“RAK SEČNEGA MEHURJA” - Splošna Bolnišnica … sečnega mehurja : [zbornik predavanj] = Urinary bladder cancer : [the book of lectures] / 13. slovenski urološki simpozij v

13. slovenski urološki simpozij v sodelovanju z evropsko urološko šoloin9. simpozij urološke zdravstvene nege“RAK SEČNEGA MEHURJA”

13th Slovene Urological Simposium with ESU participationand9th Urological Nurses Symposium“URINARY BLADDER CANCER”

Velenje, Slovenija 2. in 3. junij 2011June 2-3, 2011

13. SLOVENSKI UROLOŠKI SIMPOZIJ V SODELOVANJU Z EVROPSKO UROLOŠKO ŠOLO 13TH SLOVENE UROLOGICAL SYMPOSIUM WITH ESU PARTICIPATION

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CIP - Kataložni zapis o publikacijiNarodna in univerzitetna knjižnica, Ljubljana

616.62-006-08(082)

SLOVENSKI urološki simpozij v sodelovanju z Evropsko urološko šolo (13 ; 2011 ; Slovenj Gradec) Rak sečnega mehurja : [zbornik predavanj] = Urinary bladder cancer : [the book of lectures] / 13. slovenski urološki simpozij v sodelovanju z Evropsko urološko šolo [in] 9. simpozij urološke zdravstvene nege = 13th Slovene Urological Symposium with European School of Urology Participation [and] 9th Urological Nurses Symposium, Slovenj Gradec, Slovenija, June 2-3, 2011 ; [urednik Marko Zupančič]. - Slovenj Gradec : Oddelek za urologijo, Splošna bolnišnica = Department of Urology, General Hospital, 2011

ISBN 978-961-91364-6-11. Gl. stv. nasl. 2. Vzp. stv. nasl. 3. Zupančič, Marko, 26.5.1960- 4. Simpozij urološke zdravstvene nege (9 ; 2011 ; Slovenj Gradec)256246784

Zbornik predavanj / The book of lectures

Urednik / Editor: Marko Zupančič

Za jezikovno pravilnost prispevkov so odgovorni avtorji samiLinguistic corrections of the contributions are responsibility of the authors themselves

Organizacijski odbor / Organizing committe:

Predsednik / President: Marko ZupančičGlavni tajnik / Secretary General: Franc KramerČlani / Members: Boris Pospihalj Zoran Krstanoski Ljubo Koršič Ivan Parać Andrej Grajn Boris Košuta Majda Topler Cvetka Smrtnik

Naklada / Circulation: 200 izvodov


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Kazalo / IndexEpidemiologija raka sečnega mehurja ................................................................................................................ 7Epidemiology of bladder cancerMaja Primic Žakelj, Vesna Zadnik

Classification on non-invasive bladder neoplasms: is it time for a revised 2004 WHO scheme? .............. 13Rodolfo Montironi

ICUD Recommendations on Bladder Cancer .................................................................................................... 18Mark S. Soloway

Diagnosis of Bladder Cancer: which are the best tools .................................................................................. 21Maria J. Ribal

TUR and Re-TUR in Non Muscle Invasive Bladder Cancer. TUR in Muscle Invasive Bladder Cancer ....... 22Maurizio A. Brausi

Intravesical Chemotherapy: early and adjuvant ............................................................................................... 23Maria J. Ribal

Radical Surgery: Pros and Con of Different Techniques and Evaluation of Complications ........................ 24Maurizio A. Brausi

Neoadjuvant and adjuvant Chemotherapy in invasive or metastatic disease ............................................... 25Maria J. Ribal

Obravnava bolnikov z mišično neinvazivnim rakom sečnega mehurja: 5-letno sledenje ............................ 29Treatment of patient with non-muscle invasive Bladder Cancer: 5-years follow upZ. Krstanoski, M. Zupančič, F. Kramer, L. Koršič, I. Parać

Uporaba Mitomycina C pri zdravljenju raka mehurja – naše izkušnje ........................................................... 32The use of Mitomycin C in Bladder Cancer treatment – our experianceKlemen Jagodič, Igor Bizjak, Uroš Četina

Hyperthermia during intravesical doxorubicin application in patients with superficial Urinary Bladder Carcinoma ............................................................................................................................................................ 33M.M. Bernat, Ž. Kaštelan, D. Hauptman, I. Krhen, I. Mokos, N. Knežević

Significance of Fluorescence in situ hybridisation in detection of Bladder Cancer reccurence ................ 34Ante Reljić, Sanja Mrsić, Silva Ćurić, Božo Krušlin, Ana-Maria Šimundić, Ognjen Kraus, Davor Trnski

Preprečevanje trzljajev mišic stegenskih adduktorjev z blokom obturatornega živcapri transuretralni resekciji stransko ležečih tumorjev mehurja ..................................................................... 41The prevention of obturator jerk reflex with obturator nerve block during transurethral resection of lateral bladder wall tumorsSimon Hawlina, Jure Bizjak, Borut Gubina, Tomaž Smrkolj, Robert Kordič, Miro Mihelič, Dominik Cotič, Boris Sedmak


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Bladder sparing treatment for muscle invasive Bladder Cancer: solution or an option? ............................ 44Aleksandar Janjić, Cane Tulić, Aleksandar Vuksanović, Nebojsa Bojanić, Nale Djordje

The role of partial cystectomy in the treatment of muscle invasive Bladder Cancer ................................. 49V. Vukotić, M. Lazić, S. Savić. D. Kojić, S. Jovanović

Radical Surgical Treatment of the Urinary Bladder Cancer: Our Experiences .............................................. 55Anton Maričić, Maksim Valenčić, Romano Oguić, Stanislav Sotošek, Dean Markić, Josip Španjol, Kristian Krpina,Juraj Ahel, Anton Gršković, Dražen Rahelić, Željko Fučkar

Modification of Padovana ileal neoblader ........................................................................................................ 60V. Sekulić, J. Bogdanović, G. Marušić, J. Đozić, R. Herin

Izkušnje z zdravljenjem bolnikov s karcinomom mehurja po odprti ali laparoskopski radikalni cistektomiji v intenzivni enoti: retrospektivna analiza ..................................................................................... 62ICU experience with Bladder Cancer patients after open or laparoscopic radical cystectomy:retrospective analysisJasna Uranjek, Darja Kasnik

Quality of life after radical cystectomy measured by “Sickness impact profile” score .............................. 67A. Prcić, D. Aganović, B. Kulovac, O. Hadžiosmanović

Quality of life in patient with orthotopic neobladder ....................................................................................... 68I. Vuković, S. Mićić, N. Bojanić, D. Djordjević

Sestava:

Indikacije:

zelo pogosti:pogosti:

CASODEX 50 MG (BIKALUTAMID)

CA

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4/10

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Samo za strokovno javnost. Pred predpisovanjem si preberite celoten povzetek glavnih značilnosti zdravila.

Denosumab je povsem humano monoklonsko protitelo (IgG2) proti ligandu receptorja za aktivacijo jedrnega dejavnika kB (angl. receptor activator of nuclear factor kB ligand - RANKL), na katerega se veže z veliko afi niteto ter zelo specifi čno. Tako prepreči aktivacijo receptorja RANK na površini predhodnikov osteoklastov in samih osteoklastov in s tem zavre nastajanje, delovanje in preživetje osteoklastov. Posledično denosumab zmanjša resorpcijo kosti v kortikalnem in trabekularnem kostnem tkivu. FARMACEVTSKA OBLIKA: Raztopina za injiciranje (injekcija).KAKOVOSTNA IN KOLIČINSKA SESTAVA: Ena napolnjena injekcijska brizga vsebuje 60 mg denosumaba v 1 ml raztopine (60 mg/ml). Pomožne snovi s prepoznavnim delovanjem: En mililiter raztopine vsebuje 47 mg sorbitola (E420). TERAPEVTSKE INDIKACIJE: Zdravljenje osteoporoze pri ženskah po menopavzi z večjim tveganjem zlomov. Zdravilo Prolia® znatno zmanjša tveganje zlomov vretenc, nevretenčnih zlomov in zlomov kolka. Zdravljenje izgubljanja kostne mase, povezanega z ablacijo hormonov pri moških z rakom na prostati, ki imajo večje tveganje zlomov. Pri moških z rakom na prostati, ki prejemajo zdravljenje z ablacijo hormonov, zdravilo Prolia® znatno zmanjša tveganje zlomov vretenc.ODMERJANJE IN NAČIN UPORABE: Priporočeni odmerek zdravila Prolia® je 60 mg enkrat na 6 mesecev v enkratni subkutani injekciji v stegno, trebuh ali zadnjo stran roke. Bolniki morajo dobivati zadostne dodatke kalcija in vitamina D. Bolniki z okvaro ledvic: Prilagoditev odmerka ni potrebna. Bolniki z okvaro jeter: Varnost in učinkovitost denosumaba pri bolnikih z okvaro jeter nista raziskani. Starejši bolniki (stari > 65 let): Prilagoditev odmerka ni potrebna. Pediatrični bolniki: Uporaba zdravila Prolia® ni priporočljiva za pediatrične bolnike (stare < 18 let), ker njegovi učinkovitost in varnost pri teh bolnikih nista dokazani. Zdravilo mora aplicirati oseba, ki se je za injiciranje ustrezno usposobila. Za subkutano uporabo.KONTRAINDIKACIJE: Hipokalciemija in preobčutljivost za zdravilno učinkovino ali katerokoli pomožno snov. POSEBNA OPOZORILA IN PREVIDNOSTNI UKREPI: Za vse bolnike je pomembno, da uživajo dovolj kalcija in vitamina D. Hipokalciemijo je treba še pred začetkom zdravljenja odpraviti z zadostnim uživanjem kalcija in vitamina D. Bolniki s hudo okvaro ledvic (očistek kreatinina < 30 ml/min) in bolniki na dializi imajo večje tveganje za pojav hipokalciemije. Pri bolnikih, ki so nagnjeni k hipokalciemiji, je priporočljivo klinično spremljati koncentracijo kalcija. Pri bolnikih, ki dobivajo zdravilo Prolia®, se lahko pojavijo okužbe kože (predvsem celulitis), ki zahtevajo bolnišnično zdravljenje. Ob pojavu znakov ali simptomov celulitisa naj bolniki takoj poiščejo zdravniško pomoč. Pri bolnikih, zdravljenih z denosumabom in difosfonati, ki predstavljajo še eno skupino antiresorpcijskih zdravil, je bila opisana osteonekroza čeljusti. Večinoma je bila opisana pri bolnikih z rakom; nekaj primerov pa je bilo zabeleženih tudi pri bolnikih z osteoporozo. Osteonekrozo čeljusti so zabeležili redko v kliničnih študijah pri bolnikih, ki so dobivali denosumab v odmerku 60 mg na 6 mesecev za zdravljenje.Opisani pa so bili primeri osteonekroze v kliničnih študijah pri bolnikih z napredovalim rakom, ki so dobivali denosumab v raziskovanem odmerku 120 mg na mesec. Znani dejavniki tveganja za osteonekrozo čeljusti so rak s kostnimi spremembami, sočasna zdravljenja (npr. kemoterapija, antiangiogena biološka zdravila, kortikosteroidi, obsevanje glave in vratu), slaba ustna higiena, ekstrakcije zob in spremljajoče bolezni (npr. predhodna zobna bolezen, anemija, koagulopatija, okužba) ter predhodno zdravljenje z difosfonati. Bolniki s sočasnimi dejavniki tveganja morajo pred zdravljenjem z zdravilom Prolia® opraviti zobozdravstveni pregled, vključno z ustreznimi preventivnimi zobozdravstvenimi ukrepi. Med zdravljenjem se je treba pri teh bolnikih po možnosti izogniti invazivnim zobozdravstvenim posegom. Med zdravljenjem z zdravilom Prolia® je treba skrbeti za dobro ustno higieno. Kirurški posegi v ustni votlini lahko poslabšajo stanje bolnikov, ki se jim

med zdravljenjem z zdravilom Prolia® pojavi osteonekroza čeljusti. Če se med zdravljenjem z zdravilom Prolia ®pojavi osteonekroza čeljusti, je treba stanje klinično presoditi in oblikovati načrt zdravljenja za vsakega bolnika glede na individualno oceno koristi in tveganja. Pokrovček igle na napolnjeni injekcijski brizgi vsebuje suho naravno gumo (derivat lateksa), ki lahko povzroči alergijske reakcije. Opozorila glede pomožnih snovi: Bolniki z redko prirojeno motnjo intolerance za fruktozo ne smejo uporabljati zdravila Prolia®. To zdravilo vsebuje manj kot 1 mmol (23 mg) natrija na 60 mg, kar pomeni, da je praktično ,,brez natrija“.MEDSEBOJNO DELOVANJE Z DRUGIMI ZDRAVILI IN DRUGE OBLIKE INTERAKCIJ: Študij medsebojnega delovanja niso izvedli. Kliničnih podatkov o sočasni uporabi denosumaba in hormonskega nadomestnega zdravljenja (estrogena) ni, vendar je možnost farmakodinamičnih medsebojnih delovanj predvidoma majhna. Po izsledkih študije, opravljene pri prehodu z alendronata na denosumab, predhodno zdravljenje z alendronatom pri ženskah po menopavzi z osteoporozo ni spremenilo farmakokinetike in farmakodinamike denosumaba. NOSEČNOST IN DOJENJE: O uporabi zdravila Prolia® pri nosečnicah ni zadostnih podatkov. Ni znano, ali se denosumab pri človeku izloča v materino mleko. Odločiti se je treba, ali naj ženska neha dojiti ali naj neha uporabljati zdravilo Prolia®. NEŽELENI UČINKI: Varnost zdravila Prolia® so ocenjevali v kliničnih preskušanjih II. in III. faze, kontroliranih s placebom, v katere je bilo vključenih 10.534 žensk po menopavzi z osteoporozo (v trajanju do 5 let) ter bolnic oz. bolnikov z rakom na dojki ali na prostati, ki so se zdravili z ablacijo hormonov. Pogosti (≥ 1/100 do < 1/10): okužba sečil, okužba zgornjih dihal, išias, katarakte, zaprtost, izpuščaj, bolečina v okončini. Občasni (≥ 1/1.000 do < 1/100): divertikulitis, celulitis, okužba ušesa, ekcem. Zelo redek (< 1/10.000): hipokalciemija. POSEBNA NAVODILA ZA SHRANJEVANJE: Shranjujte v hladilniku (pri temperaturi od 2 °C do 8 °C). Ne zamrzujte. Napolnjeno injekcijsko brizgo shranjujte v zunanji ovojnini za zagotovitev zaščite pred svetlobo. Ne stresajte premočno. Zdravilo Prolia® se lahko shranjuje pri sobni temperaturi (do 25 °C ) do 30 dni v originalnem vsebniku. Ko vzamete zdravilo Prolia® iz hladilnika, ga morate uporabiti v 30 dneh. POSEBNI VARNOSTNI UKREPI ZA ODSTRANJEVANJE IN RAVNANJE Z ZDRAVILOM: Raztopino zdravila Prolia® je treba pred injiciranjem pregledati. Raztopine ne smete injicirati, če vsebuje delce, če je motna ali obarvana. Za preprečitev nelagodja na mestu dajanja je treba zagotoviti, da napolnjena injekcijska brizga pred injiciranjem doseže sobno temperaturo (do 25 °C), zdravilo pa je treba injicirati počasi. Injicirajte celotno vsebino napolnjene injekcijske brizge. Morebitni ostanek zdravila v napolnjeni injekcijski brizgi je treba zavreči.NAČIN IN REŽIM PREDPISOVANJA TER IZDAJE ZDRAVILA: Predpisovanje in izdaja zdravila je le na recept.IMETNIK DOVOLJENJA ZA PROMET: Amgen Europe B.V., Minervum 7061, NL-4817 ZK Breda, NizozemskaDodatna pojasnila lahko dobite v lokalnih pisarnah: Amgen zdravila d.o.o., Šmartinska 140, SI-1000 LjubljanaGlaxoSmithKline d.o.o., Knezov štradon 90, 1001 LjubljanaDATUM ZADNJE REVIZIJE BESEDILA: 20. september 2010Podrobne informacije o zdravilu so objavljene na spletni strani Evropske agencije za zdravila http://www.ema.europa.eu

Literatura:1. Povzetek glavnih značilnosti zdravila Prolia, 2010

PROLIA® (denosumab) - SKRAJŠAN POVZETEK GLAVNIH ZNAČILNOSTI ZDRAVILA

Amgen zdravila d.o.o.Šmartinska 140, SI-1000 LjubljanaTel.: +386 1 585 1767, faks: +386 1 585 2024, www.amgen.com

GSK d.o.o., LjubljanaKnezov štradon 90, 1001 LjubljanaTel.: +386 1 28 02 500, faks: +386 1 28 02 550, www.gsk.si SLO-DB-AMG-019-2011-M

SAMO ZA STROKOVNO JAVNOST.PRED PREDPISOVANJEM SI PREBERITE CELOTEN POVZETEK GLAVNIH ZNAČILNOSTI ZDRAVILA.


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Epidemiologija raka sečnega mehurjaEpidemiology of bladder cancer

Maja Primic Žakelj, Vesna Zadnik

Epidemiologija in register raka, Onkološki inštitut Ljubljana, SlovenijaEpidemiology end Cancer Registries, Institute of Oncology Ljubljana, Slovenia

IzvlečekIzhodišča: Rak sečnega mehurja je bil leta 2008 pri moških sedmi najpogostejši rak na svetu, pri ženskah je redkejši. Kazalnike bremena raka, predvsem incidenco, je treba primerjati med posameznimi državami pazljivo, saj registracija raka sečnega mehurja po svetu ni enotna. Ponekod vštevajo med raka tudi primere in situ in neinvazivni papilarni karcinom (stadija Ta in Tis). Register raka Republike Slovenije (RRRS) vsa leta upošteva pravilo, da v incidenco raka šteje le primere invazivnega raka sečnega mehurja, površinskega (T1) in mišično invazivnega (T2-T4), posebej pa vodi primere in situ skupaj z nainvazivnim papilarnim karcinomom. Na podlagi mednarodnih podatkovnih zbirk in podatkov RRRS so opisani osnovni kazalniki bremena raka sečnega mehurja v svetu, v Evropi in v Sloveniji: incidenca, umrljivost in preživetje ter nevarnostni dejavniki in možnosti primarne in sekundarne preventive.

Rezultati: V Sloveniji je leta 2007 za rakom sečnega mehurja zbolelo 281 ljudi, 203 moških in 78 žensk, umrlo pa 168 bolnikov, 130 moških in 38 žensk. In situ primerov je bilo registriranih 171, 130 pri moških in 41 pri ženskah. Ocenjujemo, da je leta 2010 zbolelo okrog 313 ljudi, 220 moških in 93 žensk. Groba in starostno standardizirana incidenčna stopnja se v zadnjih desetih večata pri obeh spolih, bolj groba kot starostno standardizirana. Okrog polovica bolnikov zboli v starosti 50–74 let, v letih 2003–2007 je bilo v tej starostni skupini 65,2 % moških in 48,7 % žensk. Petletno relativno preživetje vseh zbolelih v obdobju 2001–2005 je bilo 51 %; bolniki, ki preživijo prvo leto, pa lahko pričakujejo 67-odstotno petletno relativno preživetje. Preživetje naših bolnikov še vedno zaostaja za evropskim povprečjem.

Zaključki: V preventivi raka sečnega mehurja je treba preprečiti izpostavljenost delavcev znanim karcinogenom, na ravni posameznika pa je najpomembnejše nekajenje in opuščanje kajenja.

Ključne besede: rak sečnega mehurja, epidemiologija, nevarnostni dejavniki, preventiva

AbstractBackground: Bladder was the seventh most common cancer site in males in 2008 worldwide, while it was less frequent among females. The cancer burden indicators, especially incidence, should be interpreted and even more, compared between countries, with caution, as the registration of bladder cancer is not uniform in all cancer registries. In some registries, non-invasive bladder cancers (in situ and noninvasive papillary carcinoma) are included in cancer incidence (stages Tis and Ta). In the Cancer Registry of Republic of Slovenia (CRRS), stages Tis and Ta are not included in the bladder cancer incidence, but only stages T1–T4. In this presentation, basic measures of bladder cancer burden (incidence, prevalence and survival) are presented using the data from international databases and the CRRS database as well as bladder cancer risk factors and primary and secondary prevention measures.

Results: There were 281 cases of bladder cancer registered in Slovenia in 2007, 209 in males and 78 in females and 171 in situ cases, 130 in males and 41 in females; there were 168 bladder cancer deaths, 130 in males and 38 in females. It is estimated that in 2010 there were 313 new cases, 220 in males and 93 in females. The crude and age standardized incidence rates have been increasing in the last 10 years, more crude than age standardized. At diagnosis, about half of patients are aged 50–74; in the period 2003–2007 there were 65.2% of males and 48.7% of females in this age group. The 5-year relative survival of patients diagnosed in 2001–2005 was 51%; patients surviving the first year can expect 67% relative survival. The survival of Slovenian patients is still lower than European average.

Conclusions: The most important primary prevention measure is the state regulation of exposure of workers to known occupational carcinogens, while at the individual level nonsmoking and quitting smoking reduces bladder cancer risk.

Key words: bladder cancer, epidemiology, risk factors, prevention


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UvodRak sečnega mehurja je bil leta 2008 pri moških sedmi najpogostejši rak, pri ženskah je redkejši (1). Kazalnike bremena raka, predvsem incidenco, je treba primerjati med posameznimi državami pazljivo, saj registracija raka sečnega mehurja v vseh registrih ni enotna. Ponekod vštevajo med raka tudi primere in situ (Tis) in neinvazivni papilarni karcinom (stadija Ta in Tis). RRRS vsa leta upošteva pravilo, da v incidenco raka šteje le primere invazivnega raka sečnega mehurja, površinskega (T1) in mišično invazivnega (T2-T4), posebej pa vodi primere in situ skupaj z nainvazivnim papilarnim karcinomom.

Breme raka sečnega mehurja v tem pregledu prikazujemo z osnovnimi epidemiološkimi kazalniki, incidenco, umrljivostjo in s preživetjem bolnikov. Povzeli smo jih iz objavljenih analiz podatkov registrov raka in statistike umrljivosti (1, 2). Incidenca pomeni število vseh v enem koledarskem letu na novo ugotovljenih primerov raka v točno določeni populaciji. Groba incidenčna stopnja je število novih primerov, preračunano na 100.000 oseb opazovane populacije. Če analiziramo incidenco v daljšem časovnem obdobju (in se starostna struktura prebivalstva v času spreminja) ali če primerjamo incidenco med populacijami z različno starostno strukturo, je treba uporabiti eno od metod starostne standardizacije. Starostno standardizirana stopnja je teoretična incidenčna stopnja, pri kateri predpostavimo, da je starostna struktura opazovane populacije enaka starostni strukturi v standardni populaciji. V našem prikazu smo za standard uporabili svetovno prebivalstvo (3).

Za Slovenijo so prikazani objavljeni in neobjavljeni podatki RRRS (3, 4). Za prikaz incidence po stadiju nismo uporabili klasične klasifikacije TNM, pač pa poenostavljeno, ki jo uporabljajo registri. Po tej klasifikaciji se bolezen razvršča v omejeni stadij, stadij regionalne razširitve, stadij oddaljene razširitve ter neznani stadij (4). Preživetje bolnikov je prikazano kot relativni odstotek preživetja, ki pomeni razmerje med opazovanim preživetjem proučevane skupine in preživetjem, ki bi ga pričakovali pri enako stari skupini istega spola v slovenski populaciji. Je približek preživetja bolnikov v primeru, da bi upoštevali kot vzrok smrti samo izbranega raka. Metoda je natančneje opisana v knjigi Preživetje bolnikov z rakom v Sloveniji 1991–2005 (5).

Rak sečnega mehurja v svetu in v EvropiPo ocenah Mednarodne agencije za raziskovanje raka je leta 2008 po svetu za rakom sečnega mehurja zbolelo 382.660 ljudi, 294.345 moških in 88.315 žensk in predstavlja 4,4 % vseh rakov pri moških in 1,5 % vseh rakov pri ženskah (1). Razmerje med spoloma je v splošnem okrog 3:1. Tri četrtine

novih primerov je iz ekonomsko razvitejših svetovnih področij in saharske Afrike. Ocenjena starostno standardizirana incidenčna stopnja raka sečnega mehurja je bila leta 2008 pri moških največja v Izraelu, Španiji, Egiptu, na Danskem, Češkem in v S Ameriki, pri ženskah pa na Islandiji, na Danskem, Češkem in v S Ameriki (1).

V Evropi je bila pri moških leta 2008 ocenjena starostno standardizirana incidenčna stopnja največja v Španiji, sledile so Danska, Nizozemska, Norveška in Češka, najmanjša pa na Finskem, v Sloveniji, v Luksemburgu, Angliji in Romuniji. Pri ženskah je bila največja stopnja na Danskem, Nizozemskem, Norveškem in Irskem, najmanjša pa v Franciji, Litvi, Grčiji in na Cipru (2).

Za rakom sečnega mehurja je leta 2008 v svetu umrlo 150.282 ljudi, 112.308 moških in 37.974 žensk (1), v Evropi pa 51.056 ljudi, 38.606 moških in 12.450 žensk.

Rak sečnega mehurja v SlovenijiV Sloveniji je leta 2007 za rakom sečnega mehurja zbolelo 281 ljudi, 203 moških in 78 žensk, umrlo pa 168 bolnikov, 130 moških in 38 žensk. Med vsemi raki je bil rak sečnega mehurja s 3,3 % vseh novih primerov na 7. mestu, pri ženskah pa z 1,4 % na 16. mestu. In situ primerov je bilo registriranih 171, 130 pri moških in 41 pri ženskah. Ocenjujemo, da je leta 2010 za rakom sečnega mehurja zbolelo okrog 313 ljudi, 220 moških in 93 žensk (3).

Groba in starostno standardizirana incidenčna stopnja se v zadnjih desetih letih (1998–2007) večata pri obeh spolih, bolj groba kot starostno standardizirana. Ocenjeni delež letne spremembe starostno standardizirane incidenčne stopnje pri moških je 1 %, pri ženskah pa 2 % (3). Starostno standardizirana umrljivostna stopnja je v zadnjih 10 letih pri obeh spolih nista bistveno spremenili (Sliki 1 in 2) (3). Slika 1. Groba in starostno standardizirana incidenčna stopnja raka sečnega mehurja po spolu, Slovenija 1988–2007.


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Figure 1. Crude and age-standardized incidence rate of bladder cancer by sex, Slovenia 1988–2007.

Slika 2. Groba in starostno standardizirana (SSS) umrljivostna stopnja raka sečnega mehurja po spolu, Slovenija 1988–2007.

Figure 2. Crude and age-standardized (ASR)mortality rate of bladder cancer by sex, Slovenia 1988–2007.


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V obdobju 2003–2007 je bilo 95 % primerov raka sečnega mehurja potrjenih s histološko preiskavo, 1 % samo s citološko, drugi s kliničnimi preiskavami. Delež histološko potrjenih primerov se v zadnjih 10 letih ni bistveno spremenil. Največ bolnikov je imelo karcinom prehodnega epitela (87,4 %), 1,5 % je bilo adeno- in ploščatoceličnih karcinomov, pri ostalih bolnikih histološka vrsta ni bila določena.

Okrog polovica bolnikov zboli v starosti 50–74 let, v letih 2003–2007 je bilo v tej starostni skupini 65,2 % moških in 48,7 % žensk. V starosti 75 let in več je v tem obdobju zbolelo 32 % moških in 47 % žensk. Rak sečnega mehurja je pri obeh spolih pred 50. letom starosti izjemno redka bolezen, starostno specifična incidenčna stopnja se pri obeh spolih veča s starostjo (Slika 3) (3).

Slika 3. Starostno specifična incidenčna stopnja raka sečnega mehurja po spolu, Slovenija 2003–2007.Figure 3. Age specific incidence ratesof bladder cancer by sex, Slovenia 2003–2007.

Največ bolnikov ima ob diagnozi omejeno bolezen; v letih 2003–2007 je bilo takih 72,3 % (40,8 % pT1 in 21,9 % pT2; pri 9,6 % pT ni bil določen). Sedemnajst odstotkov bolnikov je imelo ob diagnozi razširjeni stadij, 6,6 % pa razsejanega; delež bolnikov z razsejanim stadijem se je od obdobja 1993–997 sicer nekoliko povečal, predvsem na račun boljše opredelitve stadija, saj se je zmanjšal delež brez določenega stadija. V letih 1993–1997 stadija ni imelo določenega 8 % bolnikov, deset let kasneje pa 4 % (3).

V obdobju 2003–2007 ni bilo specifično zdravljenih 7,7 % bolnikov. Med specifično zdravljenimi se je pri 69 % primerov prvo zdravljenje zaključilo z operacijo (natančnejših podatkov o tem, koliko je bilo radikalnih cistektomij, koliko pa transuretralnih resekcij, v RRRS ni), 12 % jih je bilo poleg operacije dodatno zdravljenih s kemoterapijo, 6 % pa z obsevanjem, 5 % je poleg operacije prejelo kemo- in radioterapijo, 6 % pa je po operaciji prejelo še intravezikalno zdravljenje; preostala 2 % bolnikov je bilo zdravljenih z drugimi kombinacijami.

Relativno preživetje bolnikov z rakom sečnega mehurja, zbolelih v letih 1991–2005, smo leta 2009 objavili v posebni

monografiji (5). Izkazalo se je, da se preživetje naših bolnikov v 15 letih ni bistveno povečalo; v zadnjem obdobju se je celo zmanjšalo (na 51 % v primerjavi z leti 1996–2000, ko je bilo 53 %), bolj pri ženskah kot pri moških. Stadij ob diagnozi je sicer napovedni dejavnik izida bolezni, saj je preživetje največje pri bolnikih z omejenim stadijem, vendar tudi pri teh bolnikih v zadnjem obdobju ni pomembnega izboljšanja: petletno relativno preživetje bolnikov z omejenim stadijem v letih 2001–2005 je bilo 65-odstotno. Napovedni dejavnik je tudi starost, saj je relativno preživetje najslabše pri starih 75 let in več, pri katerih se je v zadnjem obdobju tudi najbolj zmanjšalo; manjši napredek je le bil le pri bolnikih, diagnosticiranih v starosti 50–74 let.

Petletno relativno preživetje vseh zbolelih v obdobju 2001–2005 je bilo 51 %; bolniki, ki preživijo prvo leto, pa lahko pričakujejo 67-odstotno petletno relativno preživetje.

Rezultati študije EUROCARE-4 za zbolele v obdobju 2000–2002 kažejo, da je preživetje slovenskih bolnikov z rakom sečnega mehurja statistično značilno manjše od evropskega povprečja za 20 % (5).


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Razloge za slabše preživetje pri nas je v svojem magistrskem delu iskala Urška Bizjak Ogrinc. Zaključila je, da je eden od razlogov za slabše preživetje pri nas verjetno tudi premajhen delež bolnikov, zdravljenih z radikalno cistektomijo. Ugotovila je, da je bilo v letih 1987, 1992 in 1997 samo 6,6 % bolnikov (5 % stadija T2 in 16 % stadija T3) deležnih radikalne cistektomije (6). To je standardno zdravljenje mišično invazivnega raka sečnega mehurja, s katerim je mogoče ozdraviti okoli polovico bolnikov. V teh letih je 57 % bolnikov v okviru kirurškega zdravljenja imelo opravljeno samo trensuretralno resekcijo (TUR), ki za večino bolnikov ni najustreznejši način zdravljenja. Drugi način zdravljenja za izbrane bolnike z mišično invazivnim rakom mehurja je ohranitveno zdravljenje s TUR, kemoterapijo in obsevanjem. To zdravljenje je primerno le za malo bolnikov z mišično invazivnim rakom, zato je delež tako zdravljenih bolnikov povsod po svetu, pa tudi pri nas, majhen. Pri nas je bilo tako zdravljenih v letih 1992 in 1997 le okoli 6 % bolnikov z mišično invazivnim rakom mehurja.

Nevarnostni dejavniki raka sečnega mehurjaStarost in spol: Najbolj zanesljiv nevarnostni dejavnik raka sečnega mehurja je starost, saj se verjetnost bolezni veča s staranjem. Večja pogostnost med moškimi ni v celoti pojasnjena, lahko da gre na račun večje izpostavljenosti karcinogenom; v kolikšni meri imajo vlogo pri nastanku spolni hormoni in njihovi receptorji v mehurju, še ni znano (7).

Kajenje: Pomemben nevarnostni dejavnik je kajenje, ki ga povezujejo s 65 % raka pri moških in 30 % pri ženskah. Epidemiološke raziskave, opravljene v različnih populacijah so pokazale, da je zveza med trajanjem in intenziteto kajenja linearna in da je od svetlejšega nevarnejši temni tobak. Domnevajo, da so za mehur nevarni 2-naftilamin in drugi aromatski amini iz cigaretnega dima, ki jih je več v temnem tobaku (8). Delež rakov, ki jih je mogoče pripisati kajenju, je odvisen od stanja epidemije kajenja v posameznih svetovnih področjih; v skupni analizi evropskih raziskav primerov s kontrolami so ocenili, da je kajenju mogoče pripisati 66 % primerov pri moških in 30 % pri ženskah (9, 10).

