The Tumour-Node-Metastasis (TNM) classification system of tumour stage does not always reflect the actual tumour mass present at diagnosis. Recent reports propose that volumetric analysis may allow improved stratification of disease recurrence and survival in head and neck squamous cell cancer (SCC). This study aims to assess the prognostic value of tumour volume on the outcome of patients with oral cavity and oropharyngeal SCC. / A retrospective review of 73 patients was completed. Tumours were outlined semi-automatically in digitized computed tomography scans, and volumes computed based on surface triangulations of three-dimensional reconstructions with novel software developed at McGill. / Results illustrate significant interstage variability within the current TNM model. Moreover, in oral cavity and oropharyngeal SCC, tumour volume as well as T-stage are significant and independent predictors of disease free survival and overall survival.

Submitted by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2014-10-29T14:29:22Z No. of bitstreams: 1 Paulo Roberto Fontes Athanazio. Um método de contagem... 2014.pdf: 318362 bytes, checksum: 072e0651f6d0f2f5e3be2d66a40acc39 (MD5) / Made available in DSpace on 2014-10-29T14:29:22Z (GMT). No. of bitstreams: 1 Paulo Roberto Fontes Athanazio. Um método de contagem... 2014.pdf: 318362 bytes, checksum: 072e0651f6d0f2f5e3be2d66a40acc39 (MD5) Previous issue date: 2014 / Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, Brasil / Introdução. É consenso que o laudo anatomopatológico de produtos de prostatectomia radical deve relatar de forma quantitativa a extensão do carcinoma prostático, mas qual o método a ser usado não é consensual. Objetivos. Relatar a experiência de um método de contagem de pontos adaptado em produtos de prostatectomias (n= 143) adaptado de Billis et al., Int Braz J Urol. 2003.29:113-120. Material e métodos. As margens basal e apical foram processadas pelo método do cone. O restante da próstata foi dividido em 12 regiões em forma de quadrantes: cada uma representada com duas secções. Em cada fragmento, oito pontos equidistantes foram marcados diretamente sobre a lamínula com caneta permanente. Os pontos presentes dentro da área do tumor foram contados e expressos na forma de percentagem de envolvimento por carcinoma (PEC) ou como volume do tumor (VT). Estes foram comparados com o método quantitativo mais usual de número de secções envolvidas (NSE). Resultados. Os três métodos apresentaram correlação moderada significante com níveis pré-operatórios de PSA, mas esta foi maior para os métodos baseados na contagem de pontos: NSE (r = 0.32), PEC (r = 0.39) e VT (r = 0.44). Quando estratificados em três categorias, os três métodos mostraram associação com escore de Gleason ≥7, Gleason primário ≥4, invasão angiolinfática e perineural, extensão extraprostática, envolvimento de vesículas seminais e margens positivas. Conclusão. Os três métodos quantitativos estão associados a marcadores morfológicos de progressão do carcinoma da próstata. Os métodos baseados na contagem de pontos proposta apresentam mais forte correlação com níveis pré-operatórios de PSA sérico. / Objective: To evaluate a modified point-count method for quantifying carcinoma in prostatectomy specimens (n=143), adapted from Billis et al., Int Braz J Urol. 2003.29:113-120. Methods: The basal/apical margins were sampled using the cone method. The remainder of the gland was divided into 12 quadrant-shaped regions which had two slices sampled. Eight equidistant points were marked directly on the coverslip over each fragment. The points inside the tumoral areas were counted and expressed as the percentage of prostate gland involvement by carcinoma (PGI) and as the tumor volume (TV). Results: A significant correlation between the preoperative PSA level and each of the three quantitative estimations was found, but it was higher for both values (PGI and TV) obtained using the point-count method, viz.: number of slices involved (NSI) (r = 0.32), PGI (r = 0.39) and TV (r = 0.44). When the data sets were stratified into three categories, all three methods correlated with Gleason scores ≥7, primary Gleason scores ≥4, perineural / angiolymphatic invasion, extraprostatic extension, seminal vesicle invasion and positive margins. Conclusion: All three quantitative methods were associated with morphologic features of tumor progression. The results obtained using the modified point-count method correlated better with the preoperative PSA levels.

No description available.

