morning voided urine is the most appropriate sample for the cytopathological ex­amination as it contains enough of preserved cells. The first morning urine contains more cells but they show different degrees of degeneration be­ing exposed to the acid milieu of urine through the 208 Strojan Flezar M / Urine and bladder washing cytology TABLE 1. Cytological-histological correlation in 125 cases of urines and bladder washings with subsequent tissue biopsy from 2007 to 2009 LG** papillary urothelial carcinoma 5 4 8 9 2 28 HG*** papillary urothelial carcinoma 1 - - 4 17 22 Invasive urothelial carcinoma - 1 2 2 21 26 Invasive and in situ urothelial carcinoma - - - - 2 2 In situ urothelial carcinoma - - 1 3 7 11 No malignancy 21 4 2 8 1 36 Total 27 9 13 26 50 125 * NOS = not otherways specified; **LG = low-grade; ***HG = high-grade night and are less suitable for the cytological evalu­ation. Because the cells exfoliate from the urothe­lium intermittently, three urine samples should be examined from three consecutive days to ensure that diagnostic cells were sampled.2 The bladder washing sample is obtained during or prior cystoscopy which is an invasive diagnostic procedure for the macroscopical evaluation of the bladder mucosa. First the bladder should be emp­tied by a catheter. Then 50 to 100 ml of normal sa­line is instilled and recovered and this procedure is repeated three times.2Bladder washing exfoliates large sheets of urothelium and even three-dimen­sional urothelial fragments. Therefore, bladder washing samples are highly cellular and contain well preserved cells. When fluid samples cannot be delivered to the cytology laboratory within three hours after they were obtained, they can be prefixed with a mixture of 2% polyethylen glycol (Carbowax™) and 50% to 70% ethanol. Different techniques are used for the cytopatho-logical preparation of fluid samples of the urinary tract. Some laboratories still use a centrifugation of fluid and then the pellet is directly smeared onto the glass slide. Other laboratories introduced the commercial ThinPrep™ technique for the prepara­tion of samples from the urinary tract.7ThinPrep™ was first developed for the preparation of cervical cytology samples. The membrane filtration tech­nique is used in several laboratories including ours. Urine or bladder washing sample is filtered through the polycarbonate membrane filter with 5 µm pores (Costar® filter system, Costar Europe Ltd., Netherlands, Europe; Nucleopore® filter, di­ameter 47 mm, pores 5 µm, Whatman Inc., New Jersey, USA), so predominantly urothelial cells re­main on the filter. Usually the majority of erytro­cytes and leukocytes are removed because the gen­tle negative pressure is applied to assist filtration, which deforms these cells so they pass through the filter. The cell monolayers are obtained by gently imprinting filter onto a pair of glass slides. The cell sample on the slide should be fixed by the imme­diate immersion into Delaunay fixative (acetone: 96% ethanol 1:1 + 0.5 ml/l trichoracetic acid) or fixed by spraying with Merckofix® (Merck KGaA, Darmstadt, Germany). Cell preparations are subse­quently stained by the Papanicolaou method. Cytopathological diagnosis of urothelial tumours The last WHO classification of the tumours of the urinary system (published in 2004) divides urothe­lial neoplasms into infiltrating (invasive) urothelial carcinomas and non-invasive urothelial carcino­mas.8,9Later they are further subdivided into low and high-grade papillary carcinomas, papillary urothelial neoplasms of low malignant poten­tial (PUNLMP) and papillomas on one side and urothelial carcinomas in situ on the other side.9 In his last edition of Diagnostic cytology and its histopathologic bases, Koss suggested that for the purpose of cytopathological evaluation the urothe­lial carcinomas should be divided into papillary and non-papillary carcinomas.5The reason is that cytopathological diagnosis of non-papillary carci­nomas, including invasive and in situcarcinomas is very reliable (specificity ranging from 88.1 to 99.%, mean 97.1%; our data 96%, Table 1), while the cy­topathological evaluation of papillary neoplasms which are often of low-grade is notorious for being of limited usefulness.5,10-12 Another obstacle of the cytopathological evalua­tion is that the true origin of malignant cells found in urine cannot be reliably identified. Malignant Strojan Flezar M / Urine and bladder washing cytology 209 cells found in urine can originate not only from bladder, but from any part of the urinary tract, namely from renal pelvis, urether or urethra. Infiltrating (invasive) urothelial carcinoma Among non-papillary carcinomas the cells of inva­sive urothelial carcinomas usually exhibit clear cy­tological and nuclear characteristics of malignancy in voided urine or bladder washing samples.5,6,10Specifically, polymorphous cells with increased nuclear-cytoplasmic ratio, polymorphous nuclei, nuclear hyperchromasia with coarsely granular and unevenly distributed chromatin, and nucleoli are observed (Figure 1). The cellularity of samples partially depends on the type of specimen, namely larger number of malignant cells is found in blad­der washing, while the cell degeneration with py­knosis is more pronounced in voided urine sam­ples. Cells lay singly or in poorly cohesive clusters. Background may contain necrotic debris, blood and inflammatory cells. Sensitivity of cytology for the detection of invasive urothelial carcinoma is high (81-100%, our data: 100%, Table 1).5,10,11 Urothelial in situ carcinoma Alsotheurothelialinsitucarcinomaexfoliatescells withevidentmalignantmorphology,similartocells ofinvasiveurothelialcarcinoma(Figure2).5,6In voidedurinesamplesthecellsareofanintermedi­atesizeorsmall,mostlylayingsingly.Singlebizarre cellscanbeobserved.Nucleiarelarge,ofirregular shape,hyperchromatic,containcoarsechroma­tin,largenucleoli;pyknosisispresentfrequently. Cytoplasmisscanty.Incontrasttoinvasiveurothe­lialcarcinoma,generallynonecrosis,scantyeryth­rocytesorleukocytesarefoundinthebackground ofsamplescontainingcellsofurothelialinsitucar­cinoma.Duetotheobviousmorphologicalsignsof malignancythesensitivityofcytologyforthedetec­tionofurothelialinsitucarcinomaishigh(70-100%; ourdata:100%,Table1).5,10,11However,itisdifficult totellapartreliablythemalignantcellsoftheinsitucarcinomafromthecellsofinvasivecarcinomaeven whenthecharacteristicsofthebackgroundarecon­sideredinthecytopathologicaldiagnosis. High-grade papillary urothelial carcinomas Among papillary tumours, high-grade papillary urothelial carcinomas (including former WHO clas­sification grade II and III) shed cells with cytologi-cal atypia consistent with malignancy, as described above. The majority of high-grade carcinomas of former grade III exfoliate evident malignant cells, while in 20-30% of former grade II carcinomas the cytological atypia is less pronounced. Sensitivity of cytology for the detection of high-grade papil­lary urothelial carcinomas of former grade II and III combined is 72%, however for papillary urothe­lial carcinomas of former grade III is 91% (our data 94%, Table 1).5,10,11 Low-grade papillary urothelial carcinomas and other low-grade papillary neoplasms On the contrary, low-grade papillary urothelial carcinomas are difficult to diagnose in cell sam­ples, because the cytological signs of malignancy are not obvious.5,6Cells and nuclei are rather uni­ 210 Strojan Flezar M / Urine and bladder washing cytology form, nuclear-cytoplasmic ratio is not obviously in­creased. Nuclei are only slightly or moderately en­larged, chromatin is relatively bland. These nuclei are difficult to recognize as malignant in cytology. The background is typically clean, some erythro­cytes can be found. Only rarely true papillary frag­ments containing fibrovascular core can be found, but are not specific for papillary carcinomas; they could belong to PUNLMP or papillomas (Figure 3). Urinary cytology is not reliable for diagnosing low-grade papillary carcinoma and other low-grade papillary neoplasms. Sensitivity for the detection of low-grade papillary tumours is low, however various percentages are reported in the literature ranging from 0-73% (majority between 30 to 40%; our data: sensitivity 18% for the positive diagnosis and 55% for the combined positive/suspicious di­agnosis, Table 1).5,10-13 Differential diagnosis of inconclusive cytological atypia In low-grade papillary urothelial carcinomas and other low-grade papillary neoplasms cells exhibit some degree of cytological atypia described above. However, several benign lesions can show similar cytological atypia, namely reactive atypia related to inflammation, stones in the urinary tract or in­strumentation.5,6Also the post-treatment reactive urothelial changes could be pronounced and have to be taken into consideration. Cytological atypia of reactive type can be very prominent after the irradiation of bladder, intravesical chemotherapy with mitomycin or immunotherapy with Bacillus Calmette-Guérin (BCG) (used for the therapy of carcinoma in situ). The polyoma virus infection produces the so called decoy cells with enlarged, usually round nuclei that have typical intranuclear viral inclusions(Figure 4). The chromatin has ap­pearance of ground glass, with condensation of chromatin at the nuclear border, so called type 1 nuclear changes. The cytoplasm of decoy cells is scarce to moderate, thickened or degenerated, may have a comedo shape. Other three types of poly­oma related cytological changes are described but are not so reliably recognized in routine setting.2 Non-urothelial carcinomas of the urinary tract In rare instances also non-urothelial malignant cells are observed and can be diagnosed by the cytopathological examination of cell samples from the urinary tract. The most common non-urothe­lial carcinoma is squamous cell carcinoma.5It can exfoliate cells with obvious squamous features, namely orangeophylic cytoplasm that is well dem­onstrated in Papanicolaou stained cell prepara­tions. When combined with malignant cytological features the diagnosis of squamous cell carcinoma can be made on urine or bladder washing sample. However, it is difficult if not impossible to differen­tiate whether malignant squamous cells originate from squamouscell carcinomaof bladder or they belong to the part of urothelial carcinoma of blad­der with squamous differentiation. One also has to bear in mind that in the urinary samples from fe­male patients the malignant squamous cells could originate from squamous cell carcinoma of the uterine cervix with exfoliated cells in the vaginal excretions washed by urine or by direct invasion of squamous cell cervical carcinoma into the bladder. Strojan Flezar M / Urine and bladder washing cytology 211 In males, adenocarcinoma of the prostate can exfoliate cells into the urine, occasionally they are found in bladder washings.5Roundish glandular like structures of malignant cells can be found, with the cytological atypia roughly reflecting the grade of prostate adenocarcinoma. Immunocytochemical staining with antibody to prostate specific antigen (PSA) can confirm the final diagnosis of prostatic adenocarcinoma. Ancillary urine-based techniques for the diagnosis of urothelial bladder cancer Although the cytopathological examination of urine or bladder washing cell samples is very spe­cific (97%; our data: 96%, Table 1) it suffers from low sensitivity especially in the case of low-grade papillary tumours.5,10-13This type of tumours is prone to recurrence and it is found in 70% of pa­tients, furthermore 5% of them develop invasive carcinoma.13A specific clinical problem are pa­tients with early invasion into lamina propriaat first diagnosis. In these patients the disease progresses to the muscular invasive form in 20-30% of cases and the progression potentially leads to a fatal out­come.13The patients treated previously for urothe­lial carcinoma are therefore followed-up regularly with cystoscopy and cytology. Due to the above mentioned limitations of cytology the need for new non-invasive techniques to detect recurrences has emerged.13However, although the new mark­ers exhibit better sensitivity than cytology only few could reach the high specificity of cytology. DNA ploidy In the seventies and eighties of the last century the researchers and pathologists were using DNA cy­tometry to measure DNA ploidy of urothelial tu­ mors.14,15 There was found that the non-invasive low-grade urothelial tumours were predominantly diploid, while grade II urothelial carcinomas were diploid in about 50% of cases while the other 50% were aneuploid. The grade III tumours and car­cinomas in situwere predominantly aneuploid. When correlating the DNA ploidy to clinical data they found that aneuploid tumours were associ­ated with tumour persistence, recurrence, and pro­gression to invasion.16However, DNA diploidy in low-grade tumours could not improve the predic­tion of recurrence which is very frequent in these tumours. DNA ploidy measurement in urothelial tumours has reached its limitations, so new ancil­lary methods were searched for. ImmunoCyt/uCyt™ Thiscytologybasedtestwasdevelopedin1997.It isanimmunofluorescencebasedtest,usingthree monoclonalantibodies,twoofthem(M344and LDQ10,labelledwithfluoresceingreen)aredirect­edagainstmucin-likeantigensrelatedtourothelial carcinoma.17,18Theywerefoundtobepositivein 71%ofnon-invasive(pTa)orearlyinvasive(pT1) tumours.Thethirdantibody(19A211labelledwith Texasred)isdirectedagainsthighmolecularweight carcinoembrionicantigen(CEA).Itwasfoundto bepositivein90%ofnon-invasive(pTa)orearly invasive(pT1)tumours.Sensitivityofthetestwas showntobe53-100%(mean90%)alsoforlow-grade tumours,whilethespecificitywas64-95%(74%), whichislessthancytology.ThetestobtainedFDA clearancein2000forthedetectionofmalignantcells inurineinpatientstreatedforurothelialcancer. BTA stat® BardBTAstat®(bladdertumourantigentest)®(Polymedco,CortlandManor,NY,USA)isasolu­bleurinemarkertestthatwasaimedatthebasal membraneantigendetection(complementfactor H-relatedprotein)intheurineusinglatexagglutina­tiontest(immunoassay).13Thetestshowedvariable sensitivity(34%-100%)andespeciallyitssensitivity forlow-gradetumourswasrathermodest,whilethe specificitywasinthesamerange(40-96%).However, thehighfalsepositiverate(4-34%)makesthetestde­batableforawiderclinicaluse.FDAapprovedthe testtodetectbladdercancerinvoidedurine. NMP22 (nuclear matrix protein)™ immunoassay NMP22™ test (Matritech, Newton, MA, USA) is a soluble urine marker test. NMP22 (nuclear matrix protein) is a member of family of nuclear matrix proteins that are involved in DNA configuration, structure and function.13,19,20It was shown that the sufficient difference existed between normal and urothelial cancer cells to be used as a diagnostic test. The NMP22™ detection method is an immu­noassay that showed high sensitivity (60-86%) for the detection of urothelial neoplasia, however the specificity is bellow that of cytology (48-81%) pro­ducing many false positive tests. Besides, the test 212 Strojan Flezar M / Urine and bladder washing cytology TABLE 2. Results of the first set of the UroVysion™ test in patients with different cytopathological diagnoses on cell samples. Cytology No malignancy (negative) 1 - 1 Mild Atypia 1 1 2 Moderate atypia / suspicious for carcinoma - 5 5 Carcinoma (positive) - 3 3 Total 2 9 11 FISH = fluorescence in situ hybridization was reported to be rather inconvenient and costly. Anyhow, the FDA approved to detect bladder can­cer in voided urine, adjunct to cystoscopy. Other potential urinary markers of urothelial carcinoma Many other markers either cell based (microsatel-lite analysis, telomerase detection, Quanticyt nucle­ar karyometry) or soluble urine markers (BLCA-4, BLCA-1, HA-HAse, survivin) were reported to be useful for the detection of urothelial cancer.13The majority exhibited higher sensitivity than cytology, however they didn’t reach the high specificity of cytology and did not obtain the FDA approval for the clinical use. Multitarget multicolour fluorescence in situ hybridization (FISH)UroVysion™ test High frequency of specific chromosomal abnor­malities in urothelial cancers was found in the nineties and several DNA probes were made to detect these abnormalities.21,22Initial studies tested single DNA probes using FISH for the detection of urothelial carcinoma, however single probes resulted in limited specificity and sensitivity. The procedures were also time consuming, therefore they could be not introduced into the routine clini­cal management of the patients. ThestudyofSokolovaetal.showedthatthe applicationofseveralDNAprobescombinedsig­nificantlyincreasedthesensitivityforthedetection ofabnormalcells.23Intheirstudytheytestedten FISHprobesandfoundthatthehighestsensitivity wasachievedusingthreechromosomeenumera­tionprobes(CEP),namelyforchromosome3(la-belledbySpectrumred),chromosome7(labelled bySpectrumgreen),chromosome17(labelledby Spectrumaqua)andonelocus-specificidentifier (LSI)probefor9p21(labelledbySpectrumgold). Intheirstudythecut-offvaluesetat5abnormal cellsyieldedsensitivity84%,specificity92%forthe detectionofurothelialcarcinoma.Basedontheir observationthecommerciallyavailablemulticolour multitargetFISHUroVysion™test(AbbottMolecul Inc.,DesPlaines,IL,USA)incorporatingallfour DNAprobeswasmade.24InitiallyitwasFDAap­provedin2001forthesurveillanceofpatientswith bladdercancer,lateritwasapprovedalsoforthe detectionofbladdercancerinpersonswithhaema­turiasuspectedofhavingbladdercancer.Inother words,UroVysion™canbeusedforscreeningof bladdercancerinpatientswithhaematuria. Alreadyin2002thestudiesusingcommercial UroVysion™testwerepublished.Oneofthefirst wasthestudybyBubendorfetal.whoshowed thatUroVysion™couldfacilitatethediagnosisof bladdercanceranddetecttherecurrence.25They claimedthatthetestwasarapid,simpleandpow­erfuldiagnosticmethod.Eithervoidedurineor bladderwashingsamplespreparedascytospins couldbeused.Theyfoundthatthesensitivityfor thedetectionofnon-invasivecarcinomawas73%, whilelaterstudiesshowedsensitivityrangingfrom 36-86%.Thesensitivityforthedetectionofinvasive carcinomawasevenhigherreaching100%,and otherstudiesconfirmed94-100%sensitivity.The specificityintheirstudywas96%,inthelaterstud­iesupto100%.26-29Theysuggestedthatthecystos-copyexaminationshouldfollowapositivetesteven intheabsenceofsuspiciousorpositivecytology. Althoughthetestisratherexpensive,thecostben­efitratiowassupposedlylowertakingintoaccount thedecreasedneedforthediagnosticcystoscopy. In one of the later studies Yoder et al.suggested that if cytology was positive and used as the first diagnostic test no UroVysion™ test was needed, as cytology is nearly 100% specific.26If cytology was negative or atypical cells were found, the re­flex UroVysion™ test was performed on the same urine or bladder washing specimen. The problem arose if FISH was positive and the subsequent cys­ Strojan Flezar M / Urine and bladder washing cytology 213 FIGURE 5. Mild cytological atypia of urothelial cells (arrow) in routine cytology bladder washing specimen (Papanicolaou, x400) (A). Positive UroVysion test: 9 aneuploid cells (B). Majority were diploid cells (C). toscopy was negative. The authors found that these were anticipatory positive cases because 50 to 80% patients with FISH positive test developed cancer within 29 months. In one of the last published studies using UroVysion™ test, Kipp et al.have shown that also the percentage of polysomic cells (cells having an extra copy of one or more chromosomes) in the FISH positive patients is important.27The result of more than 5% of abnormal cells correlated with the recurrence and the progression of urothelial carcinoma to muscle invasion in patients with non­(muscle)-invasive carcinoma. Furthermore, the re­sult of more than 31% of abnormal cells was corre­lated to muscle invasion. However, a similar prob­lem appeared as in previous studies, many patients with FISH positive test had negative cystoscopy, so the further treatment of these patients would have to be determined. Obviously, as any diagnostic test also the UroVysion™ FISH test could give false positive re­sults, namely signal splitting, few tetrasomic cells (cells of the G2M phase) or overlapping cells could be interpreted as polysomic cells. On the other hand the test could also be false negative, specifically if there are no diagnostic cells in the sample or due to certain technical problems. As in other diagnostic tests, including cytology, it was also found to be negative in some low-grade urothelial tumours. Nevertheless, there is a general agreement among cytopathologists that UroVysion™ FISH test is a new promising diagnostic tool in urinary cytology.28,29 Experience of the Institute of Pathology, Faculty of Medicine, University of Ljubljana with UroVysion™ test We started introducing UroVysion™ test by the end of 2008. The performance of the UroVysion™ test on a Papanicolaou stained slides of urine or bladder washings prepared by membrane filter imprint technique routinely used at our institute, was not yet reported. Our approach was to find the area on the slide containing well preserved and well distributed atypical /representative cells which were marked by a diamond pencil for the subsequent testing by UroVysion™. UroVysion™ test was performed ac­cording to the manufacturer’s guidelines with two minor adjustments, the slides were first decolor­ized in acid ethanol and the enzyme digestion was lengthened to 28 minutes. Eighteen out of 29 tests were used to introduce and optimize a new method and further, eleven tests were used on diagnostic samples (Table 2). We found that all 5 cases of unde­termined and suspicious atypia were UroVysion™ test positive, while also one case of mild cytological atypia that would be regarded as negative/benign was positive in a patient who was previously treat­ed for non-invasive low-grade papillary carcinoma (Figure 5). As expected all 3 cases with positive/ malignant cytology were UroVysion™ test posi­tive and one case with negative cytology was also negative on UroVysion™ test. We concluded that the cytopathological diagnosis could be improved in 6/7 (88%) of atypical-suspicious cases. However, further experience with the test will be needed and the correlation of the UroVysion™ test results to histopathological diagnosis on tissue biopsies is awaited in order to improve the diagnosis in in­creasing number of patients with urothelial carci­noma in Slovenia.30 OurinitialimpressionisthattheUroVysion™ testrequiresoptimizationtosuittheproceduresal­readyusedinone’slaboratoryforthepreparation ofthefluidsamplesfromtheurinarytract.Thein­troductionofUroVysion™testrequiresinitialstaff trainingandadditionalequipment,foremostfluo­rescencemicroscopewithappropriatefilters.Atthe presentthetestisrathercostlyandtimeconsuming. 214 Strojan Flezar M / Urine and bladder washing cytology Conclusions Malignant cytomorphological characteristics of ex­foliated cells in urine or bladder washing can facili­tate the diagnosis of primary or recurrent urothe­lial carcinoma, therefore the method remains a use­ful diagnostic test with high specificity. However, in cases with less pronounced cellular and nuclear atypia the cytopathological diagnosis is not reli­able giving too many false negative results. Many ancillary tests were developed on urinary samples in the past two decades to overcome the low sensi­tivity of cytology for the detection of bladder can­cer. The newest and most promising test is com­mercially available multicolour multitarget FISH UroVysion™ test which was introduced into rou­tine diagnostics also at the Institute of Pathology, Faculty of Medicine, University of Ljubljana. Acknowledgement The article resumes the invited lecture given by the author during the 24th meeting of the Adriatic Society of Pathology in Duino, Italy in June 26-28, 2009. References 1. Grunze H, Springss AI. History of clinical cytology. A selection of documents. Darmstadt: G-I-T Verlag Ernst Giebler; 1980. 2. Koss LG. The lower urinary tract in the absence of cancer. In: Koss LG, Melamed MR, editors. Koss’s diagnostic cytology and its histopathologic bases. 5th edition. Philadelphia: Lippincott Williams & Wilkins; 2006. p. 738–776. 3. Grossfeld GD, Litwin MS, Wolf JS Jr, Hirack H, Shuler CL, Agerter DC, et al. Evaluation of asymptomatic microscopic hematuria in adults: The American Urological Association best practice policy – part I: definition, detection, prevalence, and etiology. Urology 2001; 57: 599-603. 4. Grossfeld GD, Litwin MS, Wolf JS Jr, Hirack H, Shuler CL, Agerter DC, et al. Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy – part II: patient evaluation, cytology, voided markers, imaging, cystoscopy, nephrology evaluation, and follow-up. Urology 2001; 57: 604-10. 5. Koss LG. Tumors of the urinary tract in urine and brushings. In: Koss LG, Melamed MR, editors. Koss’s diagnostic cytology and its histopathologic bases. 5th edition. Philadelphia: Lippincott Williams & Wilkins; 2006. p. 777-846. 6. RosenthalDL,RaabSS.Cytologicdetectionofurotheliallesions.In:Rosenthal DL, editors. Essentials in cytopathology series. New York: Springer; 2005. p. 57-62. 7. http://www.thinprep.com/ [assessed July 1st, 2010] 8. Lopes-Beltran A, Sauter G, Gasser T, Hartman A, Schmitz-Dräger BJ, Helpap B, et al. Infiltrating urothelial carcinoma. In: Eble JN, Sauter G, Epstein JI, Sesterhenn IA, editors. WHO classification of tumours: pathology and ge­netics of tumours of the urinary system and male genital organs. Lyon: IARC Press; 2004. p. 93-109. 9. Sauter G, Algaba F, Amin MB, Busch C, Cheville J, Gasser T, et al. Non­invasive urothelial tumors. In: Eble JN, Sauter G, Epstein JI, Sesterhenn IA, editors. WHO classification of tumours: pathology and genetics of tumours of the urinary system and male genital organs. Lyon: IARC Press; 2004. p.110-9. 10. Bastacky S, Ibrahim S, Wilczynski SP, Murphy WM. The accuracy of urinary cytology in daily practice. Cancer (Cancer Cytopathol) 1999; 87: 118-28. 11. Curry JL, Wojcik EM. The effect of the current World Health Organisation/ International Society of Urologic Pathologists bladder neoplasm classifica­tion system on urine cytology results. Cancer 2002; 96: 140-5. 12. Greene LF, Hanash KA, Farrow GM. Benign papilloma or papillary carcinoma of the bladder? J Urol 1973; 110: 205-7. 13. RossJS,CohenMB.Ancillarymethodsforthedetectionofreccurenturothe­lial neoplasia. Cancer 2000; 90: 75-86. 14. Us-Krašovec M. Pretocna in slikovna citometrija: novi kvantitativni metodi. Onkologija 1998; 2: 40-2. 15. Böcking A, Striepecke E, Auer H, Füzesi L. Static DNA cytometry. Biological background, technique and diagnostic interpretation. In: Wied GL, Bartels PH, Rosenthal D, Schenk U, editors. Compendium on computerized cytology and histology laboratory. Chicago: Tutorials of cytology; 1994. p. 107-28. 16. Tribukait B. Flow cytometry in assessing the clinical agressiveness of geni­tourinary neoplasms. World J Urol 1987; 5: 108-22. 17. Sullivan PS, Nooraie F, Sanchez H, Hirschowitz S, Levin M, Rao PN, et al. Comparison of ImmunoCyt, UroVysion and urine cytology in detection of recurrent urothelial carcinoma: a “split-sample” study. Cancer Cytopathol 2009; 117: 167-73. 18. Tetu B. Diagnosis of urothelial carcinoma from urine. Modern Pathol 2009; 22: S53-9. 19. Soloway MS, Briggman V, Carpinito GA, Chodak GW, Church PA, Lamm DL, et al. Use of a new tumor marker, urinary NMP22, in the detection of occult and rapidly recurring transitional cell carcinoma of the urinary tract follow­ing surgical treatment. J Urol 1996; 156: 363-7. 20. Nguyen CT, Jones JS. Defining the role of NMP22 in bladder cancer surveil­lance. World J Urol 2008; 26: 51-8. 21. Richter J, Beffa L, Wagner U, Schraml P, Gasser TC, Moch H, et al. Patterns of chromosomal imbalances in advanced urinary bladder cancer detected by comparative genomic hybridization. Am J Pathol 1998; 153: 1615-21. 22. Zhao J, Richter J, Wagner U, Roth B, Schraml P, Zellweger T, et al. Chromosomal imbalances in noninvasive papillary bladder neoplasms (pTa). Cancer Res 1999; 59: 4658-61. 23. Sokolova IA, Halling KC, Jenkins RB, Burkhardt HM, Meyer RG, Seeling SA, et al. The development of a multitarget, multicolor fluorescence in situ hybridization assay for the detection of urothelial carcinoma in urine. J Mol Diag 2000; 2: 116-23. 24. http://www.urovysion.com/ [assessed July 1st, 2010] 25. Bubendorf L, Grilli B, Sauter G, Mihatsch MJ, Gaser TC, Dalquen P. Multiprobe FISH for enhanced detection of bladder cancer in voided urine specimens and bladder washings. Am J Clin Pathol 2001; 116: 79-86. 26. Yoder BJ, Skacel M, Hedgepeth R, Babineau D, Ulchaker JC, Liou LS, et al. Reflex UroVysion testing of bladder cancer surveillance patients with equiv­ocal or negative cytology: a prospective study with focus on the natural his­tory of anticipatory positive findings. Am J Clin Pathol 2007; 127: 295-301. 27. 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Ljubljana: Institute of Oncology; 2009. 215 research article Imaging findings in bisphosphonate-induced osteonecrosis of the jaws Katarina Surlan Popovic1, Miha Kocar2 1 Department of Neuroradiology, Institute of Radiology, University Medical Centre Ljubljana, Ljubljana, Slovenia 2 Department of Maxillofacial and Oral Surgery, University Medical Centre Ljubljana, Ljubljana, Slovenia Received 26 May 2010 Accepted 10 June 2010 Disclosure: No potential conflicts of interest were disclosed. Correspondence to: Katarina Šurlan Popovic, MD MSc, Department of Neuroradiology, Institute of Radiology, University Medical Centre Ljubljana, Zaloška 7, 1000 Ljubljana, Slovenia. Phone: +386 1 522 3057; E-mail: katarina.surlan@gmail.com Background. Bisphosphonates are drugs used in the treatment of lytic bone metastases, multiple myeloma, hyper-calcemia of malignant origin, osteoporosis, and diseases such as Paget’s disease. Recently osteonecrosis of the jaw has been associated with the use of bisphosphonates. This study describes the imaging findings of bisphosphonate-associated osteonecrosis of the jaws. Patients and methods. Eleven patients, receiving bisphosphonate medication for approximately 28 months, with pain on affected side, nonhealing extraction sockets, purulent discharge and swelling in soft tissue were examined. Imaging consisted of non-contrast enhanced CT and contrast enhanced MRI. All patients underwent surgery of af­fected bone and histology confirmed osteonecrosis. Results. CT scan showed osteolytic and sclerotic lesions with cortical bone destruction in all patients. The osteonecro-sis was identified as delimited focal lesions with reduction of the signal on T1-weighted imaging and T2-weighted imaging. All the patients had soft-tissue involvement with enhancement in orbicular, buccinator muscle of the mouth or masticator space and adenopathy in submandibular and jugular digastric chain. Conclusions. Bisphosphonate related osteonecrosis of the jaw presents a variety of imaging findings that help to determine the extent of the disease and track the progression, however they are not specific for this disease. Key words: bisphosphonates; osteonecrosis; jaw; CT; MRI Introduction Bisphosphonates are drugs used in the treatment of lytic bone metastases, multiple myeloma, hyper-calcaemia of malignant origin, osteoporosis, and diseases such as Paget’s disease.1,2Bisphosphonates which decrease bone turnover by inhibiting os­teoclast mediated bone resorption are providing a significant improvement in the symptoms as a re­sult of reducing pain, bone demineralization, and bone fractures, either pathologic or due to insuf­ficiency.2,3Given the prevalence of these diseases, bisphosphonates are one of the most prescribed drug groups in the world, particularly in patients with high incidence cancer and frequent bone me­tastases.1,2,4,5Recently osteonecrosis of mandibula and maxilla has been associated with the use of bi­phosphonates.6-10 Such patients are referred to radiological insti­tutes for the evaluation of bisphosphonate-induced changes in their jaws, the exclusion of other dis­eases of the jaws (infected osteoradionecrosis, chronic osteomyelitis or pathological fractures) and the evaluation of the jaws before orofacial pro­cedures.10 The objective of this study was to examine the use of CT and MRI in the assessment of bone le­sions caused by this disease. Patients and methods Eleven patients, 6 men and 5 women, mean age 52 years (range 41- 76 years) who were treated with bisphosphonates were prospectively exam­ined. They were referred to the Department of the 216 Surlan Popovic K and Kocar M / Bisphosphonate-induced osteonecrosis Maxillofacial and Oral Surgery with pain on affect­ed side, nonhealing extraction sockets, purulent discharge and swelling in soft tissue. The indication for treatment with bisphospho­nates was multiple myeloma in 6 patients (55%), breast cancer bone metastases in 3 patients (27%) TABLE 1. Findings in CT imaging of the jaws of 11 patients with bisphosphonate-induced osteonecrosis of the jaws Sclerotic changes 11 Osteolytic changes 11 Periostal bone proliferation 7 Sequestration 1 Inferior alveolar canal involvement 4 and prostate cancer bone metastases in 2 patients (18%). Nine patients were treated with zolendronic acid and two with zolendronic and pamidronic acid. The patients had taken bisphosphonate medi­cation for approximately 28 months (range: 13- 36 months). The trigger factor in 8 patients was a tooth extraction and unknown in 3 patients. Clinical ex­amination revealed non-healed extraction sockets in the mandibula of 6 patients and in maxilla of 2 patients. Three patients were present with pain along the mandibular nerve region and swelling of the mouth floor and in four patients palpa­tion revealed exposed bone with irregular bone depositions. The histology of specimens showed osteonecrosis with actinomyces infection in all pa­tients. All patients underwent unenhanced CT and gadolinium-enhanced MRI of the jaw. CT imag­ing was performed in a 16-section CT machine (Somatom 16, Siemens Medical Systems, Erlangen, Germany; 45 eff. mAs, 120 kV). The CT images were reconstructed with a section thickness of 1 mm (0.6 mm increment) and multiplanar dental reconstruc­tions were generated using commercially available dental dedicated CT software, respectively. The MRI images (3T unit; Magnetom Trio, Siemens Medical Systems) included unenhanced axial T1- weighted imaging [repetition time (TR) 470 ms, echo time (TE) 11 ms], and T2-weighted imaging (TR 6000 ms, TE 91 ms), as well as axial short-tau inversion recovery (STIR)-weighted imaging (TR 5000 ms, TE 32 ms). After an injection of contrast medium (gadolinium; Magnevist, Schering, Berlin, Germany; 0.2 mmol/kg), using a power injector, fat-saturated axial T1-weighted images (TR 612 ms, TE 11 ms) were acquired. Two radiologists reviewed all imaging studies in consensus. In MRI studies we assessed the signal intensity change of bony structures, pathological gadolinium enhancement and soft tissue involve­ment. CT studies were reviewed for the presence of Surlan Popovic K and Kocar M / Bisphosphonate-induced osteonecrosis 217 TABLE 2. Findings in contrast-enhanced imaging of the jaws of 11 patients with bisphosphonate-induced osteonecrosis of the jaws Intensity changes of the cortical and subcortical bone structures 11 Contrast enhancement in necrotic bone area 11 Soft-tissue involvement 11 Cervical lymphadenopathy 11 osteolytic and sclerotic changes of the jaw, cortical bony destruction, periostal bone proliferation and involment of inferior alveolar canal. Results The degree of bone involvement on CT scan (Table1) showed osteolytic and sclerotic lesions with cortical bone destruction in all patients, fol­lowed by periostal bone proliferation in 7 patients. The sclerotic change encroached on the mandibu­lar (inferior alveolar) canal in 4 patients and 1 pa­tient had sequestration of mandibula. On gadolin­ium- enhanced MRI of the jaw (Table 2) the inten­sity changes of the cortical and subcortical bone structures in all patients were recorded (Figures 1 and 2). The osteonecrosis was identified as delim­ited focal lesions with reduction of the signal on T1- weighted imaging and T2- weighted imaging. In the regions of the open wound low T1-weighted signal correlated with high T2-weighted signal. However in the regions without open wound there was no bright signal from the lesion on the T2-wighted images and enhancement after the administration of paramagnetic contrast material was significantly lower compared to the lesions with bright T2-weighted signal. All the patients had soft-tissue involvement with enhancement in orbicular, buccinator muscle of the mouth or mas-ticator space and adenopathy in submandibular and jugular digastric chain. Maxillary sinus lesions were recorded in 2 patients. Discussion Bisphosphonate-associated osteonecrosis is a new disease that is becoming increasingly more com­mon.1The adverse effect of bisphosphonat drugs was first described in 2003 by Marx7, Migliorati8 FIGURE 2. CT and MRI image of a 78-year-old man with multiple myeloma. (A) Axial CT image reveals osteolytic region in the right maxilla (arrow). There is periostal bone reaction, as well as a sclerosis of the maxilla bone marrow on the left side (arrow­head). (B) The corresponding axial T1-weighted, fat-saturated, contrast-enhanced, MRI image demonstrates enhancement in pterygoid and masseter regions (thick arrow). There is also enhancement of necrotic region in right maxilla (thin arrow) and right mandibular ramus with medial cortex resorbtion and periostal reaction (arrow­head). (C) Exposed infected (Actinomyces) bone in the same patient. 