Poklicna izpostavljenost: Rak sečnega mehurja je prvi rak notranjih organov, za katerega je bila ugotovljena povezanost s kemičnimi karcinogeni na delovnem mestu. Že Rehn je leta 1895 poročal o 4 bolnikih z rakom sečnega mehurja, ki so delali v tovarni anilinskih barvil (11). Danes veljajo za dokazane karcinogene za sečni mehur štirje aromatski amini: benzidin, 2-naftilamin, 4-aminodifenil in 4-nitrodifenil, za potencialne pa avramin, magenta, nekateri derivati benzidina in še nekateri drugi aromatski amini. Nekatere teh snovi so se uporabljale ali se še uporabljajo za izdelavo barv za tekstil, usnje, papir,

lase, pleskarske barve, kot antioksidanti v izdelavi gume za avtomobilske pnevmatike in električne kable, pa tudi kot dodatki pri izdelavi epoksidnih smol in poliuretanov. Nekatere epidemiološke raziskave so bolj ali manj utemeljile sum, da so karcinogeni za sečni mehur še aromatski ogljikovodiki v premogovem prahu, sajah in katranu, plinih, ki se sproščajo pri varjenju, v naftnih derivatih in neznane snovi v prahu lesa, usnja in v pesticidih. Ocene deleža poklicne etiologije v incidenci raka sečnega mehurja se v svetu razlikujejo, kar gre pripisati razliki v uporabi karcinogenov v industriji v posameznih državah. Tako so npr. v Angliji na osnovi dognanj o karcinogenosti 2-naftilamina priznali raka sečnega mehurja za poklicno bolezen že v začetku petdesetih let prejšnjega stoletja, njegovo proizvodnjo in uporabo pa prepovedali sredi šestdesetih; v ZDA so ga prepovedali šele leta 1970. Podobno so države postopno prepovedale benzidin in 4-aminodifenil v proizvodnji gume in barv za tekstil (12).

Poleg intenzitete in trajanja izpostavljenosti k verjetnosti bolezni prispeva tudi individualna genetska občutljivost. V razgradnji aromatskih aminov sodelujejo različni encimi, med njimi N-acetiltransferaza in glutation-S-transferaza. Encimsko aktivnost N-acetil-transferaze uravnavata dva gena, NAT1 in NAT2, ki kažeta polimorfizem. Nekateri ljudje imajo manjšo aktivnost encima, s tem je razgradnja aminov počasnejša, njihova koncentracija v mehurju pa večja; počasni acetilatorji imajo zato večje tveganje (13).

Zdravila: Tudi nekatera zdravila večajo tvaganje: ciklofosfamid, fenacetinski analgetiki in izoniazid. Ciklofosfamid verejtno zato, ker zavira imunsko obrambo, fenacetin, ker iz njega v presnovi nastaja karcinogen metabolit, izoniazid pa prek vpliva na presnovo triptofana (14).

Okužbe: V endemičnih področjih Afrike je rak sečnega mehurja posledica kronične shistosomiaze; približno 70 % bolnikov s to okužbo zboli za ploščatoceličnim rakom (15). Zaenkrat še ni dovolj dokazov, da bi bilo mogoče raka sečnega mehurja povezati tudi z drugimi okužbami, bakterijskimi ali virusnimi, čeprav proučujejo številne, med drugim tudi okužbe s HPV (16).Kava in alkohol: Čeprav so morebitno povezavo med pitjem kave in alkoholnih pijač proučevali v številnih raziskava, zaenkrat o večji ogroženosti ni soglasja; če tveganje obstoji, je zelo majhno (16).

ZaključekV preventivi raka sečnega mehurja je po eni strani pomembna zakonodaja, s katero je treba prepovedati stik delavcev z dokazanimi karcinogeni; na ravni posameznika pa je najpomembnejše nekajenje in opuščanje kajenja.


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Presejalni testi so pomembni za ogrožene skupine, kamor sodijo izpostavljeni delavci, predvsem pa bolniki, ki so že bili zdravljeni, saj se bolezen pogosto ponavlja. Ugotavljanju mikrohematurije in citološki preiskavi se v zadnjem času pridružujejo molekularne metode, njihovo širšo uporabnost pa zaenkrat še preverjajo v raziskavah (17).

Literatura1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C and

Parkin DM. GLOBOCAN 2008, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010 (http://globocan.iarc.fr).

2. ECO, European Cancer Observatory. International Agency for Research on Cancer (http://eu-cancer.iarc.fr)

3. Zadnik V, Primic Žakelj M. SLORA: Slovenija in rak. Epidemiologija in register raka. Onkološki inštitut Ljubljana (www.slora.si).

4. Incidenca raka v Sloveniji 2007. Ljubljana: Onkološki inštitut, Register raka za Slovenijo; 2010.

5. Primic-Žakelj M, Zadnik V, Žagar T, Zakotnik B. Preživetje bolnikov z rakom, zbolelih v letih 1991–2005 v Sloveniji. Ljubljana: Onkološki inštitut Ljubljana, 2009.

6. Bizjak Ogrinc U. Preživetje bolnikov z invazivnim rakom sečnega mehurja glede na stadij in način zdravljenja v Sloveniji v obdobju 1987-1997 v treh izbranih letih. [magistrska naloga]. Ljubljana: Univerza v Ljubljani; 2007.

7. Shariat SF, Sfakianos JP, Droller MJ, Karakiewicz PI, Meryn S, Bochner SM. The effect of age and gender on bladder cancer: a critical review of the literature. BJUI International 2009; 105: 300–8.

8. Boffeta P. Tobacco smoking and risk of bladder cancer. Scand J Urol Nephrol Suppl 2008; 42: 45–54.

9. Brennan P, Bogillot O, Cordier S, Greiser E, Schill W, Vineis P e tal. Cigarette smoke and bladder cancer in men: a pooled analysis of 11 case-control studies. Int J Cancer 2000; 86: 289–94.

10. Brennan P, Bogillot O, Greiser E, Chang-Claude J, Wahrendorf J, Cordier S e tal. The contribution of cigarette smoking to bladder cancer in women (pooled European data). Cancer Causes Control 2001; 12: 411-7.

11. Weisburger JH. Comments on the history and importance of aromatic and heterocyclic amines in public health. Mutat Res 2002; 506: 9-20.

12. Delclos GL, Lerner SP. Occupational risk factors. Scand J Urol Nephrol Suppl 2008; 42: 58–63.

13. Vineis P, Caporaso N, Cuzick J, Lang M, Malats N, Boffeta P. Genetic susceptibility to cancer: metabolic polymorphisms. IARC Sci Publ 148. Lyon: IARC, 1999.

14. Nilsson S, Ullen A. Chemotherapy-induced bladder cancer. Scand J Urol Nephrol Suppl 2008; 42: 89–92.

15. Abol-Enein H. Infection: is it a cause of bladder cancer? Scand J Urol Nephrol Suppl 2008; 42: 79–84.

16. Pelucchi C, La Vecchia C. Alcohol, coffee and a bladder cancer risk: a review of epidemiologic studies. Eur J Cancer Prevention 2009;18: 62–8.

17. Mitra AP, Cote RJ. Molecular screening for bladder cancer: progress and potential. Nat Rev Urol 2010; 7: 11–20.


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Classification on non-invasive bladder neoplasms: is it time for a revised 2004 WHO scheme?

Rodolfo Montironi

Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy

IntroductionThe non-invasive urothelial lesions and neoplasms can be flat (planophytic), papillary (exophytic) and inverted (endophytic), depending on their growth pattern relationship with the surface of the surrounding urothelial mucosa [1]. Extensive clinico-pathological studies have been published related to the first two growth patterns. The clinical significance of the third has been dealt with only at a very limited extent.

Flat (planophytic) lesions and neoplasmsThe 2004 WHO classification of the flat lesions includes flat hyperplasia, dysplasia and carcinoma in situ. In addition, this classification also lists reactive atypia, secondary to inflammation, and atypia of unknown significance.

Flat urothelial hyperplasiaUrothelial hyperplasia is characterized by markedly thickened urothelium with an increase in the number of cell layers, usually 10 or more. The cells do not show cytological abnormalities, although slight nuclear enlargement may be focally present. Morphologic evidence of maturation from base to surface is evident. Mitoses are absent. It has been described in association with inflammatory disorders as well as adjacent to low-grade papillary tumours [2]. Molecular analyses have shown that this lesion may be clonally related to the papillary tumours in bladder cancer patients and suggest a role in the pathogenesis of low-grade papillary urothelial carcinoma [3,4].

Urothelial dysplasiaUrothelial dysplasia is characterized by architectural distortion and a variable degree of atypia. The thickness is usually normal and cytological changes are restricted to the intermediate and basal cells The nuclei are irregularly enlarged with loss of polarity and pleomorphism. Scant is the mitotic activity, usually involving only the basal and intermediate cell layers. Overall the features are those of a neoplastic atypia but fall short of the criteria for CIS. There is some evidence, largely genetic, that dysplasia shares some abnormalities with CIS and therefore likely represents a precursor lesion. One study indicates a 19% risk of developing cancer with a mean follow up of 4.9 years [5].

Urothelial carcinoma in situ (CIS)CIS is characterized by architectural disorder and nuclear pleomorphism. There is loss of nuclear polarity and the cells show a high degree of atypia. Mitoses are generally frequent and may be seen at any level of the epithelium. Since the histological criteria for distinguishing severe dysplasia from CIS are unreliable, it is recommended to combine them into a single category, i.e., CIS. The development of invasion is seen in 20 to 30% of the cases [6-11].CIS with microinvasion (CISmic) of the urinary bladder is defined by invasion into the lamina propria to a depth of 5 mm from the basement membrane, or, according to Lopez-Beltran et al, should not exceed 20 cells in the sub-epithelial connective tissue [12,13]. CISmic is a clinically relevant lesion. 34% of totally embedded cystectomy specimens that contain extensive CIS, i.e., involving at least 25% of the bladder, are found to contain microinvasion. 5.8% have lymph node metastases and die of disease.

Papillary (exophytic) lesions and neoplasmsThe lesions and neoplasms of this group grow exophytically into the lumen of the urinary system with a papillary configuration. According to the 2004 WHO classification, this group includes urothelial papilloma, papillary urothelial hyperplasia, papillary urothelial neoplasm of low malignant potential (PUNLMP), low-grade papillary carcinoma and high-grade papillary carcinoma.Urothelial papilloma is characterized by a few fine papillary fronds lined by normal urothelium and shows a very low recurrence rate. Papillary urothelial hyperplasia is defined as undulating urothelium arranged into thin mucosal papillary folds of varying heights occurring in a non inflamed setting [14]. The lack of cytological atypia and fibrovascular cores characterize this lesion. Papillary urothelial hyperplasia appears to be a precursor lesion to papillary urothelial neoplasms, predominantly lower grade lesions [15].Papillary urothelial neoplasm of low malignant potential, low-grade papillary carcinoma and high-grade papillary carcinoma show a morphological spectrum with similarities with flat hyperplasia, dysplasia and CIS, respectively.


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Papillary urothelial neoplasm of low malignant potentialPUNLMP largely, though not completely, corresponds to grade 1 papillary carcinoma of the 1973 WHO system. The lesion consists of delicate papillae with little or no fusion. The covering urothelium shows minimal architectural irregularity. Nuclei lack significant nuclear hyperchromasia or pleomorphism. The chromatin is fine and nucleoli are inconspicuous. Mitoses are infrequent and basally located. This tumor has a significantly lower rate of recurrence than either low- or high-grade papillary carcinomas and a very low rate of grade and stage progression. In a review of published studies, a mean tumor recurrence rate to be 36% and stage progression rate to be 3.7% [4].

Low-grade papillary carcinomaThe majority of cases would have been considered as grade 2 in the 1973 WHO system. WHO grade 1 neoplasms showing slight cytological atypia and mitoses, are diagnosed in the 2004 WHO system as low-grade papillary urothelial carcinomas. At low magnification there is a generally ordered appearance of the cells within the epithelium. The nuclei tend to be uniformly enlarged but retain the elongated to oval shape of normal urothelial cells. The chromatin remains fine with small nucleoli. Mitoses may be present but are few and remain basally located. These tumors have a significantly higher recurrence rate than for PUNLMP. They also have a significantly higher rate of stage progression than PUNLMP but significantly lower than for high-grade papillary carcinoma. A review of the literature reveals a mean recurrence rate of 50% and mean stage progression rate of 10%.

High-grade papillary carcinomaIt corresponds to grade 3 papillary carcinoma in the 1973 WHO system. It includes WHO grade 2 lesions bordering on higher grade lesions, which in many institutions are called WHO grade 2-3. Individual cells are haphazardly arranged within the epithelium and have a generally discohesive nature. Nuclei are hyperchromatic and pleomorphic. The chromatin is dense, irregularly distributed and often clumped. Nucleoli may be single or multiple and are often prominent. Mitoses are generally frequent and may be seen at any level of the epithelium. It is often associated with invasive disease at the time of diagnosis [16-23].These tumors not only have a risk of invasion but have a significant risk of recurrence and progression. The overall progression rate (to invasive carcinoma) ranges from 15% to 40%.

Inverted (endophytic) lesions and neoplasmsThe lesions and neoplasms of this group is basically characterized by an epithelium that shows a non-infiltrative

growth into the subepithelial connective tissue, even though, cystoscopically they might show a polypoid appearance. von Brunn’s nests and cystitis cystica and glandularis are the benign prototypes of inverted (endophytic) lesions. von Brunn’s nests refer to small groups of basal-like cells lying in the subepithelial connective tissue and attached the basal cell layer of the urothelium. Cystitis glandularis is composed of glands in the lamina propria which are lined by Cuboidal or columnar cells surrounded by urothelial cells. Cystitis cystica is made of cystically dilated von Brunn’s nests acquiring a luminal space.Inverted urothelial papilloma, included in the 2004 WHO classification, shows a polypoid appearance and consists of thin anastomosing trabeculae of urothelial cells within the subepithelial connective tissue and covered by a normal or attenuated urothelium [24-26]. There is no nuclear pleomorphism and few mitoses can be seen. Inverted papilloma is associated with a low risk of recurrence (< 5%). Cases of synchronous inverted papilloma and papillary carcinoma are known.Reports of a non-invasive urothelial carcinoma with inverted growth pattern are found in the literature and mentioned in some recent books [2,27-29]. The endophytic growth pattern in this carcinoma has been described either as inter-anastomosing cords and columns of urothelium, often with a striking resemblance to inverted papilloma (inverted papilloma-like pattern), or as broad, pushing bulbous invaginations into the lamina propria (broad-front pattern) (Table 1). A diagnosis of invasion requires the unquestionable presence within the lamina propria of irregularly shaped nests or single cells that may have evoked a desmoplastic or inflammatory response. When a stromal response is absent, irregularity of the contours of the invasive nests, architectural complexity and recognition of single-cell invasion are helpful (Table 2).

Morphologic spectrum of the non-invasive urothelial neoplasms with an inverted growth patternMorphologically the urothelial neoplasms with an inverted growth pattern (other than inverted urothelial papilloma) show a spectrum of architectural and cytological features. In comparison with inverted urothelial papilloma, the architectural features favouring a diagnosis of a urothelial neoplasm with an inverted growth pattern include thick columns with irregularity in their width and transition into more solid areas. The characteristic orderly maturation, spindling, and peripheral palisading seen in inverted papilloma are generally absent or inconspicuous. The histological appearance of urothelial neoplasms with a broad-front pattern is the pushing broad-front extension into the lamina propria, akin to cutaneous


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and mucosal verrucous carcinoma and reminiscent of the growth pattern of the von Brunn’s nests. The downward projection can be so pronounced that the base of the tumour lies on the muscularis propria. There is a wide range in the severity of cytological atypia, such as nuclear pleomorphism, irregularities of nuclear borders and chromatin distribution, prominent nucleoli, and mitotic rate [30].When diagnosing inverted urothelial neoplasms, pathologists have used a variety of terms, including: inverted urothelial papilloma, inverted urothelial papilloma with atypia [30], inverted growth pattern of PUNLMP, urothelial carcinoma with an inverted growth pattern, without any further specification to the degree of cellular anaplasia, or even as invasive urothelial carcinoma [30].Similarly to the flat neoplasms, the overall cytological changes range from hyperplasia to carcinoma in situ. Similarly to the papillary neoplasms and in agreement with the approach used in two books published very recently [30,31], three subgroups could be defined in such range, i.e., neoplasms that have the least degree of cytological atypia, neoplasms with the most severe degrees of cytological atypia and those that lie in between, i.e.,:1. Inverted urothelial neoplasm of low malignant potential

(IUNLMP)2. Low-grade inverted urothelial carcinoma3. High-grade inverted urothelial carcinoma

ConclusionsThe evaluation of the urothelial lesions and neoplasms with an inverted or endophytic growth pattern shows a morphological spectrum similar to that seen in the flat and papillary counterparts (Table 3). However, this is not fully recognized in the current literature in which, besides inverted urothelial papilloma, only one form of neoplasms is reported, i.e., urothelial carcinoma with an inverted growth pattern. Scant molecular and clinical studies on the urothelial carcinoma with an inverted growth pattern have been published [28], mainly focussing on the differences with the inverted urothelial papilloma. A classification and terminology consistent with those of the flat and papillary urothelial lesions and neoplasms should be adopted.

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A, Cheng L. Morphological diagnosis of urothelial neoplasms. J Clin Pathol 2008;61:3-10.

2. Amin MB, Gómez JA, Young RH. Urothelial transitional cell carcinoma with endophytic growth patterns: a discussion of patterns of invasion and problems associated with assessment of invasion in 18 cases. Am J Surg Pathol. 1997;21:1057-68.

3. Hodges KB, Lopez-Beltran A, Davidson DD, Montironi R, Cheng L. Urothelial dysplasia and other flat lesions of the urinary bladder: clinicopathologic and molecular features. Hum Pathol 2010;41:155-62.

4. Montironi R, Lopez-Beltran A, Scarpelli M, Mazzucchelli R, Cheng L. Morphological classification and definition of benign, preneoplastic and non-invasive neoplastic lesions of the urinary bladder. Histopathology 2008;53:621-33.

5. Cheng L, Cheville JC, Neumann RM, Bostwick DG. Natural history of urothelial dysplasia of the bladder. Am J Surg Pathol. 1999;23:443-7.

6. Birkhahn M, Mitra AP, Williams AJ, et al. Predicting recurrence and progression of noninvasive papillary bladder cancer at initial presentation based on quantitative gene expression profiles. Eur Urol 2010;57:12-20.

7. Burger M. Editorial comment on: prognostic accuracy of individual uropathologists in noninvasive urinary bladder carcinoma: a multicentre study comparing the 1973 and 2004 World Health Organisation classifications. Eur Urol 2010;57:858.

8. Guey LT, García-Closas M, Murta-Nascimento C, et al; EPICURO/Spanish Bladder Cancer Study investigators. Genetic susceptibility to distinct bladder cancer subphenotypes. Eur Urol 2010;57:283-92.

9. May M, Brookman-Amissah S, Roigas J, et al. Prognostic accuracy of individual uropathologists in noninvasive urinary bladder carcinoma: a multicentre study comparing the 1973 and 2004 world health organisation classifications. Eur Urol 2010;57:850-8.

10. van Rhijn BW, Burger M, Lotan Y, et al. Recurrence and progression of disease in non-muscle-invasive bladder cancer: from epidemiology to treatment strategy. Eur Urol 2009;56:430-42.

11. Yorukoglu K, Tuna B, Kirkali Z. Re: Matthias May, Sabine Brookman-Amissah, Jan Roigas, et al. Prognostic accuracy of individual uropathologists in noninvasive urinary bladder carcinoma: a multicentre study comparing the 1973 and 2004 World Health Organisation classifications. Eur Urol 2010;57:850-8. Eur Urol 2010;58: e7

12. Cheng L, Montironi R, Davidson DD, Lopez-Beltran A. Staging and reporting of urothelial carcinoma of the urinary bladder. Mod Pathol. 2009;22 (Suppl 2):S70-95.

13. Lopez-Beltran A, Cheng L, Andersson L, et al. Preneoplastic non-papillary lesions and conditions of the urinary bladder: an update based on the Ancona International Consultation. Virchows Arch 2002;440:3–11.

14. Taylor DC, Bhagavan BS, Larsen MP, Cox JA, Epstein JI. Papillary urothelial hyperplasia. A precursor to papillary neoplasms. Am J Surg Pathol 1996;20:1481-8.


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15. Readal N, Epstein JI. Papillary urothelial hyperplasia: relationship to urothelial neoplasms. Pathology. 2010;42:360-3.

16. Babjuk M. Second resection for non-muscle-invasive bladder carcinoma: current role and future perspectives. Eur Urol 2010;58:191-2.

17. Dalbagni G, Vora K, Kaag M, et al. Clinical outcome in a contemporary series of restaged patients with clinical T1 bladder cancer. Eur Urol 2009;56:903-10.

18. Divrik RT, Sahin AF, Ergör G. Reply from authors re: Marko Babjuk. Second resection for non-muscle-invasive bladder carcinoma: current role and future perspectives. Eur Urol 2010;58:191-2 and Giacomo Novara, Vincenzo Ficarra. Does routine second transurethral resection affect the long-term outcome of patients with T1 bladder cancer? Why a flawed randomized controlled trial cannot address the issue. Eur Urol 2010;58:193-4. Eur Urol 2010;58:195-6.

19. Divrik RT, Sahin AF, Yildirim U, Altok M, Zorlu F. Impact of routine second transurethral resection on the long-term outcome of patients with newly diagnosed pT1 urothelial carcinoma with respect to recurrence, progression rate, and disease-specific survival: a prospective randomised clinical trial. Eur Urol 2010;58:185-90.

20. Fritsche HM, Burger M, Svatek RS, et al. Characteristics and outcomes of patients with clinical T1 grade 3 urothelial carcinoma treated with radical cystectomy: results from an international cohort. Eur Urol 2010;57:300-9.

21. Kulkarni GS, Hakenberg OW, Gschwend JE, et al. An updated critical analysis of the treatment strategy for newly diagnosed high-grade T1 (previously T1G3) bladder cancer. Eur Urol 2010;57:60-70.

22. Novara G, Ficarra V. Does routine second transurethral resection affect the long-term outcome of patients with T1 bladder cancer? Why a flawed randomized controlled trial cannot address the issue. Eur Urol 2010;58:193-4.

23. van Rhijn BW, Zuiverloon TC, Vis AN, et al. Molecular grade (FGFR3/MIB-1) and EORTC risk scores are predictive in primary non-muscle-invasive bladder cancer. Eur Urol 2010;58:433-41.

24. Cheng L, Bostwick DG. Overdiagnosis of bladder carcinoma. Anal Quant Cytol Histol 2008;30:261-4.

25. Lott S, Wang M, Zhang S, et al. FGFR3 and TP53 mutation analysis in inverted urothelial papilloma: incidence and etiological considerations. Mod Pathol 2009;22:627-32.

26. Sung MT, Maclennan GT, Lopez-Beltran A, Montironi R, Cheng L. Natural history of urothelial inverted papilloma. Cancer 2006;107:2622-7.

27. Cheng L, Lopez-beltran A, MacLennan GT, Montironi R, Bostwick DG. Neoplasms of the urinary bladder. In: Bostwick DG, Cheng L, editors, Urologic Surgical Pathology, ed. 2. Philadelphia USA: Mosby /Elsevier, 2008. p. 289-292.

28. Hodges KB, Lopez-beltran A, MacLennan GT, Montironi R, Cheng L. Urothelial lesions with inverted growth patterns: histogenesis, molecular genetic findings, differential diagnosis and clinical management. BJU int 2010 (in press).

29. Jones TD, Zhang S, Lopez-Beltran A, et al. Urothelial carcinoma with an inverted growth pattern can be distinguished from inverted papilloma by fluorescence in situ hybridization, immunohistochemistry, and morphologic analysis. Am J Surg Pathol 2007;31:1861-7.

30. Epstein JI, Amin MB. Urothelial neoplasms with inverted growth patterns. In: Epstein JI, Amin MB, editors. Biopsy Interpretation of the Bladder, ed. 2. Philadelphia, USA: Lippincot Williams & Wilkins 2010. p.79-93.

31. McKenney JK, Vankalakunti M. Overview of urinary bladder neoplasms. In: Amin MB, editor. Diagnostic Pathology: Genitourinary, ed. 1. Manitoba, Canada: AMIRSYS 2010. p. 50.


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Table 1. Morphologic, immunologic and molecular genetic features of inverted urothelial papilloma and urothelial carcinoma with inverted pattern

Characteristic Inverted urothelial papilloma Urothelial carcinoma with inverted growth Surface Smooth, domed shaped, usually intact

cytologically normalUsually exophytic papillary lesions present

Growth pattern Endophytic, expansive, sharply delineated, anastomosing cords and trabeculae

Endophytic, lesional circumscription variable

Cytologic features Orderly polarized cells, some with spindling and palisading at the periphery. No significant atypia, mitoses rare

Variable, nuclear pleomorphism and atypia present

Immunohistochemistry Low p53 expression and Ki-67 proliferation index

Variable, usually high p53 and Ki-67 proliferation index

Molecular analysis Rare deletions at chromosome 9 or 17, rare FGFR3 mutations, low rate of LOH**

Frequent FGFR3 mutation, chromosome 9 and 17 deletions

Biological potential Benign, rare recurrences* Recurrences and progression may occur*Rare recurrences related to incomplete excision**Loss of heterozygosity

Table 2. Urothelial carcinoma with inverted pattern. Criteria for invasion.

Features Non-invasive InvasiveContours of neoplastic nests/cords Regular IrregularSize and shape of nests Similar, rounded edges Variable, irregular and jagged edgesInflammatory and desmoplastic stroma Absent Present

Table 3. Proposed sub-grouping of the non-invasive urothelial neoplasms with an inverted growth pattern

Group No 1. Flat Urothelial hyperplasia Urothelial dysplasia Urothelial carcinoma in situGroup No 2. Papillary Papillary urothelial neoplasm

of low malignant potentialLow-grade papillary carcinoma

High-grade papillary carcinoma

Group No 3. Inverted Inverted urothelial neoplasm of low malignant potential

Low-grade inverted urothelial carcinoma

High-grade inverted urothelial carcinoma


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ICUD Recommendations on Bladder CancerMark S. Soloway

Department of Urology, Miller School of Medicine, University of Miami, USA

The decision making for the patient with a newly diagnosed or recurrent bladder tumor requires a great deal of judgement. Like many tumors BC is not one entity. There is a vast spectrum of histologic types each of which can be further defined by its grade and stage. Tumors are either unifocal or may occur in multiple areas of the bladder. They may be papillary or flat. Carcinoma in situ may be associated. These and many other factors will play a part in the decision on treatment. Then there is the technical aspects of treatment – beginning with the initial endoscopic resection (urologist), correct diagnosis (pathologist), and treatment plan (urologist, medical oncologist, radiation oncologist depending on the above variables).

The heterogeneity of BC is best illustrated by the great difference between the low grade Ta tumor which rarely impacts the patient’s life and the muscle invasive BC which can be lethal. There are tumors which are in between these extremes and their management requires the most judgement. In my opinion these decisions are among the most challenging in all of urologic oncology.

Over 100 experts in urology, urologic pathology, medical and radiation oncology in 10 committees have worked for 12 months to outline a set of recommendations based on the literature and where available prospective randomized trials to guide us as we serve our patients with BC. The culmination of their work was delivered at the EAU in an all day symposium on March 18.

I was honored to be asked to organize and chair this effort to summarize the state of the art in bladder cancer and provide recommendations for treatment and am pleased to present the highlights at the conference on bladder cancer in Slovenia.

Here are some of the recommendations that were presented.

Over 30 urologic pathologists combined their expertise to emphasize the critical nature of providing an accurate diagnosis. In most cases this is straightforward but there are

a number of ingredients involved in “getting it right”. These were illustrated by the chair of this committee Mohammed Amin. There are many subtypes of bladder cancer and in certain instances, e.g. micropapillary, nested variant, small cell, adenocarcinoma subtypes, the treatment will be different from an urothelial (transitional cell) carcinoma.

Dr. Kamat and Dr. Hegarty discussed the recommendations regarding the diagnostic work up beginning with hematuria and proceeding to the endoscopy and proper tumor resection. There have been some improvements in the methodology of diagnosing and identifying bladder tumors via the endoscope, e.g. blue light fluorescent endoscopy and narrow band imaging. Are they now sufficiently useful to be a part of routine endoscopy/tumor resection when a patient has a bladder tumor? What is the role of urine based markers including cytology? What is the role of imaging in the diagnosis and staging of BC? These and many more areas were discussed in this committee report.

Dr. Shariat discussed the role of urine based and tissue markers as they relate to BC. There are many candidate urine based markers that are approved by regulatory bodies for the detection and monitoring of BC. How do they compare with urinary cytology and in which circumstances, if any, should they be used? Can they be used for an early detection program in an effort to diagnose BC at an early stage? In other words do we have a “PSA for BC”? At this moment the answer is basically “no”.

Dr. Konety and Dr. Oosterlinck co chaired the committee on low grade Ta BC. They emphasized the very low risk such patients have to ever develop a life threatening BC and much of the presentation dealt with the balance between minimizing treatment (tumor resections, imaging, even endoscopy) and monitoring for the relatively uncommon event of progression. The recommendation for a single instillation of intravesical chemotherapy after tumor resection is an attempt to minimize the chance of a new or recurrent tumor yet avoiding multiple instillations or the instillation of BCG for the low risk subset. This group also stressed the avoidance of regular imaging of the upper tract. There are cost and safety concerns with repetitive imaging with radiation.


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They also discussed the role of surveillance in some patients with small low grade Ta tumors to delay or obviate the cost and morbidity of repeated tumor resections.

The committee charged with discussing high grade (HG) Ta and T1 BC was co chaired by Dr. Witjes and Dr. Burger. They emphasized the critical nature of performing a complete endoscopic resection. Before initiating a treatment plan for the patient with a high grade T1 tumor the urologist must consider returning the patient to the operating theater and performing another TUR to ensure there is no remaining tumor. Only then can the clinician be certain of the grade and stage of the tumor. The team delineated when it is necessary to abandon a bladder preserving strategy and recommend bladder removal.

Dr. Stenzl discussed some of the recommendations from the committee charged with assessing the literature concerning muscle invasive BC. There are three parts to this discussion. First there is the data regarding this major operative intervention. How to safely perform it, what are acceptable morbidity and mortality figures, and possibly who should be performing these procedures? The second aspect presented by Jason E an experienced radiation oncologist was the role of bladder preservation using chemotherapy and external beam radiation intervention. The third part of this committee report was a summary of the data on perioperative systemic chemotherapy with the hope of improving the survival of this often lethal cancer. Dr. Quinn delivered this information.

Urinary diversion is an important aspect of the bladder removal procedure. For the patient it is critical as it contributes to the morbidity and recovery from this operation and he/she must contend with the type of diversion they elect. Dr Hautmann presented the recommendations of his group and emphasized the rationale for electing one diversion vs another. He stressed that a key component is the expertise of the surgeon. In 2011 approximately 40% of men/women elect a neobladder in leading centers who specialize in cystectomy.

Dr. Palou discussed the importance of urothelial cancer of the prostatic urethra. When should the urologist biopsy/resect the prostatic urethra (PU) to determine whether an urothelial cancer is present in the urothelium, ducts, or the stroma? Should this be performed before deciding on a neobladder? What is the treatment for CIS (carcinoma in situ) of the PU? For TCC in the stroma of the prostate?

Cora Sternberg provided the data on what is to be expected from systemic chemotherapy for the patients with metastatic

BC. She emphasized the role of cisplatin combination chemotherapy (either with gemcitabine or as part of the 4 drug M – VAC regimen). What if the patient can not receive cisplatin because of reduced renal function?

The final committee discussed the treatments for the 10% of BCs which are not urothelial/transitional cell. These consist of squamous cell, small cell, or adenocarcinoma. Total cystectomy alone is the primary treatment for many of these tumors however the patient with small cell carcinoma requires initial treatment with chemotherapy. Thus back to the key role of the pathologist. He/she must inform the urologist when these unusal subtypes are found so the proper treatment can be delivered. Dr. Baniel discussed the importance of proper diagnosis and treatment for these non – urothelial bladder cancers.

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Diagnosis of Bladder Cancer: which are the best toolsMaria J. Ribal

Department of Urology, Hospital Clínic, University of Barcelona, Spain

Bladder tumours are diagnosed with the same tools for more that 20 years, and white-light cystoscopy and cytology are the standard tools to diagnose bladder cancer (BC). Cystoscopy and cytology are the standard methods used to detect and monitor bladder urothelial cell carcinoma (UCC). Cystoscopy is an invasive technique that has a high sensitivity (91%), except in cases of flat malignancies such as Tis. Cytology has the advantage of being noninvasive with a high specificity (90-96%) but it lacks sensitivity (11-76%), especially for low-grade disease.Fluorescence cystoscopy has been shown in numerous clinical studies to improve the detection of papillary and flat bladder lesions over conventional cystoscopy. Photosensitizing agents like aminolevulinic acid (ALA) and its derivative hexaminolevulinate (HAL) have undergone the most extensive investigation. Some prospective clinical trials have demonstrated improved diagnostic ability, enhanced tumour resection, and reduced tumour recurrence although recently other randomized trials have questioned its value in reducing recurrence and progression. Since the results are still controversial the EAU Guidelines for Non Muscle-Invasive Bladder Cancer recommend that photo-dynamic diagnosis is most useful for detection of CIS, and therefore, it should be restricted to those patients who are suspected of harbouring a high-grade tumour, e.g. for biopsy guidance in patients with positive cytology or with a history of high-grade tumour. Because of conflicting data on recurrence rate this panel restricts the indication for PDD to patients with positive cytology, presence of Cis, or as a teaching tool in a recently published review. Optical coherence tomography is an emerging technology that shows promise in revealing subsurface information about bladder lesions in real-time, potentially leading to more accurate staging. Narrow-band imaging may augment standard endoscopic tools by providing increased contrast between normal and abnormal tissue. Raman molecular imaging (RMI) is an optical technology that combines the molecular chemical analysis of Raman spectroscopy with high-definition digital microscopic visualization and has the potential to become a powerful diagnostic tool that allows noninvasive, accurate diagnosis of UC. Molecular markers are promising tools for diagnosis of BC. Significant efforts have been made in developing noninvasive methods for detecting and predicting

the biological behavior of UCC. In fact, the Food and Drug Administration has already accepted some of these tumor marker tests for use in routine patient care. Even though initial studies with these markers were promising, later reports often fail to confirm the results. It is likely that a panel of markers will overcome the limitations of these single markers.