Welche Ursachen führen bei Keimzelltumoren zu Spätrezidiven? Sind es ungünstige Tumorkonstellationen, Behandlungsfehler oder individuelle Faktoren, die zu Spätrezidiven von Keimzelltumoren (KZT) führen? Ziel der Untersuchung war es, diese Fragen zu beantworten, um Patienten zu identifizieren, für die sich daraus Konsequenzen in der Therapie und Verlaufskontrolle ergeben. Indem wir Spätrezidive nach 4 Jahren auswerteten, wollten wir die besonderen Merkmale dieser Patientengruppe herausarbeiten. Unter 759 erfassten Patienten sahen wir 165 Frührezidive (< 2 Jahre), 92 Rezidive nach 2 Jahren und 73 Spätrezidive mehr als 4 Jahre nach der Initialdiagnose. Unsere statistische Auswertung bezieht sich auf die Spätrezidive mit einer mittleren Beobachtungszeit von 143 Monaten. Die initiale Konstellation der Tumormarker spielt eine bedeutende Rolle. 66% der Patienten hatten sowohl AFP als auch ß-HCG erhöht (gegenüber 47% bei den Frührezidiven und 33% im Gesamtkollektiv). Das gonadal reine Embryonalzellkarzinom (EZK) führt häufiger zu Spätrezidiven als andere Keimzelltumoren. Risikobehaftet sind höhere Stadien, von denen sich unter den Spätrezidiven 85% fanden; initial aber nur 57%. Demgegenüber ist poor-prognosis nach IGCCCG kein Risikofaktor. Mehr als die Hälfte der spätrezidivierten Patienten hatte bereits vorher mindestens ein Rezidiv gehabt. Eine initial von der heutigen Leitlinie abweichende Behandlung war bei 40% der Spätrezidive zu finden. Gründe hierfür waren eine falsche Histologie, die ungenaue Stadienzuordnung oder eine fehlende bzw. inkomplette Residualtumorresektion. Eine günstige Prognose haben die Patienten, bei denen eine Metastasenresektion vorgenommen werden kann. Die Heilungsrate (NED) war bei den operierten Spätrezidiven (70%) deutlich hoher als denjenigen, die zusätzlich chemotherapiert (46%) oder lediglich mit Chemotherapie behandelt worden waren (36%). Als Grund hierfür, ist die Früherkennung und noch vorhandene Operabilität des Befundes anzunehmen. Alle Seminom-Spätrezidive mit initialer Radiatio haben von der Chemotherapie profitiert. Bis auf einen Todesfall in der Chemotherapie wurden alle geheilt. Spätrezidive von KZT sollten als besondere Entität definiert werden. Krankheitsverlauf, Behandlung und Nachsorge weichen von dem üblichen Muster ab. Nur Seminome oder chemonaive Patienten sind zytostatisch zu behandeln. Bei den Nichtseminomen, die bereits initial oder im Frührezidiv eine Chemotherapie erhalten haben, sollte wenn möglich, eine operative Behandlung erwogen werden. Patienten mit initial erhöhten Tumormarkern (AFP + ß-HCG), reinem gonadalem EZK, höheren Krankheitsstadien oder einem Rezidiv innerhalb der ersten 4 Jahre haben eine ungünstige Prognose und erfordern eine jährliche lebenslange spezielle Nachsorge. Die Nachsorge sollte neben der klinischen Untersuchung und AFP-Bestimmung ein Schnittbildverfahren des Thorax und Retroperitoneums beinhalten. / What are the reasons for late relapse of testicular germ cell tumor? Do unfavourable tumor constellations, mismanaged treatment or individual factors; lead to the late relapse of testicular germ cell tumor? The aim of this investigation was to find an answer to this question and to identify the patients, who would benefit from modified treatments and follow-up modalities. By researching the late relapses diagnosed at least 4 years later, we wanted to identify the special characteristics of this group of patients. Among the 759 patients with testis cancer we found 165 early relapses (

Introdução: Os principais objetivos do tratamento das metástases cerebrais (MC) são no auxílio do controle da doença no encéfalo e a melhora da qualidade de vida dos pacientes. A cirurgia convencional tem um importante papel no tratamento das MCs e os métodos de monitoração intraoperatória podem auxiliar na obtenção de resultados cirúrgicos melhores. Objetivos: Avaliar a influência da ultrassonografia encefálica durante cirurgia para ressecção de MC no índice de Karnofsky e no grau de ressecção do tumor. Métodos: Neste estudo prospectivo controlado e não randomizado, doentes com indicação de tratamento cirúrgico de MCs foram incluídos. A ultrassonografia intraoperatória (USIO) foi realizada por um neurossonologista. O índice de Karnofsky foi avaliado por equipe multidisciplinar de oncologia; o grau de dificuldade para ressecção cirúrgica do tumor foi avaliado pelo cirurgião e o volume tumoral foi avaliado pelo neurorradiologista por meio da RM realizada no pré e pós-operatório. Resultados: Dos 78 doentes, 40 homens e 38 mulheres com idade média de 53 anos, 35 foram submetidos a tratamento cirúrgico com auxílio da USIO. Não houve diferença estatística no KPS e volume tumoral pré-operatório entre os grupos. O KPS pós-operatório no grupo da USIO foi de 80 e no grupo-controle de 70 (p=0,045). Considerando-se a melhora do KPS no