218 Surlan Popovic K and Kocar M / Bisphosphonate-induced osteonecrosis and Pogrel9; however, connection of phospho­rus with osteonecrosis was first established in the 19thcentury in workers of the matchmak­ing industry.10,11Bisphosphonats are structurally analogous to inorganic pyrophosphates with tro­pism for solid calcium phosphate. Resistant to enzymatic degradation, they accumulate in bone tissue at high concentrations for long periods of time. Their mechanism of action is based on their ability to inhibit bone resorption: they increase os­teoclast apoptosis while inhibiting osteocyte and osteoblast apoptosis. The addition of an amine radical increases the potency of bisphosfonat drugs. It is only with the availability of newer gen­eration bisphosphonat drugs, the aminobisphos­phonates (alendronate, ibandronate, risedronate, pamidronate, zoledronate), that side effects like osteonecrosis of the jaw have been described.12,13The underlying pathophysiology of bosphos­phonats osteonecrosis remains incompletely un­derstood.10Bisphosphonates inhibit endothelial proliferation, interrupt intraosseous circulation and bone blood flow, contributing to the develop­ment of osteonecrosis.14It remains unclear whether patients receiving intravenous bisphosphonates are at a greater risk than those receiving oral bi­sphosphonates.1,10,15Similarly, it remains unclear whether there is a predilection for the jaws. In the literature, mandibular involvement occurs in 59% of cases, maxillary involvement in 27% of cases, and combined mandibular and maxillary involve­ment in 8% of cases.16It seemsthat bones exposed to constant trauma (like invasive dental procedures in the jaws) have impaired healing that may result in necrosis.17Acute exacerbations of bone and soft-tissue infections are the hallmarks of osteonecro-sis.1,10,18While spontaneous osteonecrosis of the jaw may occur, a triggering event such as dental extrac­tion or surgery is reported in 61.5% of cases.13,19 The American Association of Oral and Maxillofacial Surgeons has indicated that for the clinical diagnosis to be made, patients need to ex­hibit the following 3 criteria: 1)current or previ­ous treatment with a bisphosphonate; 2)exposed, necrotic bone in the maxillofacial region that has persisted for more than 8 weeks; and 3)no history of radiotherapy.20Although the radiographic find­ings are not a part of the diagnostic criteria, they provide valuable information to the clinician with regard to the course, magnitude, and progression of the disease.16,20The radiologic findings of bi-sphosphonate-associated osteonecrosis of the jaw are not specific and are found in other conditions such as osteomyelitis, osteoradionecrosis and can­cer metastasis.1,12,21CT is very useful for the ability to see and characterize the extension of the lesions and in detecting cortical involvement while MRI should be reserved for those patients who have soft tissue extension of the disease6, as the alteration of soft tissue is more detectable with MRI.22 Cross-sectional CT imaging of 11 patients from our study with initial and advanced diverse symp­toms produceda range of findings, where cortical disruption with mixed lyses and sclerosis of the involved bone were the predominant imaging fea­tures. Periostal new bone formation and sequestra­tion was recorded in the patients with advanced stage of the disease. CT finding in our study are consistent with findings in the other reports of the disease.6,14,23,224In all our patients we detected le­sions with no clinical correlation including focal sclerosis with disorganized trabeculae and difficult cortico-medullary differentiation on CT and low signal on T1 and T2 –weighted MRI images. We believe that these focal lesions are affected areas of the jaw on which a factor (i.e.tooth extraction) triggering the process of infection and opening up the focal lesion has not acted. This concurs with another study conducted on fourteen patients with bisphosphonate-induced osteonecrosis.1 In MRI the osteonecrosis appeared hypointense on T1-weighted images, but the signal intensity on T2-weighted sequence and after gadolinium enhancement varied. The lesions with intermedi­ate signal on T2-weighted sequence showed very little contrast enhancement, which was sugges­tive of nonviable bone and the enhancement was probably due to inflammatory reaction caused by Actinomyces infection.25Actinomyces infection was present in all specimens of our patient’s popu­lation. Same observations have been described in study of Bisdas et al.10and Hansen et al.26The in­fection was causing cervical lymphadenopathy in all patients. In patients with necrosis of mandibula pathological enhancement after contrast agent included muscles of the mouth floor, buccinator muscle and orbicular muscle, enhancement of mas-seter and pterygoid muscle was present in patients with maxilla and mandibular ramus necrosis. Similar MRI findings can be observed in metastatic disease, thus colleration with osseous changes on CT, clinical history and previous therapy is impor­tant for correct interpretation of MRI findings. In conclusion, bisphosphonate related os­teonecrosis of the jaw is a well described clinical condition with consistent radiographic findings; however they are not specific for this disease. It is important for radiologist to recognize this entity, Surlan Popovic K and Kocar M / Bisphosphonate-induced osteonecrosis 219 because imaging could be used for early detection in patients susceptible to this disease, which means better prognosis due to early treatment, avoiding biopsy and less necessity of surgery. References 1. García-Ferrer L, Bagán JV, Martínez-Sanjuan V, Hernandez-Bazan S, García R, Jiménez-Soriano Y, et al. MRI of mandibular osteonecrosis secondary to bisphosphonates. Am J Roentgenol 2008; 190: 949-55. 2. HorvatAG,KovacV,StrojanP.Radiotherapyinpalliativetreatmentofpainful bone metastases. Radiol Oncol 2009; 43: 213-24. 3. Cheng A, Mavrokokki A, Carter G, Stein B, Fazzalari NL, Wilson DF, et al. The dental implications of bisphosphonates and bone disease. Aust Dent J 2005; 50: 4-13. 4. Debevec L, Jeric T, Kovac V, Bitenc M, Sok M. Is there any progress in routine management of lung cancer patients? A comparative analysis of an institu­tion in 1996 and 2006. Radiol Oncol 2009; 43: 47-53. 5. Rajer M, Kovac V. Malignant spinal cord compression. Radiol Oncol 2008; 42: 23-31. 6. Phal PM, Myall RW, Assael LA, Weissman JL. Imaging findings of bisphos­phonate-associated osteonecrosis of the jaws. Am J Neuroradiol 2007; 28: 1139-45. 7. MarxRE.Pamidronate(Aredia)andzoledronate(Zometa)inducedavascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003; 61: 1115-7. 8. Migliorati CA. Bisphosphonate-associated oral osteonecrosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005; 99: 135. 9. Pogrel MA. Bisphosphonates and bone necrosis. J Oral Maxillofac Surg 2004; 62: 391-2. 10. Bisdas S, Chambron Pinho N, Smolarz A, Sader R, Vogl TJ, Mack MG. Biphosphonate-induced osteonecrosis of the jaws: CT and MRI spectrum of findings in 32 patients. Clin Radiol 2008; 63: 71-7. 11. Marx RE, Sawatari Y, Fortin M, Broumand V. Bisphosphonate-induced ex­posed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recogni­tion, prevention, and treatment. J Oral Maxillofac Surg 2005; 63: 1567-75. 12. Arce K, Assael LA, Weissman JL, Markiewicz MR. Imaging findings in bisphosphonate-related osteonecrosis of jaw. J Oral Maxillofac Surg 2009; 67: 75-84. 13. Orlandini F, Bossard D, Blanc G, Bodard AG, Gourmet R. Osteonecrosis of the jaw and biphosphonates: imaging features. J Radiol 2009; 90: 199-205. 14. Krishnan A, Arslanoglu A, Yildirm N, Silbergleit R, Aygun N. Imaging find­ings of bisphosphonate-related osteonecrosis of the jaw with emphasis on early magnetic resonance imaging findings. J Comput Assist Tomogr 2009; 33: 298-304. 15. Elad S, Gomori MJ, Ben-Ami N, Friedlander-Barenboim S, Regev E, Lazarovici TS, et al. Bisphosphonate-related osteonecrosis of the jaw: clinical correla­tions with computerized tomography presentation. Clin Oral Investig 2010; 14: 43-50. 16. Allen MR, Burr DB. The pathogenesis of bisphosphonate-related os­teonecrosis of the jaw: so many hypotheses, so few data. J Oral Maxillofac Surg 2009; 67: 61-70. 17. Thumbigere-Math V, Sabino MC, Gopalakrishnan R, Huckabay S, Dudek AZ, Basu S, et al. Bisphosphonate-related osteonecrosis of the jaw: clinical features, risk factors, management, and treatment outcomes of 26 patients. J Oral Maxillofac Surg 2009; 67: 1904-13. 18. Williamson RA. Surgical management of bisphosphonate induced os­teonecrosis of the jaws. Int J Oral Maxillofac Surg 2010; 39: 251-5. 19. Migliorati CA, Siegel MA, Elting LS. Biphosphonate-associated osteonecro-sis: a long term complication of biphosphonate treatment. Lancet Oncol 2006; 7: 508-14. 20. Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws – 2009 update. J Oral Maxillofac Surg 2009; 67: 2-12. 21. Thumbigere-Math V, Sabino MC, Gopalakrishnan R, Huckabay S, Dudek AZ, Basu S, et al. Bisphosphonate-related osteonecrosis of the jaw: clinical features, risk factors, management, and treatment outcomes of 26 patients. J Oral Maxillofac Surg 2009; 67: 1904-13. 22. Podobnik J, Kocijancic I, Kovac V, Sersa I. 3T MRI in evaluation of asbestos-related thoracic diseases -preliminary results. Radiol Oncol 2010; 44: 92-6. 23. Bedogni A, Blandamura S, Lokmic Z, Palumbo C, Ragazzo M, Ferrari F, et al. Bisphosphonate-associated jawbone osteonecrosis: a correlation between imaging techniques and histopathology. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008; 105: 358-64. 24. Chiandussi S, Biasotto M, Dore F, Cavalli F, Cova MA, Di Lenarda R. Clinical and diagnostic imaging of bisphosphonate-associated osteonecrosis of the jaws. Dentomaxillofac Radiol 2006; 35: 236-43. 25. Naik NH, Russo TA. Bisphosphonate-related osteonecrosis of the jaw: the role of actinomyces. Clin Infect Dis 2009; 49: 1729-32. 26. Hansen T, Kunkel M, Springer E, Walter C, Weber A, Siegel E, et al. Actinomycosis of the jaws--histopathological study of 45 patients shows significant involvement in bisphosphonate-associated osteonecrosis and infected osteoradionecrosis. Virchows Arch 2007; 45: 1009-17. 220 research article MRI in evaluation of perianal fistulae Amela Sofic, Serif Beslic, Nedzad Sehovic, Jasmin Caluk, Damir Sofic Institute of Radiology, Clinical Centre of University of Sarajevo, Sarajevo, Bosnia and Herzegovina Received 17 May 2010 Accepted 9 July 2010 Correspondence to: Amela Sofic, MD, MSc, Institute of Radiology, Clinical Centre of University of Sarajevo, Bolnicka 25, 71000 Sarajevo, Bosnia and Hercegovina. Phone/Fax:+387 33 444 553; E-mail: amelasofic@yahoo.com Disclosure: No potential conflicts of interest were disclosed. Background. Fistula is considered to be any abnormal passage which connects two epithelial surfaces. Parks’ fistulae classification demonstrates the biggest practical significance and divides fistulae into: intersphincteric, trans-sphincteric, suprasphincteric and extrasphincteric. Etiology of perianal fistulae is most commonly linked with the in­flammation of anal glands in Crohn’s disease, tuberculosis, pelvic infections, pelvic malignant tumours, and with the radiotherapy. Diagnostic method options are: RTG fistulography, CT fistulography and magnetic resonance imaging (MRI) of pelvic organs. Patients and methods. We have included 24 patients with perirectal fistulae in the prospective study. X-rays fistu­lography, CT fistulography, and then MRI of the pelvic cavity have been performed on all patients. Accuracy of each procedure in regards to the patients and the etiologic cause have been statistically determined. Results. 29.16% of transphincteric fistulae have been found, followed by 25% of intersphincteric, 25% of recto-vaginal, 12.5% of extrasphincteric, and 8.33% of suprasphincteric. Abscess collections have been found in 16.6% patients. The most frequent etiologic cause of perianal fistulae was Crohn’s disease in 37.5%, where the accuracy of classification of MRI was 100%, CT was 11% and X-rays 0%. Ulcerous colitis was the second cause, with 20.9% where the accuracy of MRI was 100%, while CT was 80% and X-rays was 0%. All other etiologic causes of fistulae were found in 41.6% patients. Conclusions. MRI is a reliable diagnostic modality in the classification of perirectal fistulae and can be an excellent diagnostic guide for successful surgical interventions with the aim to reduce the number of recurrences. Its advantage is that fistulae and abscess are visible without the need to apply any contrast medium. Key words: perianal fistulae; X-rays; CT; MRI; fistulography; abscess Introduction As per definition, a fistula is any abnormal pas­sage connecting two epithelial surfaces. Anal fistulae have been known ever since the times of Hypocrates and have been described through centuries. In 1835, Frederick Salmon performed a successful operation in London on the writer Charles Dickens. Goodsall describes the fistulous passage in details, and Parks’ classification shows the most practical significance until nowadays. The classification refers to classifying fistulae on: intersphincteric, transsphincteric, suprasphincteric and extrasphincteric. In the more detail anatomi­cal classification, the position of fistulae is used (“clockwise”) in respect to the clock hands to avoid any misinterpretation. Complex anal fistulae are those which are followed by risk factors: affected external sphincter anal muscle, forward location in women, multiple passages, incontinence, re­currences of fistulae, local radiation, chronic diar­rhoea, Crohn’s disease.1 Aetiology of perianal fistulae is most commonly associated with the inflammation of anal glands in the Crohn’s disease, tuberculosis, pelvic infections, pelvic malignant tumours and with radiotherapy. Idiopathic fistulae are rare and are generally ex­plained by chronic intramuscular anal infection (cryptoglandular hypothesis). In about 70% cases fistulous system drains through skin. Males are af­fected twice more than females, in ratio 2:1.2 Scope of the study The scope of the study is to indicate a possibility of pre-operative diagnostics with magnetic resonance Sofic A et al. / MRI and perianal fistulae 221 TABLE 1. Fistulae classification and the etiology 1 34 M Crohn’s disease Intersphincteric + 2 25 M Crohn’s disease Transsphincteric + 3 38 M Crohn’s disease Transsphincteric + 4 56 F Ca cerv-radiation Transsphincteric + 5 33 M Crohn’s disease Transsphincteric + 6 67 F Crohn’s disease Intersphincteric + 7 28 M Crohn’s disease Transsphincteric + 8 33 M Crohn’s disease Transsphincteric + 9 25 F Unknown Intersphincteric + 10 44 M Unknown Suprassphincteric + + + 11 56 F Crohn’s disease Suprassphincteric + + + 12 56 F Postpartum Rectovaginal + + 13 45 F Ca recti Rectovaginal + + 14 31 M Ulcerous colitis Intersphincteric + 15 19 M Ulcerous colitis Extrasphincteric + + + 16 55 F Ca recti-radiation Rectovaginal + + + 17 45 F Infla.dermoid cysts Rectovaginal + + + + 18 30 F Postpartum Rectovaginal + + 19 34 F Ulcerous colitis Extrasphincteric + + + + 20 44 F Ulcercous colitis Transsphincteric + + 21 42 M Ulcerous colitis Extrasphincteric + + + 22 54 M Ca recti Intersphincteric + 23 41 M Crohn’s disease Intersphincteric + 24 60 F Ca recti Rectovaginal + + 9 12 20 4 Accuracy 37,5% 50% 83% 16,6% imaging (MRI) in viewing and classifying perianal fistulae, with the aim to have as successful surgical treatment as possible, without recurrences. From the practical surgical point of view, it is of crucial importance to avoid incontinence as a post-opera­tive complication. Patients and methods Fromthe2008to2009weincludedintheprospec­tivestudy24patientswithexistingperirectalfistu­lae.Theaverageageofpatientswas41.45±2.6years, rangingfrom19to67years,withthesamenumber offemales50%(n=12)andmales50%(n=12). X-rays fistulography was performed first on all patients, followed by CT fistulography, and then by MRI of the pelvis. X-rays fistulography was performed on X-ray diascope (Practix 100, Philips, Aidhoven, the Netherlands), and after the applica­tion of Ultravist contrast medium through peri-anal fistulous openings. Immediately after that procedure, while the fistulous system was filled with the same contrast medium, the pelvic CT was performed on MDCT (Volume zoom, Siemens, Erlangen, Germany). The MRI pelvic examination was performed on 1.5 T machine (Avanto, Siemens, Erlagen, Germany) by using a routine protocol for pelvic examinations containing T1 3-plane views (axial, coronal and saggital planes), T2 axial and saggital planes, as well as bi-plane (axial and sag-gital planes) without the application of a contrast medium. Based on the data obtained, a comparison of all findings has been done, using each particular method. 222 Sofic A et al. / MRI and perianal fistulae FIGURE 1. Suprasphincteric fistula with the abscess collection in the gluteal region (T2W, sagital). FIGURE 2. Intersphincteric fistula in the shape of a horseshoe with the opening to the left posterior ( T2 Fs and T2W tra). Results Thefollowinghasbeenclassifiedin24patients: transsphinctericfistulaein29.16%ofpatients(n= 7),intersphinctericin25%(n=6),rectovaginalin 25%(n=6),extrasphinctericin12.5%(n=3)andsu­prasphinctericin8.33%ofpatients(n=2).Abscess collectionswerefoundin16.6%ofpatients(n=4) (Table1). Only9fistulaewereidentifiedbyX-raysfis­tulography;12fistulaewereidentifiedbyCTfis­tulography;and20byMRI(Table1).Foridenti­fyingfistulousrationinrespecttothesphincter complex,MRIwasasuperiormethod,whilefor rectovaginalfistulae,CTandX-raysfistulography werebetter. Themostfrequentcauseoffistulaeinoursam­plewasCrohn’sdiseasewith37.5%(n=9),fol­lowedbyulcerouscollitiswith20.9%(n=5),rectal cancer16.7%(n=4),postpartum8.3%(n=2),un­knownaetiology8.3%(n=2),cervicalcancer4.2% (n=1),andinflammatorydermoidcysts4.2% (n=1)(Table1). X-raysfistulographydemonstratedtheaccu­racyof37.5%.(.2=4.444,p=0.035),CTfistulog­raphyhadaccuracyof50%,(.2=6.000,p=0.014), andtheMRIdemonstratedaccuracyof83.3%. (.2=4.800,p=0.028)(Table2). Thecomparisonofresultsinrespecttothesex ofthepatientsdemonstratedthatthereweredif­ferencesinaccuracyinfavouroffemalepatients (Table2).Twenty-six%ofallfistulaeinourstudy arerectovaginal,wherethetotalaccuracyinfe­malesisonincrease.TheaccuracyofX-raysfistu­lographyinfemaleswas75%vs.males25%.The MRIaccuracyforfemaleswas66%vs.males33%. Slightlyhigheraccuracyforfemaleswasdemon­stratedinCTfistulography,inrespecttotheMRI, Sofic A et al. / MRI and perianal fistulae 223 TABLE 2. Accuracy of all three procedures M Sex F Total M Sex F Total M Sex F Total X-rays Neg. (-) Pos. (+) Number % Number % 10 83.3 2 16.7 5 41.7 7 58.3 15 62.5 9 37.5 9 75.0 3 25,0 3 25.0 9 75,0 12 50.0 12 50.0 0 0.0 12 100,0 4 33.3 8 66,7 4 16.7 20 83.3 Number 12 12 24 12 12 24 12 12 24 Total % 50.0 50.0 100.0 50.0 50.0 100.0 50.0 50.0 100.0 .2=4.444 p=0.035 .2=6.000 p=0.014 .2=4.800 p=0.028 TABLE 3. The accuracy of procedures varies depending on the aetiology – X-rays Aetiology Total Cervical cancer Rectal cancer Inflammatory dermoid cysts Crohn’s disease Unknown Postpartum Ulcerous colitis Number 1 1 0 9 2 0 2 15 Neg. (-) % 100.0 25.0 0.0 100.0 100.0 0.0 40.0 62.5 Number 0 3 1 0 0 2 3 9 Pos. (+) % 0.0 75.0 100.0 0.0 0.0 100.0 60.0 37.5 Number 1 4 1 9 2 2 5 24 Total % 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 .2=17.600 p=0.014 becauseitidentifiedmorerectovaginalfistulae comparedtotheMRI.Thelowestaccuracywas foundinX-raysfistulography. Theaccuracyofproceduresvariesdepend­ingontheaetiologyaswell.X-raysfistulography demonstratestheaccuracyinidentifying:ulcerous colitis60%,Crohn’sdisease0%,rectalcancer75%, cervicalcancer0%,inflammatorydermoidcysts 100%,postpartum100%andofunknownaetiol­ogy0%(Table3.).CTfistulographydemonstrates theaccuracyinidentifying:ulcerouscolitis80%, Crohn’sdisease11.1%,rectalcancer75%,cervi­calcancer0%,inflammatorydermoidcyst100%, postpartum100%,andofunknownaetiology 50%(Table4.).MRIdemonstratestheaccuracyin identifying:ulcerouscolitis100%,Crohn’sdisease 100%,rectalcancer50%,cervicalcancer100%,in­flammatorydermoidcyst100%,postpartum0%, andofunknownaetiology100%(Table5.)(Figures 1,2,3). Discussion Not so long time ago, surgeons performed opera­tions on perirectal fistulae without the previous radiological assessment. The surgical examina­tion under anaesthetics (EUA) consisted of visual inspection, palpation with the probe of a fistulous passage under general anaesthesia. Numerous di­agnostic modalities failed in visualisation and clas­sification of perianal fistulae. Fistulography,astheearliestX-raysmethod, cannotclassifyfistulaeduetotheinadequate 224 Sofic A et al. / MRI and perianal fistulae showingofanatomicstructures,sothatfrequently itisunclearanddifficultfortheinterpretation.CT canidentifytheexistenceoffistulouspassages, eitherthroughnon-ionicwatersollublecontrast mediabeinginsertedperrectumorthroughthe fistulousopening.However,itisnotsufficiend foramoredetailedanalysisofthewholecomplex ofprimaryandnumeroussecondarybranchesin thefistuloussystem.Althoughtheapplicationof multidetectorCTfistulographywiththeoption ofisotropicvoxelsandmultiplanedimagingcan bridgetheaforementionedissues,researchersdo notshowenoughinterestinthisfield.Itisobvi­ousthatthesuperiorityofMRIandendorectalul­trasound(EUS)examinationintheevaluationof perirectalfistulaeprovidesabettermotivationto theresearchers.3 MRI with the superficial body-coil, besides other anatomic structures in the pelvis, shows ex­cellent results in showing rectum, perianal region, internal, external anal sphincter, levator ani, ish­iorectal and ishioanal region.4In the evaluation of perirectal fistulae, it is very important to describe the relationship between fistula and the sphincter-ic mechanism in the coronal plane (Figure 3). It is equally important to describe the primary fistulous passage as well as the secondary ramification and possible associated abscess due to axial images. Images in the saggital plane are suitable for show­ing rectovaginal fistulae and the pre-sacral region. The surgical exploration without previous MRI di­agnostics can be made difficult due to the presence of fibrosis and oedema, so that the MRI can iden­tify the hidden intersphincteric space with the cap­ Sofic A et al. / MRI and perianal fistulae 225 TABLE 4. The accuracy of procedures varies depending on the aetiology - CT CT Aetiology Total Cervical cancer Rectal cancer Inflammatory dermoid cysts Crohn’s disease Unknown Postpartum Ulcerous colitis Number 1 1 0 8 1 0 1 12 Neg. (-) % 100.0 25.0 0.0 88.9 50.0 0.0 20.0 50.0 Number 0 3 1 1 1 2 4 12 Pos. (+) % 0.0 75.0 100.0 11.1 50.0 100.0 80.0 50.0 Number 1 4 1 9 2 2 5 24 Total % 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 .2=14.444 p=0.087 TABLE 5. The accuracy of procedures varies depending on the aetiology - MRI MR Aetiology Total Cervical cancer Rectal cancer Inflammatory dermoid cysts Crohn’s disease Unknown Postpartum Ulcerous colitis Number 0 2 0 0 0 2 0 4 Neg. (-) % 0.0 50.0 0.0 0.0 0.0 100.0 0.0 16.7 Number 1 2 1 9 2 0 5 20 Pos. (+) % 100.0 50.0 100.0 100.0 100.0 0.0 100.0 83.3 Number 1 4 1 9 2 2 5 24 Total % 100 100.0 100.0 100.0 100.0 100.0 100.0 100.0 .2=16.800 p=0.019 tured puss without rupturing the cutaneous layer. It is also useful in high fistulae – both transsphinc­teric and extrasphincteric. Fistulous passage, ab­scess, as well as all inflamed structures, show on T2W sequences high signal intensity, so they are easily noticed in respect to the muscles which have low signal intensity. On non-contrasted T1W se­quences, fistulous passages (especially the second­ary ones, the smaller ones), as well as abscess col­lections are identified with difficulties due to the moderate signal intensity of normal structures of the sphincter muscle and levatore ani. Therefore, it is recommended to use sequences with suppressed fats as the i.v. application of Gadolinium as a con­trast medium. The fistulous opening on skin can be filled with Gadolinium, thus obtaining the picture of fistulous system in hipersignal in T1W time, or by a cheaper method – by injecting physiological solution with showing the fistulous system in hi-persignal in T2W time. There is not a large number of published stud­ies in relation to the fistulography. Thus, Kuipers and Schulpen as far as in 1985 emphasized that fistulography is a reliable and accurate method in 226 Sofic A et al. / MRI and perianal fistulae only 16% cases.5The best results were obtained by Weisman et al.who managed to obtain reliable fis­tulography in half of the examined cases – 27 pa­tients in his study, which generally represents only very modest results.6 The first reporting on the accuracy of MRI in detection and classification of perianal fistulae was from 1992 – 1994 in Lunnis’ publications, with the matching of 86-88% between MRI and surgi­cal findings.7,8 EUS is not a comfortable procedure, however, it has a very good spatial resolution due to the close contact of the probe (10MHZ) with the rectal wall, which gives it the superiority in evalu­ation of fistulous openings within the rectum and the level of disruption of the sphincter in post-sur­gically incontinent patients. MRI is more comfort­able4and better shows intersphincteric abscesses. Halligan and Stoker claim that MRI assists the surgeon to reduce post-surgical recurrences for 75%, and that the EUS is only an alternative when it is not possible to perform the MRI.9 Hussain et al.from the Netherlands, in his study from 1996, talked about the superiority of MRI in classifica­tion of fistulae compared to the EUS (89 vs 61%).10 Spenser’s study from 1996, in which body-coil was used, demonstrated the accuracy of the MRI in showing perirectal fistulae of 88%.11 The same au­thor, two years later, in 1988, obtained the classifi­cation of fistulae by EUS of 81%, and by the MRI of 90%.12 Sensitivity of the primary fistulous passage reaches up to 100%, however, with the specificity of 86%. Yee et al.concludes in his study that the native endoscopic ultrasound does not detect rec-tovaginal fistulae.13 Intherecenttimes,ultrasoundvisibilityoffis­tulaefilledwithperoxidehasbeenresearched, whichisstrictlyrecommendedforthepre-surgical evaluationinpatientswithrecurrencesoffistulae. Gustafsonetal.claimedthattheendoscopicEUS complementedtheMRIinclassificationoffistulae.14 The optimal diagnostic approach is a combina­tion of EUS, examination under anaesthesia (EUA)and MRI in patients with fistulae who have the Crohn’s disease, reports Schwartz et al.in his ar­ticle.15 The Viennese group of radiologists, in their study, obtains the accuracy in classification of fis­tulae by the MRI of 84%, vs EUS of 60%.16 Gravante and Giordano in 2008 promoted 3D EUS as equal to the MRI in the examination of fis­tulae. The accuracy of the MRI was obtained in the range of 90 % compared with the EUS which ob­tained 81%.17Schratter-Sehn et al.obtained higher sensitivity by theEUS of 82% compared to n CT of 24% in the classification of perianal fistulae in the Crohn’s disease, while Schaefer et al.obtains the matching with the surgical findings of 89%.18,19 In our study, we obtained the accuracy in classifi­cation of fistulae by X-rays of 37.5%, with the CT accuracy was 50%, and the MRI accuracy was 83%. The most frequent aetiological cause of perianal fistulae was Crohn’s disease of 37.5%, where the accuracy of classification by the MRI was 100%, by CT of 11% and by X-rays was 0%. Ulcerous colitis was on the second place with 20.9%, where the ac­curacy in that respect was 100% by the MRI, 80% by CT and 0% by X-rays. All other etiological causes of fistulae including radiation, which is a serious side effect after oncological treatment20,21, were 41.6%. Abscess collection was found in 16.6 patients. Conclusions MRI is a reliable diagnostic modality in the classifi­cation of perirectal fistulae and can be an excellent diagnostic guide for successful surgical interven­tions with the aim to reduce the number of recur­rences. Its advantage is that fistulae and abscess are visible without the need to apply any contrast medium. References 1. Whiteford MH. Perianal abscess/fistula disease. Clin Colon Rectal Surg 2007; 20: 102-9. 2. Sainio P. Fistula-in-ano in a defined population. Incidence and epidemiologi­cal aspects. Ann Chir Gynaecol 1984; 73: 219-24. 3. Jones J, Tremaine W. Evaluation of perianal fistulas in patients with Crohn’s disease. Med Gen Med 2005; 7: 16. 4. Sofic A, Šehovic N, Bešlic Š, Prnjavorac B, Bilalovic N, Caluk J, et al. MR rectum imaging with ultra sound gel as instrumental contrast media in tubulovillous adenoma. Radiol Oncol 2008; 42: 136-42. 5. Kuijpers HC, Schulpen T. Fistulography for fistula-in-ano. Is it useful? Dis Colon Rectum 1985; 28: 103-4. 6. Weisman RI, Orsay CP, Pearl RK, Abcarian H. The role of fistulography in fistula-in-ano. Report of five cases. Dis Colon Rectum 1991; 34: 181-4. 7. Lunniss PJ, Armstrong P, Barker PG, Reznek RH, Phillips RK. Magnetic reso­nance imaging of anal fistulae. Lancet 1992; 340: 394-6. 8. Lunniss PJ, Barker PG, Sultan AH, Armstrong P, Reznek RH, Bartram CI, et al. Magnetic resonance imaging of fistula-in-ano. Dis Colon Rectum 1994; 37: 708-18. 9. Halligan S, StokerJ. Imaging of fistula in ano. Radiology 2006; 239: 18-33. 10. Hussain SM, Stoker J, Schouten WR, Hop WC, Lameris JS. Fistula in ano: en-doanal sonography versus endoanal MR imaging in classification. Radiology 1996; 200: 475-81. 11. SpencerJA,WardJ,BeckinghamIJ,AdamsC,AmbroseNS.Dynamiccontrast enhanced MR imaging of perianal fistulas. AJR Am J Roentgenol 1996; 167: 735-41. 12. Spencer JA, Chapple K, Wilson D, Ward J, Windsor AC, Ambrose NS. Outcome after surgery for perianal fistula: Predictive value of MR imaging. AJR Am J Roentgenol 1998; 171: 403-6. Sofic A et al. / MRI and perianal fistulae 227 13. Yee LF, Birnbaum EH, Read TE, Kodner IJ, Fleshman JW. Use of endoanal ultrasound in patients with rectovaginal fistulas. Dis Colon Rectum 1999; 42: 1057-64. 14. Gustafsson UM, Kahvecioglu B, Astrom G, Ahlstrom H, Graf W. Endoanal ultrasound or magnetic resonance imaging for preoperative assessment of anal fistula: a comparative study. Colorectal Dis 2001; 3: 189-97. 15. Schwartz DA, Wiersema MJ, Dudiak KM, Fletcher JG, Clain JE, Tremaine WJ, et al. A comparison of endoscopic ultrasound, magnetic resonance imag­ing, and exam under anesthesia for evaluation of Crohn’s perianal fistulas. Gastroenterology 2001; 121: 1064-72. 16. Maier AG, Funovics MA, Kreuzer SH, Herbst F, Wunderlich M, Teleky BK, et al. Evaluation of perianal sepsis: comparison of anal endosonography and magnetic resonance imaging. J Magn Reson Imaging 2001; 14: 254-260. 17. Gravante G, Giordano P. The role of three-dimensional endoluminal ultra­sound imaging in the evaluation of anorectal diseases: a review. Surg Endosc 2008; 22: 1570-8. 18. Schratter-Sehn AU, Lochs H, Vogelsang H, Schurawitzki H, Herold C, Schratter M. Endoscopic ultrasonography versus computed tomography in the differential diagnosis of perianorectal complications in Crohn’s disease. Endoscopy 1993; 25: 582-6. 19. Schaefer O, Lohrmann C, Langer M. Assessment of anal fistulas with high-resolution subtraction MR-fistulography: comparison with surgical findings. J Magn Reson Imaging 2004; 19: 91-8. 20. Botros M, Quevedo JF, Miller RC. Angiosarcoma of the liver after multimo­dality therapy for gallbladder carcinoma. Radiol Oncol 2009; 43: 126-31. 21. Piekarski JH, Jereczek-Fossa BA, Nejc D, Pluta P, Szymczak W, Sek P, et al. Does fecal diversion offer any chance for spontaneous closure of the radiation-induced rectovaginal fistula? Int J Gynecol Cancer 2008; 18: 66-70. 