References• Babjuk, M, Oosterlinck, W., Sylvester, R., Kaasinen,

E., Böhle, A., Palou, J., et al. (2011). Guidelines on Non-muscle invasive Bladder Cancer ( TaT1 and CIS ). Update, 1-36.

• Cauberg, E. C. C., Bruin, D. M. de, Faber, D. J., Leeuwen, T. G. van, Rosette, J. J. M. C. H. de la, & Reijke, T. M. de. (2009). A new generation of optical diagnostics for bladder cancer: technology, diagnostic accuracy, and future applications. European urology, 56(2), 287-96.

• Shah, J. B., & Kamat, A. M. (2010). Fluorescence cystoscopy for nonmuscle invasive bladder cancer: is the honeymoon over for the blue light special? Cancer, 1-2.

• Tatsugami, K., Kuroiwa, K., Kamoto, T., Nishiyama, H., Watanabe, J., Ishikawa, S., et al. (2010). Evaluation of narrow-band imaging as a complementary method for the detection of bladder cancer. Journal of endourology / Endourological Society, 24(11), 1807-11.

• Gladkova, N., Streltsova, O., Zagaynova, E., Kiseleva, E., Gelikonov, V., Gelikonov, G., et al. (2010). Cross-polarization optical coherence tomography for early bladder-cancer detection: statistical study. Journal of biophotonics, 14, 1-14.

• Shapiro, A., Gofrit, O. N., Pizov, G., Cohen, J. K., & Maier, J. (2011). Raman molecular imaging: a novel spectroscopic technique for diagnosis of bladder cancer in urine specimens. European urology, 59(1), 106-12. European Association of Urology.

• Mengual, L., Burset, M., Ribal, M. J., Ars, E., Marín-Aguilera, M., Fernández, M., et al. (2010). Gene Expression Signature in Urine for Diagnosing and Assessing Aggressiveness of Bladder Urothelial Carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research, 16(9), 2624-2633.


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TUR and Re-TUR in Non Muscle Invasive Bladder Cancer (NMIBC). TUR in Muscle Invasive Bladder Cancer (MIBC)

Maurizio A. Brausi,

Department of Urology, Ausl Modena, Italy

TUR and Re-TUR in NMIBCThe standard treatment for transitional cell carcinoma (TCC) of the bladder is TUR of the bladder tumor under white light cystoscopy. However TUR must be adequate.The goals of an adequate TUR are to remove all the visible tumours, to accurate stage the tumor (Detrusor Muscle (DM) must be present in the specimen: if not is called Tx), to evaluate the extension of the tumour (bladder biopsies) and finally to avoid complications like bladder perforation or bleeding (good hemostasis).With a correct TUR pathologists should be able to tell us if basal membrane or lamina propria are invaded, if DM is present and/or invaded, if lymph-vascular invasion is present together with CIS and finally tumour grade.However even after an accurate and adequate TUR 50-70% of patients will recur in time. Possible causes of recurrence are an incomplete TUR, tumour not seen at the time of TUR, tumour cell implantation and aggressive tumour biology. Do we have parameters to evaluate the quality of our TUR? Yes. The 3 month recurrence rate (3-RR), the presence of DM in the specimen, the rate of CIS diagnosed.The EORTC-GU group (Brausi et al 2002) evaluated the adequacy of TUR by analysing the 3-RR in a phase III study which include 2410 patients from European Institutions. The results showed a great variability in £-RR between the institutions, from 0 to 46% and this could not be explained with the clinical and pathological parameters anaized. The surgeon was indicated as responsible of these results.A subsequent EORTC trial (Brausi et al 2004) that collected informations on the quality of TUR confirmed that using a bladder diagram at the time of cystoscopy and being a staff member rather than a resident were important prognostic factors in obtaining a lower 3-RR. The presence of DM in the specimen is also an important parameter of TUR quality. From different studies emerged that it varies from 34% to 64% only, even in experienced, tertiary urological centres. Why these results ? Because urologists perform the first TUR in inadequate way.However we can improve our results using : a) dedicating teaching programs b) performing a second TUR c) using new techniques and technologies (Bipolar resectoscope, PDD, NBI, Physion).

TUR Alone in MIBCThe EAU 2009 guidelines state “ TUR alone is not recommended as a curative treatment option for the majority of patients with localised MIBC (Grade rec. B ). However there are some patients who can benefit from this approach: a) elderly patients with multiple comorbidities, at risk (ASA score III-IV) b) patients refusing surgery c) patients refusing surgery after neo-adjuvant chemotherapy has determined the disappearance of the tumour (pT0).Teoretically it is possible to remove all the bladder tumour even if infiltrative with an adequate, deep and very accurate TUR. However the real risk in MIBC is the presence of tumour cells in the lamina propria and DM where the lymphatic and blood vessels are well represented. The result is that the risk of micrometastases and of systemic disease cannot be prevented by TUR even if complete, deep and extended.Can we cure a patient with cT2 TCC of the bladder with TUR alone? The data tell us that up to 10-15% of patients with MIBC treated with TUR alone have no pathological residual disease at RC (pT0). Moreover long term studies support the importance of down-staging to pT0 after TUR.The 10-year DSS after TUR alone varied from 74-76% (Herr, Solsona). However a delay in performing a RC increases the risk of lymph-node metastases (from 15% to 30%). When a bladder sparing procedure is planned a multi-modality approach should be considered (TUR + Chemo, TUR + RT, Neo-adjuvant Chemo + TUR + RT).

Summary An initial, very accurate TUR is crucial for a correct staging, future treatment and prognosis. A meticulous teaching of this surgery should be a special part of the residency program. New technologies should be incorporated and adopted to improve results. A second TUR is indicated only in selected cases (DM not present in the specimen, in referred patients, when urologists and pathologists are uncertain, when a bladder sparing approach is planned).TUR alone is not reccomended for the treatment of MIBC. When a bladder sparing approach is planned a multi-modality treatment is a must.


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Intravesical Chemotherapy: early and adjuvant

Maria J. Ribal


Bladder cancer is a heterogeneous disease; approximately 75% of its forms are non-muscle invasive neoplasms (NMIBC). Standard treatment for NMIBC consists of complete transurethral resection (TURB) of all visible lesions.

Recurrence and progression are the major problems for many patients and are dependent on multiple clinical and pathological factors, the most important of which are tumor stage, grade, multifocality, size, recurrence patterns, and the association with carcinoma in situ. Accurate assessment of clinical stage and tumour grade is critical in determining management and surveillance strategies. Recurrence rates following TURB and intravesical chemoprophylaxis seem to decrease to 25-50% in 2 years of follow-up. Adjuvant therapy is effective in avoiding post-TURBT implantation of tumour cells, eradicating residual disease, preventing tumour recurrence, and to delay or reduce tumor progression through direct cytoablation or immunostimulation.Major controversies still exist with regard to the indication, type and regimen of intravesical therapy for NMIBC. Mitomycin C (MMC), the most commonly used intravesical chemotherapy to date, decreases the risk of disease recurrence but not disease progression when used after TURB compared with TURB alone.Immediate instillation of intravesical chemotherapy after TURB of NMIBC is widely used. The practice is supported by level 1a evidence from meta-analyses and is recommended by the major international urological societies, including the European Association of Urology (EAU) and American Urological Association (AUA). In a meta-analysis of seven randomised trials (1,476 patients), one immediate instillation of chemotherapy after TURB significantly reduced recurrence rate compared to TURB alone. In absolute values, the reduction was 11.7% that implies a 24.2% decrease in the corresponding relative risk. However, recent publications have questioned its value in the clinical setting. No prospective data are available showing that the single instillation significantly reduces recurrence rates in patients with recurrent tumours. Furthermore, there are no statistically relevant data that address the role of immediate chemotherapy instillation in tumours at high risk of progression before further BCG intravesical treatment, and finally quality-of-life studies and economic calculations have not been done.

References

• Babjuk, M., Oosterlinck, W., Sylvester, R., Kaasinen, E., Böhle, A., Palou, J., et al. (2011). Guidelines on Non-muscle invasive Bladder Cancer ( TaT1 and CIS ). Update, 1-36.

• Sylvester RJ, van der Meijden AP, Oosterlinck W, et al. Predicting recurrence and progression in individual patients with stage TaT1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 2006 Mar;49(3):466-5.

• Sylvester RJ, Oosterlinck W, Witjes JA. The schedule and duration of intravesical chemotherapy in patients with non muscle invasive bladder cancer: a systematic review of the published results of randomized clinical trials. Eur Urol 2008 Apr;53(4):709-19

• Au JL, Baladament RA, Wientjes MG, et al; International Mitomycin C Consortium. International Mitomycin C Consortium. Methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial. J Natl Cancer Inst 2001 Apr;93(8):597-604

• Sylvester RJ, Oosterlinck W, van der Meijden AP. A single immediate postoperative instillation

of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: a metaanalysis of published results of randomized clinical trials. J Urol 2004 Jun;171(6 Pt 1):2186-90.

• Böhle A, Leyh H, Frei C, et al. Single postoperative instillation of gemcitabine in patients with non muscle-invasive transitional cell carcinoma of the bladder: a randomised, double-blind, placebo controlled phase III multicentre study. Eur Urol 2009 Sep;56(3):495-503

• Cai, T., Nesi, G., Tinacci, G., Zini, E., Mondaini, N., Boddi, V., et al. Can early single dose instillation of epirubicin improve bacillus Calmette-Guerin efficacy in patients with nonmuscle invasive high risk bladder cancer? Results from a prospective, randomized, double-blind controlled study. The Journal of Urology, 2008 180(1), 110-5.

• Holmäng, S. (2009). Early Single-Instillation Chemotherapy Has No Real Benefit and Should Be Abandoned in Non–Muscle-Invasive Bladder Cancer. European Urology Supplements,2009; 8(5), 458-463.


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Radical Surgery: Pros and Con of Different Techniques and Evaluation of Complications

Maurizio A. Brausi

Department of Urology, Ausl Modena, Italy

Radical Cystectomy (RC) is considered the treatment of choice for infiltrative (T2-T4) and for recurrent, BCG resistant Ta-T1 high grade bladder cancer (BC). The surgical technique itself may play an important role on final results (Extensive surgery + lymphadenectomy).

Delaying RC may impact on survival. From a systematic review of the literature appear that the window of opportunity is less than 12 weeks from diagnosis to RC (Fahmy et al EUR Urol 2006).

The risk factors predicting survival are : stage, nodal status, histology Type, age, pre-op RT, Lymph-vascular invasion, surgical margins, concomitant Cis (International Consortium Nomogram).

The Techniques of RC include:

• Intraperitoneal RC + LAD (standard)• Extraperitoneal, mininvasive RC (Modena technique)• Prostate sparing/gynec sparing RC• Laparoscopic and Robotic RC

Unregardeless of the technique used an extended lymphadenectomy should be performed with the removal of more than 15-20 nodes.

Oncological resultsIn the earlier studies the 5 year survival rate was 40%. Recent reports show a 5-year survival of more than 60%. The reasons are in the advances in medical therapy used before and after surgery, improvements in anesthesiology techniques, new surgical strategies, early diagnosis and wider indications (Ta-T1 high grade).

The mortality rate of RC was up to 12% in old series (before 1990). In recent series it varies from 0 to 3%.

ComplicationsFrom the recent National Surgical Quality Improvement Program (NSQIP) data on 2538 RCs appeared that 30.5% of patients experienced medical or surgical complications.

They were in order: Ileus (32%), UTI (7.8%),wound dehiscence (5.5%), Wound infection (5.2%), deep vein trombosis (4.7%). The re-operation rate was 6.2-12%.

Laparoscopic and Robotic RC have been introduced in recent years. The advantages of these techniques are: • higher quality of dissection• < blood loss• < Post-op pain and use of analgesics• Shorter hospital stay• Earlier resumption work

The disadvantages:• Prolongation of OR time• Possible severe complications (bowel perforation)• Conversion to open surgery (0.5-3%) • Open surgery for urinary diversion• LAD sometimes difficult (< nodes taken)• > costs• Possible tumour cell spreading (pneumoperitoneum

= high vein pressure) with appearance of unusual metastatic sites in time (3 years)

For a complete and long term analysis of the oncological results a longer follow-up is needed.


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Neoadjuvant and adjuvant Chemotherapy in invasive or metastatic disease

Maria J. Ribal


Advanced bladder cancer (BC) is a chemosensitive tumour. Response rates differ with respect to patient-related factors and pretreatment disease. Prognostic factors for response and survival have been established. A major prognostic factor is the suitability of patients for treatment with a cisplatin-based combination chemotherapy. Cisplatin remains the most effective single agent for treatment of BC. MVAC regimen increases overall survival. The combination cysplatin-gemcitabine proved equal efficacy while reducing side effects.

Although the widely spread use of adjuvant chemotherapy in the setting of locally advanced bladder cancer, there is no conclusive evidence, at present, of its benefits.

The standard treatment for patients with muscle-invasive bladder cancer is radical cystectomy. However, this ‘gold standard’ only provides 5-year survival in about 50% of patients. In order to improve these unsatisfactory results, the use of peri-operative chemotherapy has been explored since the 1980s.

There are many advantages of neoadjuvant chemotherapy, i.e. administering chemotherapy to patients with operable urothelial carcinoma of the urinary bladder before the planned definitive surgery (or radiation). These advantages include:• Chemotherapy is delivered at the earliest time point, when

the burden of micrometastatic disease is expected to be low• In vivo chemosensitivity is tested• The tolerability of chemotherapy is expected to be better

before than after cystectomy.

The disadvantages of neoadjuvant chemotherapy include:• For clinical staging with CT or MRI, over- and under-

staging is likely to happen with a staging accuracy of only 70%. Overtreatment is the possible negative consequence

• Delayed cystectomy might compromise the outcome in patients not sensitive to chemotherapy.

• Side effects of chemotherapy might affect outcome of surgery and type of urinary diversion.

In the most recent meta-analysis, published in 2005 with

updated independent patient data (IPD) of 11 randomized trials (3,005 patients), a statistically significant survival benefit in favour of neoadjuvant chemotherapy was seen. The results of this analysis confirmed the previously published data and showed 5% absolute improvement in survival at 5 years. Of note, only cisplatin combination chemotherapy with at least one additional chemotherapeutic agent resulted in a meaningful benefit; the regimens tested were MVA(E)C, CMV, CM, cisplatin/adriamycin, cisplatin/5- fluorouracil (5-FU), and CarboMV. To date, it is unknown if more modern chemotherapy regimen are as effective. Probably the major unsolved question is which patients are those who really benefit of neoadjuvant chemotherapy, since only one third of the patients will response cumulating the already stated survival advantage, while two third of the patients will not response suffering side effects of chemotherapy and a delay in cystectomy.

In metastatic patients the use of M-VAC and GC both result in prolonged survival of up to 14.8 and 13.8 mo, respectively, also with long-term follow-up. The lower toxicity of GC, however, has resulted in GC increasingly becoming a new standard regimen. Up to 50% of patients are ineligible for cisplatin-containing chemotherapy, either because of a poor PS and/or impaired renal function or because of comorbidity preventing high volume hydration. In this situation carboplatin based regimens are used. In those patients who failed to Cisplatin based regimens second line regimens could be tested. Second-line chemotherapy data are highly variable in this setting. Vinflunine is a novel, third-generation vinca alkaloid that has shown objective response rates of 18% and disease control in 67% of trial subjects.

References• Stenzl, A, Witjes, J A, Cowan, N C, Santis, M. D., Kuczyk,

M., Lebret, T., et al. (2011). Guidelines on Bladder Cancer and Metastatic. Update.

• Stenzl, Arnulf, Cowan, Nigel C, De Santis, M., Kuczyk, M. a, Merseburger, Axel S, Ribal, Maria José, et al. (2011). Treatment of Muscle-invasive and Metastatic Bladder Cancer: Update of the EAU Guidelines. European urology, 59(6), 1009-18. doi: 10.1016/j.eururo.2011.03.023.


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• von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol 2005 Jul;23(21):4602-8.

• Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003 Aug;349(9):859-66.

• Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol 2005 Aug;48(2):202-205; discusión 205-6.

• Brausi MA. Words of wisdom. Re: open to debate. The motion: perioperative chemotherapy in muscle invasive bladder cancer improves survival. Eur Urol. 2010 Feb;57(2):354-5.

• David KA, Milowsky MI, Ritchey J, Carroll PR, Nanus DM. Low incidence of perioperative chemotherapy for stage III bladder cancer 1998 to 2003: a report from the National Cancer Data Base. J Urol. 2007 Aug;178(2):451-4.

• De Santis M, Bellmunt J, Mead G, et al. Randomized phase II/III trial assessing gemcitabine/ carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer “unfit” for cisplatin based chemotherapy: phase II--results of EORTC study 30986. J Clin Oncol. 2009 Nov 20;27(33):5634-9.

• Sternberg CN, de Mulder PH, Schornagel JH, et al; European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol 2001 May;19(10):2638-46.

• Bellmunt J, Théodore C, Demkov T, et al. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transicional cell carcinoma of the urothelial tract. J Clin Oncol 2009 Sep 20;27(27):4454-61

SKRAJŠAN POVZETEK GLAVNIH ZNAČILNOSTI ZDRAVILAIME ZDRAVILACombodart 0,5 mg/0,4 mg trde kapsuleKAKOVOSTNA IN KOLIČINSKA SESTAVA Ena trda kapsula vsebuje 0,5 mg dutasterida in 0,4 mg tamsu-lozinijevega klorida (to ustreza 0,367 mg tamsulozina). Zdravilo vsebuje barvilo sončno rumeno FCF (E 110). Ena kapsula vsebu-je ≤ 0,1 mg barvila sončno rumeno FCF (E 110). Seznam pomožnih snovi: Ovojnica trde kapsule: hipro-meloza, karagenan (E 407), kalijev klorid, titanov dioksid (E 171), rdeči železov oksid (E 172), sončno rumeno FCF (E 110), karnauba vosek, koruzni škrob. Vsebina mehke kapsule duta-sterida: monogliceridi in digliceridi kaprilske/kaprinske kisline, butilhidroksitoluen (E 321), Ovojnica mehke kapsule: želatina, glicerol, titanov dioksid (E 171), rumeni železov oksid (E 172), srednjeverižni trigliceridi, lecitin. Pelete tamsulozina: mikrokri-stalna celuloza, kopolimer metakrilne kisline in etilakrilata, 1 : 1, 30-odstotna disperzija (vsebuje tudi polisorbat 80 in natrijev lavrilsulfat), smukec, trietilcitrat. Črno črnilo (SW-9010 ali SW-9008): šelak, propilenglikol, črni železov oksid (E 172), kalijev hidroksid (samo v črnem črnilu SW-9008).KLINIČNI PODATKITerapevtske indikacije: Zdravljenje zmernih do hudih simpto-mov benigne hiperplazije prostate (BHP). Zmanjšanje tveganja za akutno retenco urina (ARU) in potrebe po kirurškem posegu pri bolnikih z zmernimi do hudimi simptomi BHP. Odmerjanje in način uporabe: Odrasli (vključno s starejšimi bolniki): Priporočeni odmerek zdravila Combodart je ena kap-sula (0,5 mg/0,4 mg), ki se vzame peroralno, in sicer vsak dan približno 30 minut po istem obroku. Bolnik mora kapsulo po-goltniti celo in je ne sme žvečiti ali odpirati. Ob stiku z vsebino kapsule dutasterida, ki je v trdi ovojnici kapsule, lahko pride do draženja ustne in žrelne sluznice. Kadar je to primerno, se za poenostavitev zdravljenja lahko zdravilo Combodart uporabi kot zamenjavo za sočasno uporabo dutasterida in tamsulozi-nijevega klorida v obstoječem dvotirnem zdravljenju. Kadar je klinično primerno, se lahko pretehta možnost neposrednega prehoda z monoterapije z dutasteridom ali tamsulozinijevim kloridom na zdravilo Combodart. Okvara ledvic: Vpliv okvare ledvic na farmakokinetične lastnosti dutasterida-tamsulozina ni bil raziskan. Po predvidevanjih pri bolnikih z okvaro ledvic odmerka ni treba prilagajati. Okvara jeter: Vpliv okvare jeter na farmakokinetične lastnosti dutasterida-tamsulozina ni bil raziskan, zato je pri bolnikih z blago do zmerno okvaro jeter po-trebna previdnost. Pri bolnikih s hudo okvaro jeter je uporaba zdravila Combodart kontraindicirana.Kontraindikacije: Uporaba zdravila Combodart je kontra-indicirana pri: - ženskah, otrocih in mladostnikih; bolnikih, ki so alergični (preobčutljivi) na dutasterid, druge zaviralce 5-alfa-reduktaze, tamsulozin (vključno z angioedemom zaradi tamsulozina) ali katerokoli pomožno snov zdravila Combodart; bolnikih z anamnezo ortostatske hipotenzije; bolnikih s hudo okvaro jeter. Posebna opozorila in previdnostni ukrepi: Zdravilo Com-bodart je treba predpisati po natančni oceni koristi in tveganja ter ob upoštevanju drugih možnosti zdravljenja, vključno z možnostjo monoterapij. V štiriletni klinični študiji je bila in-cidenca srčnega popuščanja (sestavljeni dogodek poročanih dogodkov, predvsem srčnega popuščanja in kongestivnega srčnega popuščanja) večja med bolniki, ki so uporabljali

kombinacijo dutasterida in antagonista alfa adrenegičnih re-ceptorjev tamsulozina, kot med bolniki, ki te kombinacije niso uporabljali. Vzročne povezanosti med dutasteridom (samim ali v kombinaciji z antagonistom alfa) in srčnim popuščanjem niso ugotovili. Preden se uvede zdravljenje z zdravilom Combodart, je treba pri bolnikih z BHP opraviti digitalni rektalni pregled in tudi druge preiskave, povezane z odkrivanjem raka na prostati ali drugih bolezni, ki lahko povzročijo enake simptome kot BHP, ter jih nato ponavljati v rednih časovnih presledkih. Se-rumska koncentracija za prostato specifi čnega antigena (PSA) je pomembna komponenta pri odkrivanju raka na prostati. Na splošno: skupna serumska koncentracija PSA, večja od 4 ng/ml (Hybritech), zahteva nadaljnje vrednotenje in razmislek o biopsiji prostate. Pri bolnikih, ki jemljejo zdravilo Combodart, vrednost PSA, nižja od 4 ng/ml, ne izključuje diagnoze raka na prostati in tega se morajo zdravniki pri presojanju vrednosti za-vedati. Pri bolnikih z BHP se po šestih mesecih jemanja zdravila Combodart vrednosti PSA v serumu zmanjšajo za približno 50 %, in to celo v prisotnosti raka na prostati. Individualna odsto-panja so sicer mogoča, kljub temu pa se sme predvidevati, da se bodo vrednosti PSA zmanjšale za približno 50 %, saj je bilo tako zmanjšanje opaženo pri vrsti izhodiščnih vrednosti PSA (1,5 do 10 ng/ml). Pri moških, ki se šest mesecev ali več zdra-vijo z zdravilom Combodart, je tako treba med interpretacijo posamezne vrednosti PSA le-to podvojiti, podvojena vrednost pa je nato primerljiva z normalnimi vrednostmi pri moških, ki se z zdravilom Combodart ne zdravijo. Taka prilagoditev zagotavlja občutljivost in specifi čnost testa PSA ter ohranja njegovo sposobnost za odkrivanje raka na prostati. Vsako vztrajno povečevanje vrednosti PSA pri bolnikih, ki se zdravijo z zdravilom Combodart, je treba pazljivo ovrednotiti, treba pa je oceniti tudi morebitno neustrezno jemanje zdravila. Skupne serumske vrednosti PSA se v šestih mesecih po prekinitvi zdra-vljenja vrnejo na izhodiščne vrednosti. Razmerje med prostim in skupnim PSA ostaja nespremenjeno tudi pod vplivom zdravila Combodart. Če zdravniki izberejo odstotek prostega PSA kot pomoč pri odkrivanju raka na prostati pri moških, ki se zdravijo z zdravilom Combodart, odstotka prostega PSA domnevno ni treba prilagoditi. Pri zdravljenju bolnikov s hudo okvaro ledvic (očistek kreatinina manj kot 10 ml/min) je potrebna previdnost, kajti uporaba pri teh bolnikih ni raziskana. Tako kot pri drugih antagonistih alfa adrenergičnih receptorjev se lahko tudi med zdravljenjem s tamsulozinom zniža krvni tlak, kar lahko v red-kih primerih povzroči sinkopo. Bolnike, ki začenjajo zdravljenje z zdravilom Combodart, je treba opozoriti, naj ob prvih znakih ortostatske hipotenzije (omotica, šibkost) sedejo ali ležejo, dokler simptomi ne minejo. Med operacijo katarakte so pri nekaterih bolnikih, ki so trenutno ali predhodno dobivali tam-sulozin, opažali medoperacijski sindrom ohlapne šarenice (IFIS - Intraoperative Floppy Iris Syndrome, ki je različica sindroma majhne zenice). IFIS lahko povzroči več postopkovnih zapletov med operacijo. Zdravila Combodart zato ni priporočljivo vpeljati bolnikom, pri katerih je predvidena operacija katarakte. Zdrav-niki, ki operirajo katarakto, in oftalmološke ekipe morajo med predoperacijsko oceno preveriti, ali bolnik, predviden za opera-cijo katarakte, prejema ali je prejemal zdravilo Combodart, zato da lahko pripravijo ustrezne ukrepe za obvladanje IFIS med operacijo. Če se je tamsulozin prenehal uporabljati od 1 do 2 tedna pred operacijo katarakte, naj bi to v posameznih primerih pomagalo, toda korist in ustrezen čas prenehanja zdravljenja

pred operacijo katarakte še nista ugotovljena. Dutasterid se ab-sorbira skozi kožo, zato se morajo ženske, otroci in mladostniki izogibati stiku s kapsulami, ki puščajo vsebino. Če pride do stika z vsebino kapsule, je treba stično površino kože takoj umiti z milom in vodo. Pri bolnikih z boleznijo jeter uporaba zdravila Combodart ni bila raziskana. Pri dajanju zdravila Combodart bolnikom z blago do zmerno okvaro jeter je potrebna previ-dnost. To zdravilo vsebuje barvilo sončno rumeno FCF (E 110), ki lahko povzroči alergijske reakcije. Medsebojno delovanje z drugimi zdravili in druge oblike interakcij: Študij medsebojnega delovanja zdravila Combodart z drugimi zdravili niso izvedli. Naslednje navedbe vsebujejo in-formacije, ki so na voljo za posamezni učinkovini. Dutasterid: Za informacije o zmanjšanju serumskih vrednosti PSA med zdravljenjem z dutasteridom in o smernicah glede odkrivanja raka na prostati. Učinki drugih zdravil na farmakokinetične la-stnosti dutasterida: Sočasna uporaba zaviralcev CYP3A4 in/ali zaviralcev P-glikoproteina: Dutasterid se večinoma izloča s pre-snovo. Študije in vitro kažejo, da njegovo presnovo katalizirata CYP3A4 in CYP3A5. Posebnih študij o interakcijah z močnimi zaviralci CYP3A4 niso izvedli. Vseeno pa so bile pri majhnem številu bolnikov, ki so bili v farmakokinetični populacijski študiji sočasno zdravljeni z verapamilom ali diltiazemom (zmerna za-viralca CYP3A4 in zaviralca P-glikoproteina), ugotovljene večje serumske koncentracije dutasterida kot pri drugih bolnikih, in sicer pri sočasnem zdravljenju z verapamilom v povprečju za 1,6-krat in pri sočasnem zdravljenju z diltiazemom v povprečju za 1,8-krat. Zaradi dolgotrajne uporabe dutasterida v kombina-ciji z močnimi zaviralci encima CYP3A4 (npr. ritonavir, indinavir, nefazodon, itrakonazol in ketokonazol v peroralni obliki) se lahko serumske koncentracije dutasterida povečajo. Nadaljnja inhibicija 5-alfa-reduktaze zaradi povečane izpostavljenosti dutasteridu ni verjetna, vendar pa je pri pojavu neželenih učin-kov treba oceniti možnost za podaljšanje časovnega intervala med posameznimi odmerki dutasterida. Treba se je zavedati, da se lahko ob encimski inhibiciji dolg razpolovni čas še do-datno podaljša in tako lahko sočasno zdravljenje traja več kot 6 mesecev, preden se vzpostavi novo stanje ravnovesja. Dajanje 12 g holestiramina eno uro pred dajanjem dutasterida v enkratnem odmerku 5 mg ni vplivalo na farmakokinetične lastnosti dutasterida. Učinki dutasterida na farmakokinetične lastnosti drugih zdravil: V majhni dvotedenski študiji (n = 24) pri zdravih moških dutasterid (v odmerku 0,5 mg na dan) ni vplival na farmakokinetiko tamsulozina ali terazosina. Ta študija prav tako ni pokazala farmakodinamičnih interakcij. Dutasterid ne vpliva na farmakokinetične lastnosti varfarina ali digoksina. To kaže, da dutasterid ne inhibira/inducira CYP2C9 ali transportnega P-glikoproteina. Študije interakcij in vitro kažejo, da dutasterid ne inhibira encimov CYP1A2, CYP2D6, CYP2C9, CYP2C19 ali CYP3A4. Tamsulozin: Sočasna uporaba tamsulozinijevega klorida z zdravili, ki lahko znižajo krvni tlak, vključno z anestetiki in drugimi antagonisti alfa-1 adrenergič-nih receptorjev, lahko povzroči močnejše hipotenzivne učinke. Kombinacije dutasterid-tamsulozin se ne sme uporabljati v kombinaciji z drugimi antagonisti alfa-1 adrenergičnih recep-torjev. Sočasna uporaba tamsulozinijevega klorida (0,4 mg) in cimetidina (400 mg na šest ur šest dni) je zmanjšala očistek (26 %) in povečala AUC (44 %) tamsulozinijevega klorida. Če se dutasterid-tamsulozin uporabi v kombinaciji s cimetidinom, je potrebna previdnost. Defi nitivne študije medsebojnega delova-nja med tamsulozinijevim kloridom in varfarinom niso izvedli. Rezultati maloštevilnih študij in vitro in in vivo so nedokončni.