pós-operatório, a quantidade de doentes tiveram melhora do KPS foi superior no grupo da USIO (p=0,036) destacando-se os seguintes subgrupos: tumores com grau de dificuldade de ressecção < 4 (p=0,037), tumores nas áreas eloquentes (p=0,043), tumores não relacionados aos grandes vasos e nervos (p=0,007), e lesões únicas no leito cirúrgico (p=0,038). O tumor residual na RM pós-operatória foi menor no grupo da USIO: 9,5% no grupo da USIO e 30,8% no grupo-controle; 1,6 mm3 no grupo da USIO e 9 mm3 do grupo-controle; p=0,05. Considerando-se doentes com KPS >= 70, o número de doentes com volume de tumor residual inferior a 10% em relação ao volume pré-operatório foi superior no grupo da USIO (p=0,032 e OR de 3,8). Conclusão: Os achados deste estudo sugerem que a USIO encefálica pode influenciar na melhora do índice de Karnofsky e na redução do volume de tumor residual / Object: The goals of treating a cerebral metastasis (CM) are to achieve local control of the disease and to improve patient quality of life. The aim of this study was to analyse the effect of using conventional surgery supported by intra-operative ultrasound (IOUS) to approach a CM. To perform this analysis, we determined Karnofsky post-operative scores (KPS) and tumour resection grades. Methods: Patients with CM who were eligible to undergo a surgical approach were included in this study. Surgical treatment was either supported or not supported by IOUS. A neural oncology team determined the pre- and post-operative KPS. A radiologist examined the tumour volume using pre- and post-operative magnetic resonance imaging. Before the surgery, the surgeon determined whether it was possible to perform a total CM resection. Results: A total of 78 patients with CM diagnosis were treated using a surgical approach (35 with and 43 without IOUS). The post-operative median KPS was higher in the IOUS group (80 versus 70, p=0.045). Within the IOUS group, KPS evolution was superior (p=0.036), especially in the following CM subgroups: a difficulty of tumour resection ranking score<4 (p=0.037), the tumour was in an eloquent area (p=0.043), the tumour was not associated with vessels or nerves (p=0.007), and solitary lesions (p=0.038). The volume of residual tumours was lower in the IOUS group (9.5% and 1.6 mm3 versus 30.8% and 9 mm3, p=0.05). In patients with a KPS >= 70, the residual tumour volume was categorized as < 10% or >= 10%, and 62% of patients had < 10% residual tumours (76% in the IOUS group and 45% in the non-IOUS group; p=0.032 and OR=3.8). Conclusion: This study suggests that IOUS can play a role in improving post-operative KPS and in decreasing residual tumours in CM surgeries

Introdução: Os principais objetivos do tratamento das metástases cerebrais (MC) são no auxílio do controle da doença no encéfalo e a melhora da qualidade de vida dos pacientes. A cirurgia convencional tem um importante papel no tratamento das MCs e os métodos de monitoração intraoperatória podem auxiliar na obtenção de resultados cirúrgicos melhores. Objetivos: Avaliar a influência da ultrassonografia encefálica durante cirurgia para ressecção de MC no índice de Karnofsky e no grau de ressecção do tumor. Métodos: Neste estudo prospectivo controlado e não randomizado, doentes com indicação de tratamento cirúrgico de MCs foram incluídos. A ultrassonografia intraoperatória (USIO) foi realizada por um neurossonologista. O índice de Karnofsky foi avaliado por equipe multidisciplinar de oncologia; o grau de dificuldade para ressecção cirúrgica do tumor foi avaliado pelo cirurgião e o volume tumoral foi avaliado pelo neurorradiologista por meio da RM realizada no pré e pós-operatório. Resultados: Dos 78 doentes, 40 homens e 38 mulheres com idade média de 53 anos, 35 foram submetidos a tratamento cirúrgico com auxílio da USIO. Não houve diferença estatística no KPS e volume tumoral pré-operatório entre os grupos. O KPS pós-operatório no grupo da USIO foi de 80 e no grupo-controle de 70 (p=0,045). Considerando-se a melhora do KPS no pós-operatório, a quantidade de doentes tiveram melhora do KPS foi superior no grupo da USIO (p=0,036) destacando-se os seguintes subgrupos: tumores com grau de dificuldade de ressecção < 4 (p=0,037), tumores nas áreas eloquentes (p=0,043), tumores não relacionados aos grandes vasos e nervos (p=0,007), e lesões únicas no leito cirúrgico (p=0,038). O tumor residual na RM pós-operatória foi menor no grupo da USIO: 9,5% no grupo da USIO e 30,8% no grupo-controle; 1,6 mm3 no grupo da USIO e 9 mm3 do grupo-controle; p=0,05. Considerando-se doentes com KPS >= 70, o número de doentes com volume de tumor residual inferior a 10% em relação ao volume pré-operatório foi superior no grupo da USIO (p=0,032 e OR de 3,8). Conclusão: Os achados deste estudo sugerem que a USIO encefálica pode influenciar na melhora do índice de Karnofsky e na redução