Base teórica: o tratamento do carcinoma endometrial é feito através do estadiamento cirúrgico, que envolve histerectomia com salpingo-oforectomia bilateral e linfadenectomia pélvica e para-aórtica. Questiona-se o benefício da linfadenectomia sistemática em todos os pacientes, já que o risco de disseminação linfática em tumores de baixo risco é pequeno e não há evidências de benefício terapêutico em sua realização. Desse modo, tentam-se encontrar modos de determinar, na avaliação pré-operatória, quais são os pacientes que poderão se beneficiar da linfadenectomia e aqueles que podem prescindir do procedimento. Objetivos: avaliar a concordância da avaliação anatomopatológica entre a amostra endometrial pré-operatória e a peça cirúrgica das pacientes submetidas a tratamento cirúrgico primário do carcinoma de endométrio, correlacionando com características das pacientes e das amostras da patologia. Métodos: foram incluídos pacientes submetidos a tratamento cirúrgico para carcinoma de endométrio que tinham diagnóstico pré-operatório através de amostragem endometrial. Os prontuários foram revisados e as amostras disponíveis na instituição foram procuradas para posterior releitura por dois patologistas cegados para as demais informações anatomopatológicas. Resultados: foram incluídos 166 pacientes, com uma idade média de 64,6 anos. Das biópsias, 118 eram tumores endometrioides, 38 não-endometrioides e as demais, hiperplasia. As taxas de concordância foram de 93,2% para tumores endometrioides e 68,9% para não-endometrioides, com um índice kappa (k) de 0,73 para o tipo histológico. O grau tumoral distribui-se na amostra como G1 em 37,1%, G2 em 35,7% e G3 em 27,1%, com uma taxa de concordância de 61,5%, 56% e 78,9%, respectivamente, e k=0,46. Dos tumores G1, somente 1,9% teve upgrade para G3, em comparação com 16% das lesões G2. Não houve diferença estatística na taxa de concordância do tipo histológico e grau tumoral em função do local de execução da biópsia, método de amostragem e intervalo biópsia-cirurgia. Biópsias com pés > 3g tiveram uma concordância do grau tumoral significativamente melhor (p=0,040). Amostras de 105 pacientes estavam disponíveis no HCPA e foram reavaliadas por dois patologistas, com uma taxa de concordância interobservador geral de 73,3% (k=0,58) para o tipo histológico e 57,9% (k=0,54) para o grau tumoral. Conclusão: a acurácia da biópsia pré-operatória em predizer as características da peça cirúrgica não é ideal. Deve-se ter cuidado ao utilizar essa informação para determinar a extensão da cirurgia a ser realizada, sob risco de ser realizado subestadiamento. Estas baixas taxas de concordância correlacionam-se também com as baixas taxas de concordância interobservador. Novos sistemas de graduação e equipes de especialistas são possibilidades para melhorar esta questão. / Background: endometrial carcinoma treatment is based on surgical staging, including hysterectomy with bilateral salpingo-oophorectomy and pelvic and paraortic lymphadenectomy. The benefits of systematic lymphadenectomy in all patients have been questioned, since the risk of dissemination in low risk tumors is small and there is no evidence of benefits in its execution. Thereby, researches are looking for ways to determine, by preoperative evaluation, which patient will benefit from full staging and those who can do without the procedure. Objectives: evaluate the agreement between the preoperative endometrial samples and the surgical specimens in endometrial carcinoma, correlating it with characteristics of the samples and patients included, and evaluate the interobserver agreement of the preoperative biopsy. Methods: patients submitted to surgery as primary treatment for endometrial carcinoma at HCPA with a preoperative endometrial sampling were included. Their medical charts were reviewed. The available samples of the preoperative biopsies were recollected for reanalyzes by two pathologists. Inadequate transcriptions of the biopsy report were excluded. Results: we included 166 patients, with a mean age of 64.6 years. Of the biopsies, 118 were endometrioid, 38 were non-endometrioid and the remaining, hyperplasia. The agreement rates were 93.2% for endometrioid tumors and 68.9% for non-endometrioid, with a kappa index of 0.73 for the tumor cell type. The tumor FIGO grade distributed as G1 in 37.1%, G2 in 35.7% and G3 in 27.1%, with an agreement rate of 61.5%, 56% and 78.9%, respectively. The general kappa index for FIGO grading was 0.46. Of the G1 tumors, only 1.9% upgraded to G3, while 16% of the G2 lesions upgraded. There was no statistical difference in the agreement rates of tumor cell type and FIGO grading in function of place of biopsy execution, method of endometrial sampling and biopsy-surgery interval. Biopsies weighing more than 3g had a significantly better agreement in FIGO grading (p=0.040). Samples of 105 were available at HCPA and were reevaluated by 2 pathologists, with a general interobserver agreement 73.3/% (k=0.58) for tumor cell type and 57.9% (k=0.54) for grading. Conclusion: the accuracy of the preoperative biopsy in predicting the definite surgical characteristics it is not ideal. Caution must be taken when using this information to determine the surgical extension, due to the risk of under staging. These low rates of agreement are correlated with the low interobserver agreement. New grading systems and specialists teams are possible ways of improving this issue.