Če se sočasno uporabljata varfarin in tamsulozinijev klorid, je potrebna previdnost. Pri uporabi tamsulozinijevega klorida sočasno z atenololom, enalaprilom, nifedipinom ali teofi linom niso opazili medsebojnih učinkov. Sočasna uporaba furosemida povzroči znižanje koncentracije tamsulozina v plazmi, vendar koncentracija ostane v normalnem območju, zato odmerjanja ni treba prilagoditi. Diazepam, propranolol, triklormetiazid, klormadinon, amitriptilin, diklofenak, glibenklamid in simva-statin in vitro ne spremenijo proste frakcije tamsulozina v člo-veški plazmi. Prav tako tamsulozin ne spremeni prostih frakcij diazepama, propranolola, triklormetiazida in klormadinona. V študijah z jetrnimi mikrosomskimi frakcijami (ki predstavljajo s citokromom P450 povezani encimski sistem za presnovo zdra-vil) in vitro z amitriptilinom, salbutamolom in glibenklamidom niso ugotovili interakcij na ravni jetrne presnove. Diklofenak pa lahko poveča hitrost izločanja tamsulozina. Nosečnost in dojenje: Pri ženskah je uporaba zdravila Com-bodart kontraindicirana. Študij o vplivu zdravila Combodart na nosečnost, dojenje in plodnost niso izvedli. Naslednje navedbe vsebujejo informacije, ki so na voljo za posamezni sestavini. Plodnost: Poročali so, da dutasterid pri zdravih moških vpliva na značilnosti semena (zmanjšano število semenčic, zmanjšan volumen semena in gibljivosti semenčic). Možnosti zmanjšane plodnosti moških ni mogoče izključiti. Vplivi tamsulozinijevega klorida na število semenčic in njihovo funkcijo niso bili ovre-dnoteni. Nosečnost: Tako kot drugi zaviralci 5-alfa-reduktaze tudi dutasterid zavira pretvorbo testosterona v dihidrotestoste-ron in lahko, če se daje nosečnicam, ki nosijo plod moškega spola, zavre razvoj zunanjih spolovil ploda. V spermi oseb, ki so prejemale dutasterid, so bile dokazane manjše količine dutasterida. Na podlagi študij na živalih je malo verjetno, da bi izpostavljenost nosečnice spermi bolnika, ki se zdravi z du-tasteridom, škodljivo prizadela plod moškega spola (tveganje je največje v prvih 16 tednih nosečnosti). Kljub temu pa se pri-poroča, tako kot pri uporabi vseh zaviralcev 5-alfa-reduktaze, da bolnik v primeru, ko je partnerka noseča ali bi lahko bila noseča, uporablja kondom in tako prepreči, da bi partnerka prišla v stik s spermo. Uporaba tamsulozinijevega klorida pri brejih podganah in kunčjih samicah ni pokazala škodljivosti za plod. Dojenje: Ni znano, ali se dutasterid ali tamsulozin izločata v materino mleko.Vpliv na sposobnost vožnje in upravljanja s stroji: Študij o vplivih zdravila Combodart na sposobnost vožnje in upravljanja s stroji niso izvedli, vendar je bolnikom treba povedati, da med jemanjem zdravila Combodart obstaja možnost pojava simpto-mov, povezanih z ortostatsko hipotenzijo, na primer omotice. Neželeni učinki: Terapevtskih kliničnih preskušanj z zdravilom Combodart niso izvedli, dokazana pa je bioekvivalentnost zdravila Combodart ter sočasno uporabljenega dutasterida in tamsulozina. Tukaj prikazani podatki se nanašajo na sočasno uporabo dutasterida in tamsulozina iz dveletne analize študije CombAT (Combination of Avodart and Tamsulosin), ki je pri-merjala dutasterid 0,5 mg in tamsulozin 0,4 mg enkrat na dan štiri leta med sočasno uporabo ali kot monoterapijo. Vključene so tudi informacije o profi lu neželenih učinkov obeh posame-znih učinkovin (dutasterida in tamsulozina).SOČASNA UPORABA DUTASTERIDA IN TAMSULOZINA: Po-datki iz kliničnih preskušanj: Podatki 2. leta študije CombAT so pokazali, da je bila incidenca katerihkoli, po raziskovalčevi presoji z zdravilom povezanih, neželenih učinkov v prvem oz. drugem letu zdravljenja 22 % oz. 5 % za sočasno zdravljenje z dutasteridom in tamsulozinom, 14 % oz. 5 % za monoterapijo z

dutasteridom in 13 % oz. 4 % za monoterapijo s tamsulozinom. Večja incidenca neželenih učinkov v prvem letu zdravljenja v skupini, ki je dobivala kombinirano zdravljenje, je posledica večje incidence motenj reprodukcije, natančneje ejakulacijskih motenj, v tej skupini. Naslednji, po raziskovalčevi presoji z zdra-vilom povezani, neželeni učinki so bili zabeleženi z incidenco, ki je večja ali enaka 1 % v prvem letu zdravljenja v analizi študije CombAT 2. Leto. Incidenca neželenih učinkov, glede na organ-ski sistem v 1. letu zdravljenja (Dutasterid + tamsulozin (n = 1610); Dutasterid (n = 1623); Tamsulozin (n = 1611)) in v 2. letu zdravljenja (Dutasterid + tamsulozin (n = 1424); Dutasterid (n = 1457); Tamsulozin (n = 1468)): Motnje reprodukcijskega sistema in dojk, psihiatrične motnje in preiskave: erektilna disfunkcija v 1. letu zdravljenja ( 6,5%; 4,9%; 3,3%) v 2. letu zdravljenja ( 1,1%; 1,3%; 0,7%); Sprememba (zmanjšanje) libi-da v 1. letu zdravljenja ( 5,2%; 3,8%; 2,5%) v 2. letu zdravljenja ( 0,4%; 0,9%; 0,6%); Ejakulacijske motnje v 1. letu zdravljenja (8,9%; 1,6%; 2,7%) v 2. letu zdravljenja ( 0,5%; 0,3%; 0,5%); Motnje dojk (vključno s povečanjem in/ali občutljivostjo dojk) v 1. letu zdravljenja (2,0%; 1,8%; 0,8%) v 2. letu zdravljenja ( 0,9%; 1,2%; 0,3%) ter bolezni živčevja v 1. letu zdravljenja ( 1,4%; 0,6%; 1,3%) v 2. letu zdravljenja ( 0,2%; 0,1%; 0,4%).MONOTERAPIJA Z DUTASTERIDOM: Podatki iz kliničnih preskušanj: V treh s placebom kontroliranih študijah III. faze zdravljenja z dutasteridom (n = 2167) v primerjavi s placebom (n = 2158) sta bili vrsta in pogostnost po raziskovalčevi presoji z zdravilom povezanih neželenih učinkov po enem in dveh letih zdravljenja podobni kot v kraku monoterapije z dutasteridom v študiji CombAT. V nadaljnjih dveh letih med odprto podaljša-no fazo teh študij niso ugotovili sprememb profi la neželenih učinkov. Postmarketinški podatki: Neželeni učinki, opaženi med spremljanjem zdravila po začetku trženja, temeljijo na spontanih postmarketinških prijavah, zato njihova dejanska incidenca ni znana. Bolezni imunskega sistema: Alergijske re-akcije, vključno z izpuščajem, srbenjem, urtikarijo, lokaliziranim edemom in angioedemom.MONOTERAPIJA S TAMSULOZINOM: Podatki iz kliničnih pre-skušanj in postmarketinški podatki: Neželeni učinki in katego-rije pogostnosti, temeljijo na javno dostopnih informacijah. Po-gosti in občasni učinki se skladajo s tistimi, ki so bili ugotovljeni v kliničnih preskušanjih, in kategorije pogostnosti na splošno kažejo incidenco nad placebom. Redki in zelo redki učinki se skladajo s tistimi, ki so bili ugotovljeni iz postmarketinških poročil, in kategorije pogostnosti pomenijo prijavljene deleže. Neželeni učinki razvrščeni po pogostnosti: pogosti: omotica; občasni: palpitacije, zaprtost, driska, navzea, bruhanje, astenija, glavobol, motnje ejakulacije, rinitis, izpuščaj, srbenje, urtikarija, posturalna hipotenzija; redki: sinkopa, angioedem; zelo redki: priapizem. Med postmarketinškim spremljanjem so z upora-bo antagonistov alfa-1 adrenergičnih receptorjev, vključno s tamsulozinom, povezali primere medoperacijskega sindroma ohlapne šarenice (IFIS), različico sindroma majhne zenice, ki se je pojavil med operacijo katarakte. Preveliko odmerjanje: Podatkov o prevelikem odmerjanju zdravila Combodart ni. Naslednje navedbe vsebujejo informacije, ki so na voljo za posamezni učinkovini. Dutasterid: V študijah so prostovoljci v obliki enkratnih dnevnih odmerkov 7 dni prejemali dutasterid v odmerku do 40 mg/dan (80-kratni terapevtski odmerek), kar ni povzročalo pomembnejših skrbi glede varnosti. V kliničnih študijah so osebe šest mesecev prejemale dutasterid v od-merku 5 mg dnevno, pri čemer, razen neželenih učinkov, ki se pojavijo že pri terapevtskih 0,5-mg odmerkih, niso opazili še

dodatnih neželenih učinkov. Za dutasterid specifi čni antidot ne obstaja, tako je ob sumu, da gre za preveliko odmerjanje, treba zagotoviti ustrezno simptomatsko in podporno zdravljenje. Tamsulozin: Opisano je akutno preveliko odmerjanje s 5 mg tamsulozinijevega klorida. Opazili so akutno hipotenzijo (sisto-lični krvni tlak 70 mmHg), bruhanje in drisko, ki so jih zdravili z nadomeščanjem tekočine, in bolnika so lahko odpustili isti dan. V primeru akutne hipotenzije po prevelikem odmerjanju je tre-ba zagotoviti kardiovaskularno podporo. Krvni tlak je mogoče korigirati, srčno frekvenco pa normalizirati tako, da se bolnik uleže. Če to ne pomaga, se lahko uporabi ekspanderje plazme, ali po potrebi vazopresorje. Treba je spremljati delovanje ledvic in uporabiti splošne podporne ukrepe. Ni verjetno, da bi dializa koristila, ker je tamsulozin v zelo veliki meri vezan na beljakovi-ne v plazmi. Za preprečitev absorpcije se lahko uporabijo ukre-pi, kot je sprožitev bruhanja. Če gre za zaužitje velike količine, se lahko uporabi izpiranje želodca, aktivno oglje in osmotsko odvajalo, na primer natrijev sulfat. FARMACEVTSKI PODATKIInkompatibilnosti: Navedba smiselno ni potrebna. Vrsta ovojnine in vsebina: Motne, bele plastenke iz polietilena veli-ke gostote (HDPE) s polipropilensko, za otroke varno zaporko s polietilensko prevlečenimi, folijskimi indukcijsko toplotno zapr-timi oblogami: 30 trdih kapsul v 100-ml plastenki.IMETNIK DOVOLJENJA ZA PROMET: GSK d.o.o., Ljubljana, Knezov štradon 90, 1000 Ljubljana, Slovenija; Tel:+386 1 280 25 00; E-pošta: [email protected]. DATUM ZADNJE REVIZIJE BESEDILA: 29.03.2010Pred predpisovanjem, prosimo, preberite celoten povzetek glavnih značilnosti zdravila.Predpisovanje in izdaja zdravila je le na recept.

Za vse morebitne nadaljnje informacije o tem zdravilu se lahko obrnete na imetnika dovoljenja za promet z zdravilom: GSK d.o.o., Ljubljana, Knezov Štradon 90, 1000 Ljubljana, tel: +386 (0)1 280 25 00, [email protected]

Combodart je zaščitena blagovna znamka skupine družb GlaxoSmithKline. © 2010 GlaxoSmithKline. Vse pravice pridržane.

Datum priprave materiala: maj 2011.Veljavnost materiala 1 leto SL

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Sestava Ena tableta vsebuje 5 mg ali 10 mg solifenacinijevega sukcinata, kar ustreza 3,8 mg ali 7,5 mg solifenacina. Tablete vsebujejo laktozo. Terapevtske indikacije Simptomatsko zdravljenje urgentne inkontinence in/ali povečane pogostosti in nujnosti uriniranja, ki se lahko pojavita pri bolnikih s sindromom prekomerno aktivnega sečnega mehurja. Odmerjanje in način uporabe Priporočeni odmerek je 5 mg enkrat na dan. Po potrebi se odmerek lahko poveča na 10 mg enkrat na dan. Zdravilo Asolfena se jemlje peroralno. Tableto je treba pogoltniti celo, s tekočino. Lahko se vzame s hrano ali brez nje. Varnost in učinkovitost pri otrocih še nista bili ugotovljeni, zato zdravila Asolfena otroci ne smejo jemati. Za bolnike z blago do zmerno ledvično okvaro (kreatininski očistek > 30 ml/min) odmerka ni treba prilagajati. Bolnike s hudo ledvično okvaro (kreatininski očistek ≤ 30 ml/min) je treba zdraviti previdno; ne smejo dobiti več kot 5 mg enkrat na dan. Pri bolnikih z blago jetrno okvaro prilagajanje odmerka ni potrebno. Bolniki z zmerno jetrno okvaro (Child-Pughova lestvica od 7 do 9) ne smejo dobiti več kot 5 mg enkrat na dan. Največji odmerek zdravila Asolfena je treba omejiti na 5 mg, kadar bolnik sočasno jemlje ketokonazol ali terapevtske odmerke drugih močnih zaviralcev CYP3A4, npr. ritonavirja, nelfinavirja, itrakonazola. Kontraindikacije Preobčutljivost za zdravilno učinkovino ali katerokoli pomožno snov. Zastoj urina. Hude prebavne težave (vključno s toksičnim megakolonom). Miastenija gravis. Glavkom ozkega zakotja in nevarnost za taka stanja. Hemodializa. Huda jetrna okvara. Huda ledvična okvara ali zmerna jetrna okvara ter sočasno zdravljenje z močnim zaviralcem CYP3A4, npr. ketokonazolom. Posebna opozorila in previdnostni ukrepi Pred začetkom zdravljenja je treba oceniti druge vzroke za pogosto uriniranje (npr. srčno popuščanje ali ledvično bolezen). Če gre za okužbo sečil, je treba začeti s primernim protibakterijskim zdravljenjem. Previdnost je potrebna pri bolnikih: s klinično pomembno zaporo sečnega mehurja, pri kateri lahko pride do zastoja urina; z zaporo v prebavilih; z nevarnostjo zmanjšane gastrointestinalne motilitete; s hudo ledvično okvaro (kreatininski očistek ≤ 30 ml/min); z zmerno jetrno okvaro (Child-Pughova lestvica od 7 do 9); pri bolnikih, ki sočasno dobivajo močan zaviralec CYP3A4, npr. ketokonazol; pri bolnikih s hiatusno kilo ali gastroezofagealnim refluksom ter bolnikih, ki sočasno jemljejo zdravila, ki lahko povzročijo ali poslabšajo ezofagitis (npr. bisfosfonate); pri bolnikih z avtonomno nevropatijo. Največji učinek zdravila Asolfena je mogoče ugotoviti šele po 4 tednih. Bolniki z dedno intoleranco za galaktozo,

laponsko obliko zmanjšane aktivnosti laktaze ali malabsorpcijo glukoze/galaktoze ne smejo jemati tega zdravila. Medsebojno delovanje z drugimi zdravili in druge oblike interakcij Sočasno zdravljenje z drugimi zdravili z antiholinergičnimi lastnostmi lahko povzroči bolj izražene terapevtske in neželene učinke. Po prenehanju zdravljenja z zdravilom Asolfena naj sledi približno en teden premora do začetka zdravljenja z drugim antiholinergikom. Terapevtski učinek solifenacina lahko zmanjša sočasno dajanje agonistov holinergičnih receptorjev. Solifenacin lahko zmanjša učinek zdravil, ki pospešujejo motiliteto prebavil, kot sta na primer metoklopramid in cisaprid. Solifenacin se presnavlja s CYP3A4. Sočasno dajanje ketokonazola (200 mg na dan oz. 400 mg/dan) je povzročilo dvakratno oz. trikratno povečanje površine pod krivuljo plazemske koncentracije (AUC) solifenacina. Kadar se Asolfena daje sočasno s ketokonazolom ali terapevtskimi odmerki drugih močnih zaviralcev CYP3A4 (npr. ritonavirja, nelfinavirja, itrakonazola), je največji odmerek 5 mg. Sočasno zdravljenje s solifenacinom in močnim zaviralcem CYP3A4 je kontraindicirano pri bolnikih s hudo ledvično okvaro ali zmerno jetrno okvaro. Jemanje solifenacina ni spremenilo farmakokinetike R-varfarina ali S-varfarina ali njunega učinka na protrombinski čas niti ni imelo učinka na farmakokinetiko digoksina. Nosečnost in dojenje Ni kliničnih podatkov. Pri predpisovanju zdravila nosečnicam je potrebna previdnost. Ni podatkov o prehajanju zdravila v materino mleko. Zdravila Asolfena zato ne dajemo materam, ki dojijo. Vpliv na sposobnost vožnje in upravljanje s stroji Solifenacin, kot drugi antiholinergiki, lahko povzroči zamegljen vid, včasih tudi zaspanost in utrujenost, kar lahko negativno vpliva na vožnjo in upravljanje s stroji. Neželeni učinki Pogostost antiholinergičnih neželenih učinkov je povezana z odmerkom. Zelo pogosti: suha usta. Pogosti: zamegljen vid, zaprtje, slabost, dispepsija, bolečine v trebuhu. Občasni: gastroezofagealna refluksna bolezen, suho grlo, suha usta, suhe oči, suh nos, suha koža, okužba sečil, cistitis, zaspanost, sprememba okusa, težave pri uriniranju, utrujenost, periferni edem. Redki: črevesna zapora, zapeka, zastoj urina. Ostali se pojavljajo zelo redko. Poročali so tudi o podaljšanju intervala QT in ventrikularni tahikardiji, vendar pogostost teh dogodkov niti vloga solifenacina pri nastanku teh neželenih učinkov nista bili določeni. Imetnik dovoljenja za promet Krka, tovarna zdravil, d. d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenija. Načinizdajanja Samo na zdravniški recept. Oprema 30 filmsko obloženih tablet po 5 mg ali 10 mg. Datum priprave besedila Januar 2011.

Samo za strokovno javnost.Pred predpisovanjem preberite celoten povzetek glavnih značilnosti zdravila. Objavljen je tudi na www.krka.si.Krka, d. d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, www.krka.si

Novo Krkino zdravilo za lajšanje simptomov prekomerno aktivnega sečnega mehurja

filmsko obložene tablete, 5 mg, 10 mg solifenacin

Mehurpod nadzorom!Vse ostalo je stvar odločitve.

2011-14731_ASOLFENA_ad-A4_SI.indd 1 23.5.2011 9:20:27


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Obravnava bolnikov z mišično neinvazivnim rakom sečnega mehurja: 5-letno sledenje

Treatment of patient with non-muscle invasive Bladder Cancer:5-years follow up

Z. Krstanoski, M. Zupančič, F. Kramer, L. Koršič, I. Parać

Oddelek za urologijo, Splošna bolnišnica Slovenj Gradec, SlovenijaDepartment of Urology, General Hospital Slovenj Gradec, Slovenia

Izvleček

Izhodišča: Rak sečnega mehurja je najbolj pogost tumor sečil. Pri moških je med raki na sedmem mestu, redkejši je pri ženskah. Cilj naše raziskave je bila retrospektivna analiza naših rezultatov 5-letnega spremljanja obravnave bolnikov z mišično neinvazivnim rakom sečnega mehurja in primerjava z objavljenimi rezultati.Bolniki in metode: V raziskavi smo obravnavali 91 bolnikov, ki so bili zaradi mišično neinvazivnega raka sečnega mehurja prvič operirani v letih 2005 in 2006. 82(90%) bolnikom smo 1-2 uri po TUR tumorja sečnega mehurja intravezikalno aplicirali 40 mg Mitomycina C. Za dodatno intravezikalno imuno ali kemoterapijo smo se odločili pri vseh bolnikih s stadijem bolezni T1 in pri vseh bolnikih s CIS. Med bolniki s Ta pa so terapijo prejeli tisti, pri katerih je šlo za gradus II in III, ali če je bil tumor multifokalen. Pri bolnikih s stadijem bolezni T1 in Ta+CIS ali CIS ter bolnikih s ponovitvijo bolezni, smo izvajali podaljšano imunoterapijo. Po prvih šestih aplikacijah BCG so sledile 3 mesečne, 2 trimesečni, 2 šestmesečni in nato 1 aplikacija letno.Rezultati: Recidiv bolezni smo ugotovili pri 29(31,8%) bolnikih, od katerih se je pri 16(55%) pojavil v prvem letu po operaciji. Pri 9(31%) bolnikih je do ponovitve bolezni prišlo 2-3 krat. Od 29 bolnikov s ponovitvijo bolezni je pri 18(62%) ob prvi operaciji šlo za 2-7 tumorjev, s stopnjo diferenciacije G II-III. Pri 4(4,3%) bolnikih z recidivom bolezni smo ugotovili progres v mišično invazivni stadij T2. Od 14 bolnikov, ki po prvi operaciji niso prejeli imunoterapije ali kemoterapije, je do ponovitve bolezni prišlo pri 4(29%), pri vseh pa je bil izhodiščni stadij Ta G II.Zaključek: Če primerjamo naše rezultate z objavljenimi v strokovni literaturi, lahko ugotovimo, da so glede odstotka ponovitve bolezni sicer boljši, vendar v obravnavanem obdobju še nismo pri vseh bolnikih ocenjevali velikosti in števila tumorjev ob prvem operativnem zdravljenju.

Abstract

Objective: Urinary Bladder Cancer is the most common malignant disease of urinary tract. Among cancers in men is Bladder Cancer in seventh place and less common in women. The aim of this study was retrospective analysis of our results in five years follow up on patients with non-muscle invasive Bladder Cancer and comparison with published data.Patients and methods: From 2005 to 2006 we treated 91 patients with non-muscle invasive bladder cancer surgery. In 82(90%) patients 1-2 hours after TURB 40 mg of Mitomycin C was instilled intravesically. For additional intravesical immuno or chemotherapy, we decided in all patients with stage T1 disease and with CIS. Among patients with Ta, additional therapy was given to those with Grade II and III, or if the tumor was multifocal. In patients with stage T1, and those with Ta+CIS or CIS, and patients with relapse, we performed extended immunotherapy and after the first six applications, BCG was followed 3-times monthly, 2-times every three months, 2-times every six months and then 1 application per year.Results: Relapse of the disease was observed in 29(31.8%) patients, of which in 16(55%) occurred within the first year after surgery. In 9(31%) patients the recurrence of illness was 2-3 times. Of the 29 patients with relapsed disease in 18(62%) at first operation were 2-7 tumors with Grade II-III. In 4 (4.3%) patients with recurrence, disease progressed to muscle invasive stage T2. In 14 patients who after the first surgery did not receive immunotherapy or chemotherapy, disease occurred again in 4(29%), and all of them had starting stage G II.Conclusion: If we compare our results with published in the literature, we find that our data of recurrence of the disease are better, but in this period we have not in all patients exactly evaluated the size and number of tumors at the first operative treatment.


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UvodRak sečnega mehurja je najbolj pogost maligni tumor sečil. Pri moških je na sedmem mestu po pogostnosti raka, pri ženskah je redkejši. Pojavi se lahko v kateremkoli obdobju življenja, tudi v otroštvu. Srednja starost pri moških s tem rakom je 69 let, pri ženskah pa 71[1]. V Evropi vsako leto odkrijemo 20 novih primerov raka sečnega mehurja na 100.000 prebivalcev [2]. Prehodnocelični karcinom je najpogostejša oblika in predstavlja 90% te bolezni. 75-85% rakov ob prvi diagnozi je mišično neinvazivnih, in sicer omejenih na mukozo (Ta) ali pa z zajetjem lamine proprie mukoze (T1). Poseben problem so areali malignih celic, omejenih znotraj mukoze (CIS). Možnost za ponovitev mišično neinvazivnega raka sečnega mehurja je do 70% v prvih 5 letih, najpogosteje v prvem letu po začetnem zdravljenju. Okoli 30% recidivnih tumorjev ima višjo histološko stopnjo in okoli 10% napreduje v mišično invazivno obliko tumorja, z visoko stopnjo umrljivosti [3]. Prognostični dejavniki za ponovitev bolezni so velikost tumorja, stadij, stopnja diferenciacije malignih celic, pridružen CIS in multifokalnost. Dejavniki tveganja za nastanek raka sečnega mehuja so aromatični amini, kajenje, analgetična odvisnost, ciklofosfamid in kronična vnetja sečnega mehurja [4]. Hematurija je najpogostejši znak te bolezni, pogosto jo spremljata dizurija in urgentna mikcija. V odkrivanju raka sečnega mehurja izvajamo klinični pregled, standardno cistoskopijo, fluorescentno cistoskopijo, UZ sečil, intravenozno urografijo, računalniško tomografijo, pregled sedimenta urina, citološko analizo urina, urinske molekularne teste in biopsijo sluznice sečnega mehurja [5-9]. TUR tumorjev je metoda izbire za prvo zdravljenje eksofitnih tumorjev. V nadaljevanju lahko uporabimo intravezikalno imuno ali kemoterapijo. V prispevku predstavljamo naše izkušnje pri zdravljenju mišično neinvazivnega raka sečnega mehurja in sicer 5-letno sledenje.

Pacienti in metodeV raziskavi smo obravnavali 91 bolnikov, ki so bili zaradi mišično neinvazivnega raka sečnega mehurja prvič operirani v letih 2005 in 2006. Večina smo diagnostično obravnavali v naši ambulanti. Glavni razlog za pregled je bila asimptomatska hematurija, redkeje mikrohematurija, dizurija ali urgentna mikcija. Po kliničnem pregledu smo pri vseh bolnikih naredili cistoskopijo in ocenili velikost, lokalizacijo in multifokalnost tumorja. Pred operacijo je bila pri vseh bolnikih narejena še UZ preiskava sečil in trebuha, pri nekaterih tudi intravenozna urografija. Operativno zdravljenje je pomenilo TUR tumorjev in/ali hladno biopsijo sumljivih predelov sluznice sečnega mehurja. 82(90%) bolnikom smo 1-2 uri po operaciji intravezikalno aplicirali 40 mg Mitomycina C. V primerih solitarnih in majhnih tumorjev (<2 cm premera) smo bolnikom urinski kateter odstranili naslednji dan po

operaciji in jih odpustili v domačo oskrbo. Če pa je bila potrebna obsežnejša resekcija, zaradi večjih tumorjev ali njihovega večjega števila, smo bolnikom urinski kateter odstranili 2-3 dan po operaciji. Prvo kontrolo smo naredili po enem mesecu in opravili cistoskopijo. Če je bila epitelizacija sluznice zaključena, smo nekatere bolnike dodatno zdravili z intravezikalno imunoterapijo ali kemoterapijo, v primerih rezidualnega tumorja in pri bolnikih s stadijem T1 pa smo znotraj enega meseca naredili ponovno TUR.Za dodatno intravezikalno imuno ali kemoterapijo smo se odločili pri vseh bolnikih s stadijem bolezni T1 in s CIS. Med bolniki s Ta pa so terapijo prejeli tisti, pri katerih je šlo za G II in III, ali če je bil tumor multifokalen (Tabela 1). Kontrolne cistoskopije smo naredili en mesec po končani imuno ali kemoterapiji. Če ni bilo recidiva, smo naslednjo cistoskopijo naredili po 3 mesecih, nato v dveh letih vsakih 6 mesecev in naprej enkrat letno. Pri bolnikih s stadijem bolezni T1 in Ta+CIS ali CIS ter bolnikih s ponovitvijo bolezni, smo izvajali podaljšano imunoterapijo. Po prvih šestih aplikacijah BCG so sledile 3 mesečne, 2 trimesečni, 2 šestmesečni in nato 1 aplikacija letno.

RezultatiV letih 2005 in 2006 smo na našem oddelku prvič obravnavali 91 bolnikov s patohistološko verificiranim mišično neinvazivnim rakom sečnega mehurja. Povprečna starost bolnikov je bila 64,5 let. 72(79%) je bilo moških in 19(21%) žensk. Pri 75(82,4%) bolnikih je bil ugotovljen stadij Ta in pri 16(17,6%) stadij T1. Pri 3 je bil ugotovljen CIS, pri 3 Ta+CIS in pri 2 T1+CIS. Glede stopnje diferenciranosti malignih celic je bilo 45(49,4%) bolnikov z G I, 27(29,6%) z G II in 19(21%) z G III. Recidiv bolezni smo ugotovili pri 29(31,8%) bolnikih, od katerih se je pri 16(55%) recidiv pojavil v prvem letu po operaciji. Pri 9(31%) bolnikih je do ponovitve bolezni prišlo 2-3 krat. Od 29 bolnikov, pri katerih smo ugotovili ponovitev bolezni, je pri 18(62%) bolnikih ob prvi operaciji šlo za 2-7 tumorjev, s stopnjo diferenciacije G II-III. Pri 4(4,3%) bolnikih z recidivom bolezni smo ugotovili progres v mišično invazivni stadij T2. Od 14 bolnikov, ki po prvi operaciji niso dobivali imunoterapije ali kemoterapije, je do ponovitve bolezni prišlo pri 4(29%), pri vseh pa je bil izhodiščni stadij Ta G II.

ZaključkiČe primerjamo naše rezultate z objavljenimi v strokovni literaturi, lahko ugotovimo, da so glede odstotka ponovitve bolezni sicer boljši, vendar v obravnavanem obdobju operativnega zdravljenja še nismo natančno oz. pri vseh bolnikih ocenjevali velikosti in števila tumorjev ob prvem operativnem zdravljenju [10]. Ugotavljamo tudi razmeroma visok odstotek (85%) tistih, ki so prejeli adjuvantno intravezikalno imuno ali kemoterapijo.


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Literatura

1. Campbell’s Urology eight edition. Urothelial tumors of the urinary tract 2003

2. Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics 2000. CA Cancer J Clin 2000;50:7-33

3. Heney NM. Natural history of superficial bladder cancer. Prognostic feautures and long-term disease course. Urol Clin North Am 1992;19:429-33.

4. Kiemeney LALM, Witjes JA, Heijbroek RP, Verbeek ALM, Debruyne FMJ. Predictability of reccurent and progressive disease in individual patients with primary superficial bladder cancer. J Urol 1993;150:60-4.

5. Goessl C, Knispel HH, Millar K, Klän R. Is routine excretory urography necessary at first diagnosis of bladder cancer? J Urol 1997 Feb;157(2):480-1

6. Palou J, Rodriguez-Rubio F, Huguet J, Segarra J, Ribal MJ, Alcaraz A, Villavicencio H. Multivariate analysis of clinical parameters of synchronous primary superficial bladder cancer and upper urinary tract tumors. J Urol 2005 Sep;174(3):859-61; discussion 861.

7. Holmäng S, Hedelin H, Anderström C, Holmberg E, Johansson SL. Long-term follow-up of a bladder carcinoma cohort: routine followup urography is not necessary. J Urol 1998 Jul;160(1):45-8.

8. Millán-Rodríguez F, Chéchile-Toniolo G, Salvador-Bayarri J, Huguet-Pérez J, Vicente-Rodríguez J. Upper urinary tract tumors after primary superficial bladder tumors: prognostic factors and risk groups. J Urol 2000 Oct;164(4):1183-7.

9. Raitanen M-P, Aine R, Rintala E, Kallio J, Rajala P, Juusela H, Tammela TL; FinnBladder Group. Differences between local and review urinary cytology and diagnosis of bladder cancer. An interobserver multicenter analysis. Eur Urol 2002 Mar;41(3):284-9.

10. Brausi M, Collette L, Kurth K, van der Meijden AP, Oosterlinck W, Witjes JA, Newling D, Bouffioux C, Sylvester RJ; EORTC Genito-Urinary Tract Cancer Collaborative Group. Variability in the recurrence rate at first follow-up cystoscopy after TUR in stage Ta T1 transitional cell carcinoma of the bladder: a combined analysis of seven EORTC studies. Eur Urol 2002 May;41(5):523-31.

Tabela 1: Uvedba intravezikalne imuno ali kemoterapijeTa G I

(multifokalen)Ta

G IITa

GIIIT1

GI-IIICIS Ta/T1+CIS

GI-IIIBCG 27 mg 35 23 4 8 3 4Mitomycin C 40 mg - - - 2 - -


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Uporaba Mitomycina C pri zdravljenju raka mehurja – naše izkušnjeThe use of Mitomycin C in Bladder Cancer treatment – our experiance

Klemen Jagodič, Igor Bizjak, Uroš Četina

Urološki oddelek, Splošna bolnišnica Celje, SlovenijaDepartment of Urology, General Hospital Celje, Slovenia

Rak mehurja predstavlja 3% vseh malignomov. Moški zbolevajo 3 krat pogosteje kot ženske. Ocenjujemo, da smo leta 2010 na novo odkrili 202 bolnikov in 76 bolnic z rakom mehurja. Bolezen se najpogosteje pojavlja med 60 in 75 letom starosti.

Diagnozo raka mehurja postavimo s cistoskopijo in histopatološkim pregledom reseciranega tumorja. Zdravljenje in prognoza sta odvisna od histopatološke ocene in stadija bolezni.

Na našem oddelku smo zgodnjo instalacijo mitomycina po TUR tumorja mehurja uvedli leta 2004. Bolnik prejme mitomycin 2 uri po TUR v dozi 40 mg. Kateter klemamo za 2 uri. V primeru krvavitve po TUR počakamo, da se urin zbistri in instaliramo mitomycin do 24 ur po posegu.

2010 smo na našem oddelku opravili 258 TUR tumorjev mehurja. Zdravili smo 192 bolnikov in 39 bolnic, s povprečno starostjo 69 let. Pri petih bolnikih je histološki pregled potrdil rak debelega črevesja, ki je infiltriral v mehur, pri ostalih bolnikih je šlo za prehodnocelični karcinom mehurja. 7 bolnikov je imelo mišično invazivni rak mehurja. 81% bolnikov s površinskim rakom mehurja je imelo nizko do zmerno tveganje za napredovanje bolezni (solitarni, Ta, <3cm; Ta-T1, G1-G2, multifokalni, >3cm).

Pri 22 bolnikih smo v istem letu opravili vsaj 2 TUR. Pri 4 bolnikih je šlo za hemostatske posege zaradi inoperabilnega tumorja mehurja. Pri 3 bolnikih smo opravili dodatno resekcijo po na novo odkritem tumorju mehurja (2 T1 G3, 1 T2), pri čemer je bil histološki izvid negativen. Pri 9 bolnikih je šlo za recidiv nizko do srednje rizičnega karcinoma mehurja (Ta, T1, G1, G2), 4 bolniki so imeli recidiv visoko rizičnega karcinoma mehurja (T1, G3), 2 bolnika sta imela ponovno mišično invazivni rak mehurja.

Po posegu je mitomycin prejelo 91% bolnikov. Mitomycina niso prejeli bolniki, kjer smo makroskopsko ocenili, da tumorja ni možno resecirati v zdravo, ter pri bolnikih, pri katerih smo po posegu opažali močnejšo krvavitev.

Med instalacijo mitomycina in neposredno po njej nismo opažali nobenih hujših komplikacij.

Zgodnja instalacija mitomycina po TUR tumorja mehurja zmanjša možnost ponovitve površinskih rakov mehurja za polovico. V našo analizo smo zajeli le posege opravljene v letu 2010. Tako nismo zajeli podatkov o morebitnih zgodnjih recidivih raka mehurja v letu 2010 pri bolnikih, ki so bili zdravljenji že v drugi polovici leta 2009 in bolnikov, pri katerih je prišlo do zgodnjega recidiva v prvi polovici leta 2011.

Literatura:1. Rak v Sloveniji 2007. Ljubljana: Onkološki inštitut

Ljubljana, Epidemiologija in register raka, Register raka Republike Slovenije, 2010.

2. Tolley DA et al. The effect of intravesical mitomycin C on recurrence of newly diagnosed bladder cancer: a further report with 7 years followup. J Urol 1996; 155: 1233-8.


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Hyperthermia during intravesical doxorubicin application in patients with superficial Urinary Bladder Carcinoma

M.M. Bernat, Ž. Kaštelan, D. Hauptman, I. Krhen, I. Mokos, N. Knežević

Clinical Hospital Center Zagreb, Clinic for Urology, Zagreb, Croatia

Introduction: Despite successful transurethral resection and adjuvant intravesical chemotherapy, there is still a high incidence of the superficial urinary bladder carcinoma recurrence. Thermochemotherapy primarily addresses this specific problem.