do volume de tumor residual / Object: The goals of treating a cerebral metastasis (CM) are to achieve local control of the disease and to improve patient quality of life. The aim of this study was to analyse the effect of using conventional surgery supported by intra-operative ultrasound (IOUS) to approach a CM. To perform this analysis, we determined Karnofsky post-operative scores (KPS) and tumour resection grades. Methods: Patients with CM who were eligible to undergo a surgical approach were included in this study. Surgical treatment was either supported or not supported by IOUS. A neural oncology team determined the pre- and post-operative KPS. A radiologist examined the tumour volume using pre- and post-operative magnetic resonance imaging. Before the surgery, the surgeon determined whether it was possible to perform a total CM resection. Results: A total of 78 patients with CM diagnosis were treated using a surgical approach (35 with and 43 without IOUS). The post-operative median KPS was higher in the IOUS group (80 versus 70, p=0.045). Within the IOUS group, KPS evolution was superior (p=0.036), especially in the following CM subgroups: a difficulty of tumour resection ranking score<4 (p=0.037), the tumour was in an eloquent area (p=0.043), the tumour was not associated with vessels or nerves (p=0.007), and solitary lesions (p=0.038). The volume of residual tumours was lower in the IOUS group (9.5% and 1.6 mm3 versus 30.8% and 9 mm3, p=0.05). In patients with a KPS >= 70, the residual tumour volume was categorized as < 10% or >= 10%, and 62% of patients had < 10% residual tumours (76% in the IOUS group and 45% in the non-IOUS group; p=0.032 and OR=3.8). Conclusion: This study suggests that IOUS can play a role in improving post-operative KPS and in decreasing residual tumours in CM surgeries

<p>Oralni karcinom je po učestalosti &scaron;esta najče&scaron;ća maligna bolest u svetu čija incidenca varira u različitim geografskim područjima. Predstavlja 5% svih novootkrivenih malignih tumora godi&scaron;nje i čini 14% svih malignih tumora glave i vrata. Pod oralnim karcinom podrazumevamo planocelularni karcinom obzirom na činjenicu da on čini preko 90% malignih tumora oralne lokalizacije, dok se u manjem procentu javljaju drugi tumori (maligni tumori malih pljuvačnih žlezda, limfomi, mezenhimni tumori). Oralni karcinom podrazumeva karcinome koji se javljaju u sledećim anatomskim regijama: sluznici prednje 2/3 jezika, poda usta, obraza, gingivi gornje i donje vilice, retromolarnom trouglu, kao i sluznici mekog i tvrdog nepca. Najče&scaron;ća lokalizacija oralnog planocelularnog karcinoma je sluznica pokretnog dela jezika i poda usta. Oralni karcinom se če&scaron;će javlja kod mu&scaron;karaca (odnos mu&scaron;karci:žene je 3:1) verovatno zbog većeg procenta rizičnog pona&scaron;anja kod mu&scaron;karaca. Najče&scaron;će se javlja u &scaron;estoj i sedmoj deceniji života (medijana je 62 godine) iako se poslednjih godina sve če&scaron;će javlja kod mlađih od 45 godina. Faktori rizika za oboljevanje su dobro poznati. Na prvom mestu se izdvaja pu&scaron;enje duvana (značajna je dužina pu&scaron;enja, da li pacijent pu&scaron;i lulu ili cigaretu, da li žvaće duvan, kao i dužina trajanja apstinencije). Smatra se da je smrtnost kod oralnog karcinoma direktno povezana sa brojem popu&scaron;enih cigareta na dan. Preko 75% pacijenata sa oralnim karcinomom anamnestički daje podatak o prekomernoj upotrebi alkohola. Postoji sinergističko dejstvo alkohola i cigareta, dugotrajna ekspozicija ovim faktorima rizika dovodi do pojave &ldquo;polja kancerizacije&ldquo;, pojave genetske nestabilnosti i razvoja tumora. Kod oralnog planocelulranog karcinoma primećene su hromozomske abnormalnosti koje su rezultat o&scaron;tećenja DNK i uključuju promene genetskog materijala na hromozomima.Jedna od najče&scaron;ćih genetskih abnormalnosti kod oralnog planocelularnog karcinoma je mutacija r53 gena koji se nalazi na kratkom kraku hromozoma 17 i predstavlja tumor supresor gen. Planocelularni karcinom nije te&scaron;ko dijagnostikovati kada postane simptomatski. Pacijent se žali na bol, krvavljenje, otalgiju, otežano gutanje, smanjenje pokretljivosti jezika. Neretko je prvi simptom metastatski uvećan limfni čvor na vratu jer bolesnici ne primećuju ili ignori&scaron;u oralnu patologiju. Dijagnoza oralnog karcinoma se postavlja na osnovu detaljno uzete anamneze, kliničkog pregleda i patohistolo&scaron;ke verifikacije. Oralni planocelularni karcinom se javlja u tri klinike forme: egzofitična, endofitična i infiltrativna. Zlatni standard za dijagnozu oralnog karcinoma je biopsija i patohistolo&scaron;ka verifikacija, pri čemu se može primeniti &bdquo;punch&ldquo; biopsija, inciziona biopsija ili eksciziona biopsija kod manjih promena. TNM &bdquo;staging&ldquo; sistem AJCC (American Joint Committee on