Group B Streptococcus, or GBS, is a gram positive bacteria commonly found in the gastrointestinal, genital and urinary tract of healthy adults. Between 10% and 30% of all pregnant women are colonized with GBS in the vagina or rectum. While GBS colonized mothers typically show no symptoms or adverse health effects, the bacteria can be passed to their child during labor and delivery. Although significant progress has been made in the identification and treatment of GBS, it remains the leading infectious cause of Page 14 2014 Appalachian Student Research Forum morbidity and mortality among newborns in the United States. The current guidelines recommended by the Center for Disease Control and Prevention (CDC) and endorsed by the American College of Obstetrics and Gynecology (ACOG) is to test pregnant women for GBS colonization between 34-37 weeks of gestation. The current gold standard for identification of GBS colonization is the use of selective enrichment broth (SEB) followed by culture and biochemical testing. Identified concerns with the culture procedure are: 1) the length of time it takes to get the results, 2) the lower sensitivity if the SEB step is left out to improve turn-around-time (TAT) and 3) the limited number of qualified technicians available to perform the complex test. Recently, several semi-automated molecular assays have been developed for identification of GBS which are marketed as having equivalent sensitivity and specificity to SEB followed by culture. The goals of this study were to: 1) validate the sensitivity and specificity of an FDA approved GBS molecular assay (Illumigene, Meridian Bioscience) and 2) evaluate a new testing strategy utilizing SEB followed by the Illumigene GBS assay to see if it offers an improvement in TAT when compared to SEB culture in our in-house microbiology lab and to those sent out to a national reference lab for GBS DNA assay. During the validation process, 20 consecutive samples were submitted to SEB followed by simultaneous in-house culture and Illumigene assay for GBS. The method validation experiments were analyzed using the EP Evaluator version 11 statistical software (Data Innovations). Comparison of TAT was evaluated utilizing a blinded report generated from our Laboratory Information System (Harvest, Orchard Software) for a 2 month period for the GBS tests performed using the SEB followed by Illumigene molecular assay (n=73), in-house SEB followed by culture (n=50) and send-out reference lab GBS DNA assay (n=43) procedures. The TAT (hrs) for each method (Mean±SEM) were determined from the time of collection until result approval. The Illumigene assay had a high sensitivity (100%) and specificity (100%) when compared to SEB followed by culture for identification of GBS. Utilization of the Illumigene assay following SEB significantly (p

Base teórica: o tratamento do carcinoma endometrial é feito através do estadiamento cirúrgico, que envolve histerectomia com salpingo-oforectomia bilateral e linfadenectomia pélvica e para-aórtica. Questiona-se o benefício da linfadenectomia sistemática em todos os pacientes, já que o risco de disseminação linfática em tumores de baixo risco é pequeno e não há evidências de benefício terapêutico em sua realização. Desse modo, tentam-se encontrar modos de determinar, na avaliação pré-operatória, quais são os pacientes que poderão se beneficiar da linfadenectomia e aqueles que podem prescindir do procedimento. Objetivos: avaliar a concordância da avaliação anatomopatológica entre a amostra endometrial pré-operatória e a peça cirúrgica das pacientes submetidas a tratamento cirúrgico primário do carcinoma de endométrio, correlacionando com características das pacientes e das amostras da patologia. Métodos: foram incluídos pacientes submetidos a tratamento cirúrgico para carcinoma de endométrio que tinham diagnóstico pré-operatório através de amostragem endometrial. Os prontuários foram revisados e as amostras disponíveis na instituição foram procuradas para posterior releitura por dois patologistas cegados para as demais informações anatomopatológicas. Resultados: foram incluídos 166 pacientes, com