This paper presents our initial experience with hyperthermia as a treatment method in patients with superficial urinary bladder carcinoma.

Methods: We started the application of the hyperthermia device in Clinic for urology using unithermic catheters after histologically proven higher grade (Ta i T1) malignancy transitional papillary carcinoma. The duration of a single procedure was 45 minutes at a temperature of up to 45°C. Prior to the treatment, and after the transurethral tumor resection, the urinary culture was sterile. The patient age was between 45 and 60 years.

Results: Successful intravesical doxorubicin instillation with 6 weekly applications was performed in 9 patients. In one patient it was not possible to apply the hyperthermia due to the unsuitable anatomy and prostatic urethra relations for positioning of the universal unithermic catheter, which so that the pump could not start. In two patients the therapy was aborted due to urinary infection and was successfully resumed after appropriate treatment. During a two-year follow-up no recurrence was observed in any of the patients.

Conclusion: Intravesical doxorubicin application with hyperthermia is a safe method in selected group of patients with superficial carcinoma of the urinary bladder. This method is well tolerated and does not cause inconvenience for the patient. A larger number of patients and longer follow-up period are necessary for reporting of results in terms of success and recurrence.


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Significance of Fluorescence in situ hybridisation (fish urovysion) in detection of Bladder Cancer reccurence

Ante Reljić(1), Sanja Mrsić(2), Silva Ćurić(3), Božo Krušlin(4), Ana-Maria Šimundić(5), Ognjen Kraus(1), Davor Trnski(1)

1. University clinical Center Sestre milosrdnice, Clinic of urology, Zagreb, Croatia2. University clinical Center Zagreb, Clinical Departmen of laboratory diagnostics, Zagreb, Croatia

3. University clinical Center Sestre milosrdnice, Clinic of internal diseases, Department of hemathology, Laboratory for cytological diagnostisc, Zagreb, Croatia

4. University clinical Center Sestre milosrdnice, Clinical Department for Pathology, Zagreb, Croatia5. University clinical Center Sestre milosrdnice, Clinical Department for Chemistry, Zagreb, Croatia

AbstractThe primary objective of this study were to determine the clinical utility of FISH UroVysion test in comparison with conventional cytological examination in early detection of bladder cancer reccurence.

We analysed 113 patients with reccurent bladder cancer and 40 patients with benign urological disease as controls. All patients were tested by cytology, FISH UroVysion, iv. urography and cystoscopy. In presence of tumor transurethral resection and hystological examination of tissue were performed.

Overall sensitivity and diagnostic accuracy was significantly higher in favour of FISH UroVysion (p=0,001 and p<0,001). Specificity of two methods was without statistical significance (p=0,162). When tumors were stratified by stage and grade the sensitivity of FISH UroVysion was significantly higher for noninvasive (Ta, p<0,001) and poorly differentiated (G3, p=0,038) tumors. When FISH UroVysion test reveal genetic stable tumor one can exclude invasive (T≥1) and poor differentiated (G3) likewise probably G2 (p=0,058) tumors. On te contrary, if FISH UroVysion detect an unstable tumor, this finding is not informative in terms of stage but one can safely rule out well differentiated (G1) tumors.

FISH UroVysion test can reliable reduce the number of unnecessary cystoscopies in case of following up the TaG1 tumors and negative test result. If one deal with G3 tumors FISH UroVysion is preferable method in order to secure early accurate diagnosis. We consider it advisebly to perform further study particular for TaG1 tumors, using the FISH UroVysion method, with the aim of defining different types of tumor on the basis of genetic. Laboratory report of FISH UroVysion test result should contain the type of genetic disorder which makes test positive.

1. IntroductionUrothelial cancer is limited on the bladder mucosa (Ta, Cis) or submucosal tissue (T1) in 80% and infiltrative disease (T≥2) is present in 20% of cases. Since reccurences and progression are prominent features of the superfitial bladder cancer (SBC) a frequent, and sometimes a lifelong, follow-up is neccessary. That´s why the bladder cancer (BC) is called „the most expensive disease of the western world“(1). Standard follow-up (FU) examinations are represented by urinary cytology and cystoscopy. Recent literature data warn us that sensitivity of urinary cytology is poor not only for well diferentiated but for G3 tumors also (2,3,4). Cystoscopy is invasive, expensive and has her own limitations in false positive and negative results as we learned from the experience with „fluorescence cystoscopy“ (5,6,7).

That leads investigators to search for the new, less subjective and more precise, methods of noninvasive detection of bladder cancer cells in the urine. There is almost 20 tumor markers in use nowdays. FISH UroVysion is newone, grounded in the molecular cytogenetic principles, which detect numerical and structural genetic changes in the exfoliated tumor cells. The meaning of this marker and his place in daily urologic practice is not undoubtly defined yet.

The primary objective of this study were to determine the clinical utility of FISH UroVysion test in comparison with conventional cytological examination in detection of bladder cancer reccurence. Additionally we analysed the relationship between tumor stage/grade and the kind of genetic changes, detectable by FISH UroVysion test, in order to define the role of this test in bladder cancer patients under surveillance.

2. Methods From February 1st 2003. to July 31st 2004. we included 171 patients (age range 17-93y, median 71y). There were 124


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with BC (90 males and 34 females; age median 72y) and 47 subjects (35 males and 12 females; age median 68) in control group. In all patients urinary cytology, FISH UroVysion test, cystoscopy and IVU were performed. In patients with proven BC transurethral resection (TURBT) and hystological analisys were undertaken.

Urinary cytology was performed on spontaneous voided specimens collected on three consecutive days. Papanicolau´s procedure was used to evaluate the slides. Inconculsive findings were scored as positive.

For FISH UroVysion test urine specimens (50 ml) were taken prior to cystoscopy, kept in refrigerator in 2% CarboWax solution until sending to laboratory.The laboratory process was undertaken following the manufacturer instructions (Vysis, Downers Grove, IL, USA) through next four steps: specimens processing, slide preparation, hybridisation and specimens evaluation. Criteria for FISH UroVysion test positivity was used as follow: at least 25 cells were analysed; identification of polyploidia of minimally two chromosomes 3, 7, or 17 in at least four cells or homozygous deletion 9p21 in at least 12 nuclei are considered positive result.Cystoscopy were done after the urin specimens were

collected with local urethral analgesia in men. Tranusrtheral resection of the bladder tumor (TURBT) were performed under spinal anesthesia and specimens of tumor tissue and the muscular layer were sent to pathology separate.Tumors were staged based on TNM classification (1997) and graded according to WHO system (1999).

Age of the patients was showed by range and median. Discriminating power of cytology and FISH UroVysion was tested by analyzing the diagnostic exactness and expressed with following parameters: sensitivity, specificity and accuracy. Statistical significance of difference between categorical attributes was tested with χ² and z-teset using the cut-off for P value < 0,05.

3. ResultsAmong 171 included patients there were observed no difference in gender distribution between subjects with BC and controls (χ², p=0,956). Age median of all patients was 71 (range 17-93), in patients with BC 72 (range 70-73) and in control group 68 (range 17-89). The age of males with BC and controls was similar (T-test, p=0,230) but women in the control group were significantly younger in comparison with diseased women (Mann-Whiney test, p=0,025) (table 1).

Patients with BCn=124median (range)

Control groupn=47median (range)

P=

Female examinee 74 (49-93) 59 (45-84) 0,025Male examinee 72 (46-86) 69 (17-89) 0,230

Table 1 – age distribution of females and males in the patient group and controls

From the further analysis 11 subjects (6,4%) were excluded due to low amount of cells in the urine specimens. Acellular sample was equaly frequent among cytological (7,6%) and FISH specimens (7,6%). All of 11 patients with BC and too low cells in sample had nonivasive G1/2 tumor.

Finally, we analysed 153 subjects including 113 with BC and 40 controls. Distribution of tumors depending on combination of stage and grade reveal table 2.

tumor grade t u m o r s t a g e ∑Ta Tis T1 T≥2

G1 30 0 7 0 37 (32,7%)

G2 21 0 15 3 39 (34,5%)

G3 5 4 10 18 37 (32,7%)

∑ 56(49,6%)

4(3,5%)

32(28,3%)

21(18,6%)

113

Table 2 – distribution of tumors depending on combination of stage and grade


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Overall sensitivity of cytological examination was 53,98% and for FISH UroVysion test 75,22% (p=0,001). Overall specificity was not showed difference (p=0,16) but it was slightly higher for FISH UroVysion and accuracy was significantly better in favour of FISH (z-test, p<0,001). FISH UroVysion test had a substantially higher sensitivity only for Ta (p<0,001) and poor differentiated (G3) tumors (p=0,03) although this method was better than cytology across all stages and grades.

Comparison of FISH UroVysion sensitivity in comparison with cytology regarding the combination of stage and grade criterion revealed significantly higher sensitivity for FISH in TaG1 tumors (p=0,009) only while other categories of tumors was not reveal statistical significance.

In cytologycal inconclusive findings (suspected cells) (20,9%) we found almost equal proportion among patients with BC and controls (χ² test, p=0,69). In this particular group of tumors, with inconclusive cytologycal results, sensitivity of FISH UroVysion test was 60,0% and was not better than among all tumors (χ², p==0.196, CI 95% 38-78). However, this group included substantial proprtions of G3 and T≥2 tumors which were correctly detected by FISH UroVysion and remaind unrecognised by cytology.

After that, we categorized tumors according to genetical disorders in two groups. Genetically stable urothelial tumors were detected by FISH UroVysion due to isolated homozygous deletion of LSI 9p21 and this group constitute a minority (16,5%) of all tumors. The remnant majority (83,5%) represent genetically unstable tumors detected due to polyploidia of at least two chromosomes 3,7 or 17. Only well differentiated tumors were stable and unstable with similar frequency (p=0.76) and all others, regardless stage and grade, were geneticaly unstable. FISH UroVysion test result of unstable genetic disorder can hide any tumor stage but seldom good differentiated tumor (G1 vs. G2, p=0,02).

Genetically stable tumors were far more frequent noninvasive (Ta) than T1 (p<0,001) and more probably well differentiated than G2 (p=0,058). There were no Cis, T2 and G3 tumors which was genetically stable. In the TaG1 group of tumors we observed that their genetical disorder, detectable by FISH UroVysion test, contitute almost equal proprtion of stable and unstable carcinomas(z-test, p=0,516). 4. DiscussionBC is group of hetregoneous diseases with innocent forms on the one and life threatening on the other end of the spectrum. Due to capabillity to reccure and progress to higher stage and grade a frequent FU examinations are neccessary (2).

Reccurence and progression probability for Ta/T1 tumors during the 5 years is 31-78% and <1-45%, respectively (8). Moreover, prognosis of T≥2 cancer, wich developed from the lower tumor stage, was poorer than for initially infiltrative disease (9). That´s why the early and correct diagnosis of some tumor types (at least all G3 because of potential influence on mortality) is of utmost importance.

Cytology and cystoscopy represent conventional route of FU but neither have a diagnostic accuracy high enough as recorded by recent literature (1,4,10-13). Newer molecular and cytogenetic cognitions offer a more clear picture of different pathways to BC developement and progression (2,14,15) and potentially more precise marker tests for noninvasive detection of BC (16,17). Meloni at al predicted a similar scenario almost 20 years ago (18). Moreover, genetical stratification of different BC entities is not highly coincident with histological classification (19,20). Superfitially invasive (T1) and muscle-infiltrative (T≥2) tumors are very similar at genetic level (14,19). Those findings forse us to conclude how genetic changes neccessary for development of T2 tumor were alredy present while he was superfitial. It is in concordance with clinical results of cystectomies survival for T1 vs.T≥2 published by Mainz group even 14 years ago (21).

Since Sokolova at al described and defined a FISH UroVysion® test he became a promising tool for noninvasive detection of reccurent BC (22). Present study analysed FU populations of patients and reveal a higher sensitivity, in comparison with cytology, in overall patients (p=0,001) and across all stages and grades but significance was observed in Ta and G3 tumors only. Similar figures of sensitivity were observed in another analyses of overall sensitivity in range of 71% to 86% (17,23-26). It is worthwhile to remark that some of them, but not all, analysed a patients under FU, so results cannot be comparable without caution. In this sence it might be that a review article by Van Rhijn at al is a best choice for results comparison (17).

In our study specificity were not significantly differ between two methods (p=0,162) although FISH overperformed cytology. In the abovementioned review specificity for UroVysion had median 70 with range 66-93 (17). FISH UroVysion has unique charcteristic among all BC urinary markers regarding high specificity comparable with notorious prominent specificity of cytology. However, cytology is useless with intravesical chemo- or immunotherapy just as after urinary diversion but those circumstances do not affect the FISHUroVysion specificity (27-30). Particular practical problem might be a situation when FISH is positive and


��

cystoscopy negative. It´s looks like false-positive result but some literature data underline the predictive value of FISH regarding reccurence and called that an „anticipatory positive result“ (APR) istead of false-positive (24,29,31). In opposition to mentioned argumentation we are still addherent to opinion that APR might pose a significant practical danger especially for patient in unpatient urologists hands.

Accuracy in our study was significantlly higher for FISH than cytology (p<0,001). Placer et al find insignificant difference between two methods regarding accuracy (25). Possibility of acellular urine specimen was equally frequent in cytology and FISH arm just as in patients group vs. controls. Veermachaneni at al recorded frequency of 3% urine samples without cells in cytology specimens and even 30% inadequate samples in FISH arm (32).

We observed significantly better sensitivity of UroVysion for noninvasive and poor differentiated tumors and sound reasonably, according to our results, to recommend FISH UroVysion instead of cytology for FU of those tumors. So, in Ta-low grade tumors FISH offer a rational possibility to reduce the number of cystoscopies during FU. At the same time, high specificity prevent the number of unneccessary invasive examinations. On the other hand, if we have the patient with previously detected G3 tumor where early detection of reccurence is imperative, proved significantly higher sensitivity of FISH is important in order to miss as low as possible reccurences. Moreover, if we use the FISH as an adjunct to cytology only, high specificity od FISH is cordially wellcome for G3 cancers. One can insist on opinion, so frequent among urologists, that combination of cytology and frequent cystoscopies is still the best FU-strategy for G3 cancers (17,34,35,36). It is wise to remind that only 40% of patients received FU-cystoscopy on regular basis during the first 3 FU years (33).

Majority of Ta tumors are of low grade and with good prognosis according to hystological and clinical risk factors. We observed that Ta tumors are significantly often geneticaly unstable (p<0,001) and that G1 tumors are stable and unstable with equal frequency (p=0,767). It seems that hystological and clinical parameters, in case of Ta low grade tumor, combine genetically different entities. Such result deserve a further analyses.

From the practical viewpoint it is not very interesting about dependance of genetical changes on stage or grade (since TURBT is alredy done). The right question is whether the FISH UroVysion offer any significant information regarding stage and/or grade of tumor before we undertake an invasive

procedure (cystoscopy, biopsy or TURBT)? According to our findings positive FISH result of an unstable tumor is meaningless regarding stage but very probably we are not dealing with G1 reccurence. On the opposite, if FISH UroVysion detect reccurence of stable genetic disorder all G3 and T≥2 can be safely excluded. Moreover, in group of genetically stable tumors Ta were significantly frequent than T1 (p<0,001) and difference between G1 and G2 is borderly significant (p=0,058). Although proportion of stable tumors in our study was small (16,5%) and abovementioned conclusions must be confirmated on larger number of patients with stable tumors we consider that laboratoy report of FISH UroVysion test should include information about type of genetic disorder.

5. References1. Palou J, Böhle A, Witjes JA i sur. Diagnosis of Non-

Muscle Invasive Bladder Cancer. Eur Urol Suppl 2008; 7: 627-36.

2. Wein JA. Campbell-Walsh Urology. 9. izdanje. Philadelphia: Saunders, 2007.

3. Brown FM. Urine cytology. It is still the gold standard for screening? Urol Clin North Am 2000;27:25-37.

4. Jones JS, Campbell SC. Non-muscle-invasive bladder cancer (Ta,T1 and CIS). U: Kavoussi LR, Novick AC, Partin AW, Peters CA, ur. Cambells-Walsh Urology. 9.izdanje. Philadelphia: Sauders, 2007, str.2447-67.

5. Witjes JA. Fluorescence cystoscopy in Bladder Cancer: The Case Pro. Eur Urol Suppl 2008;7:426-9.

6. Schmidbauer J, Witjes F, Schmeller N, Donat R, Susani M, Marberger M. Improved detection of urothealial carcinoma in situ with hexaminolevulinate (HAL) fluorescence cystoscopy. JUrol2004.171:135-8.

7. Grossman HB, Gomella L, Fradet Y i sur. A phase III multicenter comparison of hexaminolevulinate (HAL) fluorescenca cystoscopy and white light cystoscopy for detection of superfitial papillary lesions in patients with bladder cancer. J Urol 2007;178:62-7.

8. Sylvester RJ, van der Meijden APM, Oosterlinck W i sur. Predicting Reccurence and Progression in Individual Patients witg Stage Ta T1 Bladder Cancer Using EORTC Risk Tables: A Combined Analysis 2596 Patients from Seven EORTC Trials. Eur Urol 2006; 49: 466-77.

9. Schrier BP, Hollander MP, van Rhijn BWG, Kimeney LALM, Witjes JA. Prognosis of muscle-invasive bladder cancer: Difference between primary and progressive tumours and implications for therapy. Eur Urol 2004; 45: 292-6.

10. Halling KC, King W, Sokolova IA i sur. A comparison of cytology and fluorescence in situ hybridisation for the


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detection of urothelial carcinoma. J Urol 2000; 164: 1768-75.

11. Grossman HB, Messing E, Soloway M i sur. Detection of bladder cancer using a point-of-care proteomic assay. JAMA 2005; 293: 810-6.

12. Renshaw AA. Urine and bladder washings. U: Cibas ES, Ducatman BS, ur. Cytology-Diagnostic principles and clinical correlates. Edinburgh: WB Saunders; 2003, str. 97-117.

13. Stewart CS, Halling KC, Lieber MM. Novel detection strategies for tansitional cell carcinoma. U: Kurth KH, Mickisch GH, Schröder FH, ur. Renal, bladder, prostate and testicular cancer – an update. New York-London: The Parthenon Publishing Gorup; 2001, str 237-46.

14. Spruck CH III, Ohneseit PF, Gonzalez-Zulueta M i sur. Two molecular pathways to transitional cell carcinoma of the bladder. Cancer Res 1994; 54: 784-8.

15. Lee R, Droller MJ. The natural history of bladder cancer. Implications for therapy. Urol Clin North Am 2000; 27: 1-13.

16. Catto JWF. Old and New Urinary Markers: Which One is the PSA for Bladder Cancer? Eur Urol Suppl 2008;7:422-5.

17. Van Rhijn BWG, van der Poel HG, van der Kwast TH. Urine markers for bladder cancer surveillance: A systematic review. Eur Urol 2005; 47: 736-48.

18. Meloni AM, Peier AM, Haddad FS i sur. A new approach in the diagnosis and follow-up of bladder cancner. FISH analysis of urine, bladder washings and tumors. Cancer Genet Cytogenet 1993;71:105-18.

19. Sauter G, Algaba F, Amin M i sur. Tumours of the Urinary System: Non-invasive urothelial tumours. U: Eble JN, Sauter G, Epstein JI, Sesterhenn IA, ur. World Health Organisation Classification of the Tumours. Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. Lyon: IARC Press; 2004, p. 110-23.

20. Catto JWF, Hamdy FC. The role of Genetic Instability in the Pathogenesis and Progression of Urothelial Carcinoma. EAU Update Series 2005; 3: 180-8.

21. Stöckle M, Alken P, Engelmann U, Jacobi GH, Riedmiller H, Hohenfellner R.Radical cystectomy – Often too late? Eur Urol 1987; 13: 361-7.

22. Sokolova IA, Halling KC, Jenkins RB i sur. The development of a multitarget,multicolor fluorescence in situ hybridisation assay for the detection of urothelial carcinoma in urine. J Mol Diag 2000; 2: 116-23.

23. Laudadio J, Keane TE, Reevs HM, Savage SJ, Hoda RS, Lage JM i sur. Fluorescence in situ hybridisation for detecting transitional cell carcinoma: implications for clinical practice. BJU Int 2005; 96: 1280-84.

24. Sarosdy AF, Schellhammer P, Bokinsky G i sur. Clinical evaluation evaluation of a multi-target fluorescent in situ hybridisation assay for detection of bladder cancer. J Urol 2002;168:1121-3.

25. Placer J, Espinet B, Salido M, Sole F, Gelabert-Mas A. Clinical Utility of a Multiprobe FISH Assay in Voided Urine Specimens for the Detection of Bladder Cancer and its Reccurences, Compared with Urinary Cytology. Eur Urol 2002; 42: 547-52.

26. Varella-Garcia M, Akduman B, Sunpaweravong P i sur. The Uro Vysion fluorescence in situ hybridisation assay is an affective tool for monitoring reccurence of bladder cancer. Urol Oncol 2004; 22: 16-19.

27. Degtyar P, Neulander E, Zirkin H i sur. Fluorescence in situ hybridisation performed on exfoliated urothelial cells in patients with transitional cell carcinoma of the bladder. Urology 2004; 63: 398-401.

28. Babjuk M, Oosterlinck W, Sylvester R, Kaasinen E, Böhle A, Paolu-Redorta J. EAU Guidelines on non-muscle invasive urothelial carcinoma of the bladder. Eur Urol 2008;54:303-14.

29. Jones SJ. Dna-Based Molecular Cytology for Bladder Cancer Surveillance.Urology2006;Suppl3A: 35-45.

30. Pycha A, Mian C, Hofbauer J. Does topical instillation therapy influence chromosomal aberrations in superfitial bladder cancer? J Urol 1998;159:265-9.

31. Friedrich MG, Hellstern A, Toma MI i sur. Are False-Positive Urine Markers for the Detection of Bladder Carcinoma Really Wrong or Do They Predict Tumor Recurrence? Eur Urol 2003;43:146-51.

32. Veeramacheneni R, Nordberg ML, Shi R, Herrera GA, Turbat-Herrera EA. Evaluation of Flurescence In Situ Hybridisation as an Ancillary Tool to Urine Cytology in Diagnosing Urothelial Carcdinoma. Diagn Cytopathol, 2003; 28: 301-7.

33. Halling KC. Vysis® UroVysion for the detection of urothelial carcinoma. Expert Rev Mol Diagn 2003;3:507-19.

34. Nieder AM, Soloway MS, Harry WH. Should We Abandon the FISH Test? Eur Urol 2007;51:1469-71.

35. Moonen PMJ, Merkx GFM, Peelen P, Karthaus HFM, Smeets DFCM, Witjes JA. UroVysion Compared with Cytology and Quantitative Cytology in the Surveillance of Non-Muscle-Invasive Bladder Cancer. Eur Urol 2007;51:1275-80.

36. Nieder AM, Soloway MS, Harry WH. Re: Should we abandon the FISH test? Eur Urol 2007;51:1537-8.

(histrelin implant)

(histrelin implant)

Nova eraudobja

Vantas implantatje mehak in fleksibilen.

(dejanska velikost 3,5 cm x 3 mm)

Vantas – enoletni implantatza raka prostate

Skrajøana navodila za uporaboVantas© implantat vsebuje 50 mg histrelinijevega acetata, iz katerega se v povpreœju sproøœa 50 µg histrelina v 24 urah. Priporoœeni odmerekzdravila Vantas je en implantat na 12 mesecev. Implantat vstavimo subkutano na notranjo stran nadlahti.Indikacije: Paliativno zdravljenje napredovalega raka prostate.Kontraindikacije: Zdravilo Vantas je kontraindicirano pri bolnikih s preobœutljivostjo za histrelin ali katerokoli pomoæno snov implantata, GnRH,agoniste ali analoge GnRH ali stearinsko kislino. Poroœali so tudi o anafilaktiœnih reakcijah na sintetiœni LHRH ali na agoniste in analoge LHRH. Posebna opozorila oziroma previdnosti: Tako kot drugi agonisti LHRH, tudi Vantas v prvem tednu zdravljenja povzroœa prehodno poveœanjekoncentracije testosterona v serumu Pri bolnikih se lahko zato poslabøajo simptomi ali pa se pojavijo novi, na primer boleœine v sklepih, boleœine vkosteh, nevropatija, hematurija ali zapora iztoka iz seœnice ali seœnega mehurja. V povezavi z uporabo agonistov LHRH so poroœali tudi o primerihzapore seœnice in kompresije hrbtenjaœe, ki lahko vodi do paralize z zapleti, ki se lahko konœajo s smrtjo ali brez njih. Bolnike z metastatskimi lezijamivretenc in/ali zaporo seœil je treba skrbno spremljati v prvih nekaj tednih zdravljenja. Ti bolniki bi lahko bili primerni za profilaktiœno zdravljenje zantiandrogeni. Œe pride do kompresije hrbtenjaœe ali ledviœne okvare, pri bolniku uvedite obiœajno zdravljenje teh zapletov.Neæeleni uœinki: Tako kot drugi agonisti LHRH, lahko tudi Vantas povzroœi ginekomastijo ali impotenco, ki traja razliœno dolgo. Mogoœe je torejpriœakovati, da bodo daljøa obdobja medikamentozne kastracije pri moøkih vplivala na kostno gostoto. V kliniœnih preskuøanjih je najpogostejøineæelen uœinek povezan z Vantasom sama reakcija ob implantiranju, ki je poveœini blaga ter se umiri v prvih tednih. Vstavljanje implantata je kirurøkiposeg. Za zmanjøanje tveganja zapletov in zavrnitveno reakcijo, priporoœamo natanœno sledenje priporoœenim navodilom za vstavljanje in odstranitevimplantata.

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BISTVENE INFORMACIJE IZ POVZETKA GLAVNIH ZNAČILNOSTI ZDRAVILA

CARDURA XL 4 mg in 8 mg tablete s podaljšanim sproščanjemSestava in oblika: tableta s podaljšanim sproščanjem vsebuje 4 mg ali 8 mg doksazosina. Indikacije: hipertenzija; benigna hiperplazija prostate. Odmerjanje in način uporabe: odmerek 4 mg enkrat na dan se lahko zaužije s hrano ali brez. Tablete je treba pogoltniti cele, z zadostno količino tekočine. Odmerek se po štirih tednih lahko poveča na 8 mg enkrat na dan. Največji priporočen odmerek je 8 mg enkrat na dan. Kontraindikacije: preobčutljivost za kinazoline (npr. prazosin, terazosin, doksazosin) ali katerokoli pomožno snov; ortostatska hipotenzija; benigna hiperplazija prostate in sočasni zastoj zgornjih sečil, kronična okužba sečil ali kamni v mehurju; zapora prebavil, zapora požiralnika ali kakršnakoli stopnja zmanjšanja premera svetline prebavil; dojenje; hipotenzija; (pri monoterapiji) prenapolnjen mehur ali anurija, z napredujočo insuficienco ledvic ali brez nje. Posebna opozorila in previdnostni ukrepi: Navodila za bolnike: naj se ne vznemirjajo, če bodo občasno v blatu opazili nekaj, kar je podobno tableti. Zdravilo se nahaja v ovojnici, ki se ne absorbira. Nenormalno zmanjšan čas prehoda skozi gastrointestinalni trakt lahko vpliva na nepopolno absorpcijo zdravila. Začetek zdravljenja: nadzorujemo krvni tlak, da bi zmanjšali možne posturalne učinke. V času uvajanja terapije naj se bolnik izogiba situacijam, v katerih lahko pride do poškodb zaradi vrtoglavice ali slabosti. Previdnost pri nekaterih akutnih srčnih stanjih. Jetrna okvara: uporablja naj se previdno, pri hudi jetrni okvari se uporaba ne priporoča. Zaviralci PDE-5: sočasna uporaba zahteva previdnost, saj lahko pride do simptomatske hipotenzije. Operacija katarakte: možen medoperacijski sindrom ohlapne šarenice. Medsebojno delovanje z drugimi zdravili in druge oblike interakcij: zaviralci PDE-5, ostali zaviralci adrenergičnih receptorjev alfa in antihipertenzivi. Nosečnost in dojenje: uporaba le, če pričakovana korist odtehta potencialno tveganje. Dojenje je kontraindicirano. Vpliv na sposobnost vožnje in upravljanja s stroji: lahko vpliva na sposobnost vožnje in upravljanja s stroji, zlasti ob uvajanju terapije. Neželeniučinki: okužbe dihal, okužbe sečil; omotica, glavobol, somnolenca; vrtoglavica; palpitacije, tahikardija; hipotenzija, posturalna hipotenzija; bronhitis, kašelj, dispneja, rinitis; bolečine v trebuhu, dispepsija, suha usta, navzea; pruritus; bolečina v hrbtu, mialgija; cistitis, inkontinenca; astenija, bolečine v prsnem košu, gripi podobni simptomi, periferni edemi. Preveliko odmerjanje: v primeru hipotenzije, je bolnika treba nemudoma položiti vznak z glavo v nižjem položaju in po presoji uporabiti druge podporne ukrepe. Način izdajanja zdravila: zdravilo se izdaja le na recept. Imetnik dovoljenja za promet: Pfizer Luxembourg SARL, 51, Avenue J. F. Kennedy, L-1855 Luxembourg, Luksemburg. Datum zadnje revizije besedila: 24.9.2009Pred predpisovanjem se seznanite s celotnim povzetkom glavnih značilnosti zdravila.

TOVIAZ 4 mg / 8 mg tablete s podaljšanim sproščanjemSestava in oblika zdravila: Ena tableta s podaljšanim sproščanjem vsebuje 4 mg / 8 mg fesoterodinijevega fumarata kar ustreza 3,1 mg / 6,2 mg fesoterodina. 4 mg in 8 mg tablete vsebujejo sojin lecitin in laktozo monohidrat. Indikacije: Zdravljenje simptomov (povečana pogostnost uriniranja in/ali urgentna mikcija in/ali urgentna inkontinenca), ki se lahko pojavijo pri bolnikih s sindromom čezmerno aktivnega sečnega mehurja. Odmerjanje in način uporabe: Priporočen začetni odmerek je 4 mg enkrat na dan. Glede na odziv posameznika se odmerek lahko poveča na 8 mg enkrat na dan. Največji dnevni odmerek je 8 mg. Poln učinek zdravljenja so opazili med 2 in 8 tedni. Odmerek TOVIAZA je potrebno glede na delovanje ledvic in jeter ter v primeru sočasne uporabe zaviralcev CYP3A4 ustrezno zmanjšati, v nekaterih primerih se je potrebno zdravljenju s TOVIAZOM izogniti ali je celo kontraindicirano. Uporaba pri otrocih: uporaba TOVIAZA pri otrocih in mladostnikih, mlajših od 18 let ni priporočljiva. Kontraindikacije: Preobčutljivost za zdravilno učinkovino, arašide ali sojo ali katerokoli pomožno snov; retencija urina; želodčna retencija; nenadzorovan glavkom z zaprtim zakotjem; miastenija gravis; hude motnje v delovanju jeter (stopnje C po Child-Pughu); sočasna uporaba močnih zaviralcev CYP3A4 pri bolnikih z zmerno do hudo okvaro jeter ali ledvic; hud ulcerozni kolitis; toksični megakolon. Posebna opozorila in previdnostni ukrepi: TOVIAZ je treba uporabljati previdno pri bolnikih: s klinično pomembno obstrukcijo mehurja s tveganjem za retencijo urina; z gastrointestinalnimi obstruktivnimi motnjami; z gastroezofagealnim refluksom in/ali bolnikih, ki sočasno jemljejo zdravila, ki lahko povzročijo ali poslabšajo ezofagitis; z zmanjšano gastrointestinalno gibljivostjo; z avtonomno nevropatijo; z nadzorovanim glavkomom z zaprtim zakotjem. Previdnost pri odmerjanju ali povečevanju odmerka je potrebna pri bolnikih z okvaro jeter ali ledvic, ki sočasno uporabljajo močne ali zmerne zaviralce CYP3A4 ali močne zaviralce CYP2D6. Pred kakršnimkoli zdravljenjem z antimuskarinskimi zdravili je potrebno izključiti organske in druge vzroke (zdravljenje srčnega popuščanja, ledvične bolezni ali okužbe sečil) za pojav simptomov. TOVIAZ je treba pri bolnikih s tveganjem za podaljšanje intervala Q-T in z že obstoječimi srčnimi boleznimi uporabljati previdno. Medsebojno delovanje z drugimi zdravili: Sočasna uporaba TOVIAZA in drugih antimuskarinskih in antiholinergičnih zdravil lahko povzroči bolj izražene terapevtske in neželene učinke. Močni zaviralci CYP3A4 povečajo vrednost C

maxaktivnega presnovka

fesoterodina. Induktorji CYP3A4 zmanjšajo Cmax

aktivnega presnovka fesoterodina in lahko zmanjšajo koncentracijo fesoterodina v plazmi pod terapevtsko raven. Nosečnost in dojenje: Uporaba med nosečnostjo in dojenjem ni priporočljiva Vpliv na sposobnost vožnje in upravljanja s stroji: Potrebna je previdnost pri vožnji ali uporabi strojev zaradi možnosti pojava neželenih učinkov, kot so zamegljen vid, omotica in zaspanost. Neželeni učinki: Zelo pogosti: suha usta; pogosti: omotica, glavobol, suhe oči, suho grlo, bolečina v trebuhu, diareja, dispepsija, zaprtje, navzea, disurija. Način in režim izdajanja: Izdaja zdravila je le na recept. Imetnik dovoljenja za promet: Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, Velika Britanija. Datum zadnje revizije besedila: 10/2010Pred predpisovanjem se seznanite s celotnim povzetkom glavnih značilnosti zdravila.