Cancer) se danas standardno koristi za klinički &bdquo;staging&ldquo; oralnog karcinoma i bazira se na podacima dobijenim kliničkim pregledom i &bdquo;imaging&ldquo; metodama. Sam &bdquo;staging&ldquo; je bitan kako zbog komunikacije među lekarima koji učestvuju u lečenju bolesnika tako i zbog standardizacije prognoze. T stadijum označava veličinu primarnog tumora, N stadijum označava regionalnu nodalnu zahvaćenost dok M stadijum prikazuje prisustvo udaljenih metastaza. Terapija patohistolo&scaron;ki dokazanog oralnog karcinoma zahteva multidisciplinarni pristup. Osnova terapije oralnog planocelularnog karcinoma je hirur&scaron;ko lečenje koje podrazumeva ablativno i rekonstruktivno hirur&scaron;ko lečenje. Osnovni princip ablativne hirurgije kod oralnog karcinoma je resekcija primarnog tumora sa najmanje 1cm negativnim hirur&scaron;kim marginama. Pored ablacije tumora hirur&scaron;ko lečenje podrazumeva i uklanjanje regionalnih limfnih čvorova vrata. Cilj disekcije vrata je da se kod klinički evidentnih metastaza iste uklone (terapijska disekcija) ili da se uklone okultne metastaze koje su klinički neevidentne (elektivna disekcija). Oralni planocelularni karcinom spada u tumore sa visokom stopom smrtnosti, većom nego &scaron;to je kod limfoma, laringealnog karcinoma, karcinoma testisa i endokrinih karcinoma. Stopa petogodi&scaron;njeg preživljavanja je direktno povezana sa veličinom tumora, prisustvom metastaza u regionalnim limfnim čvorovima i prisutvom udaljenih metastaza. Prosečno trogodi&scaron;nje preživljavanje bolesnika sa oralnim karcinomom je 52% dok je prosečno petogodi&scaron;nje preživljavanje oko 39% i ove stope se nisu mnogo menjale tokom godina bez obzira na nova saznanja i nove pristupe lečenju oralnog planocelulanog karcinoma. Ciljevi istraživanja su da se utvrdi da li postoji korelacija debljine OPK izmerene kompjuterizovanom tomografijom i svetlosnim mikroskopom, da li dubina invazije OPK i volume tumora mogu biti prediktivni faktor za razvoj regionalnih cervikalnih metastaza kod oralnog planocelularnog karcinoma. Istraživanje je uključilo 65 konsekutivnih bolesnika oba pola lečenih od oralnog karcinoma na Klinici za maksilofacijalnu hirurgiju Kliničkog centra Vojvodine. Dijagnoza oralnog karcinoma je postavljena na osnovu anamneze, kliničkog pregleda i biopsije. U sklopu TNM &bdquo;staging&ldquo;-a bolesnika načinjen je pregled glave i vrata i grudnog ko&scaron;a kompjuterizovanom tomografijom (CT) na osnovu kog smo dobili podatak o dimenzijama tumora. Na osnovu kliničkog nalaza i analize CT nalaza planiralo se operativno lečenje u skladu sa bolesnikovim TNM statusom. Postoperatativni patohisto&scaron;ki preparati je pregledan od strane istog patologa. Parametri koji će su određivani su sledeći: 1. Veličina tumora (2 dimenzije) izmerene na osnovu CT pregleda izražene u cm 2. Debljina tumora izmerena na osnovu CT pregleda izražena u cm 3. Veličina tumora (2 dijametra) na makroskopskom preparatu izražena u cm 4. Debljina tumora na mikroskopskom preparatu izmerena svetlosnim mikroskopom izražena u cm 5. Dubina invazije tumora na mikroskopskom preparatu izmerena svetlosnim mikroskopom izražena u mm 6. Volumen tumora koji se izračunavao prema formuli: VT=&pi;/6 x maksimalni dijametar tumora A x minimalni dijametar tumora B x dubina invazije tumora i izražava se u cm&sup3; 7. Broj metastatski izmenjenih limfnih čvorova u disekatu vrata 8. Ukupan broj patohistolo&scaron;ki ispitanih limfnih čvorova u disekatu vrata Nakon prikupljanja planiranog materijala urađena je statistička obrada podataka. Statistička analiza podataka je uključila metode deskriptivne statistike (srednja vrednost, standardna devijacija, učestalost), kao i standardne parametrijske i neparametrijske testove za komparacije dve grupe (Studentov T test, Mann&ndash;Whitney U test, hikvadrat test). U fazi statističke analize međusobnih uticaja i povezanosti prikupljenih podataka kori&scaron;ćen je Pearsonov test korelacije. Sva testiranja sprovedena su na nivou statističke značajnosti p&lt;0,05. REZULTATI: Istraživanje je obuhvatilo 65 bolesnika, od kojih je 82% bilo mu&scaron;kog pola prosečne starosti 59 godina. 83% bolesnika su se izja&scaron;njavali kao pu&scaron;ači, dok je 69% bolesnika navelo da redovno koristi alkohol. Svim pacijentima je tokom hirur&scaron;kog lečenja OPK rađena disekcija vrata i to najče&scaron;čće selektivna disekcija vrata (91%). Kod 30 bolesnika je utvrđeno postojanje cervikalnih regionalnih metastaza na operativnom preparatu te su bolesnici podeljeni u dve grupe: sa prisustvom i bez prisustva metastaza u limfnim čvorovima vrata. Utvrđeno je da se ove dve grupe statistički značajno razlikuju u dubini invazije tumora i volumenu tumora. Utvrđeno je takođe da postoji statistički značajna korelacija između debljine tumora izmerene CT pregledom i debljine tumora izmerene svetlosnim mikroskopom. Dokazano je da dubina invazije tumora veća od 7mm i zapremina tumora veća od 4cm&sup3; predstavljaju prediktivni faktor za pojavu regionalnih cervikalnih metastaza. ZAKLjUČAK: Na osnovu istraživanja izvedeni su zaključci koji ukazuju na to da postoji statistički značajna korelacija između debljine tumora OPK izmerene CTpregledom i svetlosnim mikroskopom te se debljina tumora izmerena CT pregledom može koristiti za planiranje operativnog zahvata prilikom lečenja OPK. Dubina invazije tumora veća od 7mm i volumen tumora veći od 4 cm&sup3; predstavljaju prediktivni faktor za pojavu nodalnih cervikalnih metastaza te su značajni za određivanje stadijuma bolesti.