uma idade média de 64,6 anos. Das biópsias, 118 eram tumores endometrioides, 38 não-endometrioides e as demais, hiperplasia. As taxas de concordância foram de 93,2% para tumores endometrioides e 68,9% para não-endometrioides, com um índice kappa (k) de 0,73 para o tipo histológico. O grau tumoral distribui-se na amostra como G1 em 37,1%, G2 em 35,7% e G3 em 27,1%, com uma taxa de concordância de 61,5%, 56% e 78,9%, respectivamente, e k=0,46. Dos tumores G1, somente 1,9% teve upgrade para G3, em comparação com 16% das lesões G2. Não houve diferença estatística na taxa de concordância do tipo histológico e grau tumoral em função do local de execução da biópsia, método de amostragem e intervalo biópsia-cirurgia. Biópsias com pés > 3g tiveram uma concordância do grau tumoral significativamente melhor (p=0,040). Amostras de 105 pacientes estavam disponíveis no HCPA e foram reavaliadas por dois patologistas, com uma taxa de concordância interobservador geral de 73,3% (k=0,58) para o tipo histológico e 57,9% (k=0,54) para o grau tumoral. Conclusão: a acurácia da biópsia pré-operatória em predizer as características da peça cirúrgica não é ideal. Deve-se ter cuidado ao utilizar essa informação para determinar a extensão da cirurgia a ser realizada, sob risco de ser realizado subestadiamento. Estas baixas taxas de concordância correlacionam-se também com as baixas taxas de concordância interobservador. Novos sistemas de graduação e equipes de especialistas são possibilidades para melhorar esta questão. / Background: endometrial carcinoma treatment is based on surgical staging, including hysterectomy with bilateral salpingo-oophorectomy and pelvic and paraortic lymphadenectomy. The benefits of systematic lymphadenectomy in all patients have been questioned, since the risk of dissemination in low risk tumors is small and there is no evidence of benefits in its execution. Thereby, researches are looking for ways to determine, by preoperative evaluation, which patient will benefit from full staging and those who can do without the procedure. Objectives: evaluate the agreement between the preoperative endometrial samples and the surgical specimens in endometrial carcinoma, correlating it with characteristics of the samples and patients included, and evaluate the interobserver agreement of the preoperative biopsy. Methods: patients submitted to surgery as primary treatment for endometrial carcinoma at HCPA with a preoperative endometrial sampling were included. Their medical charts were reviewed. The available samples of the preoperative biopsies were recollected for reanalyzes by two pathologists. Inadequate transcriptions of the biopsy report were excluded. Results: we included 166 patients, with a mean age of 64.6 years. Of the biopsies, 118 were endometrioid, 38 were non-endometrioid and the remaining, hyperplasia. The agreement rates were 93.2% for endometrioid tumors and 68.9% for non-endometrioid, with a kappa index of 0.73 for the tumor cell type. The tumor FIGO grade distributed as G1 in 37.1%, G2 in 35.7% and G3 in 27.1%, with an agreement rate of 61.5%, 56% and 78.9%, respectively. The general kappa index for FIGO grading was 0.46. Of the G1 tumors, only 1.9% upgraded to G3, while 16% of the G2 lesions upgraded. There was no statistical difference in the agreement rates of tumor cell type and FIGO grading in function of place of biopsy execution, method of endometrial sampling and biopsy-surgery interval. Biopsies weighing more than 3g had a significantly better agreement in FIGO grading (p=0.040). Samples of 105 were available at HCPA and were reevaluated by 2 pathologists, with a general interobserver agreement 73.3/% (k=0.58) for tumor cell type and 57.9% (k=0.54) for grading. Conclusion: the accuracy of the preoperative biopsy in predicting the definite surgical characteristics it is not ideal. Caution must be taken when using this information to determine the surgical extension, due to the risk of under staging. These low rates of agreement are correlated with the low interobserver agreement. New grading systems and specialists teams are possible ways of improving this issue.