VIAGRA 25 mg, 50 mg, 100 mg filmsko obložene tableteSestava in oblika zdravila: Tableta vsebuje 25, 50 ali 100 mg sildenafila. Pomožna snov: laktoza. Indikacije: Zdravljenje moških z erektilno disfunkcijo. Odmerjanje in način uporabe: Za peroralno uporabo. Priporočeni odmerek pri odraslih je 50 mg, mogoče ga je spremeniti na 100 mg ali 25 mg. Viagra se lahko vzame le enkrat na dan. Le za starejše od 18 let. Kontraindikacije: Preobčutljivost za sildenafil ali katerokoli pomožno snov. Donorji dušikovega oksida ali nitrati. Moški, za katere spolna dejavnost ni priporočljiva. Bolniki, ki so izgubili vid na enem očesu zaradi nearteritične anteriorne ishemične optične nevropatije. Huda okvara jeter, hipotenzija, nedavna možganska kap ali miokardni infarkt in znane degenerativne bolezni mrežnice. Posebna opozorila in previdnostni ukrepi:Vazodilatacijski učinki. Hipotenzivni učinek nitratov. Resni kardiovaskularni dogodki in dejavniki tveganja. Nagnjenost k priapizmu, zaviralci adrenergičnih receptorjev alfa in motnje strjevanja krvi ali aktivna peptična razjeda. V primeru nenadne izgube vida, prenehati jemati Viagro in takoj obvestiti zdravnika. Sočasna uporaba z ritonavirjem ali drugimi zdravili za zdravljenje erektilne disfunkcije. Medsebojno delovanje z drugimi zdravili: Zaviralci CYP3A4, ritonavir, sakvinavir, eritromicin, cimetidin, sok grenivke, nikorandil, donorji dušikovega oksida ali nitrati, zaviralci adrenergičnih receptorjev alfa. Vpliv na sposobnost vožnje in upravljanja s stroji: Možna je omotica in spremembe vida. Neželeni učinki: glavobol, zardevanje, dispepsija, motnje vida, zamašenost nosu, omotica in motnje zaznavanja barv. Način izdajanja: le na recept. Imetnik dovoljenja za promet: Pfizer Limited, Sandwich, Kent CT13 9NJ, Velika Britanija. Datum zadnje revizije besedila: 1.7.2010Pred predpisovanjem se seznanite s celotnim povzetkom glavnih značilnosti zdravila.

Pfizer Luxembourg SARL, Grand Duchy of Luxembourg, 51, Avenue J.F. Kennedy, L-1855,PFIZER, Podružnica za svetovanje s področja farmacevtske dejavnosti, Ljubljana, Letališka 3c, 1000 Ljubljana, SLOVENIJA


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Preprečevanje trzljajev mišic stegenskih adduktorjev z blokom obturatornega živca pri transuretralni resekciji stransko ležečih

tumorjev mehurja The prevention of obturator jerk reflex with obturator nerve block

during transurethral resection of lateral bladder wall tumors Simon Hawlina, Jure Bizjak, Borut Gubina, Tomaž Smrkolj, Robert Kordič, Miro Mihelič,

Dominik Cotič, Boris Sedmak

Klinični oddelek za urologijo, Univerzitetni klinični center Ljubljana, SlovenijaClinical Department of Urology, University Clinical Center Ljubljana, Slovenia

IzvlečekUvod: Med transuretralno resekcijo stransko ležečih tumorjev mehurja lahko pride do stimulacije obturatornega živca in posledično trzljaja mišic stegenskih adduktorjev. Metoda: Med februarjem in aprilom 2011 smo na naši kliniki evaluirali deset bolnikov s stransko ležečimi tumorji mehurja. Vsi so pred transuretralno resekcijo tumorjev mehurja (TUR) prejeli tako spinalno anestezijo, kot tudi blok obturatornega živca (BOŽ). Pri nobenem bolniku ni prišlo do trzljaja mišic stegenskih adduktorjev. Za BOŽ smo uporabili 22G spinalno iglo, elektrostimulacijsko napravo in 10-20 ml 2% lidokaina, ki smo ga infiltrirali v obturatorni živec v predelu mišic stegenskih adduktorjev. Rezultati: Pri vseh desetih bolnikih smo uspešno izvedli enostranski BOŽ. Trzljaja mišic stegenskih adduktorjev nismo opazili pri nobenem izmed njih. Zaključek: BOŽ je uspešna tehnika za preprečevanje trzljajev mišic stegenskih adduktorjev pri TUR stransko ležečih tumorjev mehurja. Preprečuje globoke in nekontrolirane reze stranske stene mehurja med TUR tumorjev. Pri bolnikih ni potrebna splošna anestezija z relaksacijo, operativni čas je krajši, metoda pa ti omogoča natančnejši in bolj radikalen poseg. Elektrostimulacija obturatornega živca pred aplikacijo anestetika je enostavna, lahko ponovljiva, varna in visoko uspešna metoda.

AbstractThe obturator nerve may be stimulated by transurethral resection of lateral bladder wall tumors, causing obturator jerk reflex. Methods: Between February 2011 and April 2011 10 patients who undergone TURBT on the lateral bladder wall were evaluated at our clinic. All of them received spinal anesthesia with obturator nerve block (ONB). No obturator jerk reflex were observed in the patients. ONB was obtained with 10

ml of 2% lidocaine infiltrated through a 22G spinal needle using a nerve stimulation approach. Results: Successful ONB was performed unilateral in all of patients. Muscle spasms were absent in all of them.Conclusions: ONB for the prevention of obturator jerk reflex is a useful technique for the prevention of deep and uncontrolled cuts in the lateral part of the bladder wall during TURBT. There is no need for general anesthesia with relaxation, operating time is shorter, the procedure is more meticulous and radical. The nerve stimulation approach is a simple, safe, highly reproducible and easy procedure, with a high success rate.

UvodObturatorni živec poteka skozi obturatorni kanal in oživčuje mišice adduktorjev stegna. Izhaja iz lumbalnega pleksusa od L2 do L4 in vsebuje tako motorična, kot tudi senzorična živčna vlakna. Znotraj male medenice je njegov potek v bližini prostatične uretre, vratu mehurja in inferolateralne stene mehurja. Med transuretralno resekcijo tumorjev mehurja (TURM), ko mehur močneje napolnimo s tekočino, je obturatorni živec v tesnem stiku z lateralno steno mehurja. Tako med posegom, kjer uporabljamo električni tok, električni tokovi brez težav stimulirajo obturatorni živec, kar vodi v trzljaj mišic stegenskih adduktorjev. Ob tem lahko pride do perforacije mehurja, razlitja tumorski celic v perivezikalno področje in močnejše krvavitve. Zaradi strahu operaterja, da bo bolniku z globoko resekcijo povzročil škodo, pa je resekcija stransko ležečih tumorjev mehurja največkat neradikalna. TURM največkrat opravljamo v spinalni anesteziji, ki pa ne zavre elektrostimulacije obturatornega živca. Za blokado elektrostimulacije moramo bolnika relaksirati. Potrebna je endotrahealna intubacija, ki je visoko invaziven poseg,


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celotna operacija traja dlje, nekateri pacienti niso primerni za endotrahealno intubacijo zaradi rizičnih dejavnikov. Tako je Prentiss leta 1965 prvi predlagal uporabo regionalne anestezije za blokado obturatornega živca in trzljaja mišic adduktorjev stegna. Kljub temu, da so trzljaji mišic adduktorjev stegna glavni faktor, ki negativno vpliva na izid operacije sransko ležečih tumorjev mehurja, pa do sedaj še ni izdelanih natančnih smernic. Menim, da pri TURM na stranski steni, s kombinacijo spinalne anestezije in regionalnega bloka obturatornega živca, uspešno preprečimo trzljaje mišic adduktorjev stegna. Regionalni blok obturatornega živca je enostaven, hiter, visoko uspešen in nenevaren poseg. S preglednim prispevkom želim prikazati metodo, da bi jo lahko v vsakdanji klinični praksi uporabljalo čimveč urologov.

INDIKACIJE za regionalni blok obturatornega živcaTumorji mehurja locirani na stranski steni.

KONTRAINDIKACIJE za regionalni blok obturatornega živca1. koagulopatije, 2. povečane ingvinalne bezgake, 3. infekcija kože v ingvinalnem predelu, 4. otežen dostop (kontrakture)

AnatomijaObturatorni živec izhaja iz lumbalnega pleksusa od L2 do L4. Vsebuje tako motorična, kot tudi senzorična živčna vlakna. Poteka ob notranjem robu mišice psoas, nato po mišici obturator internus, preide skozi zgornji del obturatornega foramna in končno vstopi v mišice adduktorjev stegna. Ko zapusti obturatorni foramen se cepi v dve veji in sicer v anteriorno in posteriorno vejo. Anteriorna veja oživčuje mišice adduktor brevis, adduktor longus in gracilis, medtem ko oživčuje posteriorna veja mišici adduktor magnus in obturator eksternus. Senzorična veja oživčuje kožo notranjega, zgornjega dela stegna.V klinični praksi je potrebno obturatorni živec blokirati preden se cepi v anteriorno in posteriorno vejo.

FarmakologijaObturatorni živec je periferni živec s senzorno in motorno funkcijo. Motorna živčna vlakna so iz skupine A, ki so debelejša. Za uspešen obturatorni blok mora koncentracija anestetika dvakrat preseči koncentracijo, ki je potrebna za blokado občutka za bolečino in temperaturo, ki se sicer prevaja po tankih A in C vlaknih. Tako je bolje uporabiti 2% koncentracijo lidokaina ali 0,25% koncentracijo bupivakaina. Klinično imamo na voljo dve skupini lokalnih anestetikov. Tiste s hitrim pričetkom delovanja, a so kratkodelujoči in

tiste, ki potrebujejo dalj časa za pričetek delovanja, a so dolgodelujoči. V prvo skupino spadata lidokain in mepirakain. Lidokain je najprimernejši, saj začne delovati že po cca 4 minutah, deluje pa do 40 minut. Z 2% koncentracijo v količini 10-20 ml uspešno blokiramo obturatorni živec. V drugo skupino spadata tetrakain in bupivakain (markain). Dodatek epinefrina lokalnemu anestetiku podaljša delovanje lokalnega anestetika z vazokonstrikcijo, ki onemogoči izplavljanje lokalnega anestetika iz mesta delovanja.

OpremaOsnovna oprema za izvedbo bloka obturatornega živca:1. sterilne rokavice2. 20-ml brizga3. injekcijska igla (5-8 cm v dolžini)4. lokalni anestetik (2% lidokain or 0.25% bupivakain) 5. elektrostimulatorAnatomske orientacijske točke so tuberkel pubisa, kot kostna orientacijska točka, femoralna arterija kot žilna orientacijska točka in tetiva adduktor longusa kot mišična orientacijska točka.

TehnikaNa voljo imamo dva pristopa, ki sta po uspešnosti primerljiva. Prvi je slep, anatomski pristop, kjer se orientiraš glede na anatomske oporne točke. Drug je elektrostimulacijski pristop, kjer z elektrostimulacijsko napravo z iglo najdeš najprimernejše mesto za aplikacijo anestetika.

Slep, anatomski pristop1. Bolnika namestimo v litotomijski položaj 2. Vstopna točka igle je 1,5 cm (dva prsta) lateralno in 1,5

cm (dva prsta) inferiorno od tuberkla osis pubis. 3. Vstopno mesto igle je že anestezirano prek spinalne

anestezije, tako, da kože ni potrebno dodatno infiltrirati z lokalnim anestetikom

4. Iglo zabodemo v kožo skoraj pod pravim kotom5. Ko smo z iglo na mestu, ki ga mislimo lokalno anestezirati,

opravimo aspiracijo. Če v brizgo ne priteka kri, apliciramo v predel obturatornega živca anestetik (0.25% bupivakain ali 2% lidokain)

6. Ponavljamo točke 3 do 5, skupaj trikrat.

Elektrostimulacijski pristop1. Točke 1 do 3 so iste, le da uporabimo posebno

iglo, ki je priključena na elektrostimulativno napravo. Elektrostimuliramo s tokom od 1 do 1,5 mA. Trzljaji in moč trzljajev mišic stegenski adduktorjev nam kažejo na pravilno mesto vboda..

2. Ko najdemo pravilno mesto na obturatornem živcu bodo mišice stegenski adduktorjev ob vskem elektrostimulusu močno trznile.


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3. Ko menimo, da smo na pravem mestu, znižamo elektrostimulativni tok na 0,3 mA. Intenziteta trzlajjev mišic se zmanjša, a je še vedno prisotna, v kolikor je mesto pravo. V ta predel apliciramo anestetik (0.25% bupivakain ali 2% lidokain), dokler kontrakcije ne izzvenijo (cca 10-20 ml).

4. Nekaj minut po končani aplikaciji anestetika, ponovno ocenimo trzljaje mišic ob višjem toku (1,5mA). Če kontrakcij ni, je bil blok uspešen.

Komplikacije1. Slabša blokada obturatornega živca lahko vodi v trzljaj

mišic stegenskih aduktorjev, kar je redko. 2. Ob obturatornemu živcu poteka obturatorna arterija, ki

jo teoretično lahko z iglo poškodujemo in povzročimo krvavitev s hematomom. Omenjene komplikacije v literaturi nisem zasledil.

Pregled literatureGlede na Augsurqer et al., je uspešnost inhibicije trzljaja mišic stegenskih adduktorjev s slepo, anatomsko metodo med 83.8% in 85.7%. Z elektrostimulativno metodo dosegamo boljše rezultate in sicer glede na Gasparich et al. and Kobayashi et al., 89.4%-100%.

ZaključekPravilno razumevanje anatomije obturatornega živca in njegove inervacije, kot tudi pravilna aplikacija lokalnega anestetika nam omogočajo popolno blokado trzljajev mišic stegenskih adduktorjev med TUR tumorjev na stranski steni mehurja. Z blokom preprečujemo globoke in nekontrolirane reze stranske stene mehurja med TUR tumorjev, ki vodijo v večjo krvavitev, perforacijo mehurja in razlitje tumorskih celic v perivezikalno področje. Pri bolnikih ni potrebna splošna anestezija z relaksacijo, operativni čas je krajši, metoda pa ti omogoča natančnejši in bolj radikalen poseg. Elektrostimulacija obturatornega živca pred aplikacijo anestetika je enostavna, lahko ponovljiva, varna in visoko uspešna metoda.

Reference1. Brown DL. Atlas of Regional Anesthesia. Philadelphia,

PA: WB Saunders, 1992:103-8.2. Moore DC, ed. Obturator Nerve Block. Regional Block,

4th ed. Springfield, IL: Charles C. Thomas, 1965:289- 93.

3. Berberoglu M, Uz A, Ozmen MM, Bozkurt C, Erkuran C, Taner S, Tekin A, Tekdemir I. Corona mortis: an ana- tomic study in seven cadavers and an endoscopic study in 28 patients. Surg Endosc 2001;15:72-5.

4. Mydlo JH, Weinstein R, Shah S, Solliday M, Macchia RJ. Long-term consequences from bladder perforation and/or violation in the presence of transitional cell carcinoma: results of a small series and a review of the literature. J Urol 1999;161:1128-32.

5. Hahn RG, Sandfeldt L, Nyman C R. Double-blind randomized study of symptoms associated with absorption of glycine 1.5% or mannitol 3% during transurethral resection of the prostate. J Urol 1998;160:397-401.

6. Collado A, Chechile GE, Salvador J, Vicente J. Early complications of endoscopic treatment for superficial bladder tumors. J Urol 2000;164:1529-32.

7. Narins L, Lief P. Abolition of mass femoral muscular contractions during transurethral resection. L Mount Sinai Hosp 1957;24:23-4.

8. Hobika JH, Clarke BG. Use of neuromuscular blocking drugs to counteract thigh-adductor spasm induced by electrical shocks of the obturator nerve during transurethral resection of bladder tumors. J Urol 1961;85:295- 6.

9. Prentiss RJ, Harvey GW, Bethard WF, et al. Massive adductor muscle contraction in transurethral surgery:

cause and prevention, development of new electrical circuitry. J Urol 1965;93:263-71.

10. Augspurger RR, Donohue R E. Prevention of obturator nerve stimulation during transurethral surgery. J Urol 1980;123:170-2.

11. Parks CR, Kennedy WF Jr. Obturator nerve block: a simplified approach. Anesthesiology 1967;28:775-8.

12. Hradec E, Soukup F, Novak J, Bures E. The obturator nerve block. Preventing damage of the bladder wall during transurethral surgery. Int Urol Nephrol 1983;15: 149-53.

13. Hong Y, O’Grady T, Lopresti D, Carlsson C. Diagnostic obturator nerve block for inguinal and back pain: a re- covered opinion. Pain 1996;67:507-9.

14. Bouaziz H, Vial F, Jochum D, Macalou D, Heck M, Meuret P, Braun M, Laxenaire MC. An evaluation of the cutaneous distribution after obturator nerve block. Anesth Analg 2002;94:445-9.

15. Atanassoff PG, Weiss BM, Brull SJ. Lidocaine plasma levels following two techniques of obturator nerve block. J Clin Anesth 1996;8:535-9.

16. Kobayashi M, T akeyoshi S, T akiyama R, et al. A report of 107 cases of obturator nerve block. Jpn J Anesth 1991;40:1138-43.


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Bladder sparing treatment for muscle invasive Bladder Cancer: solution or an option?

Aleksandar Janjić, Cane Tulić, Aleksandar Vuksanović, Nebojsa Bojanić, Nale Djordje,

Urology Clinic, Clinical Centre of Serbia, Belgrade, Serbia

Abstract Background: Radical cystectomy and lymphadenectomy is the gold standard for the treatment of muscle-invasive bladder cancer (MIBC) Neither transurethral resection of the bladder (TURB) nor radiation alone provides adequate local control for unselected patients. Recent organ-preservation strategies combining TURB, chemotherapy, and radiation (trimodality treatment) have shown local control and progression results comparable to cystectomy series. In very selected patients, invasive bladder cancers can be cured by TURB alone or neoadjuvant chemotherapy and TURB.

Objective: To determine outcome of bladder sparing treatment in patients with muscle invasive bladder cancer treated with TURBT and chemotherapy.

Method: 21 patient, all males, 61 to 79 years old were eligible, fulfilling inclusion criteria for bladder preservation: Muscle invasive Transitional cell bladder cancer diagnosed after TURBT, absence of CiS, no signs of upper tract tumors, size of tumor less then 5 cm, reliable and cooperative patients. Patients included were chosen because of refusal of cystectomy, (9) or serious co morbid conditions not allowing cystectomy.(12) After initial TURBT patients were treated with chemotherapy M –VAC (4) and Gemcitabine Cis platinum (17) with 3 or 4 cycles. In three months period second TUR BT was done. On the basis of histological findings patients were treated with salvage cystectomy if muscle invasive disease exists, partial cystectomy if feasible, or if complete or partial response were achieved patients received two more cycles of chemotherapy. Regular cystoscopies in 3 months intervals, CT scans twice a year and reevaluation thereafter were done threw a mean follow up period of 27,5 months.

Results: After first TURBT, 5 complete responses (pTo) were documented, 5 superficial relapses, one endoscopical CR with inconclusive histology, and 10 patients with still present MIBC. Of those 10 patients 6 were salvaged with cystectomy, other 4 treated with partial cystectomy. 15 patients were alive with their bladders after 12 months, after 4 years 6 patients died, 4 have had salvage cystectomy after 2 to 3 years, and 5 patients were alive with functional bladders, without evidence of disease progression, and good quality of life.

Conclusion: In appropriately selected and cooperative patients, meticulously followed, combined-modality therapy can preserve a tumor-free bladder without compromising survival, maintaining the good quality of life.

Introduction Bladder cancer ranks ninth in worldwide cancer incidence. The age standardized incidence is 10.1 per 100.000 for males and 2.5 per 100.000 for females. One fourth of bladder cancer (BC) are muscle invasive at diagnosis and account for 80% of disease related deaths. Approximately one third of patients diagnosed with muscle invasive bladder tumors (MI BC) have undetected dissemination at the time of primary treatment, while up to 25% patients undergoing radical cystectomy have lymph node involvement at time of surgery. Radical cystectomy results in a 5 year survival of about 50% .One major reason for early death is unrecognized micrometastatic spread that ultimately develops into macrometastatic detectable dissemination and/or local recurrence.

As a matter of principle, operable (neoadjuvant approach), as well as unresectable primary tumours are expected to respond to systemic chemotherapy. However, chemotherapy alone rarely produces durable complete responses of the bladder primary tumours. Down staging with 2-4 cycles of MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) or Gemcitabine Cisplatinum might be one benefit. Pathological complete responses of bladder primary tumors were reached in 12-50% of patients after MVAC and in 12-22% of patients after gemcitabine/cisplatin (GC).

Patients who refused cystectomy after receiving neoadjuvant chemotherapy for muscle-invasive bladder cancer had a 64% rate of relapses in the bladder with an additional mortality of 30%.Such patients might jeopardize their survival due to the lack of definitive treatment of the primary bladder tumor, by developing relapsing tumors in the bladder.Response to chemotherapy may be confounded by patient selection. However, it is a prognostic factor for treatment outcome and eventual survival.


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For bladder preservation strategies, response is evaluated by cystoscopy/re-TURB plus eventual CT-imaging, followed by close surveillance. This approach is prone to an immanent staging error and might put the patient at risk for local recurrence and/ or consecutive metastatic disease. Radical cystectomy with extended lymphadenectomy is by far the best therapeutic option for MIBC. For very selected patients with localized disease, a bladder conserving strategy with TURB and systemic cisplatin-based chemotherapy, preferably with MVAC, or Gemcitabine – Cisplatinum has been shown to allow long term survival with intact bladder. Of note, this approach cannot be recommended for routine use, employed mainly for patients refusing cystectomy or patients unfit for major surgery due to co morbid conditions. Patients and methods21 bladder cancer patient, all males, 61 to 79 years old were eligible, fulfilling inclusion criteria for bladder preservation: Muscle invasive Transitional cell bladder cancer documented after TURBT, endoscopicaly radical TUR, disappearance of hardened zones in the bladder wall after resection on bimanual palpation. absence of CiS, no signs of upper tract tumors, size of tumor less then 5 cm., reliable, motivated and cooperative patients.Patients included were chosen because of cystectomy refusal and motivation to preserve the bladder (9) or serious co morbid conditions not allowing cystectomy.(12) After initial

TURBT patients were treated with chemotherapy M –VAC (4) and Gemcitabine Cis platinum (17) with 3 or 4 cycles. In three months period second TUR BT was done. On the basis of histological findings patients were treated with salvage cystectomy if muscle invasive disease exists, partial cystectomy if feasible, or if complete or partial response were achieved patients received two more cycles of chemotherapy. Regular cystoscopies in 3 months intervals, CT scans twice a year and reevaluation thereafter were done threw a mean follow up period of 27,5 months. (10 to 45 months)MIBC was primarily diagnosed in 12 pts (57.14%), 9 patients were included after progression of previously treated tumors (42.85%) Histopathology was transitional cell cancer (TCC) in 12 pts (57.14%) and TCC with squamocelullar and adenoid components in 9 cases (42.85%). CiS was found in 6 patients (28.57%) in peritumoral specimens, without concomitant and diffuse CiS.Tumor size was less then 3 cm in 8 pts (38%), and 3 – 5 cm in 13 pts. ( 62%) In one patient nephroureterectomy was done 2 years before bladder cancer, the other 20 patients were without signs of ureteric or renal pelvic tumors. Hydronephrosis was present in 4 patients, in 3 drained with nephrostomy tube, in one resolved during treatment.Pathology reports were examined by four uropathologists during the follow up.

Table 1 – Patient characteristics

Patients Age 61 – 79 Mean 70

Tumors Primary 12 (57.1%) Progressed 9 (42.8%)

Hystopathology TCC only 12 (57.14%) TCC+Sqc. 9 (42.8%)

Grades II 10 (47%) III 11 (52.3%)

CiS Peritumoral 6 (28.57%) Diffuse 0

Size < 3 cm: 8 (38%) 3-5 cm: 13 (62%)

Upper tracts Tumors : 0 Hydroneph. 4 (19.0%)

Stage after TURBT pT2 : 11 (52.4%) >pT2 : 10 (47.6%)

Reason for bladder sparing Refusal of cystectomy 9 (42.8%) Comorbidities 12 (57.2%)

After complete TURBT patients were treated with neoadiuvant chemotherapy with M VAC (methotrexate, doxoeubicine, viblastine, Cisplatinum) or Gemcitabine-Cisplatinum protocols with general oncological criteria for inclusion to chemotherapy: Age below 75, Hemoglobin level over 90 g/l, WBC of more then 3000, Liver function tests within 1.5 of upper normal limit, creatinine clearance of more then 60 ml/min, performance status ECOG of 2 or less. Patients have

had 3 do 4 cicles. 5 patients discontinued treatment due to toxic effects of chemotherapy, and were excluded from further follow up, other patients did not experienced major toxic effects, with dose delays due to neutripenia and low platelet counts (Gemsar / Cisplatinum group) most common.10 Patients (47.6%) had 3 cycles, 11 (52.4%) had a 4 cycles of chemotherapy.


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Table 2- Neoadiuvant chemotherapy after TURB

Protocol Patients ToxicityM VAC 4 (19%) Neutropenia

MucositisTransfusions

1

GC 17 (81%) NeutropeniaLow Plt.c. InfectionMucositis

6 (35%)9 (53%)2 (11%)2 (11%)

ResultsAfter first TURBT, and completed neoadiuvant chemotherapy 5 complete responses (pTo) were documented, 5 superficial relapses, one endoscopical CR with inconclusive histology, and 10 patients with still present MIBC. Of those 10 patients 6 were salvaged with cystectomy, other 4 treated with partial cystectomy. 15 patients were alive with their bladders after 12 months, after 4 years 6 patients died, 4 have had salvage cystectomy after 2 to 3 years, and 5 patients were alive with functional bladders, without evidence of disease progression, and good quality of life. No evidence of late toxicities were recorded due to chemotherapy .

Table 3- Resposnes after neoadiuvant chemotherapy after second TURBT

RESPONSE PTS. %CR (pTo) 5 23.8

Superficial rec. 5 23.8

Invasive tumor 10 47.6

Endoscopicaly negative with inconclusive hystology

1 4.76

Invasive bladder tumor in a group of 10 pts. (47.6%) after second TURBT was treated with cystectomy in 6 pts (28.5%) and partial cystectomy in 4 patients (19.04%)15 patients (71.4%) remain with their bladders for minimal follow up of 12 months with additional two courses of chemotherapy.

After 45 months, about half of patients (10 or 47.6%) were operated (salvage cystectomy), 6 died of metastatic disease, and 5 (23.8%) are alive, with functioning bladders and good life quality . Of those patients 4 are from neoadiuvant chemotherapy group after TURBT, one was with spared bladder and complete response with TURBT, chemotherapy and partial cystectomy. Mean age of patients was 72 years. In 3 patients tumors progressed from previously treated

superficial tumors, 2 tumors were MIBC from first diagnosis of stage pT2 with 3 tumor size. No CiS was found in peritumoral mucosa. All complete responders were treated with minimum 4 cicles of chemotherapy (maximum 6) with good tolerance profile during therapy. 3 CR were achieved with Gemcitabine- Cisplatinum protocol, a 2 with M VAC.

Table 4 – Results after follow up

Cystectomy - salvage 10 (47.6%)

Dead of disease 6 (28.5%)

Disease free - bladder spared 5 (23.8%)

Regular cystoscopic evaluation did not recorded marked bladder contracture or decrease in capacity. Most prominent finding was mucosal edema and hypervascularity. Patients with spared bladders most often have urgency, nicturia, but also other symptoms of lower urinary tract symptoms due to BPH . Sexual function was preserved at the level before initiating treatment. Quality of life was qualified as satisfactory and very good in patients with retained bladders.

Discussion In a prospective study, Solsona et al reported on 133 candidates for conservative treatment. The inclusion criteria for this group were histological confirmation of muscular infiltration, endoscopic radical TUR, disappearance of hardened areas on the bladder wall after resection on bimanual examination, and negative biopsies of the depth and periphery of the tumor bed. The control group consisted of 76 patients with invasive pathologic stage pT2-3a, N0-3 bladder cancer treated with cystectomy and followed for more than 5 years. After 5 years, 61 patients (45.9%) in the TUR group relapsed, 35 (26.3%) had disease recurrence, and 37 (27.8%) had disease progression.Of the original 133 patients, 59 were followed for a median of 10 years, and there was no significant statistical difference in survival in the two groups vs the control group. At 5 and 10 years, the cause-specific survival rates were 80.5% and 79.5% and bladder preservation rates were 82.7% and 79.0%, respectively, in each group. This was not a randomized study; selection bias toward cystectomy and TUR could be present. Evidence of CIS was the only significant statistical variable to predict progression. Other series in the literature present overall survival from 31%-68% as follows: stage T2 at 57% 70%, stage T3a at 14%-57%, and stage T3b at 2%-7%.A recent series by Memorial Sloan-Kettering evaluated 170 consecutive patients who underwent recent TUR for bladder


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tumors by a referring physician. A total of 150 patients had repeat TUR, with 114 (76%) having residual tumor on repeat TUR. In patients with superficial (Ta, Tis, T1) bladder tumors, 72 (75%) had residual tumor and 28 (29%) were upstaged to muscleinvasive disease. Only 12 (22%) of patients with an initial T2 pathologic stage had no residual tumor with repeat TUR. These data stress the importance of a repeat TUR on patients considered for bladder-sparing protocols and suggest that bladder preservation be used in controlled protocol studies and not as a standard treatment. Recent data show only a 9% incidence of nodal metastasis in patients with pathologic stage T2 on radical cystectomy specimen compared with 37% of pathologic stage T3 patients. This suggests that a tumor amenable to complete resection by TUR will have a low incidence of nodal metastasis. Herr et al. reported on 111 patients with clinical T2-3, N0, M0 transitional cell carcinoma of the bladder who were treated with neoadjuvant M-VAC, after repeat maximum TURBT. Of 60 patients with complete responses, 28 refused definitive treatment beyond TURBT,15 patients underwent partial cystectomy, and 17 patients underwent radical cystectomy. No patient received radiation. Of these 60 patients, 38 (63%) had presented with T2 disease and 22 (37%) with T3 disease.Patients with clinical T3 disease were disproportionately selected for radical cystectomy over bladder-sparing surgery by 45% vs 18%. The overall survival at 10-year follow-up was 70% in the bladder-sparing treatment arm and 65% in the radical cystectomy arm. These good results were obtained without the use of radiation therapy.Partial cystectomy as a treatment for muscle - invasive bladder cancer may be considered in patients with a tumor that is primary, solitary, and amenable to removal with 2cm surgical margins. A biopsy must be performed on the remaining urothelium to ensure that it is normal. Several publications of retrospective series, with the above criteria as well as less restrictive, resulted in the use of partial cystectomy in 5.8%-18.9% of all patients undergoing cystectomy for bladder cancer These studies show a 5-year overall survival rate of approximately 25%-60%, with local overall and recurrence rates ranging from 40%-78%. The suboptimal survival observed in many series of partial cystectomy may be attributed to loosely interpreted inclusion criteria. At the time of partial cystectomy, a frozen section is necessary for evaluation of the margins by a uropathologist.In this small series of patients choosed for bladder sparing treatment it is apparent that patient selection is crucial. It is beyond question that radical cystectomy is life sparing procedure in MIBC, but its negative drawbacks (major surgery risks, high complication rates, urinary diversion, havy impact on life quality, sexual and reproductive function,

social implications) may put some MIBC in very high risk if some serious comorbid conditions coexists. It is also true for patients who refuse this type of surgery, or are willing to take the chance to retain their bladders, awared of high risk and need for close follow up . Important role of neoadiuvant chemotherapy after initial endoscopical resection is its effect on micro metastatic sites, evaluation of tumor chemo sensitivity, possibility of achieving tumor free status with TURBT combined with Cisplatinum chemotherapy (pTo), or downstaging of primary tumor to operable stage (for cT4 stages) As inclusion criteria for chemotherapy are less rigid then for cystectomy, so this approach gives an option to achieve long survival rates with functional bladders in unfit patients. Also, if neoadiuvant treatment fails, salvage cystectomy is still an option regardless of eventual toxic effects of chemotherapy. In half of our patients we used opportunity, in all cases operation was techicaly feasible. 5 patients out of 21 spared bladders, without signs of metastatic spread and local reccurences. Toxic effects of chemotherapy, frequent cystoscopies were not significantly affected outcome.

Conclusion In appropriately selected and cooperative patients, meticulously followed, combined-modality therapy can preserve a tumor-free bladder without compromising survival, maintaining the good quality of life.Response to chemotherapy may be confounded by patient selection. However, it is a prognostic factor for treatment outcome and eventual survival. Patientrelated factors combined with molecular markers (p53, p21, mdm-2, bcl-2) and gene profiling might help to identify those who will respond well to chemotherapy and to further select patients for bladder preservation strategies. Prospective translational research programs should be incorporated in clinical trials to validate their role. In the palliative setting, unresectable tumours or bladder primary tumours in advanced or metastasised patients, chemotherapy can promote local control in a substantial number of patients and a survival benefit. For very selected patients with localised disease, a bladder conserving strategy with TURB and systemic cisplatin-based chemotherapy, preferably with MVAC, and GC, has been shown to allow long term survival with intact bladder. Of note, this approach cannot be recommended for routine use, it is still an option, not a solution.

References1. Wajsman Z, Klimberg IW. Treatment alternatives for

invasive bladder cancer. Semin Surg Oncol. 1989;5:272-281.