228 case report Mammographycally occult high grade ductal carcinoma in situ (DCIS) as second primary breast cancer, detected with MRI: a case report Marta Zebic-Sinkovec1, Maksimiljan Kadivec1, Gasper Podobnik1, Erik Skof2, Marko Snoj3 1 Department of Radiology, Institute of Oncology Ljubljana, Slovenia 2 Department of Medical Oncology, Institute of Oncology Ljubljana, Slovenia 3 Department of Surgery, Institute of Oncology Ljubljana, Slovenia Received 17 March 2010 Accepted 27 May 2010 Correspondence to: Marta Zebic-Šinkovec, MD, Department of Radiology, Institute of Oncology Ljubljana, Zaloška 2, SI-1000 Ljubljana, Slovenia. Phone: +386 1 5879 940; Fax: +386 1 5879 407; E-mail: MZebic@onko-i.si Disclosure: No potential conflicts of interest were disclosed. Background. Contralateral breast cancer (CLB) is the most common second primary breast cancer in patients di­agnosed with breast cancer. The majority of patients harbouring CLB tumours develop the invasive disease. Almost all invasive carcinomas are believed to begin as ductal carcinoma in situ (DCIS) lesions. The sensitivity of MRI for DCIS is much higher than that of mammography. Case report. We report the case of a woman who was treated with breast conserving therapy 10 years ago. At that time the invasive medullary carcinoma was diagnosed in the left breast. Ten years later mammographically occult DCIS was diagnosed with MRI-guided core biopsy in contralateral breast. Conclusions. There might be a potential role of MRI screening as part of an annual follow-up for patients diagnosed with breast cancer. Key words: high-grade DCIS; second primary breast cancer; MRI Introduction Contralateral breast cancer (CLB) is the most com­mon second primary breast cancer in patients diag­nosed with breast cancer.1The annual risk of devel­oping any CLB remains constant at approximately 0.75% and persists for at least 20 years after the treatment. The majority of patients (83%) harbour­ing CLB tumours develop the invasive disease.2There is little data on the use of MRI as a screening tool to detect a recurrence after the breast-conserv­ing therapy. Gorechland et al.concluded that MRI screening would not have been cost-effective and was unlikely to have improved the overall surviv­al.3However, the role of MRI in detection of inva­sive carcinoma had already been known, Kuhl et al.published in 2007 that MRI is more sensitive for de­tecting ductal carcinoma in situ(DCIS) than mam­mography (92% vs. 56%), especially for high-grade DCIS without necrosis (92% vs. 35%).4Almost all invasive carcinomas are believed to begin as DCIS lesions.5Therefore, some invasive carcinomas can be prevented by a timely intervention on the basis of MRI findings. Case report A 47-year-old female patient was treated by breast conserving surgery in 1999. At that time invasive medullary carcinoma was diagnosed in her left breast. The dissection of axilla has been done and there was no metastatic lymph node. She received adjuvant chemotherapy and a radiation therapy. She had the regular clinical and mammographic follow-up. In April 2009 her last mammography was obtained (Figure 1). Radiological findings were evaluated according to the Breast Imaging Zebic-Sinkovec M et al. / MRI in detection of secondary breast cancer 229 FIGURE 1. The mammograms were categorized as BI-RADS 2 (cyst, benign calcifications, postoperative changes). The breast density was categorized as ACR III. There was no change in comparison with previous mammograms. Reporting and Data System by American College of Radiology (Figure 1). In November 2009, she visited her doctor earlier because of changes in her right nipple. The nipple became retracted. She also had pain in her breast. Breast MRI was performed, using a 1.5-T magnet with a dedicated bilateral breast surface coil with prone position. The imaging protocol and param­eters were as follows: axial T1-weighted image and short-tau inversion recovery (STIR) of both breasts were obtained with 3 mm slice thickness. Next, T1-weighted images were acquired using a 3D fast low angle shot (FLASH) through both breasts. Pre-contrast images were obtained in the axial plane with a slice thickness of 1.0 mm with a distance factor 20% before the administration of the contrast agent. Then, five sequential contrast-enhanced images were acquired at every 1 min 23s. The MRI findings were categorized according to Breast Imaging Reporting and Data system (BI­RADS) lexicon. After a gadolinium injection and subtraction a bilateral enhancement was seen: On the left side there was a 7 x 5 mm mass-like enhancement in the scar area. The margins were round and well cir­cumscribed, the enhancement was homogeneous, and kinetic was 173% initial enhancement with plato BI-RADS 2 (Figure 2). Ontherighttherewasanon-masslikeenhance­ment.Theenhancementpatternwasductal-linearin distributionmeasured8x3mm.Theinternalenhance­mentwashomogenous-BI-RADS3-4(Figure3). On the precontrast T2-weighted sequence there was a hiperintensive signal in the area of ductal enhancement in the right breast. There were small cysts bilaterally (Figure 4). The targeted ultrasound was performed, using 5-12 MHz linear transducer (Toshiba Aplio, Nasu, Japan). In the right breast there was no pathology. In the left breast there was a small tumour 5 x 4 mm categorized as BI-RADS 4 (Figure 5). The fine needle US guided biopsy was performed and cy­tology was inconclusive. During the procedure the patient was very anxious and difficult to commu­nicate with. Because of the MRI finding in the right breast (mammogaphicaly occult, targeted ultrasound negative) and because of the patient’s history the 230 Zebic-Sinkovec M et al. / MRI in detection of secondary breast cancer MRI-guided core biopsy was performed. MRI-guided vacuum-assisted breast biopsy was per­formed with MRI-supported Breast Immobilization and Biopsy System with the 4-channel breast coil in prone position. Axial T1- weighted images were acquired using a 3D FLASH through both breasts. Precontrast images were obtained in the axial plane with a slice thickness of 1.0 mm with distance factor 20%. Twenty seconds after con­trast agent had been injected, another axial T1-3D FLASH sequence was performed with an injec­tion of 0.1 mmol/kg of body weight of gadopen­tetate dimeglumine. Biopsy was performed with a 9-gauge MRI compatible vacuum-assisted biopsy. The biopsy site was marked with a titanium clip. “Postclip” axial 3D FLASH was performed to as­sess clip deployment. The histological finding was DCIS-high grade, without any calcification. The patient was operat­ed. The breast conserving therapy was performed. The clip in the right breast was localized by the radioguided occult lesion localization (ROLL) method under X-ray guidance. The lesion in her left breast was localized by ROLL method under US guidance. The pathologic results were the rem­nant foci of high-grade DCIS in the right breast and benign changes in the left breast. Discussion The screening MRI has not yet been included in sur­veillance for patients treated by a breast-conserv­ing therapy. However, the patient visited her doc­tor earlier because of changes in her right nipple, what demonstrated the importance of the breast-self examination.6In addition, in our case MRI was performed because the patient had retracted nip­ple and dense breast.3DCIS was represented as a ductal-linear homogenous enhancement on MRI images. The ductal-linear homogenous enhance­ment is a type of non-masslike enhancement.7,8The path of enhancement follows the galactophoric system. The internal feature of the enhancement was homogenous in our case. DCIS and inflamma­tory disease are the most common causes for such a type of enhancement. The targeted ultrasound was negative, as we had expected. Among the non-masslike enhancement detected initially on MRI, only 11% could be retrospectively detected by ultrasound and sonographically oc­cult lesions have 22% probability of malignancy.9-12Although the ductal enhancement was small, it measured only 8 x 3 mm, we decided to perform MRI-guided core biopsy and the histological result was conclusive.13,14There was also a lesion which Zebic-Sinkovec M et al. / MRI in detection of secondary breast cancer 231 was incidentally found in the scar area of the left breast, which finally proved to be benign. High-grade DCIS with no calcifications is not easy to diagnose by mammography due to the lack of typical malignant calcifications or masses, especially in dense breasts. Calcifications with or without mass are more common in women under 50 years.11Autopsy studies have shown that almost 9% of women have undetected DCIS.15 Almostallinvasivecarcinomasarebelievedto beginasDCISlesionsbutthetimecourseoftransi­tionisunknown.WhetherallDCISwillultimately evolvetotheinvasivediseaseisunclear.16,17In2007 anarticlewaspublished,thatsensitivityofMRIfor high-gradeDCISismuchhigherthanthatofmam­mography(92%vs.56%),especiallyforhighgrade DCISwithoutnecrosis(97%vs.35%).4Ifwepickup allcasesofDCISwewouldpreventvirtuallyallcas­esofbreastcancer,includingCLB.CLBisthemost commonsecondprimarybreastcancerinpatients diagnosedwithbreastcancer.Theannualriskof developinganyCLBremainsconstantat0.75%per yearafterthetreatmentandpersistsforatleast20 years.Themajorityofpatients(83%)harbouring CLBtumoursdevelopinvasivedisease.2Thedetec­tionofsecondbreastcancersintheasymptomatic phaseleadstothedetectionofearly-stagecancer anditimprovestherelativesurvivalalikeinother cancer’slocalisationsbetween27%to47%.18,19 In conclusion, by the Breast MRI Guidelines from the European Society of Breast Imaging14, currently there is not sufficient evidence to recommend the screening with MRI to patients treated by breast conserving surgery. But we might say that our case, in accordance to the European Guidelines, justifies MRI as a problem-solving modality when: the find­ings of conventional imaging are inconclusive and it is impossible to image sufficiently the primary tumour region after the conservative therapy with mammography. References 1. Wedam SB, Swain SM. Contralateral breast cancer: Where does it all begin? J Clin Oncol 2005; 23: 4585-7. 2. Hill-Kayser CE, Harris EE, Hwang WT, Solin LJ. Twenty-year incidence and patterns of contralateral breast cancer after breast conservation treatment with radiation. Int J Radiat Oncol Biol Phys 2006; 66: 1313-9. 3. Gorechlad JW, McCabe EB, Higgins JH, Likosky DS, Lewis PJ, Rosenkranz KM, et al. Screening for recurrences in patients treated with breast-conserving surgery: is there a role for MRI? Ann Surg Oncol 2008; 15: 1703-9. 4. Kuhl CK, Schrading S, Bieling HB, Wardelmann E, Leutner CC, Koenig R, et al. MRI for diagnosis of pure ductal carcinoma in situ: a prospective observa­tional study. Lancet 2007; 370: 485-92. 5. Thomson JZ, Evans AJ, Pinder SE, Burrell HC, Wilson ARM, Ellis IO. Growth pattern of ductal carcinoma in situ (DCIS): a retrospective analysis based on mammographic findings. Brit J Cancer 2001; 85: 225-7. 6. Plesnicar A, Golicnik M, Fazarinc IK, Kralj B, Kovac V, Plesnicar BK. Attitudes of midwifery students towards teaching breast-self examination. Radiol Oncol 2010; 44: 52-6. 7. Thomassin-Naggara I, Salem C, Darai E, Bazot M, Uzan S, Marsault C, Chopier J. Non-masslike enhancement on breast MRI: interpretation pearls. J Radiol 2009; 90 (3 Pt 1): 269-75. 8. Sakamoto N, Tozaki M, Higa K, Tsunoda Y, Ogawa T, Abe S, et al. Categorization of non-mass-like breast lesions detected by MRI. Breast Cancer 2008; 15: 241-6. 9. LaTrenta LR. Breast lesions detected with MR imaging: utility and his-topathologic importance of identification with US. Radiolology 2003; 227: 856-61. 10. Abe Schmidt RA, Shah RN, Shimauchi A, Kulkarni K, Sennett CA, Newstead GM. MR-directed (“Second-Look”) ultrasound examination for breast le­sions detected initially on MRI: MR and sonographic findings. AJR Am J Roentgenol 2010; 194: 370-7. 11. Podkrajsek M, Zgajnar J, Hocevar M. What is the most common mammo-graphic appearance of T1a and T1b invasive breast cancer? Radiol Oncol 2008; 42: 173-80. 12. Kocijancic I. Diagnostic imaging of small amounts of pleural fluid: Pleural effusion vs. physioloic pleural fluid. Coll Antropol 2007; 31: 1195-99. 13. Kuhl CK, Morakkabati N, Leutner CC, Schmiedel A, Wardelmann E, Schild HH. MR imaging–guided large-core (14-gauge) needle biopsy of small le­sions visible at breast imaging lone. Radiology 2001; 220: 31-9. 14. Welch HG, Black WC. Using autopsy series to estimate the disease “res­ervoir” for ductal carcinoma in situ of the breast: how much more breast cancer can we find? Ann Intern Med 1997; 127: 1023-8. 15. Mann RM, Kuhl CK, Kinkel K, Boetes C. Breast MRI: guidelines from the European Society of Breast Imaging. Eur Radiol 2008; 18: 1307-18. 16. Leonard GD, Swain SM. Ductal carcinoma in situ, complexities and chal­lenges. J Natl Cancer Inst 2004; 96: 906-20. 17. Erbas B, Provenzano E, Arnes J, Gertig D. The natural history of ductal carcinoma in situ of the breast: a rewiev. Breast Cancer Res Treat 2006; 97: 135-44. 18. Debevec L, Jeric T, Kovac V, Bitenc M, Sok M. Is there any progress in routine management of lung cancer patients? A comparative analysis of an institu­tion in 1996 and 2006. Radiol Oncol 2009; 43: 47-53. 19. Houssami N, Ciatto S, Martinelli F, Bonardi R, Duffy SW. Early detection of second breast cancers improves prognosis in breast cancer survivors. Ann Oncol 2009; 20: 1505-10. 232 research article Effect of response quality and line of treatment with rituximab on overall and disease-free survival of patients with B-cell lymphoma Mateja Horvat, Barbara Jezersek Novakovic Department of Medical Oncology, Institute of Oncology Ljubljana, Slovenia Received 1 June 2010 Accepted 2 July 2010 Correspondence to: Assist. Prof. Barbara Jezeršek Novakovic, MD, PhD, Department of Medical Oncology, Institute of Oncology Ljubljana, Zaloška 2, 1000 Ljubljana, Slovenia Phone: +386 1 5879 280; Fax: +386 1 5879 305; e-mail: bjezersek@onko-i.si Disclosure: No potential conflicts of interest were disclosed Background. The introduction of rituximab into the treatment of patients with non-Hodgkin’s lymphomas has im­proved the overall response rate, as well as the response duration and the overall survival of patients with B-cell lym­phomas. But only a few studies have addressed the question whether the better response (complete response) and the early introduction of rituximab into the treatment translate into the better survival. The aim of this retrospective study was to assess the potential relationship between either the quality of the response or the line of the rituximab treatment and the overall survival (OS) as well as the disease-free survival (DFS) of patients with B-cell lymphomas. Patients and methods. In the study, we analysed treatment outcomes in patients with different histological types of B-cell lymphomas who were treated at the Institute of Oncology between 2003 and 2007 with rituximab and chemotherapy. We included only patients who had the level of CD20 expression assessed prior to the introduction of the treatment with quantitative flow-cytometric measurements. The OS and DFS were evaluated by Kaplan-Meier survival curves. Results. One hundred and fourteen patients were enrolled in the study. Patients who achieved a complete response after the rituximab containing treatment had a significantly longer OS than those reaching a partial response (hazard ratio [HR], 0.34; 95% CI, 0.05 to 0.91, P = 0.0375) and than patients with stable (hazard ratio [HR], 0.11; 95% CI, 0.0002 to 0.033, P < 0.0001) or progressive disease (hazard ratio [HR], 0.09; 95% CI, 0.003 to 0.03, P < 0.0001). Patients who achieved a complete response (CR; n = 70; 61.4%) had also a significantly longer DFS (hazard ratio [HR], 0.26; 95% CI, 0.021 to 0.538, P = 0.0068) than those reaching only a partial response (PR; n = 17; 14.9%). Patients treated with rituximab as the first-line treatment (n = 50; 43.9%) had a significantly longer OS than those treated with rituximab for the first (hazard ratio [HR], 0.27; 95% CI, 0.106 to 0.645, P = 0.0036) or second relapse (hazard ratio [HR], 0.22; 95% CI, 0.078 to 0.5, P = 0.0006). Also the DFS of patients treated with rituximab as the first-line treatment (n = 46; 52.9%) was significantly longer (hazard ratio [HR], 0.32; 95% CI, 0.088 to 0.9, P = 0.0325) than in patients treated with rituximab for their first relapse (n = 25; 28.7%). Conclusions. These data indicate that a better response to rituximab therapy presumably translates into an im­proved OS and DFS for patients with B-cell lymphomas. The early introduction of rituximab into the treatment (i.e. first-line treatment) might improve OS. Therefore, the response adapted first-line therapy with rituximab should be considered when the treatment decision is taken in B-cell lymphoma patients. Key words: B-cell lymphoma; rituximab; response quality, the line of treatment; overall survival; disease-free survival Introduction B-cell lymphomas are a group of diseases char­acterized by the proliferation of lymphoid tissue and occasionally by the presence of abnormal lymphoid elements in the peripheral blood.1The incidence of these malignancies has been increas­ing over the past several decades by approximately 3% per year.2Over the last two decades, there has been a significant increase in management options of these patients, consisting of the observation in case of indolent lymphomas, various chemothera­ Jezersek Novakovic B and Horvat M / Treatment with rituximab 233 pies (alkylating agent-based, fludarabine-based, 1.0 antracycline-based), hematopoietic stem-cell trans­plantation and biologic therapies among which al- so the therapy that targets the CD20 antigen, such as rituximab. The introduction of rituximab into the treatment of patients with non-Hodgkin lymphoma has im­proved the overall response rate, as well as the re­sponse duration and the overall survival of patients with B-cell lymphomas.3,4Although there has been some evidence that in the treatment of lymphoma patients the better response is associated with the prolonged disease-free survival, the correlation be­tween the quality of response and the survival still Disease-free survival 0.5 0.0 remains unknown.4-9Recently published studies have indicated that a better response to first-line treatment translates into an improved survival for patients with follicular lymphoma and also with other malignomas.10,11With our retrospective study we, therefore, wanted to assess the potential cor­relation between either the quality of response or the line of the rituximab treatment with both the overall survival (OS) and the disease-free survival Months FIGURE 1. Disease-free survival after treatment with rituximab and chemotherapy according to the response quality. CR - complete response, PR - partial response 1.0 (DFS) of patients with B-cell lymphomas. Overall survival 0.5 Patients and methods Patient population Patients with different histological types of B-cell lymphomas treated with the rituximab containing therapy between 2003 and 2007 at the Institute of Oncology Ljubljana were included in our retro­spective study. Because this study was a part of a more extensive research on the correlation between the CD20 expression and treatment outcome just patients who had the level of CD20 expression as­sessed prior to the introduction of the treatment with quantitative flow-cytometric measurements were selected. These patients represented approxi­mately 33.5% of all patients treated routinely with rituximab in that period. Patientsreceivedtreatmentsaccordingtothe thenprotocolatourInstitute.Aggressivelympho­maswerepredominatelytreatedwiththerituximab containingtherapyinthefirst-lineandjustrelaps­ingpatientswhohadnotpreviouslyreceivedrituxi­mabweretreatedinthesecondorconsecutivelines. Ontheotherhand,mostpatientswithindolentlym­phomaswereinlinewiththerecommendationsnot treatedwiththerituximabcontainingtherapyuntil relapse.Rituximab–chemotherapycombinations wereselectedaccordingtothehistologicaltype oflymphoma,extentofthediseaseandprevious 0.0 Unspecified CR PR SD PD FIGURE 2. Overall survival after treatment with rituximab and chemotherapy ac­cording to the response quality. CR - complete response, PR - partial response, SD - stable disease, PD - progressive disease, ORR - overall response rate, Unspecified – response not specified treatments.MostofthepatientsreceivedR-CHOP (75.4%).Patientswithamorelimiteddiseasewere plannedtoreceive6andpatientswithextensivedis­easeupto8chemo-immunotherapycycles. Response to treatment The treatment response data were retrospectively noted from patients’ records for the specified B-cell lymphoma patients. The quality of the response was assessed by Cheson’s criteria.12 In the next step, the OS data for all includ­ed B-cell lymphoma patients together with the 234 Jezersek Novakovic B and Horvat M / Treatment with rituximab TABLE 1. Patients’ characteristics together with the distribution of patients according to the lines of treatment Patient’s characteristics Gender 64 males (56.1%); 50 females (43.9%) Age Median 58.5 years (range 19 to 82 years) Histological type Number (%) of patients Number of patients treated with rituximab as first-line treatment (%) Number of patients treated with rituximab as second-line treatment (%) Number of patients treated with rituximab as third or subsequent line of treat­ment (%) DLBCL 42 (36.8) 33 (78.6) 8 (19) 1 (2.4) FL 30 (26.3) 6 (20) 11 (37) 13 (43) CLL 5 (4.4) 0 2 (40) 3 (60) MCL 20 (17.5) 8 (40) 6 (30) 6 (30) MZL 2 (1.8) 0 1 (50) 1 (50) Unclassified 15 (13.2) 3 (20) 5 (33) 7 (47) Total 114 (100) 50 (43.9) 33 (28.9) 31 (27.2) DLBCL = diffuse large B-cell lymphoma, FL = follicular lymphoma, CLL = chronic lymphocytic leukemia, MCL = mantle cell lymphoma, MZL = marginal zone lymphoma, Unclassified = unclassified B-cell lymphoma TABLE 2. The distribution of patients receiving rituximab according to the response quality CR 70 61.4 PR 17 14.9 SD 6 5.3 PD 19 16.7 Unspecified 2 1.8 ORR 87 76.3 Total 114 100 CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, ORR = overall response rate, Unspecified = response not specified DFS data for the B-cell lymphoma patients who achieved the complete (CR) or the partial response (PR) after the treatment were obtained. The OS was assessed by Kaplan-Meier survi­val curves from the beginning of the treatment for all patients. The response duration expressed as the DFS was evaluated by Kaplan-Meier survival curves from the end of the treatment for the pa­tients attaining CR or PR after the rituximab con­taining treatment. Statistical analysis The difference between the survival curves was assessed by a log-rank test and the difference be­tween the overall response rates by a hi-square test. Results Characteristics of the study participants One hundred and fourteen patients with different histological types of B-cell lymphomas who were treated with rituximab and chemotherapy between 2003 and 2007 and had the level of CD20 expres­sion assessed prior to the introduction of the treat­ment with quantitative flow-cytometric measure­ments were included. There were 64 males and 50 females with the median age of 58.5 years (range 19 to 82 years). The majority of patients had the dif­fuse large B-cell lymphoma (DLBCL; 42 patients; 36.8%) and follicular lymphoma (FL; 30 patients; 26.3%). Patients’ characteristics together with the distribution of patients according to the lines of the treatment are given in Table 1. In the majority of patients, rituximab was giv­en as the first-line treatment (50 patients; 43.9%), while 33 patients (28.9%) received it as the second-line treatment, and 31 patients (27.2%) as the third or subsequent line of the treatment. There was, however, some difference between aggressive and indolent lymphomas – namely 78.6% of patients with aggressive lymphomas received rituximab as the first-line treatment, 19% as the second-line treatment and 2.4% as the third/subsequent line treatment while just 23.6% of patients with indo­lent or unclassified lymphomas were treated with rituximab as the first-line, 34.7% as the second-line and 41.7% as the third/subsequent line of the treat­ment (Table 1). Jezersek Novakovic B and Horvat M / Treatment with rituximab 235 All patients received at least 3 and up to 8 cycles 1.0 of the treatment. No patients were excluded due to serious side effects. The follow-up of side effects was by all means not the objective of this study, yet we have to mention that in the routine setting serious side effects of the rituximab treatment have been during a longer period of time observed in less than 1% of patients. The effect of the response quality on OS and DFS The overall response rate (ORR) of the treatment with rituximab and chemotherapy regardless of the histological type of lymphoma or of the line Disease-free survival 0.5 0.0 of treatment was 76.3% (61.4% CR; 14.9% PR). The Months distribution of patients receiving rituximab accord- FIGURE 3. Disease-free survival after treatment with rituximab and chemotherapy ing to the response quality is given in Table 2. according to the lines of treatment. Table 3 additionally gives the distribution of 1.0 patients receiving rituximab according to the re­sponse quality and the type of lymphoma, yet the data are given just for those lymphoma type groups that comprise more than 10 patients. In continuation, the DFS was evaluated from the end of the treatment for patients achieving CR and PR to the treatment with rituximab and chemo­therapy (87 patients; 76.3%) and is according to the response quality presented in Figure 1. The B-cell lymphoma patients treated with ritux­imab who achieved a complete response (CR; n = 70; 61.4%) had a significantly longer DFS (hazard ratio [HR], 0.26; 95% CI, 0.021 to 0.538, P = 0.0068) than those reaching just a partial response (PR; n = Overall survival 0.5 17; 14.9%). In patients who achieved CR, the me­ dian response duration has not been reached yet, 0.0 while for the patients who achieved PR, it was 19 Months months. FIGURE 4. Overall survival after treatment with rituximab and chemotherapy accord­ ing to the lines of treatment. The OS was assessed from the beginning of the treatment for all 114 patients treated with rituxi­mab and chemotherapy. Figure 2 presents the OS after the treatment with rituximab and chemother­apy according to the response quality. TheB-celllymphomapatientswhoachieveda completeresponseaftertherituximabtherapyhad asignificantlylongerOSthanthosereachingapar­tialresponse(hazardratio[HR],0.34;95%CI,0.05 to0.91,P=0.0375),andthanpatientswithstable (hazardratio[HR],0.11;95%CI,0.0002to0.033, P<0.0001)orprogressivedisease(hazardratio [HR],0.09;95%CI,0.003to0.03,P<0.0001).Patients whoachievedapartialresponsehadasignificantly longerOSthanthosewithprogressivedisease(haz-ardratio[HR],0.24;95%CI,0.095to0.589,P=0.002). Inpatientswithstablediseaseaftertherituximab therapy,themedianOSwas17.1months,whilefor thepatientswithprogressivedisease,itwasonly 7.8months.ThemedianOShasnotbeenreached forpatientswithCR,PRandunspecifiedresponse. The effect of the line of the treatment with rituximab on OS and DFS The distribution of patients receiving rituximab ac­cording to the response quality and the line of the treatment is given in Table 4. The duration of the response expressed as the DFS for those 87 patients (76.3%) achieving CR and PR to the treatment with rituximab and chemother­apy is according to lines of the treatment shown in Figure 3. 236 Jezersek Novakovic B and Horvat M / Treatment with rituximab TABLE 3. The distribution of patients receiving rituximab according to the response quality and type of lymphoma CR 29 69 22 73,3 9 45 8 53,3 PR 8 19 3 10 2 10 3 20 SD 0 0 1 3,3 4 20 1 6,7 PD 4 9,5 3 10 5 25 3 20 Unspecified 1 2,4 1 3,3 0 0 0 0 ORR 37 88,1 25 83,3 11 55 11 73,3 Total 42 36.8 30 26.3 20 17.5 15 13.2 CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, ORR = overall response rate, Unspecified = response not specified, DLBCL = diffuse large B-cell lymphoma, FL = follicular lymphoma, MCL = mantle cell lymphoma, Unclassified = unclassified B-cell lymphoma TABLE 4. The distribution of patients receiving rituximab according to response quality and the line of treatment CR 70 61.4 36 72 21 63.6 13 41.9 PR 17 14.9 10 20 4 12.1 3 9.7 SD 6 5.3 1 2 2 6.1 3 9.7 PD 19 16.7 2 4 5 15.2 12 38.7 Unspecified 2 1.8 1 2 1 3 0 0 ORR 87 76.3 46 92 25 75.8 16 51.6 Total 114 100 50 43.9 33 28.9 31 27.2 CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, ORR = overall response rate The difference in response duration was statisti­cally insignificant either between the patients treat­ed with rituximab as the third or subsequent line (n = 16; 16%) and first-line treated lymphoma patients (n = 46; 52.9%) or between the patients treated with rituximab as the third or subsequent line (n = 16; 16%) and second-line treated lymphoma patients (n = 25; 28.7%). However, first-line treated lympho­ma patients (n = 46; 52.9%) had a significantly long­er DFS (hazard ratio [HR], 0.32; 95% CI, 0.088 to 0.9, P = 0.0325) than patients treated with rituximab for the first relapse (n = 25; 28.7%). The median DFS has not been reached for any patient group treated with rituximab. The OS from the beginning of the treatment for all 114 patients treated with rituximab and chemo­therapy according to the lines of the treatment is presented in Figure 4. First-line treated lymphoma patients (n = 50; 43.9%) had a significantly longer OS than those treated with rituximab for the first (hazard ratio [HR], 0.27; 95% CI, 0.106 to 0.645, P = 0.0036) or the second relapse (hazard ratio [HR], 0.22; 95% CI, 0.078 to 0.5, P = 0.0006). The median OS in patients treated with rituximab as the second-line treatment was 44.1 months. The median OS has not been reached for patients treated with rituximab as the first or third line of the treatment. Discussion We analyzed the potential influence of response quality and the line of the treatment on OS and DFS of patients with different histological types of B-cell lymphomas. Results of our study pro­vide some evidence that response quality paral­lels with the survival since patients who achieved a complete response had a significantly longer OS than those reaching a partial response or those Jezersek Novakovic B and Horvat M / Treatment with rituximab 237 experiencing stable or progressive disease. Yet, we must be aware that our study included both patients with indolent and patients with aggres­sive subtypes of lymphomas. As the two groups of B-cell lymphomas differ in their natural course, aggressiveness and above all in their susceptibility to chemo-immunotherapy, this result may have been partially influenced by the rather large pro­portion (36.8%) of aggressive lymphoma patients in our study. Aggressive lymphomas differ from the indolent ones as they can be to a certain extent cured with conventional chemotherapy or chemo-immunotherapy. The goal of the treatment of ag­gressive lymphomas is, therefore, the achievement of as many as possible complete responses in the frontline treatment since only those patients are ex­pected to be cured. On the other hand, up till now quite a few stud­ies in indolent follicular lymphomas evidenced that a better response is associated with prolonged DFS yet the correlation between the quality of response and OS has not been unequivocally confirmed.4-8This might be at least partially on account of a rather short follow-up in these studies since an im­proved long-term survival for follicular lymphoma patients who reached a CR in the first-line treat­ment (not including rituximab) compared with patients who reached only a PR has been reported in the recently published study with a longer fol­low-up (median 14.9 years).10Also another recent study in follicular lymphoma patients treated with chemo-immunotherapy (R-CHVP-IFN) showed that the achievement of CR appears to be associ­ated with an improved survival, although statis­tical significance was not reached.13This issue by our opinion needs a further clarification on a larger group of patients having the same histological type of lymphoma. We also confirmed some association between the earlier rituximab treatment and longer OS and DFS. These results are in agreement with the re­sults of our previous study reporting outcomes of the treatment with various chemo-immunotherapy combinations.14By that study it was confirmed that results of the treatment with rituximab and chem­otherapy are in all aspects superior when the pa­tients receive chemo-immunotherapy as the first-line treatment. The ORR was higher in the first-line treatment compared to the second or third/subse­quent line treatment in patients with DLBCL, FL but not in MCL. The same was determined for DFS and OS which were longer in the first-line treat­ment compared to the second or third/subsequent line treatment in patients with DLBCL, FL and MCL. These observations seem logical at least in aggressive types of lymphomas where one can ex­pect that previously untreated lymphoma patients would respond to treatment optimally as the pos­sible mechanisms of resistance to treatment have not emerged yet.15The impact of the primary treat­ment in indolent lymphoma patients on OS might be on the other hand interfered with the second or the third-line treatments which are very likely to be needed in the course of indolent lymphomas. But in general, various other studies have also reported better survival outcomes for the frontline treatment with rituximab both in indolent and in aggressive lymphomas which was simply confirmed with our research.16-21 In clinical praxis, there is no doubt about how to treat patients with CD20 positive aggressive lymphomas – they should receive rituximab in front-line therapy. On the contrary, the situation in indolent lymphomas is still somehow undefined since the recommendations for the treatment of indolent lymphomas in the last few years favour the first-line treatment with rituximab. Our results, however, demonstrate that in rituximab naďve pa­tients also the second and the third-line treatment is justifiable. In conclusion, our data indicate that a better re­sponse to the rituximab therapy presumably trans­lates into an improved OS and DFS for patients with B-cell lymphomas. The early introduction of rituximab into the treatment (i.e. first-line treat­ment) might improve OS. The proposed first-line treatment with rituximab should be considered in both types of lymphomas – the aggressive and the indolent ones. Yet, in rituximab naďve patients with indolent lymphomas also the second or subse­quent line of the treatment with rituximab should be taken in account. References 1. http://medical-dictionary.thefreedictionary.com/lymphoproliferative 2. Primic Žakelj M, Bracko M, Hocevar M, Pompe-Kirn V, Strojan P, ZadnikV, Zakotnik B and Žagar T, editors. Cancer incidence in Slovenia 2006. Ljubljana: Institute of Oncology Ljubljana, Cancer registry of Republic of Slovenia; 2009. 3. Cvetkovic RS, Perry CM. Rituximab: a review of its use in non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Drugs 2006; 66: 791-820. 4. Molina A. A decade of rituximab: improving survival outcomes in non­Hodgkin’s lymphoma. Annu Rev Med 2008; 59: 237-50. 5. Zinzani PL, Pulsoni A, Perrotti A, Soverini S, Zaja F, De Renzo A, et al. Fludarabine plus mitoxantrone with and without rituximab versus CHOP with and without rituximab as front-line treatment for patients with fol­licular lymphoma. J Clin Oncol 2004; 22: 2654-61. 238 Jezersek Novakovic B and Horvat M / Treatment with rituximab 6. Nickenig C, Dreyling M, Hoster E, Pfreundschuh M, Trumper L, Reiser M, et al. Combined cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) improves response rates but not survival and has lower hemato­logic toxicity compared with combined mitoxantrone, chlorambucil, and prednisone (MCP) in follicular and mantle cell lymphomas: Results of a prospective randomized trial of the German Low-Grade Lymphoma Study Group. Cancer 2006; 107: 1014-22. 7. Sebban C, Mounier N, Brousse N, Belanger C, Brice P, Haioun C, et al. Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: The GELF-94 randomized study from the Groupe d’Etude des Lymphomes de l’Adulte (GELA). Blood 2006; 108: 2540Hagenbeek A, Eghbali H, Monfardini S, Vitolo U, Hoskin PJ, de Wolf-Peeters C, et al. Phase III intergroup study of fludarabine phosphate compared with cyclophosphamide, vincristine, and prednisone chemother­apy in newly diagnosed patients with stage III and IV low-grade malignant non-Hodgkin’s lymphoma. J Clin Oncol 2006; 24: 1590–6. 8. Hagenbeek A, Eghbali H, Monfardini S, Vitolo U, Hoskin PJ, de Wolf-Peeters C, et al. Phase III intergroup study of fludarabine phosphate compared with cyclophosphamide, vincristine, and prednisone chemotherapy in newly diagnosed patients with stage III and IV low-grade malignant non-Hodgkin’s lymphoma. J Clin Oncol 2006; 24: 1590–6. 9. Huic D, Mutvar A, Kinda-Basic S, Aurer I, Ciglar M, Grosev D, et al. Negative predictive value of F-18-FDG coincidence PET in patients with Hodgkin’s disease and a residual mass after therapy: a retrospective diagnostic test study. Radiol Oncol 2009; 43: 258-63. 10. Bachy E, Brice P, Delarue R, Brousse N, Haioun C, Le Gouill S, et al. Long­term follow-up of patients with newly diagnosed follicular lymphoma in the prerituximab era: effect of response quality on survival -a study from the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 2010; 28: 822-9. 11. Samardziski M, Zafiroski G, Tolevska C, Kalicanin-Markovska M, Doncovska D, Anevska V, et al. Treatment of patients with “high grade” extremity local­ized chondrosarcoma. Preliminary results. Radiol Oncol 2009; 43: 187-94. 12. Cheson BD. New staging and response criteria for non-Hodgkin lymphoma and Hodgkin lymphoma. Radiol Clin North Am 2008; 46: 213-23. 13. Salles G, Mounier N, de Guibert S, Morschhauser F, Doyen C, Rossi JF, et al. Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: results of the GELA-GOELAMS FL2000 study. Blood 2008; 112: 4824-31. 