Base teórica: o tratamento do carcinoma endometrial é feito através do estadiamento cirúrgico, que envolve histerectomia com salpingo-oforectomia bilateral e linfadenectomia pélvica e para-aórtica. Questiona-se o benefício da linfadenectomia sistemática em todos os pacientes, já que o risco de disseminação linfática em tumores de baixo risco é pequeno e não há evidências de benefício terapêutico em sua realização. Desse modo, tentam-se encontrar modos de determinar, na avaliação pré-operatória, quais são os pacientes que poderão se beneficiar da linfadenectomia e aqueles que podem prescindir do procedimento. Objetivos: avaliar a concordância da avaliação anatomopatológica entre a amostra endometrial pré-operatória e a peça cirúrgica das pacientes submetidas a tratamento cirúrgico primário do carcinoma de endométrio, correlacionando com características das pacientes e das amostras da patologia. Métodos: foram incluídos pacientes submetidos a tratamento cirúrgico para carcinoma de endométrio que tinham diagnóstico pré-operatório através de amostragem endometrial. Os prontuários foram revisados e as amostras disponíveis na instituição foram procuradas para posterior releitura por dois patologistas cegados para as demais informações anatomopatológicas. Resultados: foram incluídos 166 pacientes, com uma idade média de 64,6 anos. Das biópsias, 118 eram tumores endometrioides, 38 não-endometrioides e as demais, hiperplasia. As taxas de concordância foram de 93,2% para tumores endometrioides e 68,9% para não-endometrioides, com um índice kappa (k) de 0,73 para o tipo histológico. O grau tumoral distribui-se na amostra como G1 em 37,1%, G2 em 35,7% e G3 em 27,1%, com uma taxa de concordância de 61,5%, 56% e 78,9%, respectivamente, e k=0,46. Dos tumores G1, somente 1,9% teve upgrade para G3, em comparação com 16% das lesões G2. Não houve diferença estatística na taxa de concordância do tipo histológico e grau tumoral em função do local de execução da biópsia, método de amostragem e intervalo biópsia-cirurgia. Biópsias com pés > 3g tiveram uma concordância do grau tumoral significativamente melhor (p=0,040). Amostras de 105 pacientes estavam disponíveis no HCPA e foram reavaliadas por dois patologistas, com uma taxa de concordância interobservador geral de 73,3% (k=0,58) para o tipo histológico e 57,9% (k=0,54) para o grau tumoral. Conclusão: a acurácia da biópsia pré-operatória em predizer as características da peça cirúrgica não é ideal. Deve-se ter cuidado ao utilizar essa informação para determinar a extensão da cirurgia a ser realizada, sob risco de ser realizado subestadiamento. Estas baixas taxas de concordância correlacionam-se também com as baixas taxas de concordância interobservador. Novos sistemas de graduação e equipes de especialistas são possibilidades para melhorar esta questão. / Background: endometrial carcinoma treatment is based on surgical staging, including hysterectomy with bilateral salpingo-oophorectomy and pelvic and paraortic lymphadenectomy. The benefits of systematic lymphadenectomy in all patients have been questioned, since the risk of dissemination in low risk tumors is small and there is no evidence of benefits in its execution. Thereby, researches are looking for ways to determine, by preoperative evaluation, which patient will benefit from full staging and those who can do without the procedure. Objectives: evaluate the agreement between the preoperative endometrial samples and the surgical specimens in endometrial carcinoma, correlating it with characteristics of the samples and patients included, and evaluate the interobserver agreement of the preoperative biopsy. Methods: patients submitted to surgery as primary treatment for endometrial carcinoma at HCPA with a preoperative endometrial sampling were included. Their medical charts were reviewed. The available samples of the preoperative biopsies were recollected for reanalyzes by two pathologists. Inadequate transcriptions of the biopsy report were excluded. Results: we included 166 patients, with a mean age of 64.6 years. Of the biopsies, 118 were endometrioid, 38 were non-endometrioid and the remaining, hyperplasia. The agreement rates were 93.2% for endometrioid tumors and 68.9% for non-endometrioid, with a kappa index of 0.73 for the tumor cell type. The tumor FIGO grade distributed as G1 in 37.1%, G2 in 35.7% and G3 in 27.1%, with an agreement rate of 61.5%, 56% and 78.9%, respectively. The general kappa index for FIGO grading was 0.46. Of the G1 tumors, only 1.9% upgraded to G3, while 16% of the G2 lesions upgraded. There was no statistical difference in the agreement rates of tumor cell type and FIGO grading in function of place of biopsy execution, method of endometrial sampling and biopsy-surgery interval. Biopsies weighing more than 3g had a significantly better agreement in FIGO grading (p=0.040). Samples of 105 were available at HCPA and were reevaluated by 2 pathologists, with a general interobserver agreement 73.3/% (k=0.58) for tumor cell type and 57.9% (k=0.54) for grading. Conclusion: the accuracy of the preoperative biopsy in predicting the definite surgical characteristics it is not ideal. Caution must be taken when using this information to determine the surgical extension, due to the risk of under staging. These low rates of agreement are correlated with the low interobserver agreement. New grading systems and specialists teams are possible ways of improving this issue.