</p> / <p>Oral cancer is the sixth most common malignant disease in the world which incidence varies based on geographic area. It represents 5% of all newly discovered malignant tumors annually and constitutes 14 % of all malignant tumors of head and neck. Squamous cell carcinoma is considered to be a type of oral cancer because more than 90 % of malignant tumors that occur in oral cavity are squamous cell carcinomas while other tumors (malignant tumor of minor salivary gland, lymphoma, sarcoma) rarely occur. Oral cancer is the cancer found in the following anatomic regions: mucosa of front two-thirds of the tongue, the floor of the mouth, cheeks, upper and lower gingiva, retromolar trigone as well as&nbsp; mucosa of soft and hard palates. Oral squamous cell carcinoma is most commonly localized in mucous membrane of the movable part of the tongue and floor of the mouth. Men are more affected than women (male to female ratio is 3:1) probably because of men&rsquo;s riskier behavior. It is most commonly diagnosed in the sixth and seventh decade of life (the median is 62 years old) although it has been diagnosed in patents younger than 45 in recent years. Risk factors of oral squamous cell carcinoma are well known. The major factor is tobacco smoking (the period of smoking is significant, it is also important to consider whether a patient smokes a pipe or cigarette, whether he/she chews tobacco as well as the period of abstinence). The mortality rate is believed to be directly related to the number of cigarettes smoked a day. An excessive use of alcohol has been reported in over 75% of patients with oral cancer. There is a synergistic effect of alcohol and cigarette consumption and long-term exposure to these risk factors results in &lsquo;field of cancerization&rsquo;, genetic instability and tumor development. Chromosome abnormalities, which are caused by DNA damage and include the change in genetic material of chromosomes, have been reported in patients with oral squamous cell carcinoma. One of the most common genetic abnormalities in patients with oral squamous cell carcinoma is a mutation of р53 gene which is located on a short arm of chromosome 17 and represents a tumor suppressor gene. Oral squamous cell carcinoma is not difficult to diagnose when it becomes symptomatic. The patient complains of pain, bleeding, otalgia, swallowing difficulties, decreased tongue mobility. The first symptom is rarely metastatic lymph node on the neck because patients either do not notice or ignore oral pathology. The oral cancer is diagnosed based on the detailed anamnesis, physical examination and pathohistological verification. The oral squamous cell carcinoma occurs in three clinical forms: exophytic, endophytic and infiltrative form. The gold standard for diagnosis of oral cancer is biopsy and pathohistological verification. However, in case of smaller changes, punch biopsy, incisional and excisional biopsies can also be applied. ТNМ staging system of AJCC (American Joint Committee on Cancer) is nowadays used for clinical staging of oral cancer and it is based on the data acquired by clinical examination and imaging methods. Not only is the staging itself important for communication between the doctors involved in treatment, but it is also important for standardization of prognosis. Т describes the size of primary tumor, N describes regional nodal spread and М describes distant metastasis. The treatment of histopathologically proven oral cancer requires multidisciplinary approach. The main treatment of oral squamous cell carcinoma is surgical treatment which involves ablative and reconstructive surgical treatment. The basic principle of ablative surgery for oral cancer is the resection of primary tumor with at least 1 cm negative surgical margins. Apart from tumor ablation surgical treatment also involves removal of regional lymph nodes on the neck. The aim of neck dissection is to remove clinically evident metastasis (therapeutic dissection) or to remove occult metastasis that are not clinically evident (elective dissection). The oral squamous cell carcinoma is the cancer with high mortality rate. The mortality rate is