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2. Shipley WU, Kaufman DS, Heney NM, et al. An update of combined modality therapy for patients with muscle invading bladder cancer using selective bladder preservation or cystectomy. J Urol. 1999;162:445-451.

3. Sternberg CN,Yagoda A, Scher HI, et al. Preliminary results of M-VAC (methotrexate, vinblastine,doxorubicin and cisplatin) for transitional cell carcinoma of the urothelium. J Urol. 1985;133:403-407.

4. Gschwend JE, Vieweg J, Faiv WR. Contemporary results of radical cystectomy for primary bladder cancer. Lesson 13. AUA Update Series. 1999;18. 346 Cancer Control July/August 2000, Vol.7, No.4

5. Wajsman Z, Rifkin MN. Alternative therapies for muscle-invasive transitional cell carcinoma. Probl Urol. 1992;6:493-505.

6. Herr HW. Conservative management of muscle-infiltrating bladder cancer: prospective experience. J Urol. 1987;138:1162-1163.

7. Henry K, Miller J, Mori M, et al. Comparison of transurethral resection to radical therapies for stage B bladder tumors. J Urol. 1988;140:964-967.

8. Solsona E, Iborra I, Ricos JV, et al. Feasibility of transurethral resection for muscle infiltrating carcinoma of the bladder: prospective study. J Urol. 1992;147:1513-1515.

9. Solsona E, Iborra I, Ricos JV, et al. Feasibility of transurethral resection for muscle infiltrating carcinoma of the bladder: long-term follow-up of a prospective study. J Urol. 1998;159:95-99.

10. Whitmore WF. Selection of treatment for muscle infiltrating transitional cell bladder cancer. Arch Esp Urol. 1990;43:219-222.

11. Herr HW. The value of a second transurethral resection in evaluating patients with bladder tumors. J Urol. 1999;162:74-76.

12. Sweeney P, Kursh ED, Resnick MI. Partial cystectomy. Urol Clin North Am. 1992;19:701-711.

13. Given RE,Wajsman Z. Bladder sparing treatments for muscle invasive transitional cell carcinoma of the bladder. Lesson 6. AUA Update Series. 1997;16.

14. Novick AC, Steward BH. Partial cystectomy in the treatment of primary and secondary carcinoma of the bladder. J Urol. 1976;116:570-574.

15. Faysal MH, Freiha FS. Evaluation of partial cystectomy for bladder cancer. Urology. 1979;14:352.

16. Merrell RW,Brown HE, Rose JF. Bladder carcinoma treated by partial cystectomy: a review of 54 cases. J Urol. 1979;122:471-472.

17. Lindahl F, Jorgensen D, Egvad K. Partial cystectomy for transitional cell carcinoma of the bladder. Scand J Nephrol. 1984;18:125- 129.

18. Kaneti J. Partial cystectomy in the management of bladder carcinoma. Eur Urol. 1986;12:249-252.

19. Wesson MF. Radiation therapy in regionally advanced bladder cancer. Urol Clin North Am. 1992;19:725-734.

20. 20. Holmang S, Hedelin H, Borghede G, et al. Long-term followup of a bladder carcinoma cohort: questionable value of radical radiotherapy. J Urol. 1997;157:1642-1646.

21. Montie JE. Against bladder sparing: surgery. J Urol. 1999; 162:452-457.

22. Eapen L, Stewart D, Crook J, et al. Intraarterial cisplatin (IAC) and concurrent pelvic radiation (PR) in the management of transitional bladder cancer: an organ preservation strategy. Proc Annu Meet Am Soc Clin Oncol. 1995;14:A625.

23. Wijnmaalen A, Helle PA,Koper PC, et al. Muscle invasive bladder cancer treated by transurethral resection followed by external beam radiation and interstitial iridium-192. Int J Radiat Oncol Biol Phys. 1997;39:1043-1052.

24. Miller LS. Bladder cancer: superiority of preoperative irradiation and cystectomy in clinical stages B2 and C. Cancer. 1977;39(2 suppl):973-980.

25. Scher HI, Yagoda A, Herr HW, et al. Neoadjuvant M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) affect on the primary bladder lesion. J Urol. 1987;139:470-474.

26. Herr HW, Scher HI. Neoadjuvant chemotherapy and partial cystectomy for invasive bladder cancer. J Clin Oncol. 1994;12:975- 980.

27. Sternberg CN, Arena MG, Calabresi F, et al. Neoadjuvant MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) for infiltrating transitional cell carcinoma of the bladder. Cancer. 1993;72:1975-1982.

28. Hatcher PA, Hahn RG, Richardson RL, et al. Neoadjuvant chemotherapy for invasive bladder carcinoma: disease outcome and bladder preservation and relationship to local tumor response. Eur Urol. 1994;25:209-215.

29. Scattoni V,Da Pozzo L,Nava L, et al. Five-year results of neoadjuvant cisplatin, methotrexate and vinblastine chemotherapy plus radical cystectomy in locally advanced bladder cancer. Eur Urol. 1995;28:102-107.

30. Herr HW, Bajorin DF, Scher HI, et al. Can p53 help select patients with invasive bladder cancer for bladder preservation? J Urol. 1999;161:20-23.

31. Sternberg CN. Gemcitabine in bladder cancer. Semin Oncol. 2000;27(1 suppl 2):31-39.

32. Kaufman D, Stadler W, Carducci M, et al. Gemcitabine (GEM) plus cisplatin (CDDP) in metastatic transitional cell carcinoma (TCC): final results of a phase II study. Proc Annu Meet Am Soc Clin Oncol. 1998;17:A1235.


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The role of partial cystectomy in the treatment of muscle invasive Bladder Cancer

V. Vukotić, M. Lazić, S. Savić. D. Kojić, S. Jovanović

Clinical Center “Dr Dragiša Mišović”, Department of Urology, Belgrade, Serbia

Abstract: Muscle invasive bladder cancer is usually treated by radical cystectomy, but in some selected cases with solitary tumor with appropriate localisation partial cystectomy can be the treatment of choice achieveing long term results with bladder preservation. We reviewed records of 18 patients treated by partial cystectomy in our institution in a 9 year period from June 2002 to june 2010 according to the size of the tumor, localisation, histology , multifocality, pathological and clinical stage, sex, age and survival. Male:female ratio was 2:1, mean age of the patients beeing 67 years. All patients but one had solitary lesions located in the bladder dome in 3, on lateral sides in 9 pts, 6 patients had a tumor in diverticulum. TCC Gr 1 was diagnosed in one patient, Gr 2 in 7 pts, TCC Gr 3 in 8 pts , while squamous carcinoma was detected in 2 patients. Lymphadenectomy was performed in 5 pts, in only one lymph nodes were with metastasis. Sixt patients died, five from the progression of bladder cancer, one from other reason. Mean survival time is 33 months ( 3 to 77 months). Local reccurences treated with TUR were present in 3 patients. Bladder capacity is adequate in all patients resulting in good quality of life. Our results suggest that in selected patients, cancer control can be achieved with partial cystectomy. Better selection of patients with multimodal treatment might achieve better results with preserved bladder.

Introduction: Transitional cell carcinoma of the bladder is the fifth most common malignancy in Western countries. Standard treatment protocol for patient with bladder tumor is transurethral resection with curative intent or for obtaining biopsy specimens. If tumor(s) is muscle invasive as is in 20% of patients at first presentation, additional treatment is required. For those patients, radical cystectomy with urinary diversion is considered a treatment of choice1. While in the treatment of malignancies, organ preservation protocols have become the standard options, for muscle invasive bladder cancer, organ preservation is still limited to selected cases. Bladder preservation is a challenging option for a patient confronted to bladder cancer for many reasons such as functional and continent bladder with preserved potency in male patients. Efforts in preserving a bladder with muscle invasive cancer can be obtained with uni or multimodal

approach2. The most challenging one is a surgical removal of the tumor with preservation of continent bladder and potency in males without adjuvant radio or haemiotherapy. Partial cystectomy can achieve such goals in patients with solitary tumor located primarily in the bladder dome or posterolateral sides of the bladder which can not be adequately treated with TUR alone. Wide excision of the whole thickness of the bladder wall with resection of adjacent peritoneum and regional lymphadenectomy can provide accurate staging along with adequate disease control comparable to radical cystectomy results in adequately selected patients. Adequate selection of patients is of crucial importance for the results of partial cystectomy3.

RESULTS : in the 9 year period from june 2002 to june 2010, hundred and sixty seven patients have been surgically treated by radical or partial cystectomy for muscle invasive bladder cancer. The distribution of surgical treatment is shown on table 1.

Table 1: Surgical treatment for muscle invasive bladder cancer

Radical cystectomy Partial Cystectomy2002 16 12003 12 02004 20 22005 15 02006 27 32007 16 52008 11 22009 11 02010 21 5

149 18

Only charts for 18 patients in whom partial cystectomy was performed for T2 bladder cancer have been analyzed. Patients treated with partial cystectomy for benign conditions or in wh0m partial cstectomu was performed for distal ureteral tumor were excluded from analysis. The mean age of the


50

patients was 67 (52- 80 years), 12 males ande 6 females. All patients had a T2 tumor. Only one patient had metastasis in lymph nodes confirmed hystologically at the time of partial cystectomy. The tumor was solitary in all but one patient. The localisation was at the bladder dome in 3 patients, on lateral sides in 9 patients , while tumor was in the diverticulum in 6 patients. One patient with the bladder dome tumor had also a urachal cyst bearing also a TCC tumor which was extirpated along with the bladder dome. Ureteral reimplantation was necessary in 5 patients due to the proximity of the tumor in order to achieve a wide margin. TCC grade 1 was diagnosed in 1 patient , Grade 2 in7 pts and Grade 3 in 8 pts while two patients had a squamous carcinoma of the bladder. Mean tumor size was 3 cm but the biggest one was 7 cm in diameter. Characteristic of the patients are shown on table 2.

Table 2: Clinical and pathological characteristics of patients

Sex:F: 6M: 12

Tumor histopathologyTCC: 16Squamous : 2Tumor grade:1: 12: 73: 8

Tumor localistaion: Bladder diverticulum 6Bladder dome 3 Lateral 9

Lymph node status:Pos: 1Neg: 4

Ureterocystoneostomy:Yes: 5No: 13

Grade of the tumor did not influence survival (p=0.47) ,

but the tumor size correlated with survival, the best results achived with smaller tumors Fig 1.

Fig 1. Tumor size influencing survival

Negative margins were achieved in all patients.Lymphadenectomy was not performed routinely in all patients, only one patient out of five in whom it was done, had hystologically proven metastasis in lymph nodes and is disease free for 3 years. One of four patients without lymph node metastases developped them in next 6 months, dying from disseminated bladder cancer 9 monts after partial cystectomy. None of the patients received neoadjuvant or adjuvant chemotherapy or radiotherapy. In one patient cystectomy was performed one month after partial cystectomy due to persistent urinary fistula, no tumor was found in the bladder.

Partial cystectomy is a simple surgical procedure, the median duration of intervention was 76 mnutes. There were no major complications of surgery. All of our patients preserved good bladder capacity which made them continent day ad night. The median survival is 33 months with the range of 3 to 75 months.

DISCUSSIONThe main issue in every surgical attempt with curative intent for malignancy is the achivment of long term disease free survival. Quality of life is the other issue and should be balanced with the primary treatment goal.

The golden standard for the treatment of muscle invasive bladder cancer is radical cystectomy, so the results of treatment options should be compared with the results of radical cystectomy according to oncological results and quality of life. Oncological results of radical cystectomies are not impressive, with 5 year overall survival for patients


51

with T1-4 tumors of 59-66%4. The common recurrence and progression stress the concept that surgery only for locally advanced cancers is unsuccessful and has to be complemented with systemic treatment5. Recently two randomized large randomized trials confirmed that beest results for deeply invasive bladder cancer are achieved with neoadjuvant chemotherapy followed by definitive local therapy, as compared with cystectomy or radiotherapy alone6. The main disadvantage of radical cystectomy as perceived by now is urinary diversion. Contient reconstruction and formation of neobladder with nearly normal bladder function was a reason to perform early radical cystectomies but continent diversion are used less than expected, especially in elderly patients7. Continent diversion was expected to achieve better quality of life but in a recent study continent reconstuction was not estimated superior to conduit diversion8. The rationale favoring radical cystectomy instead of partial is the multifocality of the disease and the high reccurence rate. Patients should be aware of life long controls and possible option of salvage cystectomy 9. The other issue is also important when comparing partial to radical cystectomy. Partial cystectomy is less skill demanding and with less early or late complications, which can induce it’s innapropriate use in low cystectomy volume hospitals, in elderly patients and female patients10. Since the introduction of laparoscopic partial cystectomy11 which was proven to be safe and feasible in selected patient12, partial cystectomy may become increasingly popular. Many efforts are made in order to preserve of the bladder. One of the possible options is multimodal treatment including TUR, radiotherapy and chemotherapy with results that are comparable to radical cystectomy13. Since rates of significant late pelvic toxicity for patients completing combined-modality therapy for invasive bladder cancer and retaining their native bladder are low, this treatment is gaining in importance14. With diverse possibilty of treatment of muscle invasive bladder cancer, what are our results suggesting? The limitation of our study is the short postoperative follow up period, but our results are in accordance to other authors. Acceptable outcome can be achieved with partial cystecomy in highly selected cases15, comparable in regard of 5 year overall survival to patients treated with radical cystectomy16, although quality of life might be even more important then quantity. Grade and stage of tumor are known predictor of disease progression, although in our patients only tumor volume was the predictor of survival. The localisation had no impact on postoperative course nor on survival according to our limited experience.

Better selection of patient might improve the results. A promising new marker FGFR3 mutation selectively identifies patients with favorable bladder cancer . The mutation was extremely rare in patients with cancer-positive nodes so it might be used to guide decision making on adjuvant therapy after RC17. The other possible marker which can be in order to select patients with better possible outcome used is C Reactive Protein18. Better results might be obtained with multimodal treatment such as neoadjuvant chemotherapy19 even in patients witj partial cystectomy. CONCLUSION: Radical cystectomy remains the standard of care for muscle-invasive bladder tumors but in selected patiens partial cystectomy offers acceptable oncological and quality of life outcomes.

References: 1 Kuczuk M., Turkri L., Hammerer P. Raverzy V., Is there a

role for bladder preserving strategies in the treatment of muscle invasive bladder cancer? Euro Urol 2003; 44:57-64

2 Tores-Rocca JF: Bladder preservation protocols in the treatment of musle invasive bladder cancer. Cancer control, 2004:11(6):358-363

3 Laufer M: Transurethral resection and partial cystecyomy for invasive bladder cancer. J surg Oncol, 2000; 18:296-299

4 Shariat SF., Karakiewicz PI., Palapattu G., Lotan Y, Rogers CG et al: Outcomes of radical cystectomy for transitional cell carcinoma of the bladder: a contemporary series from the bladder cancer reasearch consortium. J Urol, 2006; 176:2414-2422

5 Malmström PU. Bladder tumours: time for a paradigm shift? BJU Int. 2011 May;107(10):1543-5..

6 International Collaboration of Trialists on behalf of the Medical Research Council Advanced Bladder Cancer Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies Group), the European Organisation for Research and Treatment. International Phase III Trial Assessing Neoadjuvant Cisplatin, Methotrexate, and Vinblastine Chemotherapy for Muscle-Invasive Bladder Cancer: Long-Term Results of the BA06 30894 Trial. J Clin Oncol. 2011 Apr 18. [Epub ahead of print]

7 Gore JL, Saigal CS, Hanley JM, Schonlau M, Litwin MS; Urologic Diseases in America Project. Variations in reconstruction after radical cystectomy. Cancer. 2006 Aug 15;107(4):729-37.

8 Gerharz E., Mansoon A., Hunt Sonja, Skinner E., Manson W., Quality of life after cystectomy and urinary diversion: an evidence based analysis. J Urol, 2005; 174: 1729-1736


5�

9 Mickisch GH. Partial Cystectomy for Invasive Bladder Cancer. European Urology Supplements 4 (2005) 67–71

10 Hollenbecj BK., Taub DA., Dunn RL., Wei JT. Quality of care : partial cystectomy for bladder cancer- a case of inappropriate use? J Urol. 2005 Sep;174(3):1050-4; discussion 1054

11 Wang CK, Chueh SC. Laparoscopic partial cystectomy with endo-GIA stapling device in bladder diverticular carcinoma. J Endourol. 2007 Jul;21(7):772-5.

12 Tai HC, Chung SD, Wang SM, Chueh SC, Yu HJ. Laparoscopic partial cystectomy for various bladder pathologies. BJU Int. 2007 Aug;100(2):382-5.

13 Rene NJ, Cury FB, Souhami L. Conservative treatment of invasive bladder cancer. Curr Oncol 2009;16:36–47.

14 Efstathiou JA., Bae K. Shipley WU., Kaufman DS, Hagan MP., Heney NM., Sandler HM. Late Pelvic Toxicity After Bladder-Sparing Therapy in Patients With Invasive Bladder Cancer: RTOG 89-03, 95-06, 97-06, 99-06. J Clin Oncol 2009: 27:4055-4061

15 Holybeierlein JM., Lopez- Corona E., Bochner BH., Herr HW., Donat M., Russo P et al.: Partial cystecomy:

a contemporary review of the Memorial Sloan-Kettering Cancer Center experience and recommendation for patient selection. J Urol 2004 ; 172:878-881

16 Michaelson MD, Shipley WU, Heney NM, Zietman AL, Kaufman DS. Selective bladder preservation for muscle-invasive transitional cell carcinoma of the urinary bladder. Br J Cancer. 2004 Feb 9;90(3):578-81.

17 Van Rhijn, B.W.G., Bostrom, P.J., Shariat, S.F., Finelli, A., Sagalowsky, A.I., et al . The FGFR3 mutation identifies patients with favorable disease at radical cystectomy for bladder cancer. Abstract presented at the 26th Annual Congress of the European Association of Urologyrt

18 Gakis G., Todenhoefer T. , Renninger R. , Schilling D., Sievert K-D., Schwentner C. , Arnulf Stenzl A. Development of a new outcome prediction model in carcinoma invading the bladder based on preoperative serum C-reactive protein and standard pathological risk factors: the TNR-C score. B J U International April 2011, Epub ahead of print

19 HW Herr HW, Scher HI. Neoadjuvant chemotherapy and partial cystectomy for invasive bladder cancer Journal of Clinical Oncology, Vol 12, 975-980,

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Radical Surgical Treatment of the Urinary Bladder Cancer : Our Experiences

Anton Maričić, Maksim Valenčić, Romano Oguić, Stanislav Sotošek, Dean Markić, Josip Španjol, Kristian Krpina, Juraj Ahel, Anton Gršković, Dražen Rahelić, Željko Fučkar

Clinic of Urology, University Hospital »Rijeka«, Rijeka, Croatia

AbstractThe goal of the paper was the analysis of patients suffering from the urinary bladder cancer who underwent radical surgical treatment of the urinary bladder and establishing urine derivation. In the 1972-2010 period 2731 patients with the urinary bladder cancer were treated, 315 (11.5%) of whom underwent radical surgical treatment. The average age was between 60 and 80 years – in 224 (71%) patients. In our patients there were 290 patients (92 %) with transitional cell cancers. According to TNM classification, T3 stage in 139(44,1%) patients and T2 stage in 131 (42%) patients were predominant in our study. According to histological criteria, the most common stage was G3 stage – in 224 (71%) patients. Radical cystectomy or combined with urethrectomy was performed in 273 (86,7%) patients. Unfortunately, in 42 (13,3% of them (T3 and T4 stages) the inner iliac blood vessels were tied off due to a progressive cancer. The outer supravesical urine derivation (Bricker, U-tubing nephrostomy, ureterocutaneostomy) was done in 251 (79,7%) patients. The inner derivation (Coffey, ureteroileosigmoidostomy, Mainz-Pouch II) was performed in 28 (8,9%) patients and neovesica (Hautmann,Studer) in 35 (11.1%) patients. There were 79 (25%) patients with early postoperative complications. Among them the most dominant were the surgical complications – in 32 (10,2%) patients and distant organ complications – in 23 (7,3%) patients. In 129 (41%) patients with negative nodes the survival rate was 55% after five years. In 98 (31%) patients with positive nodes the survival rate was 27% after five years.

Key words: urinary bladder neoplasm, cystectomy, urinary diversion, incontinent ileostomy

IntroductionUrinary bladder cancer is the most frequent malignant tumour of the urinary tract, mostly occurring between the age 50 and 70. The risk in the urban areas is 50-150 times greater than in the rural areas¹. Some industries are specifically connected with the urinary bladder cancer. They are chemical, paint, varnish, rubber, oil and gas industries². The workers in high risk industries have 30 times greater chances to get the

urinary bladder cancer in comparison with other population. Four chemical industry carcinogens were discovered: 4-amino-diphenyl-xenylamine, ß-napthylamine, benzidine and 4-nitrodiphenyl.Radical cystectomy is transperitoneal “en block“ extirpation of the urinary bladder, prostate and vesicles together with pelvic lymph nodes. As a rule, this operation includes the extirpation of the uterus, adnexa and the proximal third of the vagina in woman. Nowadays, this surgical intervention is most frequently carried out in case of the invasive urinary bladder tumours. Histological finding of nodes at lymphadenectomy is the only reliable criterion for the assessment of the regional expansion of the disease. This surgical treatment is closely connected with problem of urinary derivation. Each new method of the urinary derivation has been enthusiastically accepted by urologists during this century as a hope that it will be the perfect form of the urinary bladder substitute. Unfortunately, they became disappointed after some time. Each new method of derivation would be more or less accompanied with the same complications: impossibility of physiological way of urination, social problems connected with the artificial orifice and later serious complications, with kidneys especially. Supravesical urinary derivation is called the artificial urinary derivation above the bladder level on the abdomen or into the intestine. It can be performed directly (ureterocutaneostomy), or by the isolated intestinal segment (the ileum or “the colon-conduit“). Bringing the ureter to the intestine can be dual, either with preserved intestinal continuity or using the isolated intestinal segment representing one form of the urinary bladder substitute. Urine can be directly derivated from the kidney, like in surgical and percutaneous nephrostomy.Simon (1875) is considered to be the first one in the history of urology who performed the urinary derivation by simple ureterostomy3. Tizzoni and Foggi (1888) experimentally applied the intestinal segment for the same purpose, while Couvelaire introduced supravesical derivation using the intestine in contemporary surgery4,5. Since then the supravesical urinary derivation has been developed using the most varied methods of the intestinal applications.


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Ureteroileocutaneostomy or “the ileum conduit“ was introduced by Bricker in 1951 in order to avoid bad points (stenosis and infection) of the direct ureterostomy6. The advantages of this method are unquestionable: the possibility of required radical methods in the pelvis and good renal tolerance in this kind of derivation. Bad points are permanent urinary fistula and permanent carrying of the receptaculum. Continent sigma bladder is no doubt the ideal method of preserving physiological and anatomical integrity of the patient7. However, this method is indicated only in primary invasive carcinoma of supratrigonal localisation. The rectal bladder with perineal colostomy according to Nedelec does not leave any physiological orifice the patient would be aware of, enables required radical methods, but it is characterized by greater surgical mortality and greater number of early complications in comparison with other methods8. Since late eighties the priority has been given to reservoirs formed by detubularised intestinal segment. The first urinary bladder substitute by detubularised segment of the ileum was published by Giertz in 19579. The technique with 65 cm long and split segment of the ileum has been known as Camey. Hautmann detubulated the segment of the ileum and reconstructed it in the form of the letter W or M10. Nowadays, the methods of forming isolated urinary continent ileum reservoirs, urinary depots, requesting intermittent catheterization, raise great interest. The first results were presented in 1982 by (Kock)¹¹. The so called “inner urinary derivations“, like ureterosigmoidostomy, introduced in 1911 by (Coffey) still remained¹². It generates hyperchloremic acidosis. Then ureteroileosigmoidostomy was introduced in order to avoid the aforementioned complications. Consequently, there are no ideal methods of derivation. Each of them is characterised, except the common ones, by its specific permanent morbidity, early or late complications, and even a high mortality rate.

Patients and MethodsThe goal of this study was monitoring the patients with the urinary bladder cancer who underwent radical surgical treatment at the Clinic of Urology, University Hospital »Rijeka«, Rijeka, Croatia during the 1972-2010 period. Two thousand seven hundred and five patients suffering from this disease were treated and 315 (11.5%) of them underwent radical surgical treatment (Table 1). Most of the patients, 224 (71%) of them, were between 60 and 80 years old. There were 242 (76.8%) male and 73 (23.2%) female patients. Anamnestic haematuria was the most frequent and the most important symptom of the urinary bladder tumour, being constant in 107 (34%) patients, frequently intermittent in 82 (26%) patients, combined with dysuria in 73 (23.2%) patients

or complicated with anuria and uremia in 28 (8,9%) patients. Less frequent symptom was dysuria in 25 (7,9%) patients.Diagnostic treatment included IVU, the abdominal or transrectal ultrasonography, cystoscopy, endoscopic biopsy and CT. The clinical stage of the disease was assessed on the basis of results of the aforementioned procedures and determined using the TNM classification. The tumours were divided according to the histological criteria on well differentiated (G1), moderately differentiated (G2) and poorly differentiated (G3) (Table 2).Radical surgical treatment was indicated after the endoscopic verification of the tumour and its TNM and histological classification, depending on the clinical state of the patient. Radical cystectomy, alone or in combination with urethrectomy, was successfully performed in 273 (86,7%) patients (Table 3). In connection with this operation, the problem of the urinary derivation poses itself. The outer derivation, ureteroileocutaneostomy sec. Bricker was most frequently used in our patients – in 245 (77.8%) of them (Table 4).We divided our postoperative complications into the early ones and the late ones. There were 79 (25%) patients with early postoperative complications (Table 5).Control examinations have been performed in 3-month intervals. The control includes the analysis of laboratory findings and the acidic basal status, abdominal ultrasonography and chest x-ray. The shortest observation lasts three months, and the longest 20 years. The progression of the disease during the observation time implies the occurrence of metastases and the progression of local findings.

ResultsDuring the 1972-2010 period 2731 patients with the urinary bladder cancer were treated, 315 (11,5%) of whom underwent radical surgical treatment (Table 1)13. The progressive increase of newly detected carcinomas and the number of radical operations are evident.Males have been exposed to a greater than females. The sex ratio is being changed with a change of social role of females. This relation was 8:1 in the early 19th century, being nowadays only 2-3:1 in favour of males. There were 242 males and 73 females .High frequency of the urinary bladder cancer has been also observed in people who smoke more than 22 cigarettes a day. There were 207 (65,7%) smokers.Haematuria is the most frequent and the most important symptom of the urinary bladder cancer. It is either continuous or, frequently, intermittent with intervals without bleeding. It can be macroscopical and microscopical and the level of haemorrhage does not correspond to the tumour volume. Haematuria, alone or combined with dysuria, dominated in


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our patients - in 289 (91,7%) of them. The next symptoms were dysuric difficulties characterized by frequent and painful urination in 8,3% of the patients¹. The symptoms caused by distant metastases made the third group. These symptoms were significantly less frequent in this kind of tumour, compared with the other kinds of carcinomas, because about 70% of the carcinomas were localised in the urinary bladder at the moment of the first diagnosis, and only 7% of them showed the clinical signs of distant metastases1. Most of these tumours are the transitional cell carcinomas. Planocellular tumours make only 5% of the epithelial tumours of the urinary bladder. Finally, 1% of the epithelial tumours belong to adenocarcinomas, which are considered to originate from the aberrant prostatic acinuses. In our population there were 290 (92%) patients with transitional cell carcinoma, 19 (6%) patients with planocellular tumours and 6 (2%) patients with adenocarcinomas.The invasive urinary bladder tumour metastasizes in the regional lymph nodes16. Lymphadenectomy was performed in 227 (72%) patients. The nodes were positive in 98 (31%). Haematogenous dissemination regularly develops during the later stage of the disease, involving bones (the pelvis and the lumbar spine), then liver, the kidneys and the lungs.

Discussion There are three basic characteristics of the urinary bladder tumour, on which the prognosis of the disease and the therapy choice depend: the tendency to wall penetration, the tendency of transitional cell dysplasia and the tendency to change the quality of the mucous membrane of the primary tumour surroundings.According to TNM classification, T3 stage in 139 (44.1%) patients and T2 stage in 131 (42%) patients were predominant in our study. According to histological criteria the most common stage was G3 stage in 224(71%) patients.It is very important to make preoperative preparatory measures before bringing decision on surgical treatment. It is especially important for the patients with accompanying diseases that encumber postoperative recovery. There were accompanying diseases in 119 (37,8%) patients. The most common were: heart and lungs diseases in 74 (23.3%) patients, diabetes in 37 (11,7%) patients and the diseases of the digestive system in 8 (2,5%) patients. Radical cystectomy alone or combined with urethrectomy, was performed in 273 (86,7%) patients (Table 3). Three patients underwent unilateral nephroureterectomy because of renal dysfunction. One uremic patient underwent bilateral nephroureterectomy before the cystectomy was performed. Unfortunatelly, the inner iliac blood vessels were tied off in 13,3% of patients (T3 and T4 stages) due to progressive tumours.

The great problem is what kind of urinary derivation has to be done. Demands for normal social activities do not fit into medical criteria, into postulates of radical oncologic surgery especially. Consequently, various nonmedical conditions influence the choice of method of derivation: the age of patient, occupation, the stage of civilisation and health education, financial – economic potentials etc. One of the pioneers of modern urology Howard Hanley says that it is a pure hypocrisy from us to claim that we healed the patient who underwent the abdominal urinary derivation and has been forced to carry the receptaculum under his shirt for the rest of his life17. The continent bladder, that would ensure safe excretion under own control and in a standing position (men), most frequently eliminates the possibility of radical intervention (cystourethrectomy). A golden mean that would meet both the criteria has not been found yet. In other words, all kinds of urinary derivations are predominantly methods of necessity.Modern era of ureterointestinal derivations started in 1911 with Coffey`s description of “tunnel“ technique for the implantation of ureters into the colon. Ureterosigmoidostomy represented the most popular way of the urinary derivation till 1950, when Bricker described ureteroileal cutaneous derivation. We used this kind of derivation in 16 (5%) patients till 1985. This method of supravesical derivation has been almost abandoned nowadays because of numerous complications which can be divided into the early ones and the late ones. The most frequent early complication is anuria developing from the oedema or the obstruction of ureterocolic anastomosis with faeces and the mucous membrane. Urine drainage can occur on the anastomosis with the ileus as the consequence. Late complications are pyelonephritis, calculi, ureteral obstruction and electrolytic instability. Seven of our patients developed hyperchloremic acidosis as the commonest complication. They were treated with bicarbonate compensation. One of them developed paralytic ileus. However, it must not be forgotten that this method has certain advantages, like low immediate operative mortality and morbidity. It is also important to point out that ureterosigmoidostomy does not leave any outer artificial orifice. Making efforts to improve this method because of numerous complications, the ureteroileosigmoidostomy was developed. This is so called antireflux ureterosigmoidostomy or “the inner Bricker“18. The interposed segment of the ileum, together with antireflux barrier on the anastomosis with the colon, prevents reflux from the large intestine. In spite of the decreased number of manifest pyelonephritises, persistent hyperchloremic acidosis occurred in 1/3 of our patients. This method was performed in 9 (2,9%) of our patients. Ureteroileocutaneostomy or “the ileum conduit“ was introduced by Bricker in order to avoid bad points (stenosis


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and infection) of the direct ureterostomy6. The advantages of this method are unquestionable: the possibility of required radical treatment in the pelvis and good renal tolerance in this kind of derivation. Bad points are permanent urinary fistula and permanent carrying the receptaculum. This method of derivation was performed in most of the patients, i.e. in 245 (77.8%) of them (Table 4). It was usually carried out in combination with radical cystectomy or without it in inoperable cases with ligation of the iliac blood vessels. Since late eighties the priority has been given to reservoirs formed by detubulated intestinal segment. Hautmann detubulated the segment of the ileum and reconstructed it in the form of the letter W or M. Studer (1988) described asymmetrically joined segment of the ileum 65 cm long, in the shorter end which he implanted the ureters. He split longitudinally the longer part and connected it into a hypotonic bladder19. It is especially important because the orthotopic bladder substitute enables the physiological way of urination and higher quality of life. New bladder sec. Hautmann was performed in 34 (10,8%) patients. Neovesica sec. Studer was carried out in one female patient, what is very rare in women. U-tubing nephrostomy or ureterocutaneostomy were performed in the remaining kidney in 6 (1,9%) patients in case of the disfunction of one kidney or the former nephrectomy. Mainz-Pouch II of the inner derivation was performed in two patients. There were 79 (25%) patients with early postoperative complications. Among them dominated the surgical complications in 32 (10,2%) patients and distant organs complications in 23 (7,3%) patients (Table 5). Wound dehiscence in 9 (2.8%) patients and ileus in 8 (2.5%) patients were the most frequent surgical complications. The secondary sutures were placed in cases of dehiscence. Two patients with the ileus underwent adhesiolysis and one patient adhesiolysis and ileotransversostomy. One ileus was solved with the ileum resection and ileostomy. Four patients with ileus were treated conservatively using Miller-Abbott tube.Bronchopneumonias in 7 (2.2%) patients and cerebral insults in 4 (1.3%) patients dominated among organ complications, and they were treated conservatively. One patient with melena was treated by washing out and blood transfusions. Pyloroplasty and vagotomy were done in one bleeding duodenal ulcer. Two pulmonary embolisms were the most difficult complications which ended lethally. Hyperchloremic acidosis was the most frequent complication in 11 (3,5%) patients connected with operation sec. Coffey and ureteroileosigmoidostomy. It was treated with adequate bicarbonate doses. There were unclear febrile cases among general

complications in 13 (4,2%) patients. Four patients developed septic temperatures. Pseudomonas aeruginosa in 2 patients, Seratia in 1 patient and Staphilococcus pyogenes in 1 patient were isolated in haemoculture. Urinary infection in 12 (3.8%) patients and ileus in 7 (2.2%) patients that were mainly treated conservatively, dominated among late complications. Two patients underwent adhesiolysis. Two ureteral strictures, calculus in the urinary bladder, two ureteral tumours and three ureteral stenoses were treated with endoscopy. There were three stomal stenoses and four stomal hernias that were solved with front abdominal wall plastic. The abscess of postoperative section was treated with the incision and drainage in three patients, while one patient with ureterorrhagia from the residual part of the ureter underwent urethrectomy. One stercoral fistula was solved conservatively.In 129 (41%) patients with negative nodes the survival rate was 55% after five years. In 98 (31%) patients with positive nodes the treatment continued with radiotherapy and chemotherapy. The survival rate was 27% after five years. The worst prognosis was in the group of patients (13,3%) in whom cystectomy could not be done due to the progressive process. The iliac blood vessels were tied off in these patients, and they were treated with radiotherapy and chemotherapy. The survival rate was about 7% after one year.