14. Jezeršek Novakovic B, Benigar A. Treatment of NonHodgkin’s lymphomas with rituximab in Slovene patients. Med Oncol 2010; 27: 167-76. 15. Smith MR. Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance. Oncogene 2003; 22: 7359-68. 16. Marcus R, Imrie K, Belch A, Cunningham D, Flores E, Catalano J, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 2005; 105: 1417-23. 17. Hiddemann W, Kneba M, Dreyling M, Schmitz N, Lengfelder E, Schmits R, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) sig­nificantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospec­tive randomized study of the German Low-Grade Lymphoma Study Group. Blood 2005; 106: 3725-32. 18. Herold M, Haas A, Srock S, Neser S, Al-Ali KH, Neubauer A, et al. Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemo­therapy followed by interferon maintenance prolongs survival in pa­tients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study. J Clin Oncol 2007; 25: 1986-92. 19. Feugier P, Van Hoof A, Sebban C, Solal-Celigny P, Bouabdallah R, Fermé C, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 2005; 23: 4117-26. 20. Habermann TM, Weller EA, Morrison VA, Gascoyne RD, Cassileth PA, Cohn JB, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol 2006; 24: 3121-7. 21. Pfreundschuh M, Trümper L, Osterborg A, Pettengell R, Trneny M, Imrie K, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemo­therapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006; 7: 379-91. 239 research article Second primary cancers in patients with gastric cancer Oktay Buyukasik1, Ahmet Oguz Hasdemir2, Yusuf Gulnerman3, Cavit Col1, Ozgur Ikiz1 1 Department of General Surgery, Medical Faculty of Abant Izzet Baysal University, Bolu, Turkey 2 Department of General Surgery, Ministry of Health Yildirim Beyazit Research and Training Hospital, Ankara, Turkey 3 Department of General Surgery, Ministry of Health Research and Training Hospital, Adana, Turkey Received 7 October 2010 Accepted 18 October 2010 Correspondence to: Assistant Prof. Oktay Büyükasik; Abant Izzet Baysal University, Medical School, Department of General Surgery, 14280, Bolu, Turkey. Phone: +90 374 2541000 (# 3516); GSM: +90 532 394 12 17; E-mail: oktaybuyukasik@gmail.com Disclosure: No potential conflicts of interest were disclosed Background. The risk of developing a second primary tumour in patients with gastric carcinoma is higher than among the general population. The aim was to investigate the clinicopathological characteristics of the second primary cancers in patients with gastric cancer in this study. Patients and methods. In the retrospective study, patients with gastric cancers were evaluated between 1995 and 2005 for primary tumours according to Warren and Gates’ criteria related with the second primary cancers. Results. Nine of the 112 patients with gastric cancer had second primary cancers. Seven of the patients were males and two females. Six patients with gastric cancers had synchronous, and three had metachronous tumours. The age of the patients ranged from 53 to 78 years, and the mean age was 61 ± 8.3 years. The most frequent site of occurrence of the second tumours was the colo-rectum (33%) followed by the upper respiratory system (22%), and the urogenital system (22%) in descending order of frequency. Conclusions. The incidence of the second primary cancer in gastric cancer patients was 8% in the current report. It is recommended that careful preoperative and postoperative examinations for other primary cancers, as well as for the extent of the primary gastric carcinoma, are carried out. Because colorectal cancer was the most common car­cinoma combined with gastric carcinoma, the surveillance for this carcinoma (e.g., colonoscopy, abdominopelvic CT) would be appropriate after the diagnosis of gastric carcinoma. Key words: gastric cancer; second primary cancers; synchronous cancers; metachronous cancers Introduction The first description of the term “multiple primary neoplasm” by Billroth in 1889 is defined as the de­velopment of more than one neoplasm in a patient.1Until the study of 1,259 case reports by Warren and Gates in 1932, multiple primary neoplasia were not taken seriously.2The increase of the average life span due to the improvement in the standard of living, the increase of exposure to carcinogens, and the positive progress in cancer prognosis result in a rise in the initiation of the second primary cancers (SPC).3,4 Worldwide, gastric cancer is the fourth most common cancer in population.5,6Nearly 70% of new cases is reported in developing countries. Gastric cancer is the second leading cause of cancer death in men and the fourth among women.7In Turkey, gastric cancer is the fifth most common cancer with an incidence of 10 per 100 000.8Recently, with new screening programs and the increase in the use of endoscopy, the early diagnosis of gastric cancer has increased and the survival has been prolonged with gastrectomy and extended lymph node dis­sections.9-13 The risk of development of a SPC in patients with cancer is increased considerably when com­pared to the general population.3Genetic, envi­ronmental and other (chemotherapy, radiotherapy etc.) factors are held responsible for the develop­ment of synchronous or metachronous (pre, post) SPC in patients with gastric cancer. 240 Buyukasik O et al. / Second gastric cancers TABLE 1. Clinicopathological characteristics of patients, applied treatment methods and survivals 77/M Stomach Adeno-Ca T3N0M0 Colon Synchronous Ascending colon Adeno-Ca T2N0M0 58/M Stomach Adeno-Ca T4N1M0 Kidney Synchronous Both kidneys Renal Ca (Clear cell ca) T2N0M0 78/M Stomach Adeno-Ca T2N1M0 Appendix Synchronous Appendix Mucinous carcinoma T3N0M0 68/M Stomach Adeno-Ca T3N0M0 Larynx Synchronous Larynx Squamous Cell Ca T3N1M0 54/F Stomach Adeno-Ca T2N0M0 Pancreas Synchronous Ampulla Wateri Adeno-Ca T2N0M0 50/F Colon Adeno-Ca T4N1MO Stomach Synchronous (6 months ago) Stomach Adeno-Ca T3N1M0 63/M Bladder Transitional cell-Ca T2N0M0 Stomach 3 years ago Stomach Adeno-Ca T4N1M1 53/M Larynx Squamosus cell-Ca T2N0M0 Stomach 5 years ago Stomach Adeno-Ca T4NIM0 67/F Breast Invasive ductal-Ca T2N1M0 Stomach 3 years ago Stomach Adeno-Ca T3N1M0 In this retrospective study, the aim was to inves­tigate the frequency and clinicopathological char­acteristics of SPCs associated with gastric cancers. Patients and methods In this study, 112 patients who underwent the sur­gical treatment consecutively between 1995 and 2005 were evaluated retrospectively. Gastric cancer was diagnosed and confirmed by endoscopic bi­opsy in all patients. The patients were investigated through thoraco-abdominal imaging (CT and ul­trasonography) following the routine examinations and clinical TNM staging was conducted. Clinical properties, operative findings and pathological results were evaluated from hospital records. The study were excluded those patients who were not operated on for gastric cancer due to the inoper-ability of their advanced gastric cancer stage. SPC was evaluated according to Warren and Gates criteria, requiring that both tumours should be histologically malignant. There should be mini­mum 2 cm of tumour free tissue between the two lesions; the duration between diagnoses should be minimum 5 years if the tumours are in the same lo­calization; and it should be demonstrated that the second tumour is not metastasis.2SPC is called a synchronous tumour if diagnosed at the same time with the first cancer or within the following six months, while it is called metachronous tumour if diagnosed later than six months. Results SPCwasobservedinnineof112patientswithgas­triccancer(8%).Sixofthesepatientshadsynchro­nouscancer,whiletheremainingthreehadmeta-chronouscancer.Sevenofthepatientsweremales andtwofemales,andthemeanagewas61.0±8.3 years.Accordingtotheincome,thepatientshad alowestsocioeconomiclevelandsevenofthem wereconsumedtobaccomorethan20pack-years. Nodataconcerningthepresenceofmalignant diseaseswasfoundinthefamilyhistoriesofthe patients. Six patients had synchronous SPC. In one patient, during the endoscopic retrograde cholangiopan­creatography (ERCP) performed while aetiology of extra hepatic cholestasis was being investigated, both antrum and ampulla Vater carcinomas were observed. As the second patient was being exam­ined for complaints such as dysphonia and dys­phagia, cancer of the larynx accompanying gastric cancer was observed. During the abdominal explo­ration, cancer of the appendix was observed in one of the patients who underwent the surgical treat­ Buyukasik O et al. / Second gastric cancers 241 Distal esophagectomy + Proximal gastrectomy + Splenectomy + D2 Lymph dissection + Right hemicolectomy Distal subtotal gastrectomy + D2 Lymph dissection + Bilateral partial nephrectomy Distal subtotal gastrectomy + D2 Lymph dissection + Appendectomy Total gastrectomy + D2 Lymph dissection + Laryngectomy + Bilateral neck dissection Whipple procedure Distal subtotal gastrectomy + D2 Lymph dissection Laparotomy Distal subtotal gastrectomy + D2 Lymph dissection Distal subtotal gastrectomy + D2 Lymph dissection 6 courses of 5- FU + Ca Folinat - 6 courses of Etoposide + Doxorubicine + Cisplatin Radyotherapy (Neck) 6 courses of Cisplatin + 5-FU 6 courses of 5-FU + Ca folinat 6 courses of 5-FU + Ca folinat + 3 courses of Etoposide + Doxorubicine + Cisplatin ? 6 courses of 5- FU + Ca Folinat 6 courses of CMF + Tamoxifen Disease free for 9 years 22 months Disease free for 43 months Disease free for 15 months Disease free for 45 months 18 months 4 months 12 months 4 months Alive Liver and pulmoner metastases (Renal cancer) Alive Alive Alive Brain, liver and pulmoner metastases Peritonitis carcinomatosa Peritonitis carcinomatosa and liver metastasis Cerebral embolisation ment after the diagnosis of gastric cancer, while in another patient cancer of the colon was found. In a patient with gastric cancer, in the abdominal tomography performed for the preoperative evalu­ation, tumours were observed on both kidneys and the postoperative histopathological diagnosis was reported as renal cell cancer. The last patient in the synchronous tumour group was operated for can­cer of the colon six months previously, and gastric cancer was found in the upper gastrointestinal sys­tem; endoscopy was performed during the postop­erative follow-up period. There were three patients with metachronous SPC: One patient had been followed in the urology department for urinary bladder cancer for three years. During laparotomy, it was found that local and at advanced stage (Stage IV). The second pa­tient had gone through “modified radical mastec­tomy” due to breast cancer. In the third year of the follow up period, gastric cancer was observed. The third patient had undergone total laryngectomy and the radical cervical dissection because of can­cer of the larynx five years previously. The clinical characteristics of patients, the treat­ment methods and survivals are summarized in Table 1. Gastric cancer was found in three patients in the oncological follow up period. One patient had gone through right hemicolectomy for cancer of the colon six months previously. In the other five patients, the cancer was observed in the investiga­tions done during the second malignity preopera­tive investigation period or in routine abdominal explorations done during the surgical treatment. Discussion The common use of further diagnostic methods has increased the rate of the early diagnosis of malig­nancy.14Due to the early diagnosis of cancers and current treatment methods the survival in patients with cancer has gone up recently when compared to previous years.4Compared with the general population, cancer patients were at a nearly in­creased risk for new primary cancer after cancers at many sites.3 In the presence of multiple cancers, there has been no discussion on the patients’ prognosis being worse. However, although there have been plenty of clinical studies about such patients, the number of studies about treatment methods and how the prognosis is influenced has been quite limited. In patients with multiple cancers, cancer can be de­tected in different organs and their stagings are not homogenous. Furthermore, the patients cannot be classified in groups and comparative results can­not be deduced due to different methods of the treatment. 242 Buyukasik O et al. / Second gastric cancers TABLE 2. The rate of gastric cancer and secondary primary cancer Number of patients with gastric cancer (n) 112 2250 3291 2509 4593 2668 1170 10090 Secondary primary cancer n (%) 9 (8%) 95 (4.2%) 111 (3.4%) 65 (2.6%) 159 (3.4%) 78 (3.4%) 23 (1.96%) 96 (%1.0) Synchronous tumours 6 (66%) 48 (50.5%) 111 (100%) 17 (26.2%) 49 (30.8%) 21 (27%) 12 (52%) 96 (%100) Metachronous tumours 3 (33%) 47 (49.5%) 48 (73.8%) 110 (69.2%) 57 (73%) 11 (48%) Pre metachronous 3 (33%) 36 (55.4%) 42 (26.4%) Post metachronous 0 12 (18.4%) 68 (42.8%) It is well known that synchronous and/or meta-chronous cancers can be observed in the same or different organs. These include oesophageal with oropharyngeal cancer or gastric carcinoma, breast carcinoma with contralateral breast carcinoma or endometrial carcinoma, colon and rectal carcinoma with another colorectal primary or genitourinary primary tumour, and multiple primary cancers within the urinary tract. It is thought that the pres­ence of cancer in the family history, genetic factors and chemotherapy and radiotherapy applications affect the formation of multiple cancers. Despite the fact that there have been studies showing that the synergy of gastric cancer and other cancers can be due to certain disorders, such as microsatellite instability, germ-line mutations and E-cadherin, TP53, RAS mutation; the molecular basis of the formation of tumours is still not understood com­pletely.15-17 The frequency of SPC-associated gastric cancer was found as 8% in the current study. As it can be seen in Table 2, in previous studies this rate var­ies between 1 and 4.2%.9,10,18-23Our incidence was higher than that of other reports. In this study, the number of patients with second primary cancers is small and thus important statistical limitations ex­ist. A better improved national cancer record sys­tem and broader series are required. However, this higher incidence might be due to the fact that this study analyzed patients who had undergone sur­gical intervention. On the other hand, in order to draw attention to the fact that the frequency of SPC in Turkey is higher than other societies Concerning second primary cancers in gastric cancer patients, environmental factors, such as dietary habits or tobacco use, and genetic factors have also been suggested to be risk factors. In pub­lished series, it is seen that the frequency of finding SPC accompanying gastric cancer is higher in older male patients, as it is in other types of cancer.3,10,18,22In the series presented, the mean age was 61.0 ± 8.3 (Min 53 - Max 78), the male/female ratio was 7/2. It is accepted that smoking is an important risk factor for multiple primary cancers just as in other types of cancers. In this study, it was observed that 78% of the patients consumed tobacco. The tumour determining the prognosis in SPC is gastric cancer.16However, second malignancies in patients with early gastric cancer have a determi­nant effect on prognosis.22The method of the treat­ment of synchronous cancers should include the primary cancer about which malignancy prognosis is expected. Synchronous cancer should be treated with curative intent if possible.5 In a study in which gastric cancer was inves­tigated as the SPC, an increase in gastric cancer development risk was observed within 10 years following cervical, ovarian, testicular cancers and Hodgkin and non-Hodgkin lymphoma. Treatments of the initial cancer, such as the radiation therapy or chemotherapy were found to be responsible for this increase in risk in gastric cancer and SPC.24It is stated that the highest risk is after esophagus can­cer in sporadic patients.5In the patients followed in the current study, gastric cancer developed as SPC following breast, larynx and bladder cancer. These are sporadic cases. Hereditary conditions known to increase the risk of gastric cancer include: familial cancer syn­dromes such as hereditary non-polyposis colorec­tal cancer, Li-Fraumeni syndrome, breast-ovarian cancer syndrome, multiple endocrine neoplasia Peutz-Jegher syndrome and Cowden syndrome.2 In hereditary cancers, the average age of onset for the gastric cancer is in the late 30s with the majority of cancers occurring before age 40. Among the SPCs associated with gastric cancer, colorectal cancers are the most frequent and their rate is reported to be between 20% and 70%.19,21In our study, synchronous colorectal cancer was found (33.3%) in three patients (of the colon in two patients and of the appendix in one patient). It is reported that lung cancer is the second most fre­quently occurring cancer among all SPCs.3,9,18,19,21Many researchers state that performing gastroduo­denoscopy and colonoscopy is necessary in the preoperative evaluation and in the postoperative follow up of patients with gastric and colorectal cancers; whereas some researchers suggest that bronchoscopy should be added to these investiga­ tions.14,21,25 In the present series, the rate of SPC associated with gastric cancer is 8%. This relatively high rate indicates that it would be highly significant to pay attention to the development of SPC in the preop­erative evaluation period, in the exploration during surgery, and in the postoperative follow up period. The systemic investigation and examination of pa­tients with gastric cancer should be performed in detail, and all organs should be examined carefully during surgery. In addition, while investigating possible recurrence and metastasis of the primary cancer, all systems should be examined for the pos­sible presence of SPC. Not only for patients with gastric cancer, but also for all malignant cases it is extremely necessary to inform the patients about signs and symptoms of other organs and to per­form the systemic investigation and the full physi­cal examination in each control in case multiple primary cancers develop. The early diagnosis of SPC provides a longer survival and a better quality of life. To conclude, the probability of the development of multiple primary cancers should be considered in the diagnosis and the treatment of all malig­nant tumours. Since gastric and colorectal cancer synergy is quite frequent, the importance of gas­trointestinal panendoscopy should be highlighted. The treatment should be appropriate for observed synchronous or metachronous cancer and it is nec­essary to try to be treated with curative intent in combined radical resections. References 1. Watson TA. Incidence of multiple cancer. Cancer 1953; 6: 365-71. 2. Warren S, Gates O. Multiple primary malignant tumours. A survey of the literature and a statistical study. Am J Cancer 1932; 16: 1358-14. 3. Dong C, Hemminki K. Second primary neoplasms in 633,964 cancer patients in Sweden, 1958-1996. Int J Cancer 2001; 93: 155-61. 4. Oblak I, Anderluh F, Velenik V. Postoperative radiochemotherapy for gastric adenocarcinoma: long term results. Radiol Oncol 2009; 43: 274-81. 5. Ji J, Hemminki K. Second gastric cancers among patients with primary spo­radic and familial cancers in Sweden. Gut 2006; 55: 896-08. Buyukasik O et al. / Second gastric cancers 243 6. Lag Melbert D, Krapcho M, Stinchcomb DG, Howlader N, Horner MJ, Mariotto A, et al. Surveillance, epidemiology and end results (SEER) Cancer Statistics Review, 1975-2005, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2005/ based on November 2007 SEER data submission, posted to the SEER web site, 2008. 7. American Cancer Society. Global Cancer Facts & Figures 2007. http:// www.cancer.org/docroot/STT/content/STT_1x_Global_Cancer_Facts_and_ Figures_2007.asp 8. TC Saglik Bakanligi Kanserle Savas Dairesi Baskanligi. 2005 Turkiye Kanser Istatistikleri. http://www.saglik.gov.tr/KSDB/dosyagoster.aspx?DIL=1&BELG EANAH=34879&DOSYAISIM=Kanser Istatistikleri.xls. 9. Bae JS, Lee JH, Ryu KW, Kim YW, Bae JM. Characteristics of synchronous cancers in gastric cancer patients. Cancer Res Treat 2006; 38: 25-9. 10. Lee JH, Bae JS, Ryu KW, Lee JS, Park SR, Kim CG, et al. Gastric cancer patients at high-risk of having synchronous cancer. World J Gastroenterol 2006; 12: 2588-92. 11. Ikeda Y, Mori M, Koyanagi N, Wada H, Hayashi H, Tsugawa K, et al. Features of early gastric cancer detected by modern diagnostic technique. J Clin Gastroenterol 1998; 27: 60-2. 12. Maruyama K, Okabayashi K, Kinoshita T. Progress in gastric cancer surgery in Japan and its limits of radicality. World J Surg 1987; 11: 418-25. 13. Tepes B, Kavalar R. Gastric cancer, screening possibilities and proposals for endoscopic and histologic follow-up of premalignant gastric lesions. Zdrav Vest 2010; 79: 366-74. 14. Zokalj I, Culinovic-Caic R, Magas Z, Pavcec Z, Saghir H, Igrec J, et al. Gastric gastrointestinal stromal tumour. Radiol Oncol 2008; 42: 187-95. 15. Ohtani H, Yashiro M, Onoda N, Nishioka N, Kato Y, Yamamoto S, et al. Synchronous multiple primary gastrointestinal cancer exhibits frequent microsatellite instability. Int J Cancer 2000; 86: 678-83. 16. Yang HK, Linnoila RI, Conrad NK, Krasna MJ, Aisner SC, Johnson BE, et al. TP53 and RAS mutations in metachronous tumours from patients with can­cer of the upper aerodigestive tract. Int J Cancer 1995; 64: 229-33. 17. Pharoah PD, Guilford P, Caldas C. Incidence of gastric cancer and breast cancer in CDH1 (Ecadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology 2001; 121: 1348-53. 18. Ikeda Y, Saku M, Kawanaka H, Nonaka M, Yoshida K. Features of second primary cancer in patients with gastric cancer. Oncology 2003; 65: 113-17. 19. Park YK, Kim DY, Joo JK, Kim JC, Koh YS, Ryu SY, et al. Clinicopathological features of gastric carcinoma patients with other primary carcinomas. Langenbecks Arch Surg 2005; 390: 300-05. 20. Eom BW, Lee HJ, Yoo MW, Cho JJ, Kim WH, Yang HK, et al. Synchronous and metachronous cancers in patients with gastric cancer. J Surg Oncol 2008; 98: 106-10. 21. Dinis-RM, Lomba VH, Silva R, Moreira L, Lomba VR. Associated primary tu­mours in patients with gastric cancer. J Clin Gastroenterol 2002; 34: 533-35. 22. Muela MA, Jorquera PF, Ribas AT, Malagón RR, Espinel DV, Ballesteros del RB, et al. Multiple malignant primary neoplasms in patients with gastric ne­oplasms in the health district of León. Rev Esp Enferm Dig 2006; 98: 907-16. 23. Ha TK, An JY, Youn HG, Noh JH, Sohn TS, Kim S. Surgical outcome of syn­chronous second primary cancer in patients with gastric cancer. Yonsei Med J 2007; 48: 981-87. 24. Irimie A, Achimas-Cadariu P, Burz C, Puscas E. Multiple primary malignan­cies – epidemiological analysis at a single tertiary institution. J Gastrointestin Liver Dis. 2010; 19: 69-73. 25. Oh SY, Park DI, Yoo TW, Kang MS, Kim SH, Park JH, et al. Is gastric cancer a new indication for surveillance colonoscopy? Colon cancer is increased in gastric cancer patients. Korean J Gastroenterol 2006; 47: 191-97. 244 research article Lymphedema following cancer therapy in Slovenia: a frequently overlooked condition? Tanja Planinsek Rucigaj, Nada Kecelj Leskovec, Vesna Tlaker Zunter Department of Dermatovenereology, University Medical Center Ljubljana, Ljubljana, Slovenia Received 4 October 2010 Accepted 20 October 2010 Correspondence to: Tanja Planinšek Rucigaj, M.D., Department of Dermatovenereology, University Medical Center Ljubljana, Zaloška 2, 1525 Ljubljana, Slovenia; Phone:+386 1 522 4280; Fax:+386 1 522 4333; E-mail: t.rucigaj@gmail.com Disclosure: No potential conflicts of interest were disclosed Introduction. Secondary lymphedema following cancer therapy is a frequent, often painful, quality of life disturbing condition, reducing the patients’ mobility and predisposing them to complications, e.g. infections and malignancies. The critical aspect of lymphedema therapy is to start as soon as possible to prevent the irreversible tissue damage. Patients and methods. We performed a retrospective study of patients with lymphedema, treated at the Department of Dermatovenereology, University Medical Center Ljubljana, from January 2002 to June 2010. The pa­tients’ demographic and medical data were collected, including type of cancer, type and stage of lymphedema, and time to first therapy of lymphedema. The number of referred patients with lymphedema following the therapy of melanoma, breast cancer, and uterine/cervical cancer, was compared to the number of patients expected to experience lymphedema following cancer therapy, calculated from the incidence reported in the literature. Results. In the period of 8.5 years, 543 patients (432 females, 112 males) with lymphedema were treated. The results show that probably many Slovenian patients with secondary lymphedema following cancer therapy remain unrecog­nized and untreated or undertreated. In the majority of our patients, the management of lymphedema was delayed; on average, the patients first received therapy for lymphedema 3.6 years after the first signs of lymphedema. Conclusions. To avoid a delay in diagnosis and therapy, and the complications of lymphedema following cancer therapy, the physician should actively look for signs or symptoms of lymphedema during the follow-up period, and promptly manage or refer the patients developing problems. Key words: lymphedema, secondary lymphedema; cancer therapy, adverse effects; radiotherapy, adverse effects Introduction Lymphedema is swelling due to excess accumula­tion of lymph in the tissues caused by inadequate lymph drainage. Lymphedema differs clinically form other forms of chronic edema by its altered skin texture and brawny quality of the subcutane­ous tissues which limit pitting.Primary lymphede-ma implies a genetic or constitutive cause whereby there is an intrinsic fault in the lymph drainage determined by the lymphatic maldevelopment or functional weakness. Secondary lymphedema implies an acquired failure of previously normal lymph drainage due to an identifiable cause ex­trinsic to the lymphatic system.1Secondary types of lymphedema are more common than the prima­ry ones. In developed countries, cancer treatment dominates as a cause, whereas in tropical climates lymphedema is usually due to infections.2 The reports on worldwide incidence of lymph-edema following cancer therapy in the available literature are scarce and varying considerably. The estimated incidence of breast cancer-related lymphedema is ranging from 13-50%.3-5The intro­duction of sentinel lymph node biopsy reduced the incidence of lymphedema, however not as dra­matically as it was hoped.1The incidence of lower limb lymphedema following radical hysterectomy alone is estimated at 5-10% but can be as high as 49% by 10 years of follow-up in patients who also received the adjuvant radiation treatment.6-7The incidence of lymphedema after lymphadenectomy Planinsek Rucigaj T et al. / Lymphedema following cancer therapy 245 TABLE 1. Staging of lymphedema 0 Latent phase – no edema Negative I Soft edema Negative II Initially: pitting edema; Longstanding: elastic edema Positive III Hard, enormous edema, skin changes Positive TABLE 2. Number of patients by type of edema Total: 543 patients (432 females, 112 males) Secondary lymphedema 404 patients Primary lymphedema 139 patients Following cancer therapy Due to other causes 227 patients 177 patients (198 females, 29 males) TABLE 3. Lymphedema by localizations 776 localizations of lymphedema in 543 patients 498 localizations of lymphedema due to a non-malignant cause 278 lymphedemas following a malignant disease 199 edemas of the lower extremity 72 edemas of the upper extremity 483 edemas of the lower extremity 2 facial edemas 15 edemas of the upper extremity 2 trunk edemas 1 scrotal edema 1 penile edema 1 breast edema for melanoma can be up to 44% after therapeutic groin dissection for palpable disease,8but the in­cidence following sentinel lymph node biopsy is 7,9 much less. There are no available epidemiological reports of lymphedema following cancer surgery in Slovenia. A decade ago, an outpatient office specialized in lymphedema was introduced at the Department of Dermatovenerology, University Medical Center Ljubljana. As this is the only specialized center of this type in Slovenia, the number of referred pa­tients is constantly increasing. Besides providing the best of care for these patients, one of the future aims of the center is to establish a national registry of lymphedema to provide epidemiologic data. The clinical staging of lymphedema is shown in Table 1. Latent or subclinical (stage 0) lymphedema, even after surgical lymphadenectomy, may persist for months to years without any clinical evidence of lymphatic disturbance. Trigger events, e.g. in­sect sting, physical exertion, injuries, inflammation or warming of the limb may cause edema, which is either reversible or may, with additional lymphatic overload, proceed to the following stage. In stage I, the edema is reversible, soft, disappearing spon­taneously overnight or, with compression therapy, during the day. The skin is smooth, with small pits. Stage I may persist for several years. However, if left untreated, it sooner or later proceeds to the chronical stage II. During the stage II, edema persists despite limb elevation. In the early stage, edema is still pitting, later the edema is non-pitting, elastic. The skin feels harder, fibrotic. This phase cannot be reversed spontaneously without therapy. The Stemmer’s sign is positive – the skin on dorsal surface of the second toe cannot be pinched into a fold. During the stage III (elephantiasis) the edema is enormous. The skin shows trophic changes (fibro­sis, hyperkeratoses, papillomatosis, hyperpigmen­tations, lymphorea, ulcerations) and is prone to bacterial and fungal infections. The condition may 246 Planinsek Rucigaj T et al. / Lymphedema following cancer therapy TABLE 4. Malignancies that caused lymphedema in our patients, by the year of first referral Cause 2002 2003 2004 2005 2006 2007 2008 2009 2010 (Jan-Jun) Total Breast cancer 1 2 2 12 6 3 6 22 14 68 Uterine and cervical cancer 6 9 13 8 9 7 3 11 1 67 Melanoma 2 3 2 3 4 6 4 10 7 41 Sarcoma 1 1 1 1 1 1 1 2 1 10 Colorectal cancer 1 2 0 0 0 2 0 2 1 8 Post-radiotherapy for lymphoma 0 1 1 1 1 1 1 0 1 7 Vulvar cancer 0 0 1 2 0 1 1 1 0 6 Prostatic cancer 0 1 0 0 0 0 0 2 2 5 Ovarian cancer 1 0 0 1 0 0 2 0 0 4 Lymphadenectomy for unknown cancer 1 0 0 0 0 1 1 1 0 4 Testicular cancer 0 0 1 1 0 0 0 0 1 3 Bladder cancer 0 0 1 0 0 0 0 1 0 2 Lung cancer 0 0 0 0 1 0 0 0 0 1 Non-melanoma skin cancer 0 0 0 0 0 0 1 0 0 1 Total 13 19 22 29 22 22 20 52 28 227 only partly improve with the appropriate therapy. Occasionally, development of highly malignant lymphangiosarcoma or other malignancies may ensue.1,10-12 Pain may be present during all stages. The pa­tients also report numbness, feeling of heaviness, fatigue, paresthesias, or mobility disturbances of 10-12 the affected limb. Irreversibility of the later stages of lymphedema calls for timely therapeutic intervention. The delay in seeking medical attention for lymphedema by the patient, as well as the physicians’ unawareness or underestimation of the condition might lead to chronic, hard to manage problems. During follow­up after cancer surgery and/or radiotherapy, the physician should actively look for signs or symp­toms of lymphedema, and promptly manage or refer the patient developing problems. As in case of other side effects following cancer therapy, the therapy of lymphedema should be tailored individually.13It should consider the pa­tient’s clinical situation, history, and any coexisting illnesses. The patient’s compliance is of crucial im­portance. Therefore, the continuous patient educa­tion and encouragement are essential parts of the management. Edema should be reduced as early as possible, using the compression therapy and/or manual lymph drainage. During improvement, compres­sion stockings are required to maintain the im­proved condition.11,12,14-17 The opinions and studies on drug therapy for lymphedema are controversial. Invasive ap­proaches may be appropriate only in a minority of patients. Surgery may cause further damage to lymphatics, and lead to ulceration, fistulas, skin necrosis and exacerbation of edema.12 The recommended additional measures include mobilization to improve the muscle pump func­tion. Extreme heat, cold, and trauma should be avoided. Proper skin care to prevent infections is also an important part of the management.11 Patients and methods We performed a retrospective study of patients with lymphedema treated at the Department of Dermatovenereology, University Medical Center Ljubljana, from January 2002 to June 2010. The patients’ charts were reviewed, and the following data were collected: demographic data, type of malignancy, year and type of the oncologic pro­cedure, type, location and stage of lymphedema, time of appearance of lymphedema after the pro­cedure, and duration of lymphedema before the first intervention. The average time of appearance of lymphedema after the procedure and the aver­ Planinsek Rucigaj T et al. / Lymphedema following cancer therapy 247 TABLE 5. Slovenian total incidence of melanoma, breast cancer, and uterine/cervical cancer in 2002–200718, compared to the number of patients expected/referred for lymphedema after procedure for cancer. *Expected number of patients with lymph-edema after therapy for the relevant condition, according to the published reports3-9 Melanoma Total incidence 148 202 210 226 395 437 Expected patients with lymphedema (N)* 65 88 92 99 173 192 Referred patients with lymphedema (N) 2 3 2 3 4 6 Breast cancer Total incidence 817 856 911 944 1117 1153 Expected patients with lymphedema (N)* 106-408 111-428 118-455 122-472 145-558 149-576 Referred patients with lymphedema (N) 1 2 2 12 6 3 Uterine/cervical cancer Total incidence 449 467 476 480 442 449 Expected patients with lymphedema (N)* 22-220 23-228 24-233 24-235 22-216 22-220 Referred patients with lymphedema (N) 6 9 13 8 8 7 age duration of lymphedema before the first inter­vention were calculated by using simple statistical methods. The expected incidence of lymphedema following melanoma, breast cancer, and uterine/cervical cancer was calculated from the incidence reported in the Slovenian cancer registry in the years 2002–200718, and compared to the worldwide lymphedema incidence reports4-9, by using simple statistical methods. Results In the period of 8.5 years, 543 patients (432 females, 112 males) with lymphedema were treated. Of the 543 patients, 139 patients presented with primary and 404 with secondary lymphedema in 776 locali­zations. Secondary lymphedema following can­cer therapy was found in 227 patients. Details are shown in Tables 2 and 3. The average time from cancer therapy (sur­gery or/and radiotherapy) to the development of lymphedema was 3.4 years. In 112 patients, edema started shortly after the procedure, however, maxi­mal time to the development of lymphedema was 31 years after the cancer therapy in one patient. The average time from the appearance of lymph-edema to start of the therapy for lymphedema was 3.6 years. Only three patients received therapy for lymphedema as soon as the edema started, and maximal time from beginning of lymphedema to therapy was 28 years. The average time from can­cer intervention to start of lymphedema therapy was 7 years, maximum 39 years. Only one patient received the therapy for lymphedema immediately after the procedure for cancer. The causes of lymphedema in our oncologic pa­tients are shown in Table 4, by the year of the first referral. The number of patients referred for lymphede-ma following cancer therapy for melanoma, breast cancer, and uterine/cervical cancer from 2002 to 2007, and the comparison to the expected incidence of lymphedema is shown in Table 5. Discussion The reports on the worldwide incidence of lymph-edema following cancer therapy in the available lit­erature are scarce and varying considerably. Until present, there were no available epidemiological reports of lymphedema following cancer surgery/radiotherapy in Slovenia. The majority of patients with secondary lymph-edema following cancer referred to Department of Dermatovenerology during the observed period were patients with lymphedema of the lower ex­ 248 Planinsek Rucigaj T et al. / Lymphedema following cancer therapy tremities following uterine/cervical cancer, patients with lymphedema of the upper extremity follow­ing breast cancer, and patients following lymph-edema after procedure for melanoma, accounting together for 77.5% of all patients with secondary lymphedema following cancer. The management of lymphedema in the included patient population was delayed; the patients first received therapy for lymphedema on average 3.6 years after the first signs of lymphedema and on average 7 years after the procedure for cancer. Calculated from the reported incidence of can­cer in Slovenia18and the reported worldwide inci­dence of lymphedema due to cancer4-9, the expect­ed incidence of lymphedema in Slovenia during the period 2002-2007 following melanoma, breast cancer, and uterine or cervical cancer is much higher than the actual number of patients referred to the Department of Dermatovenerology during this period. Since the Department features the only specialized center for lymphedema in Slovenia, it can be possibly concluded that many patients with lymphedema after cancer therapy remain unrecog­nized and untreated or undertreated. Beside the adequate choice of the oncological treatment option19,20, the physician should actively look for signs or symptoms of lymphedema dur­ing the follow-up of patients. If lymphedema after cancer surgery and/or radiotherapy is observed, the patient developing problems should promptly be referred. Lymphedema during the early stages is a reversible or partially reversible state, whereas it is irreversible and very hard to manage if left to proceed to the late stages, causing great patient disability and predisposing them to complications, eg. infections and malignancies. The results of the present study also emphasize the need to establish a Slovenian national registry of lymphedema. References 1. Burns T, Breathnach S, Cox N, Griffiths C, editors. Rook’s Textbook of Dermatology. Oxford: Wiley-Blackwell; 2010. p. 48.1-25. 