higher than the mortality rate for lymphoma, laryngeal cancer, testicular cancer and endocrine cancer. The five-year survival rate is directly related to the size of the tumor, presence of metastasis in regional lymph nodes and distant metastasis. The average three-year survival rate of the patients with oral cancer is 52% and the average five-year survival rate is 39%. These rates have not changed a lot over the years regardless of new knowledge and approaches in treatment of oral squamous cell carcinoma. The aims of the study are to determine whether there is a correlation between the depth of invasion of oral squamous cell carcinoma determined by computed tomography and light microscope and whether the invasion depth of OSCC and tumor volume can be predictive factors of development of regional cervical metastases in case of oral squamous cell carcinoma. The study covered 65 consecutive patients of both sexes who received treatment for oral cancer at the Clinic for Maxillofacial Surgery of the Clinical Center of Vojvodina. The diagnosis of oral cancer was established based on the anamnesis, physical examination and biopsies. The TNM &lsquo;staging&rsquo; of the cancer involved the examination of the patient&rsquo;s head and thorax by computed tomography (CT) which enabled us to obtain reliable data about the tumor size. After obtaining clinical findings and CT results, the patients&rsquo; treatment was planned based on their TNM status. A postoperative histopathological examination was performed by the same pathologist and the following parameters were determined: 1. Tumor size (2 dimensions) measured by CT and expressed in cm 2. Tumor thickness measured by CT and expressed in cm 3. Tumor size (2 diameters) on microscopic device and expressed in cm 4. Tumor thickness on microscopic device measured by light microscope and expressed in cm 5. Depth of tumor invasion on microscopic device measured by light microscope and expressed in cm 6. Tumor volume calculated based on the following formula: VT=&pi;/6 x maximum tumor diameter А x minimum tumor diameter B x depth of tumor invasion and expressed in cm&sup3; 7. The number of metastatic lymph nodes in the neck dissection 8. Total number of pathohistologically tested lymph nodes in the neck dissection. Upon collecting the planned material, statistical analysis of all data was carried out. The statistical analysis included the methods of descriptive statistics (mean value, standard deviation, frequency) and standard parametric and nonparametric tests for comparison of two groups (Student&rsquo;s T test, Whitney U test, chi-square test). The Pearson&rsquo;s Test of Correlation was used in the phase of statistical analysis of interaction effects and correlation of obtained data. All tests were performed at the level of statistical significance of p&lt;0.05. RESULTS: The study covered 65 patients, out of which 82% were male patients aged 59. 83% of patients said they smoked and 69% of patients stated that they consumed alcohol regularly. A neck dissection was performed in all patients during surgical treatment of OSCC and it was selective neck dissection (91%). Cervical regional metastasis was found in 30 patients so they were divided into two groups: the group of patients who had metastasis in the lymph nodes and the group of patients with no metastasis in lymph nodes of the neck. It was determined that there was a statistically significant difference in depth of invasion and tumor volume between these two groups. The statistically significant difference was also determined between the thickness of tumor measured by CT and thickness of tumor measured by light microscope. Moreover, the depth of invasion of tumor greater than 7mm and volume of tumor greater than 4cm&sup3; were proven to represent a predictive factor of development of regional cervical metastasis. The study results show that there is a statistically significant correlation between the thickness of OSCC tumor measured by CT and the thickness measured by light microscope, so the thickness of tumor measured by CT can be used for planning the surgery during the treatment of OSCC. The depth of tumor invasion greater than 7 mm and tumor volume greater than 4 cm&sup3; represent a predictive factor of development of cervical metastasis, which means that they are significant for determining the stage of disease.</p>