ConclusionUrinary bladder cancer is the most frequent malignant tumour of the urinary system. It has been in tremendous increase. During 1972-1980 period there were 89 patients and in the 2000-2010 period even 1809 patients. It is the increase of 21 times, partly because of better diagnostics and education of the inhabitants. Three hundred fifteen patients underwent radical surgical treatment. Most of them, 224 (71%) patients, were over 60 years old. The cancers are more and more malignant and progressive in the diagnostic T3 stage patients (44.1%).Surgical treatment is a method of choice and the way of giving chances for full cure, if carried out in the early stage. The survival rate in this group of patients was 55% after five years. Supravesical urinary derivation is the attractive intervention for the surgeon and desperate solution for the patient, which cannot always fulfil the medical and social aspects of treatment of frequently incurable disease. Medical and social aspects of supravesical urinary derivation most often reciprocally clash, because fulfilling medical criteria aggravates or makes impossible the social life of the patient. The continent bladder, that would ensure safe excretion under own control and in a standing position (in men), most frequently eliminates the possibility of radical treatment


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(cystourethrectomy). In other words, all kinds of the urinary derivations are predominantly methods of necessity. Thus, majority of our patients (77.8%) have ileostomy, because they underwent surgical intervention in the progressive stage of tumour, and in whom neovesica could not be done due to the progressive process in the pelvis. Finally, the prognosis of the disease and the quality of patient’s life depend on as early and as fast as possible diagnosis, as well as on adequate surgical treatment.

References

1. LEVIN ML, J Natl Cancer Inst, 24 (1960) 1243. 2. VEYS C, Br J Ind Med, 31 (1974) 65. 3. SIMON CJ, Samml Klinik Vort, 88 (1875) 694. 4. TIZZONI G, FOGGI A, Centrbl Chir, 50 (1888) 921. 5. COUVELAIRE R, J Urol, 57 (1951) 408. 6. BRICKER EM, Surgery, 32 (1952) 372. 7. HRADEC E, Urologie, 2 (1966) 56. 8. NEDELEC M, Urol Int, 22 (1967) 47. 9. GIERTZ G, FRANKSSON C, Acta Chir Scan, 113 (1957)

218. 10. HAUTMANN RE, EGGHARDT G, FROHNEBERG D,

MILLER K, Urologie, 26 (1987) 67. 11. KOCK NG, NILSON AE, NOVLEN L, SUNDIN T, TRASTI

H, Scand J Urol Nephrol, 49 (1978) 23. 12. COFFEY RC, JAMA, 56 (1911) 397. 13. ĐORĐEVIĆ G, PEITL V, SINOŽIĆ E, MUSTAĆ E,

Medicina, 42 (2004) 147. 14. FLOCH RH, JAMA, 145 (1951) 295. 15. NOVAK R, DIMANOVSKI J, FIŠTER H, KRAUS O,

TRNSKI D, Lijec Vjesn, 106 (1984) 402. 16. PUGH RCB, Course of the British Council on urological

malignancies, London, 1979. 17. HANLEY HG, Br J Urol, 39 (1967) 693. 18. NOVAK R, Eur Urol, 7 (1981) 118. 19. STUDER U, ACKERMAN D, CASANOVA GA, ZINNG

EJ, Semin Urol, 6 (1988) 57.

Table 1NUMBER OF RADICAL URINARY BLADDER OPERATIONS WITH THEIR ANNUAL DISTRIBUTION

1972-1980

1981-1989

1990-1999

2000-2010

Total

No. of patients 89 196 637 1809 2731No. of radical operations

14 23 125 153 315

Table 2CLASSIFICATION ACCORDING TO HISTOLOGICAL CRITERIA

Tumour grading No. of patients (%)G1 12 (3.8%)G2 79 (25,1%)G3 224 (71.1%)

Table 3TYPES OF SURGICAL TREATMENTS Type of operation No. of patients (%)Radical cystectomy 221 (70.2%)Radical cystectomy + urethrectomy 47 (14,9%)Radical cystectomy + nephroureterectomy

5 (1.6%)

Ligatura aa. Illiaca 41 (13%)Cystectomy and resection of colon sygmoideum

1 (0.3%)

Table 4TYPES OF SURGICAL DERIVATION

Type of operation No. of patients (%)Ureterosigmoidostomy sec. Coffey 16 (5%)Ureteroileosigmoidostomy 9 (2.9%)Ureteroileocutaneostomy sec. Bricker

245 (77.8%)

Neovesica sec. Hautmann and Studer

35 (11.1%)

Mainz-Pouch II 3 (0.9%)U-nephrostomy and UCNS 6 (1.9%)

Table 5EARLY POSTOPERATIVE COMPLICATIONS

Type of complications No. of patients (%)Surgical complications 32 (10,2%)Complications on distant organs 23 (7,3%)Metabolic complications 11 (3.5%)General complications 13 (4,1%)


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Modification of Padovana ileal neoblader V. Sekulić, J. Bogdanović, G. Marušić, J. Đozić, R. Herin

Clinic of Urology, Clinical Centre of Vojvodina, Novi Sad, Serbia

Objective: This paper is aimed to present our modification of Padovana ileal neobladder using 40 cm of isolated segment. We are not aware of any previous report of similar technique in available literature.

Material and methods: 10 patients uderwent modified Padovana ileal neobladder following radical cystectomy at our institution during the period 2008 to 2010. Median age of patients were 59 years (range 45-70). Median follow up was 16 months (range 6 -36). Patients have been monitored using standard follow-up protocol according to the EAU giuidelines with urodynamic evaluation 6 months after surgery.

Results: Perioperative, early and late postoperative mortality have not been noticed. There were only 2 major complications: 1 patient (10%) with prolonged postoperative ileus and 1 with prolonged urinary leakague requiring percutaneous nephrostomy and subsequent ureteral reimplantation due to stenosis of ureterovesical anastomosis. There was no significant metabolic disorders.Average ileal neobladder capacity was 450 ml. Daytime and night continence were achieved in 9 (90%) and 6 (60%) of patients, respectively.

Conclusion: This modification of VIP neobladder has not been difficult to perform in our hands. In our opinion this technique provides clear advantage in easier ureteral implantation proximally than in original technique, requireing less length of ureter. Initial encouraging results should be confirmed in further clinical pratice.

IntroductionUrinary diversion has a history of nearly 150 years (1), and the ileal conduit has been considered as gold standard for urinary diversion. Orthotopic bladder substitution following radical cystectomy is well established currently. This procedure avoids an abdominal stoma and improve quality of life for patients undergoing radical cystectomy. (2,3,4,)In 1958, Maurice Camey, was using an ileal segment, performed an othotopic ileal bladder substitute for the urethra. After animal experiments in 1983 and 1984, ileal orthotopic bladder substitute with afferent ileal loop was introduced by UE Studer from University of Bern. In 1985, Hauttman created detubularized ileal neobladder. During the 1980s and

1990s, various orthotopic ileal neobladder urinary diversion techniques have been described, such as the Kock ileal neobladder in 1986, Vesica Ileale Padovana (VIP) in 1990 which we prefer.(2, 5,6,7, 8,9, 10, 11)In our institution we have used Studer, Hattman and VIP continent diversion after radical cystectomy. In the present study, we reviewd our modification VIP ortotopic bladder substitution.

Patients and methodsDuring the period 2001 to 2011, 319 patinets underwent radical cystectomy in our instituion. Out of them, 79 patinets received ileal orthotopic bladder substitution: Padovana ileal neobladder, modified padovana neobladder, Hautman and Studer orthotopic bladder replacement in 35, 10, 25 and 19 patients respectively. Other patients underwent heterotopic urinary diversion using dry or wet stoma.During the last 3 years 10 patients underwent modified VIP following radical cystectomy.

TechniqueBriefly, an ileal segmet 40 cm in length was isolated 25 to 30 cm proximal to ileocecal valve. An isolated ileal segment was detubularised along antimesenteric border in full lenght (Figure 1a). Aboral part of isolated ileum was folded inV-shape in the length 9 cm. Bladder neck is created by 2 running vicryl 3/0 sutures as shown on Figure 1b. The rest of isolated ileal segment is folded in form of letter M. The medial armes of M letter serve for creation of a 4 cm serosal tunel for ureteres, providing anireflux mechanism. (Figure 1c). Ureteral anastomoses are protected by splint 6 to 8 Fr. Finaly, created “M” plane is folded anteriorly and sutured to anterior part of neobladder neck using vicryl+ 3/0. Neobladder-urethral anastomosis is created with 6 interrupted sutures over 18 Fr three channel Foley catheter.

Follow-upAll patients were followed every 3 months during the first year, thereafter 2 times and once yearly, before and after 5 years respectively. Upper urinary tracts status was assesed using IVP or CT urography. Renal function was analysedusing a blood urea nitrogen and a creatinine measurement, and metabolic funtion was assesed using a blood gas analysis. Lower urianry tract function was measured by uroflowmetry and urodynamic evaluation 6 months after surgery.


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Daytime and nighttime incontinence was asses by interviwe.

Figure 1. a) isolated ileal segment 2) detubuarized ileal segment with creation of bladder neck 3) “M|” shaped dorsal side of neobladder with serosal tunels providing antireflux mechanism 4) final aspect of modified bladder

ResultsPerioperative, early an late postoperative mortality have not been noticed. There were only 2 major complications: 1 patient (10%) with prolonged postoperative ileus and 1 with prolonged urinary leakague requiring percutaneous nephrostomy and subsequent ureteral reimplantation due to stenosis of ureterovesical anastomosis. There was no significant metabolic disorders.Average ileal neobladder capacity was 450 ml. Daytime and night continence were achieved in 9 (90%) and 6 (60%) of patients, respectively.

ConclusionThis modification of VIP neobladder has not been dificult to perform in our hands. In our opinion this technique provides clear advantage in easier ureteral implantation proximally

than in original technique, requireing less length of ureter. Initial encouraging results should be confirmed in further clinical pratice.

Literature

1. Simon J. Ectopia vesicae (absence of the anterior wall of the bladder and pubic abdominal parietes): operation for directing the orifices of the ureters into the rectum. Temporary success: subsequent death: autopsy. Lancet 1952;2:568

2. Basic DT, Hadzi-Djokic J, Ignjatovic I, The history of urinary diversion. ACI Vol. LIV, 9-17

3. Wataru Obara, Kazumasa Isurugi, Daisuke Kudo, Ryo Takata, Karen Kato,Mitsugu Kanehira, Kazuhiro Iwasaki, Susumu Tanji, Ryuichiro Konda and Tomoaki Fujioka,Eight Year Experience with Studer Ileal Neobladder Jpn. J. Clin. Oncol. (July 2006) 36(7): 418-424

4. Studer UE, Danuser H, Merz VW, Springer JP, Zingg EJ. Experience in 100 patients with an ileal low pressure bladder substitute combined with an afferent tubular isoperistaltic segment. J Urol 1995;154:46–56

5. Hautmann RE, Miller K, Steiner U, Wenderoth U. The ileal neobladder: 6 years of experience with more than 200 patients. J Urol 1995;150:40–5

6. Studer UE, Danuser H, Thalmann GN, Springer JP, Tunner WH. Antireflux nipples or afferent tubular segment in 70 patients with ileal low pressure bladder substitutes: long-term results of a prospective randomized trial. J Urol 1996;156:1913–17

7. Hautmann RE, Abol-Enein H, Hafez K, Haro I, Mansson W, Mills RD, et al. Urinary diversion. Urology 2007;69:17-49

8. Hautmann RE. Urinary diversion: ileal conduit to neobladder. J Urol 2003;169:834-42

9. Abol-Enein H, Ghoneim MA. Functional results of orthotopic ilealneobladder with serous-lined extramural ureteral reimplantation:experience with 450 patients. J Urol 2001;165:1427–32.

10. Giacomo Novara, Vincenzo Ficarra,, Anila Minja, Vincenzo De Marco, Walter Artibani. Functional Results Following Vescica Ileale Padovana (VIP)Neobladder: Midterm Follow-up Analysis with ValidatedQuestionnaires Eur Urol ; 57: 1045 – 1051

11. Pagano F, Artibani W, Ligato P, Piazza R, Garbeglio A, Passerini G.Vescica Ileale Padovana: a technique for total bladder replacement. Eur Urol. 1990;17(2):149-54


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Izkušnje z zdravljenjem bolnikov s karcinomom mehurja po odprti ali laparoskopski radikalni cistektomiji v intenzivni enoti:

retrospektivna analizaICU experience with Bladder Cancer patients after open or laparo-

scopic radical cystectomy: retrospective analysisJasna Uranjek, Darja Kasnik

Oddelek za anesteziologijo in intenzivno medicino operativnih strok, Splošna bolnišnica Slovenj Gradec, Slovenija

Department for anaesthesiology and intensive care medicine, General Hospital Slovenj Gradec, Slovenia

Introduction: Bladder cancer is the second most common genitourinary malignancy and it ranges from mild disease with a low mortality rate to extremely high-grade tumors associated with high mortality (1). Radical cystectomy with pelvic lymphadenectomy (open or laparoscopic approach) remains the gold standard for the treatment of muscle invasive bladder cancer (2,3). Since bladder cancer is a tumor entity of the elderly who have many coexistent diseases these patients need good peri-operative care. Different peri-operative protocols, adapted to hospital possibilities and capabilities, are used. So, we performed an analysis of our protocol and looked for ways how to improve it.

Material and methods: A retrospective analysis of medical charts of patients who had radical cystectomy due to bladder carcinoma and were treated in our Intensive Care Unit (ICU) from 1.1.2000 till 30.4.2011 was made. Till 2004 only open radical cystectomy (ORC) was performed in our hospital, since May 2004 also laparoscopic radical cystectomy (LRC) is performed. The change in surgery type changed some postoperative needs and protocols, so we decided to analyse and compare postoperative course after ORC and LRC. Patients were divided into group O (open) and group L (laparoscopic) according to the surgery type. Patient’s biometrical, anaesthesiological and surgical data were collected. All complications during ICU stay, ICU and hospital length of stay (LOS), ICU and hospital mortality rate and six month, one year and five years survival rate were recorded. Data was analysed with SPSS 16.0 programme and p value < 0, 05 was considered as statistical significant different.

Results: 65 patients were treated in our ICU during reviewed period. Type and frequency of the operation are shown in graph 1. Patients’ major differences in biometrical, anaesthesiological and surgical data are shown in Table 1. No serious anaesthesiological complications were recorded. All but 3 patients were admitted to our ICU directly after surgery for more intensive monitoring and supervision. The ICU complications during early post-operative period developed statistically significant more frequently in group O. The most frequent complications were wound infection (9% group O, 4, 7% group L), pneumonia (7% group O, 0% group L), anastomotic leakage on different anastomosis (6, 8% group O, 0% group L) and SIRS/sepsis (9% group O, 4, 7% group L). There was no statistical difference between groups in frequency of either of stated complications. Re-admittance to ICU was more frequent in group O with longer second ICU LOS (3,8±8,9 days in group O versus 0,14±0,6 days in group L, t-test, p=0,04). Follow up data are inconclusive because 21 patients (47%) in group O and 16 patients (76%) from group L were only operated in our hospital. Their later, regular follow up is/was done by their home urologists. So the results might be different/better if we had all the data. The survival curve of the known data is showed on graph 2 and it suggests better survival after LRC, although not statistically significant (Log Rank 0,094).

Discussion: The collected data showed increasing number of laparoscopic operations which had less intra-operative blood loss with consequently smaller needs for intra-operative blood transfusion, lower early ICU complication rate, smaller needs for re-admittance to ICU and shorter hospital LOS.


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However, laparoscopic operations do carry a distinct risk of complications despite of minimal invasiveness and according to some studies the incidence of typical anaesthesiological complications is higher compared to open operations (4). No record of serious anaesthesiological complications was found in our reviewed medical charts. We believe that one of the reasons for this is our experience with laparoscopy because laparoscopic operations are standard and routine practice in all fields of surgery in our hospital although urological laparoscopic operations do have their own entities (5). Smaller intra-operative blood loss with consequently smaller needs for blood transfusion is one of the biggest advantages of LRC over ORC since peri-operative anaemia and blood transfusion are associated with excess morbidity and mortality (6). Our ORC group had higher intra-operative blood loss and higher early post-operative complications rate. Besides blood loss, known risk factors for serious peri-operative complications are age, ASA score >2 and prior pelvic/abdominal surgery (7). Other three factors didn’t differ between both our groups. Nevertheless, besides higher blood transfusion rate in ORC group, post-operative fasting was longer in ORC group. The benefits of early enteral nutrition post-operatively for reduction of infection rate, better nitrogen balance, shorter hospital LOS with tendency for risk reduction for anastomotic dehiscence have been confirmed may times (8). Also, early enteral nutrition does not lead to increased rate of post-operative ileus or to oral food intolerance (9). In last few years our ICU protocol does include early post-operative enteral feeding for all patients.

Our hospital LOS is a little longer as cited by the literature (10).We believe one of the reasons for this is the fact, that approximately half of the patients operated in our hospital don’t live near. So, we want to be sure in everything before patient’s discharge which sometimes prolongs hospital LOS.

Finally, our analysis showed postoperative follow up which should/could be better. The patients who didn’t live near our hospital returned to our institute only for the first postoperative check, later they were followed by their home urologists or oncologists and were lost from our follow up system. How to improve that is one of the problems which were revealed with this study.

Conclusion: From ICU point of view, LRC has many advantages over ORC and should be done whenever possible according to surgical and oncological demands.

Literature:

1. Sharma S, Ksheersagar P, Sharma P. Diagnosis and treatment of bladder cancer. Am Fam Physician. 2009 Oct 1;80(7):717-23.

2. Castillo OA, Abreu SC, Mariano MB, Tefilli MV, Hoyos J, Pinto I, Cerqueira JB, Gonzaga LF, Fonseca GN. Complications in laparoscopic radical cystectomy. The South American experience with 59 cases.Int Braz J Urol 2006;32:300-05.

3. Madersbacher S, Hochreiter W, Burkhard F, Thalmann GN, Danuser H, Markwalder R, Studer UE: Radical cystectomy for bladder cancer today – a homogeneous series without neoadjuvant therapy. J Clin Oncol 2003; 21:690–696.

4. Complications and contraindications of laparoscopic surgery.In: Crozier TA. Anaesthesia for minimally invasive surgery.Cambridge University Press 2004

5. I. D. Conacher*, N. A. Soomro and D. Rix Anaesthesia for laparoscopic urological surgery. Br J Anaesth 2004; 93: 859–64

6. Kumar A. Perioperative management of anemia: limits ob blood transfusion and alternatives to it. Cleve Clin J Med 2004:76 Suppl 4;S112-8.

7. Shabsigh A, Korets R, Vora KC, et al. Defining early morbidity of radical cystectomy for patients with bladder cancer using a standardized reporting methodology. Eur Urol 2009;55:164.

8. Shrikhande SV,Shetty GS,Singh K,Ingle S. Is early feeding after major gastrointestinal surgery a fashion or an advance? Evidence based review of literature.J Can Res Ther 2009;5:232-9.

9. Han-Geurts IJ,Hop WC,Kok NF,Lim A,Brouwer KL,Jeekel J. Randomized clinical trial of the impact of early enteral feeding on postoperative ileus and recovery. Br J Surg 2007;94:555-61.

10. Hautmann RE,Volkmer BG, Schumacher MC et.al.Long-term results of standard procedures in urology: the ileal neobladder. World J Urol 2006;24:305-314.


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Graph 1: The number and type of the operation

Graph 2: Survival data


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Table 1: Patientsd biometrical, anaesthersiological and surgical datas

GROUP O GROUP L P VALUENumber 44 21

Age (years)* 65,0±9,44 67,0±9,26 0,43

Sex (male/female) 37/7 16/5 0,44

BMI * 26,0±4,10 28,1±3,86 0,50

ASA score* 1,89±0,78 1,81±0,60 0,78

Operative time (minutes)* 360±98,1 390±83,2 0,22

Estimated blood loss (ml)* 1483±480 475±35 0,01

Intraoperative blood transfusion (yes/no)** 40/2 1/20 <0,001

Postoperative blood transfusion (yes/no)** 27/17 5/16 0,005

Postoperative fasting >24 hours (yes/no) 21/23 4/17 0,02

First ICU LOS (days) ** 4,23±3,6 4,81±7,9 0,73

ICU complication rate during first ICU stay** 20 3 0,01

Re-admittance to ICU(yes/no)** 11/33 1/20 0,04

ICU death (number)** 3 1 0,73

Hospital LOS(days)* 30,8±27,2 19,9±7,0 0,07

Six month survival** 13 32 0,37

One year survival** 9 28 0,11

Five years survival** 8 1 0,16

BMI – body mass index, ASA – American Society of Anesthesiologists, ICU- Intensive care medicine, LOS – length of stay, *t-test, **χ2 test


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Quality of life after radical cystectomy measured by “Sickness impact profile” score

A. Prcić, D. Aganović, B. Kulovac, O. Hadžiosmanović

Urology Clinic, Clinical Center University of Sarajevo, Bosnia and Herzegovina

Objective: to evaluate the quality of life among patients with orthotopic urinary diversion and ileal conduit following the radical cystectomy.

Methodology: the quality of life in the period of 6 months following the radical cystectomy has been analysed among 98 patients who underwent surgery at the Urology Clinic of the Clinical Center University of Sarajevo between January 2007 and January 2011. Patients were divided in two groups, one with orthotopic urinary diversion developed by Hautmann and Ghoneim, and the other with ileal conduit diversion. ‘Sickness Impact Profile’ (SIP) score has been used in this paper as a tool to measure the quality of life.

Results: 98 patients with ortotopic diversion and ileal conduit urinary diversion have been evaluated during four years

period. Average age of the patients was 65.15 years. 75 male and 23 female patients were treated for invasive bladder cancer. 20 patients underwent orthotopic diversion according to Hautmann and 12 according to Ghoneim. Remaining 66 patients underwent ileal conduit urinary diversion. Average SIP score amounted to 35% among patients who underwnet ileal conduit and 19% among those who underwent orthotopic diversion.

Conclusion: Analyses of the quality of life measured by SIP score gives considerable advantage to patients with orthotopic diversion in comparison with those with ileal conduit diversion. More importantly, it has been demonstarted that quality of life, as measured by SIP score, is reasonable and applicable for both groups of patients.


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Quality of life in patient with orthotopic neobladderI. Vuković, S. Mićić, N. Bojanić, D. Djordjević

Clinic of Urology, Clinical center of Serbia, Belgrade, Serbia

Abstract: Introduction: The aim of this study was to estimate the QoL in patients with orthotopic neobladder (sec Hauptman) and ileal conduit after the radical cystectomy and to show the possible advantages of orthotopic urinary diversions.Patients and methods: From 1998 to 2010 orthotopic derivation sec. Hauptman was performed in 65 pts due to bladder carcinoma at urologic clinic in Belgrade, but only 34 patients answered the questionnaire. Ileal conduit group had 34 patients of similar age and gender. The quality of life after the radical cystectomy in these two groups of patients was analysed with FACT-BL (Functional Assessment of Cancer Therapy-Blader) questionnaire.

Results: We have not found statistical differences among the investigated groups using the FACT-G questionaire in some domains. The difference in QoL achieved for orthotopic neobladder with FACT-G in total score was annulated by the results of the questions from specific subscale and the total score of FACT-BL has shown no statistical difference between the groups. The only difference was found for some questions in specific subscale concerning the incontinence and body image.

Conclusion: Using the FACT-BL questionaire statistical differences in QoL between orthotopic neobladder and ileal conduit group could not be achieved. Despite this fact, orthotopic neobladder group would suggest this type of urinary derivation to others because of the preservation of the body image despite the presence of some level of night incontinence.

IntroductionIleal conduit, the gold standard in urinary derivation, started to step away in front of new numerous orthotopic derivations twenty years ago. Different orthotopic derivation was formed from different parts of small bowel or colon and had the same goal to improve the patient’s quality of life. The basic principals of newly formed reservoirs were big capacity, low intraluminal pressure, high compliance, to protect upper urinary tract, minimal urinary absorption, continence and to allow urination per urethra. The medical aspect was satisfied with orthotopic bladder because it was functionally very

similar to normal bladder. On the other hand, the life without stoma from psychological and cosmetic reasons allows easier rehabilitation, better incorporation to regular life activities, better social accommodation and finally overcoming of all psychological problems connected with stoma. Frequently, this type of operation presents some type of compromise between medical and social needs. Naturally, the ideal method of continent urinary diversions does not exist but there is permanent need to do better surgical procedure which can provide similar functional characteristics of normal bladder.

Patients and methods From 1998 to 2010 orthotopic derivation sec. Hauptman was performed in 65 pts due to bladder carcinoma at urologic clinic in Belgrade. The QoL questionnaire was sent to all, but only 34 patients reply with full field questions. The Hauptman procedure was performed according to the original operative technique, the preservation of external sphincter was achieved with Walsh technique of radical prostatectomy. The other group consists of 34 patients with radical cystectomy and ileal conduit of similar age and gender due to achieve the homogeneity of groups.The quality of life after the radical cistectomy with orthotopic derivation and ileal conduit was analysed with FACT-BL (Functional Assessment of Cancer Therapy-Bladder) questionnaire translated and adjusted to serbian language. According to this questionnaire we compare the QoL of the same number of patients with orthotopic bladder and ileal conduit urinary derivation. The questionnaire consists of FACT-G (the standard version for accuracy of malignant disease treatment) which was analysed in different type of malignant diseases and Appendix, consisting of 12 questions connected with simptoms of urinary and digestive organs as well as sexual function which makes it specific for patients operated due to bladder cancer and presents specific subscale. The score of the specific subscale, plus the score of FACT-G, present FACT-BL.At the end of the questionnaire, an additional question was included: Would you suggest the same derivation to other patients with invasive bladder cancer?


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The above mentioned FACT-G, include the following four domains analysed:Physical well-being (maximum points is 28)Social and family well-being (maximum points is 28)Emotional well-being (maximum points is 24)Functional well-being (maximum points is 28)

The first four domains are same for all types of malignancies and make FACT-G questionaire with maximal score of 108.Specific subscale of additional worries, as the last group of 12 questions, is concerned the simptoms of urinary and digestive tract and the mark of sexual function. Two questions concerning only to patients with stoma as well as the question about the erection was not calculated in the total score of specific subscale. Higher number in each domain as well as in total score (FACT-G and FACT-BL) suggest better QoL.The parameters were analysed with Student t-test at the level of significance p<0.05.

ResultsThe results of questionnaire are presented in Table 1.The first domain (physical well-being) in both groups had high scores but without statistically significant differences. The same has happend with the second domain. The third domain also has no statistically differences. The fourth domain also did not reach statistical differences. The total score of all four domains, what form FACT-BL, was 86,53 to 84,06 (p=0,020). QoL was better in the group of orthotopic bladder derivation according to the Student t-test despite the fact that the difference was not present among the domains separately. The last group of questions, concerning to the additional worries, had the same scores in both groups (p>0.05). In the subscale group, higly significant statistical difference was found for the question concerning the continence in the ileal group of patients, 1,6 to 3,1 (p=0, t= -5,753), and on the other hand the question about the body image in the group of orthotopic neobladder, 3.9 to 2,2 (p=0, t=9,470), but withut the effect on the total score of specific subscale. The sum of FACT-G points and specific subscale points which form the FACT-BL was 112,21 in the orthotopic bladder group and 109,47 in the ileal conduit group (p=0,055). Student t-test did not show any difference among the groups so we did not succed to show statisticaly significant difference in the QoL in the orthotopic bladder group over the ileal conduit group of patients. 91% of pateints with orthotopic bladder vs 41% of ileal conduit group positively answered the question - would you suggest the same derivation to other patients with invasive bladder cancer.

DiscussionAccording to the study that we have performed, QoL analysed by FACT-BL questionnaire in the group of patients with orthotopic neobladder had no statistical differences with ileal conduit group. Differences was shown only in the group of questions concerning cosmetic effects of surgical procedure where the personal satisfaction of the cosmetic effect was statistically significantly higher in the group with orthotopic neobladder. The orthotopic neobladder group of patients shown through the questionnaire certain level of dissatisfaction with micturition control, especially with frequent night voiding. The loss of libido was present in both group of patients without the differences. High percentage of erectile disfunction was present in both groups of patients despite the type of derivation.The most of the patients with orthotopic neobladder (91%) versus 41% of patient in the ileal conduit group would suggest this type of operation to others despite the lack of difference between them. These results are almost the same to results in literature.The most of the authors didnot find the difference in the QoL among the different types of derivations using the same type of questionnaire (Dutta et al, Kikuchi et al and Mason et al.). Only Hobish et al. using the QLQ C 30 questionaire shown superiority of orthotopic urinary derivations. Yoneda et al and Weijrman et al used SIP questionnaire also had not sow the difference. Despite the fact that the most of patients ask and accept orthotopic urniary derivation, would suggest this type of derivation to others and that they are satisfied with it, there is no statistical significance in QoL over to incontinent derivations. It is obvious that existing types of questionnaire are not sensitive enough and there is a necesity to make the new questionnaires to show the evident advantages of orthotopic urinary derivations.

References

1. Kulaksizoglu H, Toktas G, Kulaksizoglu IB, et al. When should quality of life be measured after radical cystectomy? Eur Urol 2002;42:350 –355

2. Hardt J, Filipas D, Hohenfellner R, et al. Quality of life in patients with bladder carcinoma after cystectomy: first results of a prospective study. Qual Life Res 2000;9:1–12

3. Hobisch A, Tosun K, Kinzl J, et al. Life after cystectomy and orthotopic neobladder versus ileal conduit urinary diversion. Semin Urol Oncol 2001;19:18 –23.

4. Fujisawa M, Isotani S, Gotoh A, et al. Health-related quality of life with orthotopic neobladder versus ileal conduit according to SF-36 survey. Urology 2000;55:862– 865.


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5. Kikuchi E, Horiguchi Y, Nakashima J, Ohigashi T, Oya M, Nakagawa K, Miyajima, Murai M. Assessment of long-term quality of life using the FACT-BL questionnaire in atients with an ileal conduit, continent reservoir, or orthotopic neobladder. Jpn J Clin Oncol. 2006; 36(11): 712-6.

6. Yoneda T, Igawa M, Shiina H, Shigeno K, Urakami S. Postoperative morbidity, functional results and quality of life of patients ollowing orthotopic neobladder reconstruction Int J Urol. 2003;10(3):119-25.

7. Mansson A, Davidsson T, Hunt S, Mansson W. The quality of life in men after radical cystectomy with a continent cutaneous diversion or orthotopic bladder substitution: is there a difference? BJU Int 2002;90:386–90.

8. Dutta SC, Chang SC, Coffey CS, Smith JA, Jr., Jack G, Cookson MS. Health related quality of life assessment after radical cystectomy: comparison of ileal conduit with continent orthotopic neobladder. J Urol 2002;168:164–7.

9. Bjerre BD, Johansen C, Steven K. Health-related quality of life after cystectomy: bladder substitution compared with ileal conduit diversion. A questionnaire survey. Br J Urol 1995;75:200–5.

10. Sullivan LD, Chow VD, Ko DS, Wright JE, 11. McLoughlin MG. An evaluation of quality of life in patients with continent urinary diversions after cystectomy. Br J Urol 1998;81:699–704.

11. Weijerman PC, Schurmans JR, Hop WCJ, Schroder FH, Ruud Bosch JLH. Morbidity and quality of life in patients with orthotopic and heterotopic continent urinary diversion. Urology 1998; 51: 51–6.

Group (max.) Neobladder(mean ± SD)

Ileal conduit(mean ± SD)

p<0,05

Physical well-being (28) 24,06 ± 3,02 22,88 ± 3,65 P=0,150Soc/Family well-being (28) 23,97 ± 1,09 23,68 ± 1,43 p=0,343Emotional well-being (24) 17,21 ± 1,55 16,71 ± 2,42 p=0,314 Func. well-being (28) 21,29 ± 2,41 20,79 ± 2,31 p=0,385Total FACT-G (108) 86,53 ± 4,08 84,06 ± 4,47 p=0,020Specific subscal (36) 25,68 ± 3,69 25,41 ± 3,04 p=0,748Total FACT-BL (144) 112,21 ± 5,94 109,47 ± 5,60 p=0,055

Table 1

Documents

“RAK SEČNEGA MEHURJA” - Splošna Bolnišnica … sečnega mehurja : [zbornik predavanj] = Urinary bladder cancer : [the book of lectures] / 13. slovenski urološki simpozij v