2. Rockson SG, Rivera KK. Estimating the population burden of lymphedema. Ann N Y Acad Sci 2008; 1131: 147-54. 3. Clark B, Sitzia J, Harlow W. Incidence and risk of arm oedema following treatment for breast cancer: a three-year follow-up study. QJM 2005; 98: 343-8. 4. Ozaslan C, Kuru B. Lymphedema after treatment of breast cancer. Am J Surg 2004; 187: 69-72. 5. Deo SV, Ray S, Rath GK, Shukla NK, Kar M, Asthana S, et al. Prevalence and risk factors for development of lymphedema following breast cancer treat­ment. Indian J Cancer 2004; 41: 8-12. 6. Snijders-Keilholz A, Hellebrekers BW, Zwinderman AH, van de Vijver MJ, Trimbos JB. Adjuvant radiotherapy following radical hysterectomy for patients with early-stage cervical carcinoma (1984-1996). Radiother Oncol 1999; 51: 161-7. 7. Chatani M, Nose T, Masaki N, Inoue T. Adjuvant radiotherapy after radical hysterectomy of the cervical cancer. Prognostic factors and complications. Strahlenther Onkol 1998: 174: 504-9. 8. Allan CP, Hayes AJ, Thomas JM. Ilioinguinal lymph node dissection for pal­pable metastatic melanoma to the groin. Aust NZ J Surg 2008; 78: 982-6. 9. Wrone DA, Tanabe KK, Cosimi AB, Gadd MA, Souba WW, Sober AJ. Lymphedema after sentinel lymph node biopsy for cutaneous melanoma: a report of 5 cases. Arch Dermatol 2000; 136: 511-4. 10. International Society of Lymphology Executive Committee. The diagnosis and treatment of peripheral lymphedema. Lymphology 2003; 36: 84-91 11. Cohen SR, Payne DK, Tunkel RS. Lymphedema: strategies for management. Cancer 2001; 92 (4 Suppl): 980-7. 12. Rockson SG. Lymphedema. Am J Med 2001; 110: 288-95. 13. Ocvirk J, Rebersek M. Management of cutaneous side effects of cetuximab therapy with vitamin K1 creme. Radiol Oncol 2008; 42: 215-24. 14. Rucigaj TP, Kosicek M, Kozak M, Grmek M. Obravnava bolnikov z limfede-mom. In: Blinc A, Kozak M, Šabovic M, editors. Slikovne metode v odkrivanju in zdravljenju žilnih bolezni. Ljubljana: Združenje za žilne bolezni Slovenskega zdravniškega društva; 2005. p. 168-83. 15. ISL. The diagnosis and treatment of peripheral lymphedema. Consensus document of the ISL. Lymphology 2003; 36: 84-91. 16. Földi M. Remarks concerning the consensus document of the ISL. Lymphology 2004; 37: 168-73. 17. Planinšek Rucigaj T, Košicek M. Prednosti kompresijskega zdravljenja s kratkoelasticnimi povoji. In: Miljkovic J, editor. Dermatološki dnevi. Maribor: Združenje slovenskih dermatovenerologov; 2004. p. 78-83. 18. Register raka RS [Internet]. Available at: http://www.onko-i.si/dejavnosti/ epidemiologija_in_register_raka/registri_raka/register_raka_rs/index.html. Accessed 1 September, 2010. 19. Strojnik A. Search of the shortest regimen: fractionation of a fully isoeffec­tive combination of hyperfractionated and hypofractionated treatment. Radiol Oncol 2008; 42: 170-2. 20. Strojan P. Role of radiotherapy in melanoma management. Radiol Oncol 2010; 44: 1-12. 249 research article Evaluation of clinical interventions made by pharmacists in chemotherapy preparation Lea Knez1,2, Raisa Laaksonen1,3, Catherine Duggan1,4,5 1 Academic Department of Pharmacy, Barts and The London NHS Trust, Royal London Hospital, London, UK 2 Pharmacy Department, University Clinic of Respiratory and Allergic Diseases Golnik, Golnik, Slovenia 3 Pharmacy Practice Group, Department of Pharmacy & Pharmacology, University of Bath, Bath, UK 4 Clinical Pharmacy – Development and Evaluation for East & South East England Specialist Services, NHS, UK 5 The School of Pharmacy, London, UK Received 4 May 2010 Accepted 20 July 2010 Correspondence to: Lea Knez, University Clinic of Respiratory and Allergic Diseases Golnik, Golnik 36, 4204 Golnik, Slovenia; Phone:+386 4 2569 360; Fax:+386 4 2569 117; E-mail: lea.knez@klinika-golnik.si Disclosure: No potential conflicts of interest were disclosed Background. Cancer drugs are high risk drugs and medication errors in their prescribing, preparation and administra­tion have serious consequences, including death. The importance of a multidisciplinary approach and the benefits of pharmacists’ contribution to cancer treatment to minimise risk have been established. However, the impact of services provided by pharmacists to cancer patient care is poorly studied. This study explored the clinical interven­tions made by pharmacists in dispensing of chemotherapy doses, and evaluated pharmacists’ contribution to patient care. Methods. Pharmacists at the Chemotherapy Preparation Unit at a tertiary cancer centre in London were shadowed by two research pharmacists during the clinical screening of chemotherapy prescriptions and release of prepared drugs. An expert panel of pharmacy staff rated the clinical significance of the recorded interventions. Results. Twenty-one pharmacists’ interventions were recorded during the screening or releasing of 130 prescriptions or drugs. “Drug and therapy” (38%), “clerical” (22%) and “dose, frequency and duration” (19%) related problems most often required an intervention, identifying areas in chemotherapy prescribing that need improvement. The proposed recommendations were implemented in 86% of the cases. Many recorded interventions (48%) were ranked to have had a “very significant” influence on patient care. Conclusion. Clinical interventions made by pharmacists had a significant impact on patient care. The integration of pharmacists’ technical and clinical roles into dispensing of chemotherapy doses is required for providing high-quality cancer services. Key words: pharmacy; cancer; chemotherapy; drug compounding; medication errors Introduction Cancer drugs, involved in 15.4% of reported fatal cases, are second only to drugs acting on the cen­tral nervous system in medication error associated mortalities.1High toxicity of cancer drugs is not problematic only when these medications are used inappropriately, but life-threatening side effects may occur also during regular treatment - their use requires clinical expertise.2Thus, cancer drugs are defined as high risk drugs; the prescribing, preparation and administration of which require special regulation and the collaboration of differ­ent healthcare professionals.3,4Pharmacists have a central role in guaranteeing the safe, effective and economic use of cancer drugs.3-8 The dispensing of cancer drugs in designated centralized chemotherapy preparation pharmacy units has been extensively studied to improve its quality and minimise personnel exposure to these drugs.4-7As a result, the technical roles, responsi­bilities and duties of pharmacists in the dispens­ing of chemotherapy doses are well defined.5-7However, the same cannot be said of the clinical role of pharmacists. Although this role has been described to some extent in the Competency 250 Knez L et al. / Pharmacists’ clinical interventions in chemotherapy preparation 1. PRESCRIPTION ARRIVES TO CPU 2. PRESCRIPTION SCREENING 7. RELEASE OF DISPENSED DRUG 3. PRODUCTION OF WORKSHEET AND LABELS 6. FINAL CHECK OF RECONSTITUTED DRUG 4. ASSEMBLY OF MATERIALS 5. RECONSTITUTION OF CHEMOTHERAPY DOSES FIGURE 1. Stages in dispensing of cancer drugs in the Chemotherapy Preparation Unit (CPU). The study observed pharmacists during the stages of prescription screening and release of dispensed drugs; stages where only technical interven­tions were expected or where pharmacy technician and assistants were partici­pating were not covered in the study. Framework for Specialist Oncology Pharmacists of the British Oncology Pharmacists Association and in the German Quality Standard for the Pharmacy Oncology Service as well as emphasised in numer­ous studies, the clinical services provided by phar­macists in chemotherapy dose dispensing are not standardised across Europe.7-11This may lead to substantial variation in the quality of patient care. As a consequence of being poorly defined, phar­macists’ clinical services in chemotherapy dose dispensing are also poorly studied. The imple­mentation and benefits of these services have been described in several reports;4,9-12however, phar­macists’ contribution to patient care is rarely as­sessed. Only a recent report of the British National Confidential Enquiry into Patient Outcome and Death (NCEPOD) provided evidence on the extent of pharmacists’ contribution to patient outcomes.11The report analysed the treatment of cancer pa­tients who had died within the first 30 days after receiving systemic chemotherapy. Finding that only half of chemotherapy prescriptions of these patients had been checked by a pharmacist, the NCEPOD highlighted this service as one of the measures required to reduce the risk of death after receiving systemic chemotherapy. The evaluation of current practices and the evaluation of the im­pact of changes in routine practices on patient care are important in all fields of oncology.13 This study aimed to explore clinical interven­tions made by pharmacists in dispensing chemo­therapy doses, and to evaluate their significance for patient care. Methods Study design and sample The study was designed as a prospective, descrip­tive, cross-sectional study of interventions made by pharmacistsin dispensing of chemotherapy doses. The study complements another study that focused on exploring interventions made by phar­macists when providing routine clinical pharmacy services on cancer wards.14The study was conduct­ed at the Chemotherapy Preparation Unit (CPU) at St. Bartholomew’s Hospital, London, UK, a tertiary cancer centre. Ethics approval was not required as the study was part of the Trust’s service develop­ment. However, the study protocol was reviewed by two independent researchers at the School of Pharmacy, University of London, to assess any ethical issues. The study evaluated interventions made by pharmacists during their daily routine practice in chemotherapy dose dispensing in a hospital setting (Figure 1). The study focused on the two stages in this process that can be performed only by phar­macists: screening of prescriptions; and release of dispensed drugs. During prescription screening, pharmacists checked the correctness of clerical data, dose cal­culation, dose adjustment in altered essential pre-treatment investigation data, time and mode of administration and prescription of supportive therapy for expected toxicities. Before the release of a drug, pharmacists had to verify the correctness of the overall procedure and the quality of the dis­pensed drug.5An intervention, such as adjusting a chemotherapy dose or adding supportive therapy, may be required at any point of the described proc­esses. Both stages were observed at different times and independently of each other. Four clinical on­cology pharmacists and one advanced clinical on­cology pharmacist were working at the CPU at the time of the study. Developing the data collection form and collecting data A literature review on potential medication errors and pharmacists’ clinical interventions12-19, observa­tions of pharmacists’ work at the CPU, discussions with pharmacy practitioners and academic super­visors served as the basis for the development of a data collection form for recording and classifying the interventions. Interventions may be required due to various problems. Depending on the identi­ Knez L et al. / Pharmacists’ clinical interventions in chemotherapy preparation 251 TABLE 1. Description of the recorded interventions and their clinical significance Potentially life Trastuzumab is ordered for a patient, who has experienced a serious adverse drug event during Potentially life saving saving previous administration. Potentially life saving Chemotherapy is ordered 7 days ahead of protocol. Very significant Impaired hepatic function requires dose modification of paclitaxel. Very significant Etoposide dose was miscalculated when switching from oral to intravenous route of administration. Very significant Impaired renal function requires dose modification of cisplatin. Very significant Significant Significant Impaired renal function requires dose modification of carboplatin. Chemotherapy is ordered as 6th cycle whereas it was patient’s 4th cycle. Significant Chemotherapy order is not signed by the medical practitioner. NA* Impaired renal function requires dose modification of fludarabin. NA Grade 3 neutropenia require chemotherapy to be postponed. NA Full dose of irinotecan is ordered although patient received modified doses in previous cycles. Very significant Two chemotherapy orders with different information on body surface area are received for the same patient. Significant Significant Cancer drug that is per protocol given every week interval is ordered every fortnight. Significant The chemotherapy order does not include the required antiemetic therapy. Potentially life saving The name of the patient on chemotherapy order is illegible. Potentially life saving Cancer drugs for iv and it administration are prescribed on same chemotherapy order. NA The order for the last chemotherapy is not recorded in the CPU† patient file. Minor significance NA Incorrect information of a patient’s height. NA Wrong calculation of the body surface area. NA Grade 3 neutropenia require chemotherapy to be postponed. NA Etoposide is instable in the ordered infusion volume. * NA (not applicable) the medical consultant did not assess the clinical significance of interventions for patient care † CPU stands for Chemotherapy Preparation Unit fied problem, an intervention could be classified to be required due to “a clerical problem”, for exam­ple, missing patient or administrative data, “a drug and therapy problem”, for example, omission or commission of drugs, or presence of a contraindi­cation for the prescribed drug, “a dose, frequency and duration problem”, for example, inappropri­ate dose calculation or need for dose adjustment, wrong time or duration of the chemotherapy or “an administration and formulation problem”, for example, formulation or administration discrepan­cies with agreed treatment protocols. The data collection was carefully planned. While the observation times were randomly select­ed, they allowed observations during six morning and three afternoon shifts on five different week days, taking into account potential variation in workload. The data were collected by two research pharmacists, who independently observed, with­out interfering, the clinical pharmacists’ work; this method has been found to be superior to self-re­porting by healthcare professionals in medication error research.20 Rating the significance of interventions An expert panel of four members of pharmacy staff (the head of preparation services, two clinical on­cology pharmacists and a specialist in drug manu­facture and drug stability) was first asked to indi­vidually rate the interventions’ significance to pa­tient care (patient safety) using a five-point Likert scale (Table 1).20The clinical significance of the re­corded interventions was then determined using a modified nominal group consensus method20, each panellist’s opinions were presented and discussed until the panel reached a consensus. To further val­idate the panel’s decisions, a consultant in medical oncology independently ranked the clinical signifi­cance of a sample of 13/21 (60%) interventions that 252 Knez L et al. / Pharmacists’ clinical interventions in chemotherapy preparation TABLE 2. Characteristics of recorded interventions Number of observations 130 Number of recorded interventions Number of interventions 21 Malignant diseases & immunosupression 27 / 29† 93 % • Antimetabolites 6 / 29† 21 % • Anthracyclines & other cytotoxic antibiotics 5 / 29† 17 % BNF* group of drug involved • Vinca alkaloids & etoposide 4 / 29† 14 % • Other antineoplastic drugs: Taxanes 4 / 29† 14 % • Other antineoplastic drugs 8 / 29† 28 % Drugs outside malignant disease & immunosupression group 2 / 29† 7 % Drug and therapy Clerical Identified drug related problem Dose, frequency and duration Administration and formulation 8 / 21 7 / 21 4 / 21 2 / 21 38 % 33 % 19 % 10 % Clinician Contacted healthcare professional Nurse None 13 / 21 2 / 21 6 / 21 62 % 10 % 29 % Implemented Implementation of the intervention Implemented, with amendments Not implemented 18 / 21 1 / 21 2 / 21 86 % 5 % 10 % * BNF stands for British National Formulary † one intervention could involve more than one drug were selected using a list of randomly generated numbers (Table 1). Data handling and statistical analysis Confidentiality of patients and pharmacists was observed in handling the collected data and no names were recorded. The data on the recorded interventions were coded and entered onto an SPSS (version 14) database. Data are presented as frequencies and proportions; median values and ranges are presented where possible. Associations and differences between variables were explored using non-parametric tests: Chi square, Mann-Whitney U and Kruskal-Wallis H test, as appropri­ate.21 Results At the time of the study, the CPU received an aver­age of 230 chemotherapy orders daily. Five phar­macists were observed during the screening of 85 prescriptions and the release of 45 drugs (Table 2). Overall, 21 interventions, which concerned 29 drugs prescribed for 18 patients, were recorded: 19 during prescription screening (19/85; 22%) and two during drug release (2/45; 4%). Patient characteristics Patients, whose treatment required an interven­tion, had a median age of 49 years, ranging from 24 to 75, and most were female (15/18; 83%) (Table 3). More patients were treated for solid tumours (12/18; 67%) than for haematological malignancies. Patients were treated with standard chemotherapy (14/18; 78%) or received clinical trial treatment (4/18; 22%) and two patients received concomitant treatment with radiotherapy (2/18; 11%). Intervention characteristics The identified problems were often related to “drug and therapy” (8/21; 38%), followed by “cleri­cal” (7/21; 33%) and “dose, frequency and dura­tion” (4/21; 19%) issues whereas “administration and formulation” problems (2/21; 10%) required an intervention of a clinical nature less often (Table2). Some interventions (6/21; 28%) were required due Knez L et al. / Pharmacists’ clinical interventions in chemotherapy preparation 253 TABLE 3. Characteristics of patients Female 15 / 18 83 % Sex Male 3 / 18 17 % Solid tumours 12 / 18 67 % • Lung cancer 4 /18 22 % Diagnosis • Breast cancer 3 / 18 17 % • Other solid tumours 5 / 18 28 % Haematological malignancies 6 / 18 33 % to altered pre-treatment investigation data, for ex­ample, changes in drug doses were required be­cause of out of range blood test results, or deterio­rating renal or liver function. Certain problem types, for example, altered investigation results, were often found to require similar interventions to rectify the problem, result­ing in pharmacists making similar recommenda­tions, for example, proposing a dose modification (Table 1). The identified problem and proposed recommendation were discussed, if needed, with the responsible clinician (13/21; 62%) or nurse (2/21; 10%). Most interventions (18/21; 86%) were implemented as recommended(Table 2). One was implemented with an amendment – instead of re­ducing the dose of carboplatin due to altered re­nal function, the clinician decided to postpone the chemotherapy cycle. In two cases the interventions were not accepted. In the first case, postponing of the chemotherapy treatment of a patient with grade three neutropenia had been recommended. A clinician argued that despite the chemotherapy having been previously postponed and the dose reduced the neutropenia had been persistent; thus, the patient should be treated. In the second case, while halving the dose of paclitaxel had been rec­ommended due to altered hepatic function, a clini­cian offered no reason for not reducing the dose. Most interventions concerned cancer drugs (27/29; 93%) than supportive therapy drugs. Since all cancer drugs are renowned as high risk drugs, pharmacists’ interventions prevented serious con­sequences of errors in their use. Some interventions did not involve any drug (5/21; 24%) (Table 2). Significance of the recorded interventions for patient care The expert panel rated the interventions made by pharmacists: three had “significant” (14%); 10 “very significant” (48%); and one “potentially life saving” (5%) impact on patient care, prevent­ing detrimental effects on the patients (Table 1). Moreover, the consultant in medical oncology in­dependently ranked all of the 13 randomly selected interventions to be at least “significant” for patient care and gave exactly the same rating as the expert panel in six of 13 cases (Table 1). The consultant considered two interventions rated by the expert panel as having “minor significance” to patient care to be “potentially life saving”; these were the only two interventions where the rating differed by more than one category. The significance of re­corded interventions was not associated with any patient characteristic or drug involved; no patient or drug subgroup was identified to be at greater risk of potential medication errors that would re­quire greater vigilance. Pharmacists were more likely to independent­ly solve problems of minor significance, whereas they worked with clinicians and nurses to imple­ment interventions of higher significance (Kruskal – Wallis, X2=10.686, df=2, p=0.005). Drug related problems related to “drug and therapy” and “dose, frequency and duration” were more likely to require interventions of higher significance than those related to “clerical” and “administration and formulation” issues (Kruskal – Wallis, X2=8.003, df=3, p=0.046). Due to resource restraints it was not possible to observe all interventions made by pharmacists in one week. However, if the data are extrapolated on the weekly average of 230 chemotherapy pre­scriptions, pharmacists are expected to make ap­proximately 50 interventions during prescription screening and ten during the release of dispensed drugs. Based on this estimation and the signifi­cance of the observed interventions, three drug related problems with potential fatal consequences may be prevented every week. 254 Knez L et al. / Pharmacists’ clinical interventions in chemotherapy preparation Discussion This study provided evidence of the contribution of the clinical pharmacists in the dispensing of chemotherapy doses to the safety of patients. Strengths and limitations Studies of self-recorded clinical interventions may underestimate the frequency of required interven­tions20; in this study data were collected by inde­pendent researchers, providing a more complete picture of the interventions. Moreover, the expert panel reached consensus on the significance of the recorded interventions. However, the study presents some limitations. This cross-sectional study was limited to nine visits in a centralized CPU at one hospital. The results may not be representative, but the study aimed at providing insight into pharmacists’ clini­cal interventions in dispensing of chemotherapy doses. The low number of visits was accepted as a limitation in exchange to having the data col­lected by independent observers. While the impact of pharmacists’intervention on patient care was determined by an expert panel of pharmacy staff, one medical consultant separately evaluated the interventions, mainly confirming the panel’s deci­sions. Furthermore, the high level of significance assigned to the interventions by the consultant and the high proportion of implemented interventions suggest a high level of agreement and further con­firm the need for similar services. Findings The number of recorded interventions and their significance show that pharmacists contribute to patient care, which confirms the importance of their role in managing the risks associated with cancer drugs. Pharmacists’ interventions on pre­scribed chemotherapy observed on the wards and good and accurate risk management procedures in the dispensing of chemotherapy doses, such as the use of pre-written chemotherapy prescriptions, may have lowered the number of interventions needed as confirmed in the literature.4,9-11,14,22 The rate of interventions in the present study, 22% during prescription screening and 4% during drug release, was higher than the rate of medica­tion errors identified in chemotherapy prescrip­tion orders reported in the literature.9,11Markert et al.reported a chemotherapy error in 17.1% of received chemotherapy orders9, while Slama et al. reported a prescribing error in 12% of the received chemotherapy orders.11However, the majority of errors in the described studies, 50.9% and 74%, re­spectively, were related to problem categories not included herein: missing a patient’s informed con­sent; and physicochemical incompatibilities. The lower proportion of recorded interventions in the literature may be attributed to differences in the duties of pharmacists in the dispensing processes in different countries or to discrepancies in the methodology of the studies. The problems identified in the recorded inter­ventions indicate areas in the chemotherapy pre­scribing practice that need improvement: writ­ing of a chemotherapy order; and adjusting the dose according to blood and biochemistry data. Pharmacists were often observed to recommend changes to chemotherapy prescriptions that con­tained incorrect information; a problem that has been reported in the literature.9,11,23Correct patient details on weight and height are of utmost im­portance for the correct calculation of the chemo­therapy dose. Computerised chemotherapy order forms have been shown to diminish the number of errors4,5,9,10,24; while the possibilities for the imple­mentation of computerised prescribing should be investigated, the limitations and problems of simi­lar systems should be acknowledged.25,26 The individual dosing of cancer drugs and their important toxicity profile require constant monitor­ing of the health status of the patient. In this study, dose adjustment due to altered blood count, renal or hepatic function test results was the most com­mon intervention, preventing the occurrence of po­tential adverse events with detrimental effects on the patient. This confirms the importance and need of pharmacists’clinical knowledge in dispensing of chemotherapy doses. Moreover, the two inter­ventions observed during the release of drugs also recommended a dose adjustment due to a change in patients’ renal or hepatic function. In both cas­es, the essential pre-treatment investigation data had not been available at the time of prescription screening, thus, to avoid a delay in dispensing the chemotherapy dose, the order was forwarded to the preparation room without this check, and the investigation data were available and checked only before the release of the drug, when the need for dose adjustment was identified. While most inter­ventions (90%) have occurred before the release of drugs, such practice may result in the disposal of a dispensed drug and their re-dispensing; thus, the timely availability of essential pre-treatment in­vestigation data may not have only safety, but also Knez L et al. / Pharmacists’ clinical interventions in chemotherapy preparation 255 substantial economic implications. The literature shows that checking of chemotherapy doses with essential pre-treatment investigation has not been clearly stated as obligatory in many settings.7,9,11,23However, the results of the present study imply that this service should be integrated into the dis­pensing of chemotherapy doses. Pharmacists made highly significant interven­tions, showing the value of their contribution to cancer services. No patient characteristic or drug group was identified to require special interven­tions, perhaps due to low numbers of observations. The harm of medication errors in chemotherapy prescribing requires maximal risk control mecha­nisms per se, regardless of the treated patient or used drug. When dealing with problems of greater significance such as a contraindication for the pre­scribed treatment or a need for dose adjustment, pharmacists consulted nurses and clinicians. Clinicians agreed with most of the proposed inter­ventions, confirming their importance also from a medical perspective. Good and well established collaboration between all healthcare professionals should be routine to prevent drug related prob­lems from occurring in chemotherapy treatment. The benefits of good collaboration are not re­stricted to chemotherapy dose dispensing. In fact, the collaboration between pharmacists and clini­cians on the wards together with the tight regula­tion of the dispensing of chemotherapy doses may have solved problems of mainly minor signifi­cance14, before they reached the CPU. This, in ad­dition to the fact that most interventions involved cancer drugs that are by definition high risk drugs, may have contributed to the high clinical signifi­cance of the recorded interventions. The integra­tion of the work of pharmacists on the cancer wards and at the CPU is a great advantage for pa­tient care. To our knowledge, this study is the only study evaluating the impact of pharmacists’ clinical in­terventions in dispensing of chemotherapy doses on patient care. Studies describing pharmacists’ services in dispensing of chemotherapy doses ei­ther did not evaluate their impact on patient care or the contribution to patient care was done a pri­ori, according to the detected medical error.4,9,11,23However, the need for pharmacists’ contribution in high-quality services, shown in this study, coin­cides with other studies of pharmacists’ interven­tions in other ward settings.14-19,22Clinical services, provided by pharmacists, were shown to be impor­tant in the treatment of cancer patients, who are ex­posed to complex treatment with high-risk drugs. Conclusions This study showed the importance of the integra­tion of pharmacists’ clinical and technical knowl­edge in the dispensing of chemotherapy doses to provide high quality cancer services. Pharmacists’ clinical activities in the dispensing of cancer drugs were shown to be essential for improving patient care and preventing major toxicity, and should be defined as a standard of care in guidelines, regulat­ing the dispensing of chemotherapy doses of can­cer drugs. Acknowledgments of research support Lea Knez received a studentship under the European Leonardo da Vinci programme. We thank: Rajinder Nijjar for her practical advice on chemotherapy services; Samo Rožman for devel­oping the data collection form and collecting the data; Mitja Košnik and Mitja Lainšcak for their ad­vice on writing the manuscript; and, finally, Aleš Mrhar for his contribution to the study. References 1. Phillips J, Beam S, Brinker A, Holquist C, Honig P, Lee LY, et al. Retrospective analysis of mortalities associated with medication errors. Am J Health Syst Pharm 2001; 58: 1835-41. 2. Ocvirk J, Boc M, Rebersek M, Ros T. Cisplatin-induced non-convulsive pos­terior reversible encephalopathy syndrome in a 41-year-old woman with metastatic malignant melanoma. Radiol Oncol 2009; 43: 120-5. 3. Department of Health. The NHS cancer plan. London: HMSO; 2001. 4. Goldspiel BR, DeChristoforo R, Daniels CE. A continuous-improvement approach for reducing the number of chemotherapy-related medication errors. Am J Health Syst Pharm 2000; 57: S4-9. 5. Mort D, Lansdown M, Smith N, Protopapa K, Mason M. For better, for worse? London: National Confidential Enquiry into Patient Outcome and Death; 2008. 6. North East London Cancer Network NHS. Guidelines on the safe prescribing, handling and administration of cytotoxic drugs. London: Department of Health Publications; 2005. 7. German Society of Oncology Pharmacy. Quality Standard for the Oncology Pharmacy Service with Commentary. 4th Edition. Oldenburg: Onko-press; 2003. 8. Adams V, Blake D, Corlett S, Godward D, Low J, McMurray A, et al. Competency Framework for Specialist Oncology Pharmacists. BOPA Newsletter, 2004. 9. Markert A, Thierry V, Kleber M, Behrens M, Engelhardt M. Chemotherapy safety and severe adverse events in cancer patients: strategies to efficiently avoid chemotherapy errors in in-and outpatient treatment. Int J Cancer 2009; 124: 722-8. 10. Jaehde U, Liekwig A, Simons S, Westfeld M. Minimising treatment-asso­ciated risks in systemic cancer therapy. Pharm World Sci 2008; 30: 161-8. 11. Slama C, Jerome J, Jacquot C, Bonan B. Prescription errors with cytotoxic drugs and inadequacy of existing classifications. Pharm World Sci 2005; 27: 339-43. 256 Knez L et al. / Pharmacists’ clinical interventions in chemotherapy preparation 12. Liekweg A, Westfeld M, Jaehde U. From oncology pharmacy to pharmaceu­tical care: new contributions to multidisciplinary cancer care. Support Care Cancer 2004; 12: 73-9. 13. Debevec L, Jeric T, Kovac V, Bitenc M, Sok M: Is there any progress in routine management of lung cancer patients? A comparative analysis of an institu­tion in 1996 and 2006. Radiol Oncol 2009; 43: 47-53. 14. Knez L, Laaksonen R, Duggan C, Nijjar R. Evaluation of clinical interventions made by pharmacists in cancer services. Pharm J 2008; 280: 277-80. 15. Burtonwood AM, Hinchliffe AL, Tinkler GG. A prescription for quality: a role for the clinical pharmacist in general practice. Pharm J 1998; 261: 678–80. 