Le cancer colorectal (CCR) représente la seconde cause de mortalité par cancer dans le monde. Les tumeurs sont classées selon les grades histologiques (état de différenciation cellulaire), en bas et haut grades. Les grades les plus avancés sont associés à de faibles taux de survie globale après chimiothérapie à base de 5-Fluorouracile (5-FU). Les taux de réponse aux traitements basés sur l’utilisation du 5-FU en première ligne de traitement demeurent relativement faibles (20–30%) et associés à de mauvais pronostics et des échappements thérapeutiques, dus à la résistance des cellules cancéreuses. Ces données soulignent donc la nécessité d’identifier de nouveaux biomarqueurs de résistance des cellules de CCR au 5-FU. Les travaux réalisés au cours de cette thèse ont porté sur l’étude de la sortiline, une protéine « multi-tâches » appartenant à la famille des récepteurs à domaine VPS10P avec sorLA et sorCS1-3, qui agit comme un (co)récepteur et un régulateur du traffic et de la sécrétion de protéines. La sortiline (et non sorLA), constitue un biomarqueur d’agressivité dans le CCR et est de mauvais pronostique. In vivo et in vitro, au sein des tumeurs et des cellules de CCR (lignées cellulaires et cultures primaires) résistantes au 5-FU, seule la sortiline apparait surexprimée au niveau transcriptomique et protéique. Ces données indiquent que la sortiline constitue également un biomarqueur de résistance au 5-FU, quels que soient les grades, stades et statuts mutationnels. Cette surexpression de la sortiline est majoritairement localisée au sein de l’appareil de Golgi des cellules résistantes et semble être régulée transcriptionnellement via une down-régulation d’ATF-3. L’inhibition génétique (shRNA) ou pharmacologique (CADA) de la sortiline potentialise les effets cytotoxiques du 5-FU, résultant en une forte augmentation de la mort cellulaire. La sortiline semble donc être également impliquée dans la résistance des cellules de CCR au 5-FU ; l’expression de sorLA ne variant pas après son inhbition. Ces résultats suggèrent que la sortiline pourrait constituer un biomarqueur d’agressivité et de résistance des cellules de CCR au 5-FU, mais aussi une nouvelle cible thérapeutique potentielle. / Worldwide, colorectal cancer (CRC) is the second leading cause of cancer-related deaths. Colorectal adenocarcinomas are divided into low and high grades. More advanced tumor grade is associated with poorer global survival following 5-fluorouracil (5-FU)-based systemic chemotherapy. Even when 5-FU is used as the first-line molecule, responsiveness is only 20–30%, and drug resistance contributes to both poor patient prognosis and relapses, emphasizing the need to identify biomarkers involved in this process. In this study, we focused on sortilin, a multifunctional protein among VPS10P domain-related receptors with sorLA and sorCS1-3, that acts as a receptor and co-receptor as well as a regulator of intra- and extracellular protein sorting and trafficking. We obtained evidence that sortilin, but not sorLA, is a biomarker of CRC aggressiveness associated with poor clinical outcomes. In vivo and in vitro, in both 5-FU–resistant CRC cell lines and primary cultures, only sortilin was overexpressed at both protein and mRNA levels, indicating that it could serve as a biomarker of 5-FU resistance regardless of tumor grade and mutational status. Sortilin overexpression is especially localized in Golgi apparatus of 5-FU resistant cells and seems to be transcriptionally regulated through ATF-3 downregulation. Genetic (shRNA) and pharmacological (CADA) inhibition of sortilin potentiated 5-FU–induced cytotoxicity, resulting in a significant increase in cancer cell eradication, implying that sortilin is also actively involved in 5-FU resistance. Moreover, sorLA expression is unchanged upon sortilin inhibition. Our findings indicate that sortilin is a promising biomarker of 5-FU resistance in CRC, as well as a potential therapeutic target for overcoming 5-FU resistance.