Infiltration of myeloid cells in the tumor microenvironment is often associated with enhanced angiogenesis and tumor progression, resulting in poor prognosis in many types of cancer. The polypeptide chemokine PK2 (Bv8, PROK2) has been shown to regulate myeloid cell mobilization from the bone marrow, leading to activation of the angiogenic process, as well as accumulation of macrophages and neutrophils in the tumor site. Neutralizing antibodies against PK2 were shown to display potent anti-tumor efficacy, illustrating the potential of PK2-antagonists as therapeutic agents for the treatment of cancer. In this study we demonstrate the anti-tumor activity of a small molecule PK2 antagonist, PKRA7, in the context of glioblastoma and pancreatic cancer xenograft tumor models. For the highly vascularized glioblastoma, PKRA7 was associated with decreased blood vessel density and increased necrotic areas in the tumor mass. Consistent with the anti-angiogenic activity of PKRA7 in vivo, this compound effectively reduced PK2-induced microvascular endothelial cell branching in vitro. For the poorly vascularized pancreatic cancer, the primary anti-tumor effect of PKRA7 appears to be mediated by the blockage of myeloid cell migration/infiltration. At the molecular level, PKRA7 inhibits PK2-induced expression of certain pro-migratory chemokines and chemokine receptors in macrophages. Combining PKRA7 treatment with standard chemotherapeutic agents resulted in enhanced effects in xenograft models for both types of tumor. Taken together, our results indicate that the anti-tumor activity of PKRA7 can be mediated by two distinct mechanisms that are relevant to the pathological features of the specific type of cancer. This small molecule PK2 antagonist holds the promise to be further developed as an effective agent for combinational cancer therapy. / Dissertation

No / We identify cytochrome P450 1A1 (CYP1A1) as a target for tumor-selective drug development in bladder cancer and describe the characterization of ICT2700, designed to be metabolized from a prodrug to a potent cytotoxin selectively by CYP1A1. Elevated CYP1A1 expression was shown in human bladder cancer relative to normal human tissues. RT112 bladder cancer cells, endogenously expressing CYP1A1, were selectively chemosensitive to ICT2700, whereas EJ138 bladder cells that do not express CYP1A1 were significantly less responsive. Introduction of CYP1A1 into EJ138 cells resulted in 75-fold increased chemosensitivity to ICT2700 relative to wild-type EJ138. Negligible chemosensitivity was observed in ICT2700 in EJ138 cells expressing CYP1A2 or with exposure of EJ138 cells to CYP1B1- or CYP3A4-generated metabolites of ICT2700. Chemosensitivity to ICT2700 was also negated in EJ138-CYP1A1 cells by the CYP1 inhibitor alpha-naphthoflavone. Furthermore, ICT2700 did not induce expression of the AhR-regulated CYP1 family, indicating that constitutive CYP1A1 expression is sufficient for activation of ICT2700. Consistent with the selective activity by CYP1A1 was a time and concentration-dependent increase in gamma-H2AX protein expression, indicative of DNA damage, associated with the activation of ICT2700 in RT112 but not EJ138 cells. In mice-bearing CYP1A1-positive and negative isogenic tumors, ICT2700 administration resulted in an antitumor response only in the CYP1A1-expressing tumor model. This antitumor response was associated with detection of the CYP1A1-activated metabolite in tumors but not in the liver. Our findings support the further development of ICT2700 as a tumor-selective treatment for human bladder cancers.

PURPOSE: Cytochrome P450 2W1 (CYP2W1) is a monooxygenase detected in 30% of colon cancers, whereas its expression in nontransformed adult tissues is absent, rendering it a tumor-specific drug target for development of novel colon cancer chemotherapy. Previously, we have identified duocarmycin synthetic derivatives as CYP2W1 substrates. In this study, we investigated whether two of these compounds, ICT2705 and ICT2706, could be activated by CYP2W1 into potent antitumor agents. EXPERIMENTAL DESIGN: The cytotoxic activity of ICT2705 and ICT2706 in vitro was tested in colon cancer cell lines expressing CYP2W1, and in vivo studies with ICT2706 were conducted on severe combined immunodeficient mice bearing CYP2W1-positive colon cancer xenografts. RESULTS: Cells expressing CYP2W1 suffer rapid loss of viability following treatment with ICT2705 and ICT2706, whereas the CYP2W1-positive human colon cancer xenografts display arrested growth in the mice treated with ICT2706. The specific cytotoxic metabolite generated by CYP2W1 metabolism of ICT2706 was identified in vitro. The cytotoxic events were accompanied by an accumulation of phosphorylated H2A.X histone, indicating DNA damage as a mechanism for cancer cell toxicity. This cytotoxic effect is most likely propagated by a bystander killing mechanism shown in colon cancer cells. Pharmacokinetic analysis of ICT2706 in mice identified higher concentration of the compound in tumor than in plasma, indicating preferential accumulation of drug in the target tissue. CONCLUSION: Our findings suggest a novel approach for treatment of colon cancer that uses a locoregional activation of systemically inactive prodrug by the tumor-specific activator enzyme CYP2W1.