16. Eadon H. Assessing the quality of ward pharmacists’ interventions. Int J Pharm Practice 1992; 1: 145–7. 17. Price RN, Rogers A. Intervention monitoring on admissions wards. Hosp Pharmacists 2000; 7: 81–4. 18. Barber N, Batty R, Ridout DA. Predicting the rate of physician-accepted interventions by hospital pharmacists in the United Kingdom. Am J Health Syst Pharm 1997; 54: 397–405. 19. Hawkey CJ, Hodgon S, Norman A, Daneshmend TK, Garner ST. Effect of reactive pharmacy intervention on quality of hospital prescribing. Br Med J 1990; 300: 986–990. 20. Allan EL, Barker KN. Fundamentals of medication error research. Am J Hosp Pharm 1990; 47: 555–71. 21. Bowling A. Research methods in health. Philadelphia: Open University Press; 2002. 22. Macintyre J, Dalrymple H, MacLean F, Lannigan N, Hudson S. Development of a system for reporting pharmaceutical care issues in cancer patients receiving chemotherapy. Pharm J 2003; 271: 266-7. 23. Limat S, Drouhin JP, Demesmay K, Tissot E, Jacquet M, Woronoff-Lemsi MC. Incidence and risk factors of preparation errors in centralized cytotoxic preparation unit. Pharm World Sci 2001; 23: 102-6. 24. Bourret JA, Demeres RF, Wordell D, Irani M, Baker J, Evangelista C. Medication use review process and information systems utilized for oncol­ogy chemotherapy quality improvement. Pharm Pract Manag Q 1996; 16: 1-17. 25. Barber N, Cornford T, Klecun E. Qualitative evaluation of an electronic pre­scribing and administration system. Qual Saf Health Care 2007; 16: 271-8. 26. Nebeker JR, Hoffman JM, Weir CR, Bennett CL, Hurdle JF. High rates of adverse drug events in a highly computerized hospital. Arch Intern Med 2005; 165: 1111-6. 257 case report Digital ischemic events related to gemcitabine: Report of two cases and a systematic review Cvetka Grasic Kuhar, Tanja Mesti, Branko Zakotnik Department of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia Received 1 February 2010 Accepted 1 March 2010 Correspondence to: Cvetka Grasic Kuhar, MD. PhD, Department of Medical Oncology, Institute of Oncology Ljubljana, Zaloška c. 2, SI-1000 Ljubljana, Slovenia; Phone: +386 1 5879282; Fax: +386 1 5879305; E-mail: cgrasic@onko-i.si Disclosure: No potential conflicts of interest were disclosed. Background. Gemcitabine is a potent cytotoxic agent used in the treatment of many solid tumours, sarcomas and lymphomas. Vascular toxicity and thrombotic events related to gemcitabine seem to be underreported. Case report. We report two cases of gemcitabine related digital ischemic events. Case 1. A 65-year-old man was given the first-line treatment with gemcitabine for the advanced adenocarcinoma of pancreas. After four weekly doses of gemcitabine (total dose 4000 mg/m2) he presented with Raynaud’s like phenom­enon and ischemic fingertips necrosis in five digits of both hands. Symptoms resolved in all but one digit after stopping chemotherapy and treatment with iloprost trometamol infusion. Case 2. A 77-year-old man, ex-smoker, was administered a combination of gemcitabine and cisplatin as the first-line treatment for the locally advanced bladder cancer. After 4 cycles of the treatment (total dose of gemcitabine 4000 mg/m2) the patient suffered digital ischemia and necrosis on two digits of a right leg. Arteriography revealed preex­isting peripheral arterial occlusive disease (PAOD) of both legs with very good peripheral collateral circulation and absent microcirculation of affected two digits. The gemcitabine treatment was stopped and the patient was treated with iloprost trometamol infusion and percutaneous transluminal angioplasty with dilatation of the right superficial femoral artery. Digital changes resolved without consequences. Severe thrombocytosis (platelet count 1211 x 109/L) might have also contributed to the ischemic digital event in the second case. Conclusions. Digital ischemic events associated with gemcitabine chemotherapy seem to be more common in patients with tobacco-associated cancers, especially when used in combination with platinum salt. The treatment with gemcitabine in patients with evolving Raynaud’s phenomenon and/or preexisting PAOD should be done with caution. Key words: chemotherapy; gemcitabine vascular toxicity; digital ischemic events Introduction Gemcitabine is an important contemporary chem­otherapeutic agent for the treatment of both solid tumours and lymphomas.1 As a nucleoside analog structurally related to cytosine arabinoside, it in­terferes with the synthetic pathways of the tumour cell predominantly in the S phase of the cell cycle. It is a potent inhibitor of DNA synthesis and re­pair.2 First approved in 1996 for the treatment of un­resectable pancreatic cancer, today gemcitabine is most commonly used in the therapy of pancreatic, ovarian, breast, non-small cell lung and bladder cancer, some sarcomas, cutaneous and peripheral T-cell lymphomas as well as in relapsed Hodgkin’s lymphoma.1The use of this drug enables progress in the routine management of cancer patients.3,4 Gemcitabine is a drug with a favourable toxic­ity profile with myelosuppression, a flu-like syn­drome, skin rash and radiation recall dermatitis being the most common side effects.2 As indications for its use in oncology have been expanding, some reports showed the possibility of its vascular side effects. Among them throm­botic microangiopathy5, venous thrombembolism, acute arterial events (digital ischemia and necrosis, vasculitis), systemic capillary leak syndrome and 258 Grasic Kuhar C et al. / Digital ischemic events related to gemcitabine reversible posterior leukoencephalopathy are re­ported.1 Digital ischemic events are rare in cancer pa­tients. They are most frequently related to vascular disease due to hypercholesterolemia, arterial hy­pertension, diabetes or exposure to tobacco. They may also occur as a complication of connective tissue diseases, i.e. vasculitis with digital ischemic events. In the present article we report two cases of dig­ital ischemic events during the therapy with gem-citabine alone and in combination with cisplatin and review data in the literature regarding this rare side effect. Case 1 A65-year-oldmalewaspresentedinMarch2009 withprimarymetastaticadenocarcinomaofpan­creas(metastasesinretroperitonealandcervical nodes).Hehadahistoryofnephrolythiasisten yearsagoand5monthslastinghistoryofhydrone­phrosisoftheleftkidneyofgradeIII,causedby enlargedretroperitoneallymphnodes.Atpresenta­tionhewasoverweightwithgradeIrenalimpair­ment(creatinine129µmol/L).Hecomplainedof painintheupperabdomen.TumourmarkerCA 19-9waselevated(>12000IU);plateletcountwas 376x109/L. In March 16 2009 he started the treatment with gemcitabine monotherapy in a weekly dose 1000 mg/m2. After 3 weekly doses he had less pain in the abdomen and tumour marker CA 19-9 halved (6163 IU). Platelet count was elevated (570 x 109/L). He complained of painful swelling in three digits of right hand and acrocyanosis. After the 4thdose of gemcitabine pain in digits increased and the pa­tient was admitted to the local hospital. Raynaud’s syndrome was suspected. Criteria for paraneoplas-tic microthrombosis, which was suspected, were not met. At the beginning the patient was treated with acetylsalicylic acid. No improvement was re­corded. On the control visit in our institution (May 05 2009) the patient complained of severe pain in five digits of both hands. The examination showed dry fingertips necrosis. Radial and ulnar pulses were normal. The Doppler ultrasound of both arms showed normal macrocirculation. Digital ple­thismography showed an absent signal on digits I, II and IV of the right and digits III and V of the left hand. Gemcitabine induced vasculitis causing ischemia was suspected and gemcitabine treat­ment was stopped. The patient was treated with the prolonged infusion of a prostacycline analogue iloprost trometamol (20 mg/day for three weeks) and analgesic therapy with NSARD and opioids. Digital changes in all but one of affected digits re­solved at the next visit in June 24 2009. Ischemic changes of distal phalange of digit V of the left hand required the amputation. The patient died in August 2009 due to the progressive disease. Case 2 A77-year-oldmalepresentedinMay062009with adiagnosisoflocallyadvancedbladdercancer (T4aN2M0).Hewasheavyasmokerinthepastand hadahistoryofgastricperforationduetopeptic ulcertenyearsago.InFebruary2009hewastempo­raryonamiodaronemedicationduetoparoxysmof atrialfibrillation.Otherwisehewasingoodphysi­calcondition.InApril2009heunderwentanat­temptofradicalcistoprostatectomy.Duetothelo­calextensionofthetumouronlyBrickerneovesica andbiopsyofpelviclymphnodeswasperformed. InMay2009hewaspresentedforinductionchemo­therapyanddefinitiveradiotherapyafterwards. FromMaytoAugust2009hereceivedfourcycles ofchemotherapywithcisplatinandgemcitabine (cisplatin75mg/m2onday1andgemcitabine1000 mg/m2ondays1everythreeweeks).Noneofthe plannedgemcitabinedosesonday8wasapplied duetotheinfection.InAugust82009thepatient presentedwithpainfulblackspotsondigitsIand Grasic Kuhar C et al. / Digital ischemic events related to gemcitabine 259 IIoftherightfootandsubluxationofthethumb­nailofthesamefoot.Heunderwenttheablationof thethumbnail.Ischemicchangesinthethumbwere suspected.InAugust182009thepatientpresented withtheprogressivepainfulfingertipnecrosison fingertipsIandIIoftherightfoot(Figure1).The elevatedplateletcountwasrecorded(1211x109/L). Hewassenttoanangiologist.Dopplerultrasound showedsevereperipheralarterialocclusivedis­ease(PAOD)ofbothlegs.Pelvicarteriography showedtheocclusionofrightsuperficialfemoral artery(AFS)inthelengthof5cmandofleftAFSin lengthof18cm,withverygoodcollateralcircula­tiononbothsidesandgoodtransitionoftheboth poplithealarteries(Figure2and3).Thepatientwas treatedwithprolongedinfusionofaprostacycline analogue-iloprosttrometamol(20mg/dayfor7 days).Asuccessfulpercutaneoustransluminalan­gioplastywithdilatationoftherightAFSwasper­formedinSeptember12009.Afterthisprocedure thefootmacrocirculationimproved(warmskinof therightfoot).Thereaftertemporarywetnecrosis andwoundinfectionondigitIIoccurred,which healeduntilNovember22009.Theamputationof theaffecteddigitswasnotrequired.Acetylsalicylic acid100mg/dwasprescribed. Discussion Digital ischemicevents in cancer patients are rare. However, in cancer patients with a history of heavy smoking, dislypidemia, arterial hypertension or di­abetes, PAOD may already be presented at cancer diagnosis and may lead to ischemic events. In sys­temic sclerosis the impairment of microcirculation due to vasculitis and/or vasospasm can also cause a digital arterial obstruction.6Some anticancer agents (cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, prednisone, doxorubicin, tamoxifen, cisplatin-gemcitabine combination) are impli­cated in thrombosis and thrombembolic events.7 Therefore, in a patient with predisposing factors for the impaired microcirculation these anticancer agents may attribute to digital ischemic events.6 Among cases in the literature, Barcelo et al.7reported four cases of digital ischemic changes related to combination chemotherapy with gem-citabine plus cisplatin in patients treated for non-small cell lung cancer. In two of four cases a pre­viously asymptomatic organic vascular lesion was aggravated while on chemotherapy with cisplatin and gemcitabine. Antiplatelet agent triflusal and vasoactive agent buflomedil were successful in re­solving pain. One patient needed the additional leg amputation and two others thrombectomy. Similarly,Venat-Bouvetetal.8describedapatient withtheacuteonsetofbilateralPAODwithnecro­sisoffingerpadswhichpresentedafterthetreat­mentwithgemcitabineandplatinumsaltasafirst linetreatmentforurothelialcarcinomaoftheblad­der.Thepatienthadafavourableoutcomeafter chemotherapywithdrawalandinfusionofiloprost trometamol,asinourCase2.InourCase2cumula­tivedoseofgemcitabinewasonly4000mg/m2,in contrasttoothers(10000mg/m2,14390mg).8,9 260 Grasic Kuhar C et al. / Digital ischemic events related to gemcitabine Blaise et al.9reported two cases of digital ischemia. First was a female treated with gemcit­abine as the second line for lymph-node metastatic squamous cell carcinoma of unknown origin. The second patient was treated for bladder carcinoma with gemcitabine and carboplatine. Both resolved after the interruption of gemcitabine and addition­al medical treatment. Another case attributed to vascular toxicity of gemcitabine is reported by Holstein et al.10treat­ed with platinum plus gemcitabine for advanced urothelial carcinoma. After the second cycle of chemotherapy the patient presented with dig­ital ischemia. Digital amputation was avoided by sympathicolysis by bilateral blockade of brachial plexus and application of iloprost, heparin, corti­costeroids and acetylsalicylic acid. Patients with scleroderma are at high risk for de­veloping digital infarction because of their under­lying vascular disease and associated Raynaud’s phenomenon. Clowse et al.11presented a patient with scleroderma who developed multiple ischem­ic digits after receiving combination chemotherapy of carboplatin plus gemcitabine for lung cancer. D’Allesandro et al.12reported a case with Raynaud type phenomenon, intermittent fever, digital necrosis and a fingertip gangrene after receiving two applications of gemcitabine for bladder can­cer. The authors suggested caution in using such chemotherapy in subjects with autoimmune disor­ders (scleroderma, positive HEP-2 and cryoglobu- lin).11,13 Digital ischemic changes resolved in most cases after stopping the application of chemotherapy and the treatment with prostacyclin antagonists (iloprost or buflomedil). A more sophisticated treatment with sympathicolysis by bilateral tho­racic block was reported to be efficient in digital ischemic event in scleroderma patient, where gan­grenous ulcers occurred due to vaso-occlusive disease, which is a combination of occlusive vas­culitis and symphatically-mediated vasospasm.6Sympathectomy and iloprost infusion were report­ed to be successful in the treatment of severe acral ischemia and necrotic lesions of several fingertips after receiving palliative chemotherapy with gem-citabine for inoperable squamous cell carcinoma of the tonsil.14 In our Case 1 the first signs of the impaired dig­ital circulation (swollen and painful cold blue fin­gers) occurred after three weekly doses of gemcit­abine therapy and worsened after the next weekly application of the same drug, therefore the causal relationship between gemcitabine and digital arte­rial ischemia seems very probable. The patient had no history or symptoms of preexsisting PAOD or connective tissue disease. The Raynaud’s phenom­enon can be a paraneoplastic manifestation in dis­seminated pancreatic cancer, but would already be present at presentation of disease and would prob­ably improve with the effective anticancer therapy. The occurrence of digital ischemia was probably related to vascular toxicity of gemcitabine, as in­dicated by resolving microcirculation in 4 of 5 af­fected digits after the discontinuation of gemcitab­ine and the intervention with vasodilating agent iloprost. In Case 2 after the cumulative dose of gemcit­abine of 4000 mg/m2and cisplatin 300 mg/m2 ar­terial ischemic necrosis on two digits of the right foot occurred. After a detailed investigation of the patient, severe preexisting PAOD of both legs with the very good collateral circulation was diagnosed. Gemcitabine may also be capable to cause endothe­lial damageand thrombocytosis.1,2The latter could also attribute to impaired microcirculation in our case (platelet count at 3rdcycle of chemotherapy 1211 x 109/L). At that time the patient was on frac­tionated heparin in prophylactic dosing. Instead of heparin, the antiagregation therapy with acetylsal­icylic acid would be more appropriate in prevent­ing digital arterial thrombosis. After the dilatation of the occluded segment of the main leg arterial vessel and vasodilatation effect of iloprost infu­sion both macro and microcirculation improved, respectively. Digital ischemic necroses resolved without durable consequences. In both cases painful cold trophic skin changes were clinically suspicious of compromised arte­rial microcirculation, confirmed by absent plethys­mographic signals. In Case 1 Doppler ultrasound showed good macrocirculation, which was se­verely impaired in Case 2, as already suggestive of PAOD by patient’s long smoking history. Clinically absent pedal pulses and angiologic examination with arteriography could place angioplastic inter­vention before the initiation of chemotherapy with gemcitabine and cisplatin. A noninvasive evalu­ation of the leg arterial perfusion could be done by MRI enhanced angiography15and an invasive angiography being applied only in cases where an invasive procedure is indicated. The antiagre­gation therapy (acetylsalicylic acid 100 mg a day) in case of severe reactive thrombocytosis in cancer patients as well as in patients with cardiovascular factors is indicated and could prevent the develop­ment of digital ischemia in Case 2. Discontinuation of cisplatin plus gemcitabine and the intervention Grasic Kuhar C et al. / Digital ischemic events related to gemcitabine 261 with iloprost prometanol have been proven helpful in resolving microcirculation in both cases as docu­mented by control plethysmography. Additionally calcium channel blockers and other vasodilata-tors were shown beneficial in resolving digital ischemia.6,7,11 Conclusions Digital ischemic events associated with gemcitab­ine chemotherapy seem to be more common than previously thought, especially when used in com­bination with platinum salts and in patients with tobacco-associated cancers. In patients with known risk factors for PAOD, like dislypidemia, arterial hypertension, diabetes or tobacco smoking, and a history of intermittent claudication thorough the examination of peripheral pulses should be per­formed before the initiation of gemcitabine or plat-inum-gemcitabine doublet. In addition, if painful trophic digital changes develop while on therapy with gemcitabine, medical oncologists should re­fer the patient to an angiologist for the assessment of impaired micro or macrocirculation. In case of diagnosis of ischemic vascular event, discontinua­tion of gemcitabine and immediately therapy with prostacycline analogues should be initiated. The early diagnosis and the appropriate intervention improve not only the outcome of the ischemic vas­cular event but also the quality of life of the patient. References 1. Dasanu CA. Gemcitabine: vascular toxicity and prothrombotic potential. Expert Opin Drug Saf 2008; 7: 703-16. 2. Summary of Product Characteristics of Gemcitabine; date of revision 18 February 2009: http://emc.medicines.org.uk/medicine/596. 3. DebevecL, Jeric T, Kovac V, BitencM, SokM. Isthereanyprogressinroutine managementoflungcancerpatients?Acomparativeanalysisofaninstituti­onin1996and2006.Radiol Oncol 2009; 43: 47-53. 4. Kovac V, Smrdel U. Meta-analyses of clinical trials in patients with non-small cell lung cancer. Neoplasma 2004; 51: 334-40. 5. Izzedine H, Isnard-Bagnis C, Launay-Vacher V, Mercadal L, Tostivint I, Rixe O, et al. Gemcitabine-induced thrombotic microangiopathy: a systematic review. Nephrol Dial Transplant 2006; 21: 3038-45. 6. Kyung RH, Chan K, Un JP. Successful treatment of digital ulcers in a scle­roderma patient with continuous infusion bilateral thoracic sympathetic block. Pain Physician 2008; 11: 91-6. 7. Barcelo R, Lopez-Vivanco G, Mane JM, Rubio I, Munoz A, Fernandez R. Distal ischemic changes related to combination chemotherapy with cisplatin and gemcitabine. Description of four cases. Ann Oncol 2000; 11: 1191-4. 8. Venat-Bouvet L, Szelag JC, Martin J, Labourey JL, Genet D, Tubiana-Mathieu N. Thrombotic microangiopathy and digital necrosis; two unrecognized toxicities of gemcitabine. Anticancer Drugs 2003; 14: 829-32. 9. Blaise S, Appeltants H, Carpentier PH and Debru JL. Digital ischemia and gemcitabine. Twoo new cases. J Mal Vasc 2005; 30: 53-7. 10. Holstein A, Batge R, Egberts EH. Gemcitabine induced digital ischemia and necrosis. Eur J Cancer Care (Engl) 2009. [Epub ahead of print] 11. Clowse MEB, Wigley FM. Digital necrosis related to carboplatin and gemcit­abine therapy in systemic sclerosis. J Rheumatol 2003; 30: 1341-3. 12. D’Alessandro V, Errico M, Varriale A, Greco A, De Cata A, Carnevale V, et al. Case report: acro-necrosis of the upper limbs caused by gemcitabine therapy. Cli Ter 2003; 154: 207-10. 13. Hummers LK, Wigley FM. Management of Raynaud’s phenomenon and digital ischemic lesions in scleroderma. Rheum Dis Clin North Am 2003; 29: 293-313. 14. Buch RS, Geisbüsch R, Kunkel M. Acral ischemia as a rare paraneoplastic syndrome in the terminal phase of mouth floor carcinoma. [German]. Mund Kiefer Gesichtschir 2002; 6: 331-5. 15. Aschauer MA, Ebner F, Stollberger R. Advances in contrast-enhanced MR-angiography. Radiol Oncol 2002; 36: 103-8. 262 case report Ureteral metastasis as the first and sole manifestation of gastric cancer dissemination Vesna Bisof1, Antonio Juretic1, Josip Pasini2, Marijana Coric3, Mislav Grgic1, Marija Gamulin1, Zoran Rakusic1, Zdenko Krajina1, Martina Basic-Koretic1, Ana Misir1, Ranka Štern-Padovan4 1 Department of Oncology, Clinical Hospital Centre Zagreb, Zagreb, Croatia 2 Department of Urology, Clinical Hospital Centre Zagreb, Zagreb, Croatia 3 Department of Pathology, Clinical Hospital Centre Zagreb, Zagreb, Croatia 4 Clinical Institute for Diagnostic and Interventional Radiology, Clinical Hospital Centre Zagreb, Zagreb, Croatia. Received 10 December 2009 Accepted 5 January 2010 Correspondence to: Vesna Bišof, MD, Department of Oncology, Clinical Hospital Centre Zagreb, Kišpaticeva 12, 10000 Zagreb, Croatia. Phone: + 385 98 9697 134; Fax: + 385 1 2388 583: E-mail: vesna.bisof@zg.t-com.hr Disclosure: No potential conflicts of interest were disclosed. Background. Isolated ureteral metastasis from gastric cancer is extremely rare. Case report. We describe a 50 year old man with a history of subtotal gastrectomy who presented 4 years later with an ureteral metastasis. He was asymptomatic and diagnostic tests were performed due to the elevated creatinine level disclosed incidentally. The partial resection of distal right ureter as well as the resection of the right ureterovesi-cal junction was performed with the implantation of double J stent. Histopathology revealed a metastasis of the adenocarcinoma that matched perfectly a tumour specimen from the gastric cancer surgery. It was first and isolated manifestation of gastric cancer dissemination. Conclusions. Although rare, the ureteral metastasis from gastric cancer can be the first, sole and asymptomatic manifestation of gastric cancer dissemination after a period of time. Key words: ureteral metastasis; gastric cancer Introduction Theso-calledtruemetastasistotheureterfrom gastriccanceroccurringthroughlymphaticand/or bloodvesselsisfoundtobeveryrare.1-3Thereare alsotwootherpossibilitiesoftheuretralobstruction: directextensionfromtheprimarytumour,peritoneal depositorlymphnodemetastasisofgastriccancer totheureter-usuallyseenintheadvancedcancer stageandautopsies4;andretroperitonealfibrosisof theperiureteralspaceinducedbycancercells.5 Wereportthecaseofapatientwithureteralme­tastasisasthefirstandsolemanifestationofgastric cancerdisseminationfouryearsafterhewasfirstdi­agnosedwithgastriccancer. Case report A 50-year old man was admitted to the Department of Urology, Clinical Hospital Centre Zagreb in June 2008, due to the hydronephrosis and raised creatinine blood level disclosed incidentally dur­ing his rehabilitation from brain stroke from which he had suffered in May 2008. He had a history of subtotal gastrectomy for gas­tric cancer four years ago, stage T3N1M0. He re­ceived adjuvant chemo-radiotherapy. The patient had no pain at the admission.Routine blood test results were normal except elevated creatinine (192 mmol/L; normal range 63-107), urea (11.8 mmol/L; normal range 2.8-8.3) and C-reactive protein (CRP) (105 mg/L; normal range < 5) levels and mild ane­mia (hemoglobin 109 g/L; normal range 138-175). Urinalysis showed 3-7 erythrocytes and lot of leu­cocytes. Urine culture revealed Pseudomonas aer­uginosa (103CFU/ml). Multislice computed tomog­raphy (MSCT) disclosed atrophic left kidney and right hydronephrosis (Figure 1). Cystoscopy in­dicated normal bladder. Right retrograde pyelog­raphy (RP) was not done successfully because of the obstruction found at the 3 cm from the right Bisof V et al. / Ureteral metastasis from gastric cancer 263 ureterovescial junction. Right antegrade pyelogra­phy showed hydrourether with contrast stop 4 cm below the right sacroilical joint. On July 29, 2008, the partial resection of the dis­tal right ureter as well as the resection of the right ureterovesical junction was performed with the implantation of a double J stent. Histopathology revealed a metastasis of the ad-enocarcinoma. Fibromuscular and adipose tissue were infiltrated with tumorous tissue consisting of irregular glands lined with atypical colonic epithe­lial cells. No infiltration of a superficial transitional cell layer was found. The macroscopic observation of the periureteral region and of the retroperitoneal space did not reveal any pathology. Upon thorough comparison, tumour specimens of the resected ure­ter (year 2008) and gastric cancer (year 2004) were found to be completely identical (Figures 2a,b). After the receipt of the histopathological report gastroscopy and colonoscopy were performed without any evidence of a tumour. Tumour mark­ers were within the normal range: alpha- fetopro­tein (AFP) (1.46 mg/L; normal range <13.4), carci­noembryonic antigen (CEA) (1.79 mg/L; normal range < 3.4), cancer antigen 19/9 (CA19-9) (16.93 kIU/L; normal range < 37), prostate-specific anti­gen (PSA) (1.44 mg/L, normal range < 4). The patient was further transferred to the Department of Oncology for systemic chemother­apy. Unfortunately, he managed to receive only three cycles of chemotherapy (leucovorin, etopo-side and fluorouracil) when presented with severe acute psychosis. Brain CT was without metastasis but his general and mental condition deteriorated and chemotherapy was never resumed. Finally, af­ter several months his mental status gradually im­proved. Now, twelve months after the last chem­otherapy he is well and without any signs of the disease. Discussion Ureteral metastasis from distant organs is a rare event.1-3The most common primary sites to metas­tasize to the ureter are breast, colon, prostate and cervix.2,6MacKenzie and Ratner1first proposed a criterion for the differentiation of a true metasta­sis from the direct extension of the tumour to the ureter. Later, Presman and Ehrlich3modified the criterion as follows: “the demonstration of malig­nant cells in a portion of the ureteral wall together with the absence of any neoplasm in adjacent tis­sue”. Tumour in the ureteral wall without the in- 264 Bisof V et al. / Ureteral metastasis from gastric cancer vasion of the superficial transitional cell layer and the absence of any pathology in the periuretral and retroperitoneal space in our patient indicated the true uretral metastasis from gastric cancer. Ureteral metastases from gastric cancer are ex­tremely rare.7,8Schlagintweit9reported the first case of gastric cancer metastasizing to the ureter in 1911. Since then, cases have been occasionally re­ported. The majority of them were from Japanese population while reports from other populations were scarce.10Shimoyama et al.10reviewed 27 cases of the true ureteral metastasis from gastric cancer. The age of the patients ranged from 34 to 74 years with median age of 52 years. Eleven patients (41%) had previously undergone gastrectomy for gastric cancer. Our patient fitted the pattern. Although rare on the whole, the ureteral metas­tasis from gastric cancer can be even the first mani­festation of asymptomatic gastric cancer or the first and the sole manifestation of the gastric cancer dis­semination after a period of time-as in our case.10-12The prognosis is generally poor and the survival for more than 2 years has not been reported.10 There has been no report describing any effec­tive therapy for this condition although there are some encouraging results with the multimodality treatment in another cases of patients with gastric cancer.13The new regimens including docetaxel or oxaliplatin could show some benefit in the future. However, the pathohystology accomplished with immunohystochemistry, the establishing of extend of disease and the performance status still remain the main prognostic factors. They also enable the appropriate choice of the treatment.14 References 1. MacKenzie DW, Ratner M. Metastatic growths in the ureter. A report of three cases and a brief review of the literature. Can Med Assoc J 1931; 25: 265-70. 2. Fitch WP, Robinson JR, Radwin HW. Metastatic carcinoma of the ureter. Arch Surg 1976; 111: 874-6. 3. Presman D, Ehrlich L. Metastatic tumors of the ureter. J Urol 1948; 59: 312-25. 4. Liaw C-C, Chuang C-K, Chen J-S, Chang H-K. Gastric cancer with obstructive uropathy: clinical experience with 17 cases. Chang Gung Med J 1997; 20: 286-92. 5. Dohmen K, Mizukami Y, Tanaka K, Nakamura H, Arase K, Yokogawa Y, et al. Retroperitoneal fibrosis associated with scirrhous gastric cancer. Gastroenterol Jpn 1993; 28: 699-705. 6. Richie JP, Withers G, Ehrlich RM. Ureteral obstruction secondary to meta­static tumors. Surg Gynecol Obstet 1979; 148: 355-7. 7. Fontana D, Garbarini A, Giraudi G. A case of gastric carcinoma revealed by a ureteral metastasis. Panminerva Med 1974; 16: 165-70. 8. Heesakkers JP, Delaere KP, Nap M. Metastasis of gastric carcinoma to the ureter. Urology 1999: 54: 561. 9. Schlagintweit F. Metastatische karzinose der ureteren mit anurie bei gleichzeitiger nephritis. Z Urologie 1911; 5: 665-71. 10. Shimoyama Y, Ohashi M, Hashiguchi N, Ishihara M, Sakata M, Tamura A, et al. Gastric cancer recognized by metastasis to the ureter. Gastric Cancer 2000; 3: 102-5. 11. Cohen WM, Freed SZ, Hasson J. Metastatic cancer to ureter -review of literature and case presentations. J Urol 1974; 112: 188-9. 12. Yeh HC, Hsiao HL, Chang TH, Wang SL, Huang CH, Wu WJ. Postoperative disseminated intravascular coagulation in a patient with ureteral metastasis from gastric cancer. Kaohsiung J Med Sci 2008; 24: 319-23. 13. Oblak I, Anderluh F, Velenik V. Postoperative radiochemotherapy for gastric adenocarcinoma: long term results. Radiol Oncol 2009; 43: 274-81. 14. Žokalj I, Culinovic-Caic R, Magaš Z, Pavcec Z, Saghir H, Igrec J, et al. Gastric gastrointestinal stromal tumour. Radiol Oncol 2008; 42: 187-95. 265 letter to the editor Management of cetuximab-induced skin toxicity with the prophylactic use of topical vitamin K1 cream Janja Ocvirk Institute of Oncology Ljubljana, Ljubljana, Slovenia Received 15 May 2010 Accepted 31 May 2010 Correspondence to: Janja Ocvirk, MD, PhD, Institute of Oncology Ljubljana, Zaloška cesta 2, 1000 Ljubljana, Slovenia. E-mail: jocvirk@onko-i.si Disclosure: No potential conflicts of interest were disclosed. Cetuximab is an immunoglobulin G1 monoclonal antibody that binds to the extracellular domain of the epidermal growth factor receptor (EGFR) block­ing ligand-induced auto-phosphorylation and sub­sequent receptor mediated signalling.1,2Cetuximab in combination with chemotherapy is effective in the treatment of EGFR-expressing tumors includ­ing metastatic colorectal cancer (mCRC).2,3 EGFR is strongly expressed in the keratinocytes, cells of eccrine and sebacceous glands and in the epithelium of hair follicles, and is important for normal skin development and function.4Blocking cutaneous EGFR signalling with EGFR inhibitors leads to a spectrum of skin reactions which oc­cur in =80% of patients, the most common being acneiform rash which occurs most frequently on the head and neck regions and on the trunk. Other less frequent reactions include, pruritus, dry skin, desquamation, hypertrichosis, and paronychia.1,2Approximately 15% of cutaneous reactions are severe (= grade 3; US National Cancer Institute–Common Toxicity Criteria)5, causing cetuximab therapy to be interrupted.6 We have investigated the prophylactic treatment of patients with a topically applied skin cream con­taining urea and 0.1% vitamin K1 (Renconval K1®) during cetuximab therapy. The aim of the study was to continue cetuximab without treatment de­lays or dose reductions, which may impact on tu­mour response rates.7Four patients with mCRC receiving first-line cetuximab in combination with chemotherapy, had applied vitamin K1 cream fa­cially twice daily for 8 weeks from the first infu­sion of cetuximab. Patients were screened weekly 266 Ocvirk J / Cetuximab-induced skin toxicity TABLE 1. Assessment of acenform rash in 4 patients treated with cetuximab in combination with chemotherapy and prophylactic vitamin K1 skin cream A 0/+ 0/+ 0/+ 0/+ 0/+ 0/+ 0/+ 0/+ SD B 0/+ 0/+++ 0/++ 0/++ 0/++ 0/++ 0/+ 0/+ CR C 0/++ +/+++ +/+++ 0/++ 0/++ 0/++ 0/+ 0/+ PR D 0/+ 0/++ 0/++ 0/+ 0/+ 0/+ 0/+ 0/+ PR *Scoring system 0=no rash; += mild rash, ++= moderate rash and +++= severe rash **Three males and one female, average age: 61.75 years. F= face; T= trunk; SD, stable disease; CR, complete response; PR, partial response and photographs taken. The study was performed in accordance with the Declaration of Helsinki (5threvision, October 2000) of the World Medical Association8and approved by the National Medical Ethics Committee of the Republic of Slovenia. Patients provided written informed consent. During treatment, no topical or oral antibiotics were prescribed and other moisturizers were not needed. Only one patient was judged to have de­veloped mild facial papules and all four patients developed acneiform eruptions on the trunk rang­ing from mild to severe. The grade of acneiform rash was reduced where vitamin K1 cream was ap­plied as prophylaxis (Table 1 and Figure 1). At the end of cetuximab treatment one complete response, one stable disease and two partial re­ sponses were recorded. Vitamin K activates EGFR signalling; preclinical studies have shown that 0.1–0.5 mM vitamin K3 completely abrogated EGFR inhibition in vitroand was associated with upregulation of phosphorylat-ed EGFR in the skin when used in topically applied cream.9,10In a study of 30 patients treated with Reconval K1®on the first appearance of acneiform rash, we previously reported a median time to im­provement of 8 days, and down-staging of rash by =1 grade after 18 days. No cetuximab dose reduc­tions or treatment delays were required in patients with grade =2 cutaneous toxicity and no toxicities associated with Reconval K1® were reported.7,11 In the present study we investigated the pro­phylactic use of vitamin K1 cream to the face in comparison with the trunk, which received no treatment. Whilst curative treatment has already been reported to be effective7, prophylactic treat­ment is potentially more effective. No cetuximab dose reductions or treatment delays were required. The topical use of vitamin K1 cream for preventing or reducing cetuximab-related acneiform rash ap­pears to be promising. It remains very important to treat skin reactions related to EGFR inhibitors promptly to ensure a better patient quality of life without dose reduc­tion or drug discontinuation. We conclude that Reconval K1®has potential for prophylactic use in the treatment of cetuximab-related skin toxicity, but that further studies are required to evaluate the impact of its use on tumor response rates and pa­tient quality of life. References 1. Segaert S, van Cutsem E. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibi­tors. Ann Oncol 2005; 16: 1425-33. 2. van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic color-ectal cancer. N Engl J Med 2009; 360: 1408-17. 