Σκοπός της μελέτης ήταν η ανάδειξη της νεοαγγειογένεσης και ο προσδιορισμός της έκφρασης των VEGF-A, FGF-2, COX-2, AR και BCL-2 στην καλοήθη υπερπλασία και το αδενοκαρκίνωμα του προστάτη. Το υλικό αφορούσε σε δείγματα προστατικού ιστού μονιμοποιημένα και εγκλεισμένα σε παραφίνη, από 24 περιστατικά καλοήθους υπερπλασίας και 139 περιστατικά προστατικού αδενοκαρκινώματος. Τα τελευταία χωρίστηκαν περαιτέρω σε 3 υποομάδες (Grade I, II και ΙΙΙ) ανάλογα με το βαθμό διαφοροποίησης του νεοπλάσματος κατά Gleason (2-4, 5-7 και 8-10 αντίστοιχα). Χρησιμοποιήθηκε ανοσοϊστοχημική μέθοδος Βιοτίνης-Στρεπταβιδίνης-Υπεροξειδάσης, και εφαρμόστηκε ημιποσοτική μέθοδος για την εκτίμηση της ανοσοϊστοχημικής χρώσης. Τα ευρήματά μας ανέδειξαν σαφή αύξηση της νεοαγγείωσης (MVD) στο αδενοκαρκίνωμα του προστάτη σε σχέση με την καλοήθη υπερπλασία, η οποία εμφάνισε στατιστικώς σημαντική θετική σχέση με το βαθμό κακοήθειας των προστατικών νεοπλασμάτων (ANOVA p<0.001) και με την έκφραση των VEGF-A και COX-2 (ANOVA p<0.001). Αναδείχθηκε αντίστροφη συσχέτιση της πυρηνικής έκφρασης του ανδρογονικού υποδοχέα (AR) με το βαθμό διαφοροποίησης των νεοπλασμάτων (p<0.0001) και την έκφραση του VEGF-A στο προστατικό στρώμα (p<0.001 Spearman r = -0.312). Η έκφραση της BCL-2 παρουσιάστηκε αυξημένη στα προστατικά αδενοκαρκινώματα και σχετίστηκε με το βαθμό διαφοροποίησης των νεοπλασμάτων (p<0.001) και την έκφραση των VEGF-A και COX-2 (p<0.001). Η έκφραση του VEGF-A σε όλα τα περιστατικά αδενοκαρκινώματος του προστάτη εμφάνισε στατιστικώς σημαντική σχέση με το βαθμό διαφοροποίησης των νεοπλασμάτων (p<0.0001). Ωστόσο στα πτωχής διαφοροποίησης αδενοκαρκινώματα η μέση τιμή της έκφρασης του VEGF-A παρουσίασε πτώση. Αντίθετα, η σημασία της COX-2 στον προστατικό καρκίνο αναδείχθηκε με την έκφρασή της τόσο στην καλοήθη υπερπλασία όσο και στα αδενοκαρκινώματα του προστάτη. Η έκφραση παρουσίασε σημαντική σχέση με το βαθμό διαφοροποίησης των νεοπλασμάτων (p<0.01). Η σαφώς αυξημένη έκφραση της COX-2 σε σχέση με τη μείωση της έκφρασης του VEGF-A στα πτωχής διαφοροποίησης νεοπλάσματα πιθανόν υποδηλώνει την ύπαρξη ενός αγγειογενετικού διακόπτη στα νεοπλάσματα αυτά όπου η COX-2 φαίνεται να παίζει σημαντικότερο ρόλο από τον VEGF-A. Η σημαντική αυτή πληροφορία θα μπορούσε να βρει πιθανή θεραπευτική εφαρμογή, καθώς σε πτωχής διαφοροποίησης αδενοκαρκινώματα του προστάτη ίσως η θεραπεία με COX-2 εκλεκτικούς αναστολείς να είχε πολύ καλύτερα αποτελέσματα από τις αντι-αγγειογενετικές θεραπείες με αναστολείς του VEGF. / The aim of this study was to immunohistochemically evaluate the expression of VEGF-A, FGF-2, COX-2, AR and BCL-2 in benign prostatic hyperplasia (BPH) and prostate carcinoma in relation to microvessel density (MVD) and the Gleason grade of the neoplasms. A total of 139 cases of primary prostate carcinoma and 24 cases of benign hyperplasia were included in the study. Tumors were graded according to the Gleason grading system and further divided into 3 subgroups (GRADE I, II and III). The immunostaining was performed according to the Streptavidin-Biotin Complex Peroxidase method, in formalin fixed paraffin-embedded tissue. Mean micro vessel density (MVD) was strongly related to tumor grade, VEGF-A and COX-2 histoscore (ANOVA, p<0.001). The androgen receptor was localized in the nuclei of prostate epithelial cells in 97% of cases. The comparison of AR staining with tumor grade revealed an inverse relationship between these two parameters (ANOVA, p<0,0001). An interesting finding was the inverse relationship of stromal AR expression in relation to VEGF-A immunoreactivity. BCL-2 expression was correlated with tumor grade in prostate carcinoma cases (p<0.001) and was strongly correlated with COX-2 and VEGF-A expression (p<0.001). These findings suggest that BCL-2 may play a dual role in tumorigenesis, possibly through an angiogenetic axis. VEGF-A expression was detected in only 17% of BPH cases but all prostate cancer specimens demonstrated some degree of immunoreactivity. COX-2 immunopositivity was present in 54% of BPH specimens and in 99% of primary prostate carcinomas. The increased COX-2 expression correlated significantly with Gleason grade. In our study, high-grade neoplasms presented low to moderate VEGF staining intensity compared to COX-2 expression. These results suggest the activation of an angiogenic switch in poorly differentiated neoplasms, where COX-2 may play a crucial role compared to VEGF and the possible key role of COX-2 in poorly differentiated cancers. According to our findings, anti-VEGF therapy could prove to be more beneficial in patients with low-grade disease, while patients with high-grade prostate carcinoma are more likely to respond to selective COX-2 inhibitors. Immunohistochemical determination of VEGF-A and COX-2 content might prove a useful tool in the design of patient-tailored, anti-angiogenic treatments.