3. Ocvirk J. Advances in the treatment of metastatic colorectal carcinoma. Radiol Oncol 2009; 43: 1-8. 4. Lacouture ME. Insights into the pathophysiology and management of der­matologic toxicities to EGFR-targeted therapies in colorectal cancer. Cancer Nurs 2007; 30: S17-26. 5. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205-16. 6. Erbitux. Summary of product characteristics. Available at http://www.emea. europa.eu/humandocs/PDFs/EPAR/erbitux/H-558-PI-en.pdf [Accessed July 14, 2009] 7. Ocvirk J, Rebersek M. Management of cutaneous side effects of cetuximab therapy with vitamin K1 cream. Radiol Oncol 2008; 42: 215-24. 8. The international response to Helsinki VI – The WMA’s Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects, as adopted by the 52nd WMA General Assembly. Edinburgh; October 2000. Available at http://www.wma.net/en/20activities/10ethics/ 10helsinki/index.html [Accessed July 16, 2009] 9. Tan EH, Chan A. Evidence-based treatment options for the management of skin toxicities associated with epidermal growth factor receptor inhibitors. Ann Pharmacother 2009; 43: 1658-66. 10. Li TH, Perez-Soler R. Skin toxicities associated with epidermal growth factor receptor inhibitors. Targ Oncol 2009; 4: 107-19. 11. Ocvirk J, Rebersek M. Treatment of cetuximab-associated cutaneous side effects using topical aplication oh vitamin K1 cream. [Abstract]. J Clin Oncol 2009; 27(Suppl): e15087. Radiol Oncol 2010; 44(4): 207-214. doi:10.2478/v10019-010-0042-8 Citološka preiskava urina in izpirka secnega mehurja pri ugotavljanju urotelijskega karcinoma: standardni test in nove možnosti Strojan Fležar M Izhodišca. Svetlobnomikroskopska ocena celicne morfologije na preparatih, pripravljenih iz odlušcenih celic v vzor­cih urina in izpirka secnega mehurja, omogoca osnovno in prvo diagnostiko malignomov secnega mehurja pa tudi ostalih delov urinarnega trakta. S citopatološko preiskavo odkrivamo tudi ponovitve bolezni ob kontrolnih pregledih pri bolnikih, ki so že bili zdravljeni zaradi karcinoma secnega mehurja ali nov primarni tumor. Zakljucki. Znacilni celicni in jedrni znaki malignosti omogocajo zanesljivo citopatološko diagnostiko invazijskega urotelijskega karcinoma in in situ karcinoma ter vecine papilarnih urotelijskih karcinomov visokega gradusa. Metoda ima nizko obcutljivost in je nezanesljiva za diagnostiko papilarnih urotelijskih neoplazem nizkega gradusa, ker so celicni in jedrni znaki malignosti pri teh neoplazmah slabo izraženi. Da bi izboljšali diagnostiko karcinoma secnega mehurja iz urina, so razvili razlicne nove oznacevalce. Med najnovejšimi je test UroVysion™, to je metoda fluorescencne in situ hibridizacije, s katero ugotavljamo specificne citogenetske spremembe, znacilne za urotelijske karcinome. Radiol Oncol 2010; 44(4): 215-219. doi: 10.2478/v10019-010-0032-x Radiološki znaki osteonekroze celjustnic povzrocene z bisfosfonati Šurlan Popovic K, Kocar M Izhodišca. Bisfosfonati so zdravila, ki jih uporabljamo za zdravljenje osteoliticnih metastaz, plazmocitoma, z mali­gnimi obolenji povzrocene hiperkalcemije, osteoporoze in Pagetove bolezni. Uporaba bisfosfonatov lahko povzroci osteonekrozo celjustnic. Namen naše študije je predstaviti radiološke znake osteonekroze celjustnic povzrocene z bisfosfonati. Bolniki in metode. Pri enajstih bolnikih z bolecnino v celjusti slabšim celjenjem na mestu ekstrakcije zoba, gnojnim iztokom in otekanjem v podrocju mehkih tkiv smo opravili CT in MRI preiskavo obeh celjustnic s kontrastnim sredstvom. Povprecni cas zdravljenja z bisfosfonati je bil 28 mesecev. Vsi bolniki so bili zdravljeni kirurško z odvzemom histološkega vzorca, v katerem je bila dokazana osteonekroza. Rezultati. CT preiskava je pokazala osteoliticne in osteoskleroticne spremembe z erozijami kortikalne plasti celjustnic pri vseh bolnikih, vkljucenih v našo študijo. Na MRI preiskavi s kontrastnim sredstvom smo osteonekrozo videli kot neostro omejeno spremembo z zmanjšanim signalom tako na T1 kot T2 obteženi sekvenci. Pri vseh bolnikih smo na MRI prei­skavi opazovali oteklino mehkih tkiv s patološkim obarvanjem po kontrastnem sredstvu v podrocju bukcinatornega in mastikatornega prostora ter vnetno spremenjene bezgavke submandibularne in jugularne digastricne verige Zakljucki. Pri osteonekrozi celjustnic povzroceni z bisfosfonati smo s slikovno preiskovalnimi metodami prikazali razlic­ne radiološke znake, s katerimi bolezen lahko prepoznamo, zamejimo in jo spremljamo. Noben od radioloških znakov pa ni znacilen samo za to vrsto osteonekroze. Radiol Oncol 2010; 44(4): I-VI. Radiol Oncol 2010; 44(4): 220-227. doi:10.2478/v10019-010-0046-4 Ocenjevanje perianalnih fistul z magnetno resonanco Sofic A, Beslic Š, Šehovic N, Caluk J, Sofic D Izhodišca. Kot fistulo opredeljujemo patološko povezavo med dvema epitelialnima površinama. Parksova klasifika­cija ima veliko prakticno vrednost in fistule deli na intersfinktericne, transsfinktericne, suprasfinktericne in ekstrasfinkte­ricne. Etiologija perianalnih fistul je najveckrat povezana z vnetjem analnih žlez pri Crohnovi bolezni, tuberkulozi, me­denicnih okužbah ter z medenicnimi malignimi tumorji in radioterapijo. Fistule lahko slikovno prikažemo z rentgensko fistulografijo, fistulografijo z racunalniško tomografijo (CT) ali pa z magnetno resonanco (MR) medenicnih organov. Bolniki in metode. V prospektivno raziskavo smo vkljucili 24 bolnikov, ki so imeli perirektalno fistulo. Pri vseh smo naredili rentgensko fistulografijo, fistulografijo s CT preiskavo in preiskavo medenicnih organov z MR. Statisticno smo analizirali natancnost vsake preiskave glede na spol bonikov in etiologijo fistul. Rezultati. Ugotovili smo 29,16% transsfinktericnih fistul, 25% intersfinktericnih, 25% rekto-vaginalnih, 12,5% ekstrasfink­tericnih in 8,33% suprasfinktericnih. Absces smo prikazali pri 16,6% bolnikov. Najpogostejši vzrok perianalnih fistul je bila Crohnova bolezen (37,5%), kjer je bila natancnost opredelitve fistul z MR 100%, s CT 11% in s rentgensko preiskavo 0%. Ulcerozni kolitis je bil drugi najpogostejši vzrok za nastanek fistul (20,9%), kjer je bila natancnost opredelitve fistul z MR 100%, s CT 80% in s rentgensko preiskavo 0%. Ostale vzroke nastanka fistul smo našli pri 41,6% bolnikov. Zakljucki. MR je zanesljiva diagnosticna metoda za opredelitev perirektalnih fistul in nam lahko znatno pomaga v predoperativni pripravi za uspešen kirurški poseg. Na ta nacin lahko zmanjšamo število ponovitev bolezni. Prednost je tudi, da lahko brez uporabe kontrastnega sredstva natancno prikažemo fistulo in absces. Radiol Oncol 2010; 44(4): 228-231. doi:10.2478/v10019-010-0033-9 Mamografsko okultni duktalni rak in situ (DCIS), visokega gradusa kot drugi primarni rak dojke, odkrit z magnetno resonanco – prikaz primera Zebic-Šinkovec M, Kadivec M, Podobnik G, Škof E, Snoj M Izhodišca. Najpogostejši drugi primarni rak dojke pri bolnicah, ki so že imele rak dojke, je rak kontralateralne dojke. Ko ga odkrijemo, je najveckrat že invazivne oblike. Skoraj vsi invazivni raki dojke se razvijejo iz in situ karcinoma. Senzitivnost magnetne resonance za DCIS je precej višja od mamografije. Prikaz primera. Bolnica je bila pred 10 leti že operirana zaradi raka dojke. Naredili so ohranitveno operacijo, histo­loško pa je bil ugotovljen medularni karcinom dojke. Po 10 letih smo v drugi dojki odkrili DCIS visokega nuklearnega gradusa. DCIS je bil mamografsko neviden (okulten), odkrit z magnetno resonanco in potrjen z biopsijo pod kontrolo magnetne resonance. Zakljucki. Preiskava dojk z magnetno resonanco bi lahko postala sestavni del preiskav v sledenju bolnic z diagnozo rak dojke. Radiol Oncol 2010; 44(4): I-VI. Radiol Oncol 2010; 44(4): 232-238. doi:10.2478/v10019-010-0044-6 Ucinek kakovosti odgovora na zdravljenje in zgodnje uvedbe rituksimaba na celokupno preživetje in preživetje brez ponovitve bolezni pri bolnikih z B-celicnim limfomom Horvat M, Jezeršek Novakovic B Izhodišca. Uvedba rituksimaba v zdravljenje bolnikov z ne-Hodgkinovimi limfomi je prispevala k boljšim rezultatom zdravljenja – izboljšal se je odgovor na zdravljenje, podaljšalo trajanje remisij in celokupno preživetje bolnikov z B-celicnimi limfomi. Le malo raziskav pa je poskušalo razjasniti, ali boljši odgovor na zdravljenje (t.j. popolni odgovor) in zgodnja uvedba rituksimaba v zdravljenje prispevata tudi k daljšemu preživetju bolnikov. Namen naše retrospektivne raziskave je bil ugotoviti morebitno povezavo tako med kakovostjo odgovora na zdravljenje kot linijo zdravljenja z rituksimabom ter celokupnim preživetjem in preživetjem brez ponovitve bolezni . Bolniki in metode. V raziskavi smo preucevali rezultate zdravljenja bolnikov z razlicnimi histološkimi tipi B-celicnih limfomov, ki so bili v obdobju od 2003 do 2007 zdravljeni na Onkološkem inštitutu Ljubljana s kombinacijo rituksimaba in kemoterapije. V raziskavo smo vkljucili le bolnike, ki so imeli pred uvedbo zdravljenja opravljeno dolocitev jakosti ek­spresije CD20 s kvantitativno pretocnocitometricno metodo. Celokupno preživetje in preživetje brez ponovitve bolezni smo dolocili po Kaplan-Meierjevi metodi. Rezultati. V raziskavo smo vkljucili 114 bolnikov. Bolniki, ki so po zdravljenju z rituksimabom dosegli popolni odgovor, so imeli statisticno znacilno daljše celokupno preživetje kot tisti, ki so dosegli le delni odgovor na zdravljenje (razmerje tveganj [HR] 0,34; 95% interval zaupanja [CI] 0,05 do 0,91; P = 0,0375) ali tisti, pri katerih se je bolezen stabilizirala (HR 0,11; 95% CI 0,0002 do 0,033; P < 0,0001) ali napredovala (HR 0,09; 95% CI 0,003 do 0,03; P < 0,0001). Bolniki, ki so dosegli popolni odgovor (CR; n = 70; 61,4%), so imeli tudi statisticno znacilno daljše preživetje brez ponovitve bolezni (razmerje tveganj [HR], 0,26; 95% CI, 0,021 do 0,538, P = 0,0068) kot tisti, ki so dosegli le delni odgovor (PR; n = 17; 14,9%). Bolniki, ki so prejeli rituksimab v sklopu prvega reda zdravljenja (n = 50; 43,9%), so imeli statisticno znacilno daljše celokupno preživetje kot tisti, ki so bili zdravljeni z rituksimabom ob prvi (HR 0,27; 95% CI 0,106 do 0,645; P = 0,0036) ali drugi po­novitvi bolezni (HR 0,22; 95% CI 0,078 do 0,5; P = 0,0006). Tudi preživetje brez ponovitve bolezni je bilo pri bolnikih, ki so bili z rituksimabom zdravljeni v prvem redu (n = 46; 52,9%), statisticno znacilno daljše (HR 0,32; 95% CI 0,088 do 0,9; P = 0,0325) kot pri bolnikih, ki so rituksimab prejeli v sklopu zdravljenja prve ponovitve bolezni (n = 25; 28,7%). Zakljucki. Naši rezultati kažejo, da boljši odgovor na zdravljenje verjetno prispeva k boljšemu celokupnemu preži­vetju in preživetju brez ponovitve bolezni pri bolnikih z B-celicnimi limfomi. Tudi zgodnja uvedba rituksimaba v zdra­vljenje (t.j. prvolinijsko zdravljenje) verjetno izboljša celokupno preživetje. Ko se torej odlocamo o zdravljenju bolnikov z B-celicnimi limfomi, je smiselna uvedba rituksimaba v prvem redu zdravljenja v kombinaciji, pri kateri pricakujemo najvecji delež popolnih odgovorov na zdravljenje. Radiol Oncol 2010; 44(4): I-VI. Radiol Oncol 2010; 44(4): 239-243. doi:10.2478/v10019-010-0048-2 Drugi primarni rak pri bolnikih z želodcnim rakom Büyükasik O, Hasdemir AO. Gülnerman Y, Çöl C, Ikiz Ö Izhodišca. Pri bolnikih z želodcnim rakom je vecja nevarnost, da zbolijo za drugim rakom kot pri ljudeh v splošni po­ pulaciji. Namen raziskave je bil prouciti klinicnopatološke znacilnosti teh drugih primarnih rakov. Bolniki in metode. V retrospektivni klinicni raziskavi smo analizirali bolnike, ki smo jih zdravili od leta 1995 do 2005 zaradi primarnega želodcnega raka. Upoštevali smo merila Warrena in Gatesa za druge (sekundarne) primarne rake. Rezultati. 9 od 112 bolnikov z želodcnim rakom je imelo drugi primarni rak. 7 je bilo moških in 2 ženski; 6 jih je imelo sinhroni in 3 metahroni drug primarni rak. Bolniki so bili stari od 53 do 78 let, srednja starost je bila 61 ± 8,3 let. Najbolj pogosto smo ugotovili rak debelega crevesa in danke (33%), rak zgornjih dihalnih poti (22%) in rak secil (22%). Zakljucki. V raziskavi smo ugotovili, da je incidenca drugega primarnega pri bolnikih z želodcnim rakom 8%. Priporocamo skrbne pre-in postoperativne preiskave za odkrivanje drugega primarnega raka in preiskave za opredeli­tev razširjenosti želodcnega raka. Ker je pri bolnikih z rakom želodca rak debelega crevesa in danke najbolj pogost dru­gi primarni rak, svetujemo ob sledenju bolnika usmerjene preiskave, kot sta n.pr. abdominopelvicni CT in kolonoskopija. Radiol Oncol 2010; 44(4): 244-248. doi:10.2478/v10019-010-0047-3 Limfedem po zdravljenju raka v Sloveniji: pogosto spregledana posledica? Planinšek Rucigaj T, Kecelj Leskovec N, Tlaker Žunter V Izhodišca. Sekundarni limfedem je pogosta, velikokrat boleca posledica zdravljenja raka, ki zmanjšuje kakovost bol­nikovega življenja, ovira gibanje in predstavlja tveganje za razvoj zapletov, kot so okužbe in maligne bolezni. Pri zdra­vljenju limfedema je bistvenega pomena cim prejšnje ukrepanje, še preden pride do nepopravljivih sprememb v tkivu. Bolniki in metode. Opravili smo retrospektivno raziskavo bolnikov z limfedemom, ki smo jih od januarja 2002 do junija 2010 zdravili na Dermatovenerološki kliniki Univerzitetnega klinicnega centra Ljubljana. Zbrali smo demografske podatke bolnikov ter podatke o vrsti raka, vrsti in stadiju limfedema ter casu do prve terapije limfedema. S pomocjo osnovnih statisticnih metod smo primerjali število obravnavanih bolnikov z limfedemom po zdravljenju melanoma, ra­ka dojke in raka maternice/maternicnega vratu, in število pricakovanih slovenskih bolnikov z limfedemom, izracunano na osnovi objavljenih porocil o incidenci. Rezultati. V obdobju 8,5 let smo obravnavali 543 bolnikov (432 žensk, 112 moških) z limfedemom. Rezultati kažejo, da verjetno številnih slovenskih bolnikov s sekundarnim limfedemom po zdravljenju raka ne prepoznamo in jih ne zdravimo ali pa premalo zdravimo. Pri vecini naših bolnikov smo zaceli zdraviti limfedem pozno, povprecno šele po 3,6 letih po zacetku limfedema. Zakljucki. Da bi preprecili zapoznelo diagnozo in obravnavo limfedema po zdravljenju raka ter posledicne zaplete, mora zdravnik v casu spremljanja onkološkega bolnika aktivno iskati znake in simptome limfedema. Bolnike s težavami mora takoj zdraviti ali napotiti na zdravljenje. Radiol Oncol 2010; 44(4): I-VI. Radiol Oncol 2010; 44(4): 249-256. doi:10.2478/v10019-010-0040-x Ocena klinicnih intervencij farmacevtov pri pripravi protitumorskih zdravil Knez L, Laaksonen R, Duggan C Izhodišca. Protitumorska zdravila uvršcamo med ucinkovine z velikim tveganjem. Napake v njihovem predpisovanju, pripravi in aplikaciji imajo lahko resne posledice za bolnikovo zdravje, vkljucno z možnim smrtnim izidom. Kljub temu da je multidisciplinarno delo in sodelovanje farmacevtov v onkološki dejavnosti že uveljavljeno kot eden izmed nacinov za zmanjševanje zgoraj omenjenega tveganja, je doprinos klinicnih farmacevtov slabo raziskan. Namen prispevka je analizirati klinicne intervencije farmacevtov pri pripravi protitumorskih zdravil ter oceniti njihov prispevek k izboljšanju zdravljenja onkoloških bolnikov. Metode. Klinicne intervencije farmacevtov smo beležili v enoti za pripravo protitumorskih zdravil v terciarnem onkolo­škem centru v Londonu. Farmacevte smo opazovali med dvema procesoma: med pregledom ustreznosti predpisane terapije ter pri izdaji pripravljenega zdravila. Klinicni pomen zabeleženih intervencij smo dolocili na osnovi soglasja, ki smo ga dosegli po strokovni farmacevtski razpravi. Rezultati. Farmacevte smo opazovali pri 130 pregledih narocil ali izdaji zdravil. Zabeležili smo 21 intervencij. Problemi, ki so bili povezani z vsebinama »zdravilo in terapija« (38%) in »odmerek, režim odmerjanja in trajanje« (19%), ter pro-blemi »administrativne narave« (22%) so najbolj pogosto zahtevali farmacevtovo intervencijo in kažejo na podrocja, kjer so potrebne izboljšave. Predlagane intervencije so upoštevali v 86%. Ocenili smo, da je bilo 48% intervencij zelo pomembnih za bolnikovo zdravljenje. Zakljucki. S svojimi intervencijami klinicni farmacevti pripomorejo k boljši obravnavi onkoloških bolnikov. Za zagota­vljanje visoke kakovosti onkološke dejavnosti morajo biti v zdravljenje s protitumorskimi zdravili vkljucene tudi farma­cevtove klinicne storitve. Radiol Oncol 2010; 44(4): 257-261. doi:10.2478/v10019-010-0020-1 Ishemija prstov v povezavi z zdravljenjem z gemcitabinom: dva primera in pregled literature Grasic Kuhar C, Mesti T, Zakotnik B Izhodišca. Gemcitabin je ucinkovit citostatik, ki ga uporabljamo za zdravljenje številnih solidnih tumorjev pa tudi sarkomov in limfomov. Ob množicni uporabi gemcitabina je vedno vec tudi porocil o žilnih in tromboticnih zapletih. Prikaz primerov. Prestavljamo dva primera ishemije prstov, ki sta najverjetneje povezana z gemcitabinom. Prvi bolnik je bil star 65 let in smo ga zdravili z gemcitabinom zaradi napredovalega karcinoma pankreasa. Po šti­rih tedenskih aplikacijah gemcitabina (skupno 4000 mg/m2) so se mu na prstih rok pojavile spremembe podobne Raynaudovemu fenomenu. Po ukinitvi gemcitabina in infuziji iloprost trometamola so spremembe izzvenele brez posledic na vseh prstih razen enem. Drugi bolnik je bil star 77 let in je bil bivši kadilec. Zaradi napredovalega karcinoma secnega mehurja smo se odlocili za prvo zdravljenje s kombinirano kemoterapijo gemcitabina in cisplatina. Po 4 krogih kemoterapije (skupni odmerek gemcitabina 4000 mg/m2) je bolnik utrpel ishemijo in nekrozo dveh prstov na desni nogi. Arteriografija je pokazala preeksistentno periferno arterijsko okluzivno bolezen obeh nog z zelo dobro periferno kolateralno cirkulacijo, a odsotno mikrocirkulacijo na prizadetih dveh prstih. Zdravljenje s kemoterapijo smo prekinili. Nato smo bolnika zdravili z infuzijo iloprost trometamola in perkutano transluminalno angioplastiko z dilatacijo desne superficialne femoralne arterije. Spremembe na prstih so povsem izginile. Huda trombocitoza (število trombocitov 1211 x 109/L) je lahko dodatno pri­spevala k ishemicnim spremembam na prstih. Zakljucki. Ishemicni dogodki prstov, ki so povezani s kemoterapijo z gemcitabinom, so pogostejši pri bolnikih z raki, ki jih povezujemo s kajenjem. Pogostejši so, kadar uporabljamo kombinacijo gemcitabina s platino. Pri bolnikih z razvi­jajocim se Raynaudovim fenomenom in preeksistentno periferno arterijsko okluzivno boleznijo moramo biti pri uporabi gemcitabina pozorni na razvoj ishemije prstov. Radiol Oncol 2010; 44(4): I-VI. Radiol Oncol 2010; 44(4): 262-264. doi:10.2478/v10019-010-0015-y Ureteralni zasevek kot prvi in edini znak razširitve želodcnega raka Bišof V, Juretic A, Pasini J, Coric M, Grgic M, Gamulin M, Rakušic Z, Krajina Z, Bašic­Koretic M, Mišir A Izhodišca. Posamicni ureteralni zasevek, ki ga povzroci želodcni rak, je izredno redek. Prikaz primera. Predstavljamo 50-letnega bolnika, ki so mu pred 4 leti subtotalno odstranili želodec zaradi želodc­nega raka, nato pa se je pojavil posamicni ureteralni zasevek. Bolnik je bil brez simptomov, dodatne preiskave pa smo naredili, ker je imel ob rutinskem pregledu povišan kreatinin. Naredili smo delno resekcijo distalnega desnega ureterja in resekcijo ureterovesikalnega stika ter vstavili opornico v obliki crke J. Histopatološki pregled je potrdil adenokarci­nom, ki se je ujemal s histopatološko sliko narejeno ob operaciji želodca. To je bil prvi in edini zasevek želodcnega raka. Zakljucki. Ceprav redko je lahko ureteralni zasevek prvi in edini znak razširitve želodcnega raka. Pojavi se lahko po daljšem casu po prvem zdravljenju. Radiol Oncol 2010; 44(4): I-VI. 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. Thoracic oncology October 7 – 9, 2010 The 2nd International Thoracic Congress Dresden will be held in Dresden, Germany. E-mail profmanegold@t-online.de Oncology October 8 – 12, 2010 The “35th ESMO Congress” will take place in Milan, Italy. Contact ESMO Head Office, Congress Department, Via La Santa 7, CH-6962 Viganello-Lugano, Switzerland; or call +41 (0)91 973 19 19; or fax +41 (0)91 973 19 18; or e-mail congress@esmo.org; or see http://www.esmo.org Nuclear medicine October 9 – 13, 2010 The “EANM’10 Annual Congress of the European Association of Nuclear Medicine” will take place in Vienna, Austria. Contact EANM Executive Secretariat and call +43 1 212 80 30; or fax +43 1 212 80 309; or e-mail office@ eanm.org; or see http://www. eanm.org Therapeutic radiology and oncology October 31 – November 4, 2010 The “American Society for Therapeutic Radiology and Oncology Annual Meeting ASTRO” will take place in San Diego, California, USA. Contact ASTRO, 8280 Willow Oaks Corporate Dr., Suite 500, Fairfax, VA 22031; or call +1 703 502-1550; or see http://www.astro.org Radiation oncology November 13 – 19, 2010 The ESO/ESTRO masterclass in radiation oncology will be offered in Cascais, Portugal. Contact Chiara Gasparotto, European School of Radiotherapy, ESTRO Office, Av. E. Mounier 83, 1200 Brussels, Belgium; or phone +32 2 775 9337; or fax +32 2 779 5494; or e-mail cgasparotto@estro.org; or see www.eso. Net or www.estro.org Lung cancer December 2 – 4, 2010 The 4th Asia Pacific Lung Cancer Conference (APLCC 2010) will be held in Seoul, South Korea. E-mail hjk3425@skku.edu Lung cancer December 2 – 4, 2010 The 12th Central European Lung Cancer Conference (CELCC) will be held in Budapest, Hungary. E-mail ostorosgyula@freemail.hu Thoracic oncology December 9 – 11, 2010 The ASCO/ASTRO/IASLC/University of Chicago Multidisciplinary Symposium in Thoracic Oncology will be held in Chicago, IL, USA. E-mail evokes@medicine.bsd.uchicago.edu Clinical oncology June 3 – 7, 2011 The American Society of Clinical Oncology Conference (ASCO 2010) will be offered in Chicago, USA. E mail enews@asco.org; or see http://www/asco.org Lung cancer July 3 – 7, 2011 The “14th World Conference on Lung Cancer” will be offered in Amsterdam, The Netherlands. See http://www.iaslc.org Oncology September 23 – 27, 2011 The “16th ECCO and 36th ESMO Multidisciplinary Congress” will be offered in Stockholm, Sweden. See http://www.ecco-org.eu Nuclear medicine October 15 – 19, 2011 The “EANM’11 Annual Congress of the European Association of Nuclear Medicine” will take place in Birmingham, United Kingdom. Contact EANM Executive Secretariat and call +43 1 212 80 30; or fax +43 1 212 80 309; or e-mail office@ eanm.org; or see http://www. eanm.org Radiol Oncol 2010; 44(4): VII. authors index 2010 Authors Index 2010 Adibelli Z: 2/97-102Akansel G: 1/24-29Apaydin M: 3/164-167; 2/97-102Atalar B: 3/194-198 Bailey D: 2/124-130Barakovic F: 3/153-157Bašic-Koretic M: 4/262-264Baur M: 2/113-120Bellard E: 3/142-148Bešlic Š: 1/19-23; 3/158-163; 3/158-163; 3/158-163; 4/220-227Bišof V: 4/262-264Boardman L: 1/57-61Bratanic N: 3/187-193Bunc G: 1/13-18Buyukasik O: 4/239-243 Calli C: 2/97-102Caluk S: 3/153-157; 3/153-157Cemazar M: 1/42-51Ciric E: 2/66-78Col C: 4/239-243Coskun A: 2/121-123 Caluk J: 4/220-227 Coric M: 4/262-264 Demirci A: 1/24-29Dittrich C: 2/113-120Duggan C: 4/249-256Ecochard V: 3/142-148Elandt K: 2/113-120Eren C: 2/97-102 Faj D: 1/62-66Filipic M: 1/42-51Franekic J: 2/131-134; 3/168-173 Gamulin M: 3/168-173; 4/262-264Golicnik M: 1/52-56Golzio M: 3/142-148Grasic Kuhar C: 4/257-261Grgic M: 4/262-264Grzadziel A: 3/199-206Gulnerman Y: 4/239-243Gumustas S: 1/24-29Gunduz K: 3/194-198Gungor G: 3/194-198 Hasdemir A: 4/239-243Hassler M: 2/113-120Horvat M: 4/232-238Hrašcan R: 2/131-134; 3/168-173Hreljac I: 1/42-51Hudec M: 2/113-120 Ibralic M: 3/158-163Ikiz O: 4/239-243Ilhan E: 2/121-123Inan N: 1/24-29Ivkovic A: 1/62-66 Jereb B: 3/187-193Jeromel M: 1/30-33; 2/86-91; 3/149-152 Jezeršek Novakovic B: 4/232-238Jurdana M: 2/79-85Juretic A: 4/262-264 Kadivec M: 4/228-231Kakizawa H: 2/86-91Karovic J: 3/158-163Kecelj Leskovec N: 4/244-248Keller F: 2/86-91Kilinc F: 1/24-29Kirar Fazarinc I: 1/52-56Kitis O: 2/97-102Knez L: 4/249-256Kocijancic I: 1/19-23; 2/92-96Kocar M: 4/215-219Kores Plesnicar B: 1/52-56Kovac V: 1/52-56; 2/92-96; 3/180-186Krajina Z: 4/262-264Kralj B: 1/52-56Kranjc S: 3/174-179Kranokpiraksa P: 2/86-91Krušlin B: 3/168-173Kumaraswamy L: 2/124-130Kusljugic Z: 3/153-157 Laaksonen R: 4/249-256Lah Turnšek T: 1/42-51Ložar B: 3/174-179 Radiol Oncol 2010; 44(4): VIII-IX. authors index 2010 Marosi C: 2/113-120Mesti T: 4/257-261Miklavcic D: 1/34-41Miklavcic I: 1/62-66Miller R: 1/57-61Mišir A: 4/262-264 Nemec-Svete A: 3/174-179 Ocvirk J: 4/265-266Osmanovic E: 3/153-157Oztekin O: 2/97-102; 2/121-123; 3/164-167 Ozyar E: 3/194-198 Paganin-Gioanni A: 3/142-148Paquereau L: 3/142-148Pasini J: 4/262-264Pavcnik D: 2/86-91; 3/149-152Pecina- Šlaus N: 3/168-173Petrovic B: 3/199-206Piribauer M: 2/113-120Planinic J: 1/62-66Planinšek Rucigaj T: 4/244-248Plazar N: 2/79-85Plesnicar A: 1/52-56Podgorsak M: 2/124-130Podobnik J: 2/92-96; 4/228-231Poje M: 1/62-66Popovic M: 1/13-18Popovic P: 1/30-33Preusser M: 2/113-120Purten M: 2/121-123Radolic V: 1/62-66Rados M: 2/103-106Rakušic Z: 4/262-264Rosch J: 2/86-91Rutonjski L: 3/199-206 Sarisoy H: 1/24-29Sepe A: 3/174-179Sersa G: 1/42-51; 2/66-78; 3/174-179Serša I: 2/92-96; 3/174-179Sjekavica I: 2/103-106Slosarek K: 3/199-206Smrdel U: 1/13-18Snoj M: 4/228-231Sofic A: 1/19-23; 3/153-157; 3/158-163; 4/220-227Sofic D: 4/220-227Stanic K: 3/180-186Stanisavljevic D: 1/30-33Strojan P: 1/1-12Strojan Fležar M: 4/207-214 Šehovic N: 1/19-23; 4/220-227Šentjurc M: 3/174-179Škof E: 4/228-231Štern-Padovan R: 2/103-106; 4/262-264Šunjara V: 2/103-106Šurlan Popovic K: 4/215-219 Teissie J: 3/142-148Terzic I: 3/153-157Tlaker Žunter V: 4/244-248Towhidi L: 1/34-41Uchida B: 2/86-91 Varer M: 3/164-167Varga M: 1/62-66Velenik V: 3/135-141Velnar T: 1/13-18Vidmar J: 3/174-179Vladušic T: 3/168-173Vranic A: 2/107-112Vrhovac I: 2/131-134; 3/168-173Vukovic B: 1/62-66 Yildirim M: 2/121-123Yurtseven T: 2/97-102 Zadravec Zaletel L: 3/187-193Zager V: 1/42-51Zakotnik B: 4/257-261Zebic-Šinkovec M: 4/228-231Zhou Y: 1/57-61Zileli M: 2/97-102 Radiol Oncol 2010; 44(4): VIII-IX. subject index 2010 Subject Index 2010 31P NMR spectrascopy: 3/174-179 3T, magnetic resonance imaging: 2/92-96 abscess: 4/220-227angiography: 2/103-106antiangiogenic agents: 2/66-78apramers: 3/142-148arterial catheterization: 2/86-91asbestos-related thoracic disease: 2/92-96azygos vein: 3/149-152 B vitamins: 2/79-85balloon predilatation: 3/153-157B-cell lymphoma: 4/232-238biological effects of radiation: 3/174-179bisphosphonates: 4/215-219bladder washing: 4/207-214brain: 3/164-167brain metastases: 3/180-186 cancer: 2/79-85; 4/249-256cancer therapy, adverse effects: 4/244-248cancerology: 3/142-148carcinoma: 2/121-123cathepsin B: 2/107-112cathepsin L: 2/107-112CDKN2A: 3/168-173chemotherapy: 4/257-261; 4/249-256chest radiography: 3/158-163childhood cancer: 3/187-193chitosan-based pad: 2/86-91closure devices: 2/86-91colony growth: 2/131-134colorectal cancer: 3/135-141congenital vascular anomaly: 3/149-152coronary stenting: 3/153-157creatine kinase: 3/174-179CT: 3/158-163; 4/215-219; 4/220-227cytology: 4/207-214 diffusion-weighted imaging: 2/97-102digital ischemic events: 4/257-261disease-free survival: 4/232-238Doppler duplex ultrasonography: 2/103-106drug compounding: 4/249-256 endovascular embolization: 2/103-106enhanced dynamic wedge: 3/199-206EPID: 2/124-130; 3/199-206expenses: 3/153-157experimental animal model: 3/149-152 fistulography: 4/220-227fluorescence: 3/142-148 gastric cancer: 4/262-264; 4/239-243 gemcitabine vascular toxicity: 4/257-261 glioblastoma multiforme (GBM): 2/113-120 gonadal function: 3/187-193 hemiazygos vein: 3/149-152hemostasis: 2/86-91hemostatic pads: 2/86-91high grade glioma: 2/113-120high-grade DCIS: 4/228-231Hodgkin s disease: 3/187-193homocysteine: 2/79-85 hyperhomocysteinemia: 2/79-85 hypermethylation: 2/113-120 i.v. DSA: 3/158-163IMRT: 2/124-130inferior vena cava: 3/149-152intensity modulated radiotherapy: 3/194-198 jaw: 4/215-219 late effects: 3/187-193linear array: 3/199-206long-time survival: 2/113-120loss of heterozygosity: 3/168­ 173lymphedema, secondary lymphedema: 4/244-248 magnetic resonance imaging: 2/97-102; 3/164-167 malignant pleural mesothelioma: 2/92-96 Radiol Oncol 2010; 44(4): X-XI. subject index 2010 medication errors: 4/249-256meningioma: 2/107-112metachronous cancers: 4/239-243metastasis: 2/121-123MGMT promoter methylation: 2/113-120microwave radiation: 2/131-134Modic type 1 change: 2/97-102MRI: 3/158-163; 4/228-231; 4/215-219; 4/220-227MRI angiography: 2/103-106 nonseminomas: 3/168-173 osteonecrosis: 4/215-219overall survival: 4/232-238 PACS: 87.53.Bn, 87.53.Kn: 2/124-130paperless: 2/124-130penis: 2/121-123 percutaneous transluminal coronary angioplasty: 3/153-157 perianal fistulae: 4/220-227pharmacy: 4/249-256photonic imaging: 3/142-148portal dosimetry: 2/124-130priapism: 2/103-106proliferation index, MIB-1 antigen: 2/107-112prophylactic cranial irradiation: 3/180-186 QA: 2/124-130 radiation dosimetry: 3/174-179radiotherapy: 2/66-78; 3/194-198radiotherapy, adverse effects: 4/244-248RB1: 3/168-173rectum: 2/121-123recurrence: 2/107-112response quality, the line of treatment: 4/232-238retinablastoma: 3/194-198rituximab: 4/232-238 Saccharomyces cerevisiae: 2/131-134second primary breast cancer: 4/228-231second primary cancers: 4/239-243seminomas: 3/168-173small-cell lung cancer: 3/180-186smart probes: 3/142-148spine: 3/164-167spondylodiscitis: 2/97-102surveilance: 3/135-141synchronous cancers: 4/239-243 traumatic pseudoaneurysm: 3/158-163tumour markers: 2/107-112tumours: 3/164-167 ureteral metastasis: 4/262-264urine: 4/207-214urothelial carcinoma: 4/207-214 vascular-disrupting agents: 2/66-78vertebral end-plate: 2/97-102von Hippel-Lindau: 3/164-167 X-ray irradiation: 3/174-179X-rays: 4/220-227 Radiol Oncol 2010; 44(4): X-XI. Fundacija "Docent dr. J. Cholewa" je neprofitno, neinstitucionalno in nestrankarsko zdrućenje posameznikov, ustanov in organizacij, ki ćelijo materialno spodbujati in poglabljati raziskovalno dejavnost v onkologiji. Dunajska 106 1000 Ljubljana ĆR: 02033-0017879431 Activity of "Dr. J. Cholewa" Foundation for Cancer Research and Education – a report for the final quarter of 2010 The Dr. J. Cholewa Foundation for Cancer Research and Education is a non-profit, non-govern­ment and non-political association of individuals, institutions and organisations. In the main part of its activities it supports various initiatives in cancer research, cancer prevention and cancer education among medical and other professionals, and in general population. The Foundation distributed a number of grants to applicants wishing to extend existing or gain new knowledge in various fields of oncology. It also helped a number of professional and other associations, connected in various ways with advanced cancer research, to organise scientific and other meetings or symposia of specific interest. The support was also given to Slovenian Cancer Association for publication of various brochures and booklets. Among the activities mentioned above, the Foundation also continues to support the publication of "Radiology and Oncology” international medical scientific journal that is edited, published and printed in Ljubljana, Slovenia. “Radiology and Oncology” is an open access journal, available free of charge on its website. One of the goals of the of Dr. J. Cholewa Foundation for Cancer Research and Education is also to make modern and up to date treatments available to Slovenian patients as soon as possible; the easiest way to achieve this goal is in Foundation’s opinion the spread of knowledge about advancements in various fields of oncology. Within its possibilities, the Foundation supports the implementation of all advances in cancer therapy and education into everyday hospital, ambula­tory and health promotion practice. Hopefully, the results of cancer research will thus find their way into the practical application across Slovenia in as short a period as possible. The Foundation hopes to successfully continue with its activities in the last few remaining months of 2010, leading to greater application of the latest cancer diagnostic, therapy and education meth­ods and knowledge to research, clinical and public environment in Slovenia. Tomaž Benulic, MDBorut Štabuc, MD, PhDAndrej Plesnicar, MD Zadeli smo pravo tar;o Izredno u;inkovito zdravljenje prvega reda pri nedrobnoceli;nem plju;nem raku z mutacijo EGFR Iressa je prva in edina tar;na monoterapija, ki dokazano podaljša preživetje brez napredovanja bolezni v primerjavi z dvojno kemoterapijo kot zdravljenje prvega reda pri bolnikih z napredovalim nedrobnoceli;nim plju;nim rakom z mutacijo EGFR. 1 IRESSA® (GEFITINIB) 1. Povzetek glavih zna;ilnosti zdravila Iressa (gefitinib). Junij 2009. SKRAJŠAN POVZETEK GLAVNIH ZNA:ILNOSTI ZDRAVILA Sestava' Filmsko obložene tablete vsebujejo 250 mg gefitiniba. Indikacije' zdravljenje odraslih bolnikov z lokalno napredovalim ali metastatskim nedrobnoceli;nim plju;nim rakom z aktivacijskimi mutacijami EGFR-TK Odmerjanje in na;in uporabe' Zdravljenje z gefitinibom mora uvesti in nadzorovati zdravnik, ki ima izkušnje z uporabo zdravil proti raku. Priporo;eno odmerjanje zdravila IRESSA je ena 250-mg tableta enkrat na dan. Tableto je mogo;e vzeti s hrano ali brez nje, vsak dan ob približno istem ;asu. Kontraindikacije' preob;utljivost za zdravilno u;inkovino ali katerokoli pomožno snov, dojenje Opozorila in previdnostni ukrepi' Pri 1,3 % bolnikov, ki so dobivali gefitinib, so opažali intersticijsko bolezen plju; (IBP). Ta se lahko pojavi akutno in je bila v nekaterih primerih smrtna. :e se bolniku poslabšajo dihalni simptomi, npr. dispneja, kašelj in zvišana telesna temperatura, morate zdravljenje z zdravilom IRESSA prekiniti in bolnika takoj preiskati. ;e je potrjena IBP, morate terapijo z zdravilom IRESSA kon;ati in bolnika ustrezno zdraviti. ;eprav so bile nepravilnosti testov jetrnih funkcij pogoste, so jih redko zabeležili kot hepatitis. Zato so priporo;ljive redne kontrole delovanja jeter. V primeru blagih do zmernih sprememb v delovanju jeter je treba zdravilo IRESSA uporabljati previdno. :e so spremembe hude, pride v poštev prekinitev zdravljenja. Zdravilo IRESSA vsebuje laktozo. Bolniki z redko dedno intoleranco za galaktozo, laponsko obliko zmanjšane aktivnosti laktaze ali malabsorpcijo glukoze/galaktoze ne smejo jemati tega zdravila. Bolnikom naro;ite, da morajo takoj poiskati zdravniško pomo;, ;e se jim pojavijo kakršnikoli o;esni simptomi, huda ali dolgotrajna driska, navzea, bruhanje ali anoreksija, ker lahko vse te posredno povzro;ijo dehidracijo. Medsebojno delovanje zdravile' Induktorji CYP3A4 lahko pove;ajo presnovo gefitiniba in zmanjšajo njegovo koncentracijo v plazmi. Zato lahko so;asna uporaba induktorjev CYP3A4 (npr. fenitoina, karbamazepina, rifampicina, barbituratov ali zeliš;nih pripravkov, ki vsebujejo šentjanževko\Hypericum perforatum) zmanjša u;inkovitost zdravljenja in se ji je treba izogniti. Pri posameznih bolnikih, ki imajo genotip slabih metabolizatorjev s CYP2D6, lahko zdravljenje z mo;nim zaviralcem CYP3A4 pove;a koncentracijo gefitiniba v plazmi. Na za;etku zdravljenja z zaviralcem CYP3A4 je treba bolnike natan;no kontrolirati glede neželenih u;inkov gefitiniba. Pri nekaterih bolnikih, ki so jemali varfarin skupaj z gefitinibom, so se pojavili zvišanje internacionalnega normaliziranega razmerja (INR) in\ali krvavitve. Bolnike, ki so;asno jemljejo varfarin in gefitinib, morate redno kontrolirati glede sprememb protrombinskega ;asa (P:) ali INR. Zdravila, ki ob;utno in dolgotrajno zvišajo pH v želodcu npr. zaviralci protonske ;rpalke in antagonisti H2, lahko zmanjšajo biološko uporabnost gefitiniba in njegovo koncentracijo v plazmi in tako zmanjšajo u;inkovitost. Redno jemanje antacidov, uporabljenih blizu ;asa jemanja zdravila IRESSA, ima lahko podoben u;inek. Neželeni u;inki' V kumulativnem naboru podatkov klini;nih preskušanj III. faze so bili najpogosteje opisani neželeni u;inki, ki so se pojavili pri ve; kot 20 % bolnikov, driska in kožne reakcije (vklju;no z izpuš;ajem, aknami, suho kožo in srbenjem). Neželeni u;inki se ponavadi pojavijo prvi mesec zdravljenja in so praviloma reverzibilni. Ostali pogostejši neželeni u;inki so' anoreksija, konjunktivitis, blefaritis in suho oko, krvavitev, npr. epistaksa in hematurija, intersticijska bolezen plju; (1,3 %), navzea, bruhanje, stomatitis, dehidracija, suha usta, nepravilnosti testov jetrnih funkcij, bolezni nohtov, alopecija, asimptomati;no laboratorijsko zvišanje kreatinina v krvi, proteinurija, astenija, pireksija. Vrsta in vsebina ovojnine' škatla s 30 tabletami po 250 mg gefitiniba Na;in izdajanja zdravila' samo na recept Datum priprave besedila' junij 2009 Imetnik dovoljenja za promet' AstraZeneca AB, S-151 85, Sodertalje, Švedska Pred predpisovanjem, prosimo, preberite celoten povzetek glavnih zna;ilnosti zdravila. Dodatne informacije so na voljo pri' AstraZeneca UK Limited, Podružnica v Sloveniji, Verovškova 55, 1000 Ljubljana, telefon' 01\51 35 600. Erbitux 5 mg/ml raztopina za infundiranje (skrajšana navodila za uporabo) Cetuksimab je monoklonsko IgG1 protitelo, usmerjeno proti receptorju za epidermalni rastni faktor (EGFR). Terapevtske indikacije: Zdravilo Erbitux je indicirano za zdravljenje bolnikov z metastatskim kolorektalnim rakom in nemutiranim tipom KRAS; v kombinaciji s kemoterapijo in kot samostojno zdravilo pri bolnikih, pri katerih zdravljenje z oksaliplatinom in irinotekanom ni bilo uspešno. Zdravilo Erbitux je indicirano za zdravljenje bolnikov z rakom skvamoznih celic glave in vratu; v kombinaciji z radioterapijo za lokalno napredovalo bolezen in v kombinaciji s kemoterapijo na osnovi platine za ponavljajoco se in/ali metastatsko bolezen. Odmerjanje in nacin uporabe: Zdravilo Erbitux pri vseh indikacijah infundirajte enkrat na teden. Zacetni odmerek je 400 mg cetuksimaba na m2 telesne površine. Vsi naslednji tedenski odmerki so vsak po 250 mg/m2. Kontraindikacije: Zdravilo Erbitux je 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 National Cancer Institute, Common 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 °C). Ne zamrzujte. Vrsta ovojnine in vsebina: 1 viala po 20 ml ali 100 ml. Imetnik dovoljenja za promet: Merck KGaA, 64271 Darmstadt, Nemcija. Podrobne informacije o zdravilu so objavljene na spletni strani Evropske agencije za zdravila PM-ONC-02/09/10.04.2009 (EMEA) http://www.emea.europa.eu. Dodatne informacije so vam na voljo pri: Merck d.o.o., Dunajska cesta 119, 1000 Ljubljana, tel.: 01 560 3810, faks: 01 560 3831, el. pošta: info@merck.si www.oncology.merck.de Povzetek glavnih znacilnosti zdravila Ime zdravila: Temodal 20 mg, 100 mg, 140mg, 180 mg, 250 mg, Temodal 2,5 mg/ml prašek za raztopino za infundiranje Kakovostna in kolicinska sestava: Vsaka kapsula zdravila Temodal vsebuje 20 mg, 100 mg, 140 mg, 180 mg ali 250 mg temozolomida. Ena viala vsebuje 100 mg temozolomida Po rekonstituciji 1 ml raztopine za infundiranje vsebuje 2,5 mg temozolomida. Pomožna snov: Ena viala vsebuje 2,4 mmol natrija. Terapevtske indikacije: Zdravilo Temodal 2,5 mg/ml je indicirano za zdravljenje: odraslih bolnikov z novo diagnosticiranim multiformnim glioblastomom, socasno z radioterapijo (RT) in pozneje kot monoterapija in otrok, starih 3 leta in vec, mladostnikov in odraslih bolnikov z malignimi gliomi, npr. multiformnimi glioblastomi ali anaplasticnimi astrocitomi, ki se po standardnem zdravljenju ponovijo ali napredujejo. Odmerjanje in nacin uporabe: Zdravilo Temodal 2,5 mg/ml smejo predpisati le zdravniki, ki imajo izkušnje z zdravljenjem možganskih tumorjev. Odrasli bolniki z novo diagnosticiranim multiformnim glioblastomom Zdravilo Temodal 2,5 mg/ml se uporablja v kombinaciji z žarišcno radioterapijo (faza socasne terapije), temu pa sledi do 6 ciklov monoterapije (monoterapijska faza) z temozolomidom (TMZ). Faza socasne terapije TMZ naj bolnik jemlje v odmerku 75 mg/m2 na dan 42 dni, socasno z žarišcno radioterapijo (60 Gy, danih v 30 delnih odmerkih). Zmanjševanje odmerka ni priporoceno, vendar se boste vsak teden odlocili o morebitni odložitvi jemanja TMZ ali njegovi ukinitvi na podlagi kriterijev hematološke in nehematološke toksicnosti. TMZ lahko bolnik jemlje ves cas 42-dnevnega obdobja socasne terapije (do 49 dni), ce so izpolnjeni vsi od naslednjih pogojev: • absolutno število nevtrofilcev (ANC – Absolute Neutrophil Count) = 1,5 x 109/l; • število trombocitov = 100 x 109/l; • skupna merila toksicnosti (SMT) za nehematološko toksicnost = 1. stopnje (z izjemo alopecije, navzee in bruhanja). Med zdravljenjem morate pri bolniku enkrat na teden pregledati celotno krvno sliko. Faza monoterapije Štiri tedne po zakljucku faze socasnega zdravljenja s TMZ in RT naj bolnik jemlje TMZ do 6 ciklov monoterapije. V 1. ciklu (monoterapije) je odmerek zdravila 150 mg/m2 enkrat na dan 5 dni, temu pa naj sledi 23 dni brez terapije. Na zacetku 2. cikla odmerek povecajte na 200 mg/m2, ce je SMT za nehematološko toksicnost za 1. cikel stopnje = 2 (z izjemo alopecije, slabosti in bruhanja), absolutno število nevtrofilcev (ANC) = 1,5 x 109/l in število trombocitov = 100 x 109/l. Ce odmerka niste povecali v 2. ciklu, ga v naslednjih ciklih ne smete povecevati. Ko pa odmerek enkrat povecate, naj ostane na ravni 200 mg/m2 na dan v prvih 5 dneh vsakega naslednjega cikla, razen ce nastopi toksicnost. Zmanjšanje odmerka in ukinitev zdravila med fazo monoterapije opravite, kot je opisano v preglednicah 2 in 3. Med zdravljenjem morate 22. dan pregledati celotno krvno sliko (21 dni po prvem odmerku TMZ). Odrasli in pediatricni bolniki, stari 3 leta ali vec, s ponavljajocim se ali napredujocim malignim gliomom:Posamezen cikel zdravljenja traja 28 dni. Bolniki, ki še niso bili zdravljeni s kemoterapijo, naj jemljejo TMZ 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 zacetni odmerek 150 mg/m2 enkrat na dan, v drugem ciklu pa se poveca na 200 mg/m2 enkrat na dan 5 dni, ce ni bilo hematoloških toksicnih ucinkov. Kontraindikacije: Preobcutljivost za zdravilno ucinkovino ali katerokoli pomožno snov. Preobcutljivost za dakarbazin (DTIC). Posebna opozorila in previdnostni ukrepi: Pljucnica, ki jo povzroca Pneumocystis carinii Pilotno preskušanje podaljšane 42-dnevne sheme zdravljenja je pokazalo, da pri bolnikih, ki so socasno prejemali TMZ in RT, obstaja še posebej veliko tveganje za nastanek pljucnice zaradi okužbe s Pneumocystis carinii (PCP). Malignosti Zelo redko so porocali tudi o primerih mielodisplasticnega sindroma in sekundarnih malignostih, vkljucno z mieloidno levkemijo. Antiemeticno zdravljenje Navzea in bruhanje sta pogosto povezana z zdravljenjem s TMZ. Antiemeticno zdravljenje se lahko da pred uporabo TMZ ali po njej. Odrasli bolniki z novo diagnosticiranim multiformnim glioblastomom Antiemeticna profilaksa je priporocljiva pred zacetnim odmerkom socasne faze in je mocno priporocljiva med fazo monoterapije. Ponavljajoci se ali napredujoci maligni gliom Pri bolnikih, ki so mocno bruhali (stopnja 3 ali 4) v prejšnjih ciklih zdravljenja, je potrebno antiemeticno zdravljenje. Laboratorijske vrednosti Pred jemanjem zdravila morata biti izpolnjena naslednja pogoja za laboratorijske izvide: ANC = 1,5 x 109/l in število trombocitov = 100 x 109/l. Na 22. dan (21 dni po prvem odmerku) ali v roku 48 ur od navedenega dne, morate pregledati celotno krvno sliko in jo nato spremljati vsak teden, dokler ni ANC > 1,5 x 109/l in število trombocitov > 100 x 109/l. Ce med katerimkoli ciklom ANC pade na < 1,0 x 109/l ali število trombocitov na < 50 x 109/l, morate odmerek zdravila v naslednjem ciklu zmanjšati za eno stopnjo (glejte poglavje 4.2). Stopnje odmerka so 100 mg/m2, 150 mg/m2 in 200 mg/m2. Najmanjši priporoceni odmerek je 100 mg/m2. Pediatricna uporaba Klinicnih izkušenj z uporabo TMZ pri otrocih, mlajših od 3 let, ni. Izkušnje z uporabo tega zdravila pri starejših otrocih in mladostnikih so zelo omejene. Starejši bolniki (stari > 70 let) Videti je, da je pri starejših bolnikih tveganje za nevtropenijo ali trombocitopenijo vecje, kot pri mlajših. Zato je pri uporabi zdravila TMZ pri starejših bolnikih potrebna posebna previdnost. Moški bolniki Moškim, ki se zdravijo s TMZ je treba svetovati, naj ne zaplodijo otroka še šest mesecev po prejetem zadnjem odmerku in naj se pred zdravljenjem posvetujejo o možnostih za shranitev zmrznjene sperme. Natrij To zdravilo vsebuje 2,4 mmol natrija na vialo. To je treba upoštevati pri bolnikih na nadzorovani dieti z malo natrija. Medsebojno delovanje z drugimi zdravili in druge oblike interakcij: Študije medsebojnega delovanja so izvedli le pri odraslih. V loceni študiji 1. faze, socasna uporaba TMZ in ranitidina ni povzrocila spremembe obsega absorpcije temozolomida ali izpostavljenosti njegovem aktivnem presnovku monometiltriazenoimidazol karboksamidu (MTIK). Analiza populacijske farmakokinetike v preskušanjih 2. faze je pokazala, da socasna uporaba deksametazona, proklorperazina, fenitoina, karbamazepina, ondansetrona, antagonistov receptorjev H2 ali fenobarbitala ne spremeni ocistka TMZ. Socasno jemanje z valprojsko kislino je bilo povezano z majhnim, a statisticno pomembnim zmanjšanjem ocistka TMZ. Študij za dolocitev ucinka TMZ na presnovo ali izlocanje drugih zdravil niso izvedli. Ker pa se TMZ ne presnavlja v jetrih in se na beljakovine veže le v majhni meri, je malo verjetno, da bi vplival na farmakokinetiko drugih zdravil. Uporaba TMZ v kombinaciji z drugimi mielosupresivnimi ucinkovinami lahko poveca verjetnost mielosupresije. Neželeni ucinki: Pri bolnikih, ki se zdravijo s TMZ v kombinaciji z RT ali monoterapijo po RT zaradi novo diagnosticiranega multiformnega glioblastoma ali z monoterapijo pri bolnikih s ponavljajocim se ali napredujocim gliomom, so bili zelo pogosti neželeni ucinki podobni; slabost, bruhanje, zaprtje, neješcnost, glavobol in utrujenost. Pri bolnikih z novo diagnosticiranim glioblastomom multiforme na monoterapiji so zelo pogosto porocali o konvulzijah, medtem ko je bil izpušcaj opisan zelo pogosto pri bolnikih z novo diagnosticiranim multiformnim glioblastomom, ki so prejemali TMZ socasno z RT, ter pri tistih, ki so zdravilo prejemali v obliki monoterapije, pogosto pa pri tistih s ponavljajocim se gliomom. Pri obeh indikacijah so o vecini hematoloških neželenih reakcij porocali pogosto ali zelo pogosto. Imetnik dovoljenja za promet: Schering-Plough Europe, Rue de Stalle 73, Bruselj Belgija Nacin in režim izdaje zdravila: Zdravilo Temodal 20 mg, 100 mg, 140mg, 180 mg, 250 mg se izdaja na recept (Rp/Spec), Temodal 2,5 mg/ml prašek za raztopino za infundiranje pa je namenjeno uporabi samo v bolnišnicah (H). Datum priprave informacije: februar 2010 Literatura: 1 Povzetek temeljnih znacilnosti zdravila Temodal 2 Stupp R, et. al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised III study: 5-year analysis of the EORTC-NCIC trial Dunajska 22, 1000 Ljubljana tel: 01 300 10 70 fax: 01 300 10 80 0233 Nova, intravenska oblika zdravila Temodal, za zdravljenje bolnikov z novo diagnosticiranim glioblastomom multiforme in bolnikov s ponavljajocim se ali napredujocim malignim gliomom.1 Resnicni napredek Pomembno izboljšanje preživetja potrjeno tudi ob daljšem spremljanju bolnikov.2 Dunajska 22, 1000 Ljubljana tel: 01 300 10 70 fax: 01 300 10 80 mehurjev ali lu{~enja kože. Zelo redko so poro~ali o primerih perforacije ali ulceracije roženice; opazili so tudi druge o~esne bolezni. Zdravljenje z zdravilom Tarceva je treba prekiniti ali ukiniti, ~e se pri bolnikih pojavijo akutne o~esne bolezni, kot je bole~ina v o~eh, ali se le-te poslab{ajo. Tablete vsebujejo laktozo in jih ne smemo dajati bolnikom z redkimi dednimi stanji: intoleranco za galaktozo, laponsko obliko zmanj{ane aktivnosti laktaze ali malabsorpcijo glukoze/galaktoze. Medsebojno delovanje z drugimi zdravili in druge oblike interakcij: Erlotinib se pri ljudeh presnavlja v jetrih z jetrnimi citokromi, primarno s CYP3A4 in v manj{i meri s CYP1A2. Presnova erlotiniba zunaj jeter poteka s CYP3A4 v ~revesju, CYP1A1 v plju~ih in CYP1B1 v tumorskih tkivih. Z zdravilnimi u~inkovinami, ki se presnavljajo s temi encimi, jih zavirajo ali pa so njihovi induktorji, lahko pride do interakcij. Erlotinib je srednje mo~an zaviralec CYP3A4 in CYP2C8, kot tudi mo~an zaviralec glukuronidacije z UGT1A1 in vitro. Pri kombinaciji ciprofloksacina ali mo~nega zaviralca CYP1A2 (npr. fluvoksamina) z erlotinibom je potrebna previdnost. V primeru pojava neželenih u~inkov, povezanih z erlotinibom, lahko odmerek erlotiniba zmanj{amo. Predhodno ali so~asno zdravljenje z zdravilom Tarceva ni spremenilo o~istka prototipov substratov CYP3A4, midazolama in eritromicina. Inhibicija glukoronidacije lahko povzro~i interakcije z zdravili, ki so substrati UGT1A1 in se izlo~ajo samo po tej poti. Mo~ni zaviralci aktivnosti CYP3A4 zmanj{ajo presnovo erlotiniba in zve~ajo koncentracije erlotiniba v plazmi. Pri so~asnem jemanju erlotiniba in mo~nih zaviralcev CYP3A4 je zato potrebna previdnost. ^e je treba, odmerek erlotiniba zmanj{amo, {e posebno pri pojavu toksi~nosti. Mo~ni spodbujevalci aktivnosti CYP3A4 zve~ajo presnovo erlotiniba in pomembno zmanj{ajo plazemske koncentracije erlotiniba. So~asnemu dajanju zdravila Tarceva in induktorjev CYP3A4 se je treba izogibati. Pri bolnikih, ki potrebujejo so~asno zdravljenje z zdravilom Tarceva in mo~nim induktorjem CYP3A4, je treba premisliti o pove~anju odmerka do 300 mg ob skrbnem spremljanju njihove varnosti. Zmanj{ana izpostavljenost se lahko pojavi tudi z drugimi induktorji, kot so fenitoin, karbamazepin, barbiturati ali {entjanževka. ^e te zdravilne u~inkovine kombiniramo z erlotinibom, je potrebna previdnost. Kadar je mogo~e, je treba razmisliti o drugih na~inih zdravljenja, ki ne vklju~ujejo mo~nega spodbujanja aktivnosti CYP3A4. Bolnikom, ki jemljejo kumarinske antikoagulante, je treba redno kontrolirati protrombinski ~as ali INR. So~asno zdravljenje z zdravilom Tarceva in statinom lahko pove~a tveganje za miopatijo, povzro~eno s statini, vklju~no z rabdomiolizo; to so opazili redko. So~asna uporaba zaviralcev P-glikoproteina, kot sta ciklosporin in verapamil, lahko vodi v spremenjeno porazdelitev in/ali spremenjeno izlo~anje erlotiniba. Za erlotinib je zna~ilno zmanj{anje topnosti pri pH nad 5. Zdravila, ki spremenijo pH v zgornjem delu prebavil, lahko spremenijo topnost erlotiniba in posledi~no njegovo biolo{ko uporabnost. U~inka antacidov na absorpcijo erlotiniba niso prou~evali, vendar je ta lahko zmanj{ana, kar vodi v nižje plazemske koncentracije. Kombinaciji erlotiniba in zaviralca protonske ~rpalke se je treba izogibati. ^e menimo, da je uporaba antacidov med zdravljenjem z zdravilom Tarceva potrebna, jih je treba jemati najmanj 4 ure pred ali 2 uri po dnevnem odmerku zdravila Tarceva. ^e razmi{ljamo o uporabi ranitidina, moramo zdravili jemati lo~eno: zdravilo Tarceva je treba vzeti najmanj 2 uri pred ali 10 ur po odmerku ranitidina. V {tudiji faze Ib ni bilo pomembnih u~inkov gemcitabina na farmakokinetiko erlotiniba, prav tako ni bilo pomembnih u~inkov erlotiniba na farmakokinetiko gemcitabina. Erlotinib pove~a koncentracijo platine. Pomembnih u~inkov karboplatina ali paklitaksela na farmakokinetiko erlotiniba ni bilo. Kapecitabin lahko pove~a koncentracijo erlotiniba. Pomembnih u~inkov erlotiniba na farmakokinetiko kapecitabina ni bilo. Neželeni u~inki: Zelo pogosti neželeni u~inki so kožni izpu{~aj in driska, kot tudi utrujenost, anoreksija, dispneja, ka{elj, okužba, navzea, bruhanje, stomatitis, bole~ina v trebuhu, pruritus, suha koža, suhi keratokonjunktivitis, konjunktivitis, zmanj{anje telesne mase, depresija, glavobol, nevropatija, dispepsija, flatulenca, alopecija, okorelost, pireksija, nenormalnosti testov jetrne funkcije. Pogosti neželeni u~inki so krvavitve v prebavilih, epistaksa, keratitis, paronihija, fisure na koži. Ob~asno so poro~ali o perforacijah v prebavilih, hirzutizmu, spremembah obrvi, krhkih nohtih, odstopanju nohtov od kože, blagih reakcijah na koži (npr. hiperpigmentacija), spremembah trepalnic, hudi intersticijski bolezni plju~ (vklju~no s smrtnimi primeri). Redko pa so poro~ali o jetrni odpovedi. Zelo redko so poro~ali o Stevens-Johnsonovem sindromu/ toksi~ni epidermalni nekrolizi ter o ulceracijah in perforacijah roženice. Režim izdaje zdravila: H/Rp. Imetnik dovoljenja za promet: Roche Registration Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, Velika Britanija. Verzija: 2.0/10. Informacija pripravljena: november 2010. DODATNE INFORMACIJE SO NA VOLJO PRI: Roche farmacevtska družba d.o.o. Vodovodna cesta 109, 1000 Ljubljana. Povzetek glavnih zna~ilnosti zdravila je dosegljiv na www.roche.si ali www.onkologija.si. 079-10-TAR ^AS ZA ŽIVLJENJE. DOKAZANO PODALJŠA PREŽIVETJE PRI BOLNIKIH: z lokalno napredovalim ali metastatskim z metastatskim rakom trebu{ne slinavke1 1 Povzetek glavnih znacilnosti zdravila TARCEVA, www.ema.europa.eu Lek farmacevtska družba d.d., Verovškova 57, 1526 Ljubljana, Slovenija, www.lek.si SKRAJŠAN POVZETEK GLAVNIH ZNACILNOSTI ZDRAVILA Epufen 12,5, 25, 50, 100 in 150 mikrogramov/uro transdermalni obliži SESTAVA: 1 transdermal­ni obliž vsebuje 2,89 mg, 5,78 mg 11,56 mg, 23,12 mg ali 34,65 mg fentanila. TERAPEVTSKE INDIKACIJE: Huda kronicna bolecina, ki se lahko ustrezno zdravi le z opioidnimi analgetiki. ODMERJANJE IN NACIN UPORABE: Odmerjanje je tre­ba individualno prilagoditi ter ga po vsaki uporabi redno oceniti. Izbira zacetnega odmerka: velikost odmerka fentanila je odvisna od predhodne uporabe opioidov, kjer se upošteva možnost pojava tolerance, socasnega zdravljenja, bolnikovega splošnega zdravstvenega stanja in stopnje resnosti obolenja. Pri bolnikih, ki pred tem niso dobivali mocnih opioidov, zacetni odmerek ne sme preseci 12,5-25 mi-krogramov na uro. Zamenjava opioidnega zdravljenja: pri zamenjavi peroralnih ali parenteralnih opioidov s fentanilom je treba zacetni odmerek izracunati na osnovi kolicine analgetika, ki je bila potrebna v zadnjih 24 urah, jo pretvoriti v odgovarjajoci odmerek morfina s pomocjo razpredelnice in nato preracunati ustrezen odmerek fentanila, spet s pomocjo razpredelnice (glejte SmPC). Prvih 12 ur po prehodu na transdermalni obliž Epufen bolnik še vedno dobiva predhodni analgetik v enakem odmerku kot prej; v naslednjih 12 urah se ta analgetik daje po potrebi. Titracija odmerka in vzdrževalno zdravljenje: obliž je treba zamenjati vsakih 72 ur. Odme­rek je treba titrirati individualno, dokler ni dosežen analgeticni ucinek. Odmerek 12,5 mikrogramov/uro je primeren za titriranje odmerka v manjšem odmernem ob-mocju. Ce analgezija na koncu zacetnega obdobja nošenja obliža ni zadostna, se lahko odmerek po 3 dneh zveca. Možno je, da bodo bolniki potrebovali obcasne dodatne odmerke kratko delujocih analgetikov (npr. morfina) za prekinitev bolecine. Sprememba ali prekinitev zdravljenja: vsaka zamenjava z drugim opioidom mora potekati postopoma, z majhnim zacetnim odmerkom in pocasnim zvecevanjem. Splošno veljavno pravilo je postopna ustavitev opioidne analgezije, da bi preprecili odtegnitvene simptome, kot so navzeja, bruhanje, diareja, anksioznost in mišicni tremor. Uporaba pri starejših bolnikih: starejše in oslabljene bolnike je treba skrb-no opazovati zaradi simptomov prevelikega odmerjanja ter odmerek po potrebi zmanjšati. Uporaba pri otrocih: transdermalni obliži Epufen se lahko uporabljajo le pri pediatricnih bolnikih (starih od 2 do 16 let), ki tolerirajo opioide in peroralno že dobivajo opioide v odmerku, enakovrednemu najmanj 30 mg morfina na dan. Bolnik mora prvih 12 ur po prehodu na Epufen še vedno dobivati predhodni anal-getik v enakem odmerku kot prej. V naslednjih 12 urah je treba ta analgetik dajati odvisno od klinicnih potreb. Titracija odmerka in vzdrževalno zdravljenje: ce je anal­geticni ucinek Epufena prešibak, je treba bolniku dodati morfin ali drugi opioid s kratkim delovanjem. Odvisno od dodatnih potreb po analgeziji in jakosti bolecine pri otroku se lahko uporabi vec obližev. Odmerek je treba prilagajati korakoma, po 12,5 mikrogramov/uro. Uporaba pri bolnikih z jetrno ali ledvicno okvaro: Zara-di možnosti pojava simptomov prevelikega odmerjanja je treba te bolnike skrbno spremljati in odmerek ustrezno zmanjšati. Uporaba pri bolnikih s povecano telesno temperaturo: Pri teh bolnikih bo morda treba prilagoditi odmerek. Nacin uporabe: transdermalni obliž Epufen je treba takoj po odprtju vrecke nalepiti na nerazdraženo, neobsevano kožo, na ravno površino prsnega koša, zgornjega dela hrbta ali nadlakti. Po odstranitvi zašcitne plasti je treba obliž trdno pritrditi na izbrano mesto in z dlanjo pritiskati približno 30 sekund, da se obliž popolnoma nalepi, še zlasti na robovih. Uporaba pri otrocih: pri mlajših otrocih je obliž priporocljivo nalepiti na zgornji del hrbta, ker je manjša verjetnost, da bi otrok odstranil obliž. Transdermalnega obliža se ne sme deliti, ker podatkov o tem ni na voljo. KONTRAINDIKACIJE: Preobcu­tljivost za zdravilno ucinkovino, hidrogenirano kolofonijo, sojo, arašide ali katerokoli pomožno snov. Akutna ali pooperativna bolecina, ko v kratkem casovnem obdobju ni možno titriranje odmerka in obstaja verjetnost za življenjsko ogrožajoco respirator-no depresijo. Huda okvara osrednjega živcnega sistema. POSEBNA OPOZORILA IN PREVIDNOSTNI UKREPI: Zaradi razpolovne dobe fentanila je treba bolnika v primeru pojava neželenega ucinka opazovati še 24 ur po odstranitvi obliža. Pri nekaterih bol­nikih, ki uporabljajo transdermalni obliž Epufen, se lahko pojavi respiratorna depre­sija. Epufen je treba previdno dajati: bolnikom s kronicno pljucno boleznijo, zvišanim intrakranialnim tlakom, možganskim tumorjem, boleznimi srca, jeter in ledvic, tistim z zvišano telesno temperaturo, pri starejših bolnikih in otrocih, bolnikih z miaste­nijo gravis. Odvisnost od zdravila: kot posledica ponavljajoce se uporabe se lahko razvijeta toleranca na ucinkovino ter psihicna in/ali fizicna odvisnost od nje. Ostali: lahko se pojavijo neepilepticne (mio)klonicne reakcije. MEDSEBOJNO DELOVANJE Z DRUGIMI ZDRAVILI IN DRUGE OBLIKE INTERAKCIJ: Derivati barbiturne kisline, opioidi, anksiolitiki in pomirjevala, hipnotiki, splošni anestetiki, fenotiazini, mišicni relaksanti, sedativni antihistaminiki in alkoholne pijace, zaviralci MAO, itrakonazol, ritonavir, ketokonazol, nekateri makrolidni antibiotiki, pentazocin, buprenorfin. VPLIV NA SPOSOBNOST VOŽNJE IN UPRAVLJANJA S STROJI: Zdravilo ima mocan vpliv na sposobnost vožnje in upravljanja s stroji. NEŽELENI UCINKI: Najbolj resen neželen ucinek fentanila je respiratorna depresija. Zelo pogosti (= 1/10): drema­vost, glavobol, navzeja, bruhanje, zaprtje, znojenje, srbenje, somnolenca. Pogosti (= 1/100 do < 1/10): kserostomija, dispepsija, reakcije na koži na mestu aplikacije, sedacija, zmedenost, depresija, tesnoba, živcna napetost, halucinacije, zmanjšan apetit. Obcasni (= 1/1000 do < 1/100): tahikardija, bradikardija, tremor, parestezija, motnje govora, dispneja, hipoventilacija, diareja, zastajanje urina, izpušcaj, rdecina, hipertenzija, hipotenzija, evforija, amnezija, nespecnost, vznemirljivost. Nekateri od naštetih neželenih ucinkov so lahko posledica osnovne bolezni ali drugih zdravljenj. Drugi neželeni ucinki: odpornost, fizicna in psihicna odvisnost se lahko razvijejo med dolgotrajno uporabo fentanila. Pri nekaterih bolnikih se lahko pojavijo odtegnitveni simptomi, ko zamenjajo prejšnje opiodne analgetike s transdermalnim obilžem s fentanilom ali po nenadni prekinitvi zdravljenja. NACIN IZDAJE: Samo na zdravni­ški recept. OPREMA: Škatle s 5 transdermalnimi obliži. IMETNIK DOVOLJENJA ZA PROMET: Lek farmacevtska družba, d.d., Verovškova 57, Ljubljana, Slovenija INFOR­MACIJA PRIPRAVLJENA: avgust 2009 Novartis Oncology prinaša spekter inovativnih zdravil, s katerimi poskuša spremeniti življenje bolnikov z rakavimi in hematološkimi obolenji. Ta vkljucuje zdravila kot so Glivec® (imatinib), Tasigna® (nilotinib), A. nitor® (everolimus), Zometa® (zoledronska kislina), Femara® (letrozol), Sandostatin® LAR® (oktreotid/i.m. injekcije) in Exjade® (deferasiroks). Novartis Oncology ima tudi obširen razvojni program, ki izkorišca najnovejša spoznanja molekularne genomike, razumskega nacrtovanja in tehnologij za odkrivnje novih ucinkovin. Novartis Pharma Services Inc. • Podružnica v Sloveniji • Tivolska cesta 30 • 1000 Ljubljana Samo za strokovno javnost. NV-JA-02/09-SI zdravnikom ali sfarmacevtom. Za podro~ja: • bioznanosti SYNGENE, INVITROGEN, BIOTEK diagnostike MINERVA, MEDAC, BIOTEK • gojenja celi~nih kultur INVITROGEN-GIBCO, TPP, SANYO • merjenja absorbance, fluorescence in luminiscence BIOTEK, SHIMADZU • pipetiranja BIOHIT in BIOTEK • laboratorijske opreme in instrumentov SANYO, SHIMADZU • ~iste vode za laboratorije ELGA LABWATER • HPLC in GC instrumentov, kolon, vial in filtrov PHENOMENEX, CHROMACOL/NATIONAL SCIENTIFIC, SHIMADZU RAZMISLIMO UKREPAJMO ONKOLOGIJA BOEHRINGER INGELHEIM ONC1/oct. 2010 Samo za strokovno javnost Boehringer Ingelheim RCV, podru`nica Ljubljana, Goce Del~eva 1 Instructions Instructions for authors The editorial policyof the journal Radiology and Oncologyis topublish original scientific papers, professional papers, review articles case reports and varia (editorials, 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. The Editorial Board requires that the paper has not been published or submitted for publication elsewhere; the authors are responsible for all statements in their papers. Accepted articles become the property of the journal and therefore cannot be published else­where without written permission from the editorial board. Papers concerning the work on humans must comply with the principles of the declaration of Helsinki (1964). The approval of the ethical committee must then be stated on the manuscript. Papers with questionable justification will be rejected. The manuscript written in English should be submitted to the Editorial OfficeRadiology and Oncology, Institute of Oncology Ljubljana, Zaloska 2, SI-1000 Ljubljana, Slovenia; (Phone: +386 (0)1 5879 369, Tel./Fax: +386 (0)1 5879 434, E-mail: gsersa@onko-i.si). Authors are also asked to submit their manuscripts electronically to: gsersa@onko-i.si. A printed copy along with the manuscript on CD should be sent to the editorial office. The type of computer and word-processing package should be specified (Word for Windows is preferred). All articles are subjected to editorial review and review by independent referees selected by the editorial board. Manuscripts which do not comply with the technical requirements stated herein will be returned to the authors for correction before peer-review. The editorial board reserves the right to ask authors to make appropriate changes in the contents as well as grammatical and stylistic corrections when necessary. The expenses of additional editorial work and requests for additional reprints will be charged to the authors. General instructions·Radiology and Oncologywill consider manuscripts prepared according to the Vancouver Agreement (N Engl J Med1991; 324:424-8,BMJ1991; 302:6772; JAMA1997; 277:927-34.).The manuscript should be typed double-spaced with a 3-cm margin at the top and left-hand side of the sheet. The paper should be written in grammatically and stylistically correct language. Abbreviations should be avoided unless previously explained. The technical data should conform to the SI system. The manuscript, including the references, must not exceed 20 typewritten pages, and the number of figures and tables is limited to 8. If appropriate, organize the text so that it includes: Introduction, Materials and methods, Results and Discussion. Exceptionally, the results and discussion can be combined in a single section. Start each section on a new page, and number each page consecutively with Arabic numerals. Thetitle pageshould include a concise and informative title, followed by the full name(s) of the author(s); the institutional affiliation of each author; the name and address of the corresponding author (including telephone, fax and E-mail), and an abbreviated title. This should be followed by the abstract page, summarizing in less than 250 words the reasons for the study, experimental approach, the major findings (with specific data if possible), and the principal conclusions, and providing 3-6 key words for indexing purposes. Structured abstracts are preferred. The text of the report should then proceed as follows: Introductionshould state the purpose of the article and summarize the rationale for the study or observation, citing only the essential references and stating the aim of the study.Materials and methodsshould provide enough information to enable experiments to be repeated. New methods should be described in detail. Reports on human and animal subjects should include a statement that ethical approval of the study was obtained. Resultsshould be presented clearly and concisely without repeating the data in the figures and tables. Emphasis should be on clear and precise presentation of results and their significance in relation to the aim of the investigation. Discussion should explain the results rather than simply repeating them and interpret their significance and draw conclu­sions. It should review the results of the study in the light of previously published work. Illustrations and tablesmust be numbered and referred to in the text, with the appropriate location indicated. Graphs and photographs, provided electronically, should be of appropriate quality for good reproduction. Colour graphs and photo­graphs are encouraged. Picture size must be 2.000 pixels on the longer side. In photographs, mask the identities of the pa­tients. Tables should be typed double-spaced, with a descriptive title and, if appropriate, units of numerical measurements included in the column heading. Referencesmust be numbered in the order in which they appear in the text and their corresponding numbers quoted in the text. Authors are responsible for the accuracy of their references. References to the Abstracts and Letters to the Editor must be identified as such. Citation of papers in preparation or submitted for publication, unpublished observations, and personal communications should not be included in the reference list. If essential, such material may be incorporated in the appropri­ate place in the text. References follow the style of Index Medicus. All authors should be listed when their number does not exceed six; when there are seven or more authors, the first six listed are followed by “et al.”. The following are some examples of references from articles, books and book chapters: Dent RAG, Cole P. In vitro maturation of monocytes in squamous carcinoma of the lung.Br J Cancer 1981;43: 486-95.Chapman S, Nakielny R. A guide to radiological procedures. London: Bailliere Tindall; 1986.Evans R, Alexander P. Mechanisms of extracellular killing of nucleated mammalian cells by macrophages. In: Nelson DS, editor. Immunobiology of macrophage. New York: Academic Press; 1976. p. 45-74.Page proofswill be sent by E-mail or faxed to the corresponding author. It is their responsibility to check the proofs carefully and return a list of essential corrections to the editorial office within 48 hours of receipt. If corrections are not received by the stated deadline, proof-reading will be carried out by the editors. Reprints: The electronic version of the published papers will be available on www.versita.com free of charge. BISTVENE INFORMACIJE IZ POVZETKA GLAVNIH ZNACILNOSTI ZDRAVILA SUTENT 12,5 mg, 25 mg, 37,5 mg, 50 mg trde kapsule Sestava in oblika zdravila: Vsaka trda kapsula vsebuje 12,5 mg, 25 mg, 37,5 mg ali 50 mg sunitiniba v obliki sunitinibijevega malata. Indikacije: Zdravljenje neizrezljivega in/ali metastatskega malignega gastrointestinalnega stromalnega tumorja (GIST), ce zdravljenje z imatinibijevim mesilatom zaradi odpornosti ali neprenašanja ni bilo uspešno. Zdravljenje napredovalega in/ali metastatskega karcinoma ledvicnih celic (MRCC). Odmerjanje in nacin uporabe: Terapijo mora uvesti zdravnik, ki ima izkušnje z zdravljenjem MRCC ali GIST. Priporoceni odmerek je 50 mg enkrat dnevno, peroralno vsak dan 4 tedne zapored; temu sledi 2-tedenski premor (Shema 4/2), tako da celotni ciklus traja 6 tednov. Odmerek je mogoce prilagajati v povecanjih po 12,5 mg, upoštevaje individualno varnost in prenašanje. Dnevni odmerek ne sme preseci 75 mg in ne sme biti manjši od 25 mg. Pri socasni uporabi z mocnimi zaviralci ali induktorji CYP3A4 je potrebno odmerek ustrezno prilagoditi. Uporaba pri otrocih in mladostnikih (< 18 let): Sutenta ne smemo uporabljati, dokler ne bo na voljo dodatnih podatkov. Uporaba pri starejših bolnikih (= 65 let): med starejšimi in mlajšimi bolniki niso opazili pomembnih razlik v varnosti in ucinkovitosti. Insuficienca jeter: pri bolnikih z jetrno okvaro razreda A in B po Child-Pughu prilagoditev odmerka ni potrebna; pri bolniki z okvaro razreda C Sutent ni bil preizkušen. Insuficienca ledvic: klinicnih študij niso izvedli. Sutent se uporablja peroralno, bolnik ga lahko vzame z ali brez hrane. Ce pozabi vzeti odmerek, ne sme dobiti dodatnega, temvec naj vzame obicajni predpisani odmerek naslednji dan. Kontraindikacije: Preobcutljivost za zdravilno ucinkovino ali katerokoli pomožno snov. Posebna opozorila in previdnostni ukrepi:Koža in tkiva. Krvavitve v prebavila, dihala, secila, v možganih ter krvavitve tumorja. Ucinki na prebavila: poleg navzee in driske tudi resni zapleti. Hipertenzija. Hematološke bolezni. Bolezni srca in ožilja: zmanjšanje LVEF in srcno popušcanje. Podaljšanje intervala QT. Venski trombembolicni dogodki. Dogodki na dihalih: dispneja, plevralni izliv, pljucna embolija ali pljucni edem. Moteno delovanje šcitnice.Pankreatitis. Delovanje jeter. Delovanje ledvic. Fistula. Preobcutljivost/angioedem. Motnje okušanja. Konvulzije. Pri krvavitvah, ucinkih na prebavila, hematoloških boleznih, dogodkih na dihalih, venskih trombembolicnih dogodkih, pankreatitisu in ucinkih na jetra so opisani tudi smrtni izidi. Medsebojno delovanje z drugimi zdravili: Zdravila, ki lahko zvišajo koncentracijo sunitiniba v plazmi (ketokonazol, ritonavir, itrakonazol, eritromicin, klaritromicin ali sok grenivke). Zdravila, ki lahko znižajo koncentracijo sunitiniba v plazmi (deksametazon, fenitoin, karbamazepin, rifampin, fenobarbital, Hypericum perforatum oz. šentjanževka). Antikoagulanti. Nosecnost in dojenje: Sutenta se ne sme uporabljati med nosecnostjo in tudi ne pri ženskah, ki ne uporabljajo ustrezne kontracepcije, razen ce možna korist odtehta možno tveganje za plod. Ženske v rodni dobi naj med zdravljenjem s Sutentom ne zanosijo. Ženske, ki jemljejo Sutent, ne smejo dojiti. Vpliv na sposobnost vožnje in upravljanja s stroji: Sutent lahko povzroci omotico. Neželeni ucinki: Najpogostejši neželeni ucinki: pljucna embolija, trombocitopenija, krvavitev tumorja, febrilna nevtropenija, hipertenzija, utrujenost, diareja, navzea, stomatitis, dispepsija, bruhanje, obarvanje kože, disgevzija, anoreksija, zvišanje ravni lipaze. Zelo pogosti: anemija, nevtropenija, hipotiroidizem, zmanjšanje teka, motnje okušanja, glavobol, bolecina v trebuhu / napihnjenost, flatulenca, bolecine v ustih, sindrom palmarno plantarne eritrodizestezije, spremembe barve las, astenija, vnetje sluznice, edemi. Nacin in režim izdajanja: Izdaja zdravila je le na recept, uporablja pa se samo v bolnišnicah. Izjemoma se lahko uporablja pri nadaljevanju zdravljenja na domu ob odpustu iz bolnišnice in nadaljnjem zdravljenju. Imetnik dovoljenja za promet: Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, Velika Britanija. Datum zadnje revizije besedila: 28.10.2009 Pred predpisovanjem se seznanite s celotnim povzetkom glavnih znacilnosti zdravila. SUT-01-10 Pfizer Luxembourg SARL, Grand Duchy of Luxembourg, 51, Avenue J.F. Kennedy, L-1855, PFIZER, Podružnica za svetovanje s podrocja farmacevtske dejavnosti, Ljubljana, Letališka 3c, 1000 Ljubljana, SLOVENIJA