<p>The natural history of localized prostate cancer is not fully understood. In most patients the tumor will never progress to a lethal disease, while a subset of patients will ultimately die of the disease. Efficient tools to separate indolent from lethal disease is currently lacking which means that many patients will be offered treatment without any benefit, but still be at risk of experiencing treatment related side effects.</p><p>The aims of these studies were to get more insight into the natural history of untreated localized prostate cancer, to assess the prognostic value of established clinical parameters such as Gleason score, nuclear grade and tumor volume and, moreover, some new prognostic markers Ki-67, AMACR and MUC-1. We also aimed to study time trends in the detection of incidental tumors in Sweden.</p><p>Patients with localized disease (n=223) and no initial treatment were followed for 21 years. Most patients had a favorable outcome. However, a subset of patients developed lethal disease even beyond 15 years of follow-up and these patients define the group that may benefit most from treatment with curative intent. Patients with poorly differentiated tumors experienced a 9 time higher risk of dying in prostate cancer.</p><p>The studies on prognostic markers are based on a cohort of patients (n=253) with incidental prostate cancer detected by transurethral resection for presumed benign hyperplasia. All patients were left without initial treatment. Gleason grade, nuclear grade and tumor volume turned all out to be independent prognostic factors. MUC-1, AMACR and Ki-67 also carried prognostic information. However, after adjustment for Gleason grade, nuclear grade and tumor volume only MUC-1 and AMACR remained as statistically significant prognostic factors. When tested for sensitivity and specificity they all failed and, consequently, they seem to be of less value in daily practice for cancelling an individual patient regarding the choice of treatment.</p><p>Time trends in incidental prostate tumors in Sweden were analyzed in a cohort of patients with prostate tumors detected by transurethral resection (TUR-P). Through linkage of the national registration number (NRN) with several registers, e.g. the Swedish Cancer Registry, the National Inpatient registry and the Cause of Death Registry we identified, during the period 1970 through 2003, in total 23288 patients with incidental prostate cancer, who constituted the study group. As comparison group we choose all patients diagnosed with prostate cancer between 1970-2003 excluding those with incidental cancer, in total 112204 patients. Our result confirms earlier findings that there has been a dramatic change over time in incidence of incidental prostate cancers in Sweden, which parallels the introduction of prostate specific antigen. We also found that the cumulative incidence of prostate cancer death is high in the incidental group, opposing earlier findings that incidental tumours are a non-lethal disease.</p> / issn 1642-4063

The natural history of localized prostate cancer is not fully understood. In most patients the tumor will never progress to a lethal disease, while a subset of patients will ultimately die of the disease. Efficient tools to separate indolent from lethal disease is currently lacking which means that many patients will be offered treatment without any benefit, but still be at risk of experiencing treatment related side effects. The aims of these studies were to get more insight into the natural history of untreated localized prostate cancer, to assess the prognostic value of established clinical parameters such as Gleason score, nuclear grade and tumor volume and, moreover, some new prognostic markers Ki-67, AMACR and MUC-1. We also aimed to study time trends in the detection of incidental tumors in Sweden. Patients with localized disease (n=223) and no initial treatment were followed for 21 years. Most patients had a favorable outcome. However, a subset of patients developed lethal disease even beyond 15 years of follow-up and these patients define the group that may benefit most from treatment with curative intent. Patients with poorly differentiated tumors experienced a 9 time higher risk of dying in prostate cancer. The studies on prognostic markers are based on a cohort of patients (n=253) with incidental prostate cancer detected by transurethral resection for presumed benign hyperplasia. All patients were left without initial treatment. Gleason grade, nuclear grade and tumor volume turned all out to be independent prognostic factors. MUC-1, AMACR and Ki-67 also carried prognostic information. However, after adjustment for Gleason grade, nuclear grade and tumor volume only MUC-1 and AMACR remained as statistically significant prognostic factors. When tested for sensitivity and specificity they all failed and, consequently, they seem to be of less value in daily practice for cancelling an individual patient regarding the choice of treatment. Time trends in incidental prostate tumors in Sweden were analyzed in a cohort of patients with prostate tumors detected by transurethral resection (TUR-P). Through linkage of the national registration number (NRN) with several registers, e.g. the Swedish Cancer Registry, the National Inpatient registry and the Cause of Death Registry we identified, during the period 1970 through 2003, in total 23288 patients with incidental prostate cancer, who constituted the study group. As comparison group we choose all patients diagnosed with prostate cancer between 1970-2003 excluding those with incidental cancer, in total 112204 patients. Our result confirms earlier findings that there has been a dramatic change over time in incidence of incidental prostate cancers in Sweden, which parallels the introduction of prostate specific antigen. We also found that the cumulative incidence of prostate cancer death is high in the incidental group, opposing earlier findings that incidental tumours are a non-lethal disease.

<p>From January, 1988, to December, 1993, 113 patients with FIGO stage IA-IIC epithelial ovarian carcinoma were treated with postoperative radiotherapy. The median follow-up period was 74 months. Tumor recurrences were recorded in 33 cases (30%). The cancer-specific survival rate was 72%. Tumor grade was a significant (P = 0.007) and independent prognostic factor in the multivariate analysis. In a smaller series of 106 patients, a number of prognostic factors (age, FIGO stage, histopathological type, and tumor grade) were studied in relation to regulators of apoptosis (p53, bcl-2, and bax) and growth factor receptors (HER-2/neu and EGFR). Immunohistochemical techniques were used. In a separate series of 103 patients, the DNA content (flow cytometry) and p53 status of the tumors were also studied and related to the same clinicopathological factors. P53 was associated with tumor grade (P = 0.007) and survival status (P = 0.046). In a Cox multivariate analysis, tumor grade (P = 0.0006), bax status (P = 0.020), and EGFR status (P = 0.018) were significant and independent prognostic factors. DNA ploidy of the tumors was strongly associated with tumor grade. </p><p>From January, 1994, to December, 1998, a series of 109 patients with ovarian carcinomas (FIGO IA-IIC) were treated with postoperative adjuvant chemotherapy. The same prognostic factors were studied in this series. The median follow-up was 48 months and the cancer-specific survival rate was 75%. Twenty-five (25%) tumor recurrences were recorded. The most favorable survival rate was seen in patients with tumors negative for p53 and positive for bcl-2 or bax. In a multivariate analysis, tumor grade (P = 0.014) and p53 status (P = 0.020) were independent prognostic factors.</p><p>Clinical, histopathological and biological prognostic factors should be combined in prognostic models to render patient-tailored therapy possible and to define different prognostic groups for future clinical studies of adjuvant therapy in early stage ovarian carcinomas.</p>

From January, 1988, to December, 1993, 113 patients with FIGO stage IA-IIC epithelial ovarian carcinoma were treated with postoperative radiotherapy. The median follow-up period was 74 months. Tumor recurrences were recorded in 33 cases (30%). The cancer-specific survival rate was 72%. Tumor grade was a significant (P = 0.007) and independent prognostic factor in the multivariate analysis. In a smaller series of 106 patients, a number of prognostic factors (age, FIGO stage, histopathological type, and tumor grade) were studied in relation to regulators of apoptosis (p53, bcl-2, and bax) and growth factor receptors (HER-2/neu and EGFR). Immunohistochemical techniques were used. In a separate series of 103 patients, the DNA content (flow cytometry) and p53 status of the tumors were also studied and related to the same clinicopathological factors. P53 was associated with tumor grade (P = 0.007) and survival status (P = 0.046). In a Cox multivariate analysis, tumor grade (P = 0.0006), bax status (P = 0.020), and EGFR status (P = 0.018) were significant and independent prognostic factors. DNA ploidy of the tumors was strongly associated with tumor grade. From January, 1994, to December, 1998, a series of 109 patients with ovarian carcinomas (FIGO IA-IIC) were treated with postoperative adjuvant chemotherapy. The same prognostic factors were studied in this series. The median follow-up was 48 months and the cancer-specific survival rate was 75%. Twenty-five (25%) tumor recurrences were recorded. The most favorable survival rate was seen in patients with tumors negative for p53 and positive for bcl-2 or bax. In a multivariate analysis, tumor grade (P = 0.014) and p53 status (P = 0.020) were independent prognostic factors. Clinical, histopathological and biological prognostic factors should be combined in prognostic models to render patient-tailored therapy possible and to define different prognostic groups for future clinical studies of adjuvant therapy in early stage ovarian carcinomas.