Complex Segregation Analysis of Pedigrees from the Gilda Radner Familial Ovarian Cancer Registry Reveals Evidence for Mendelian Dominant Inheritance

Familial component is estimated to account for about 10% of ovarian cancer. However, the mode of inheritance of ovarian cancer remains poorly understood. The goal of this study was to investigate the inheritance model that best fits the observed transmission pattern of ovarian cancer among 7669 members of 1919 pedigrees ascertained through probands from the Gilda Radner Familial Ovarian Cancer Registry at Roswell Park Cancer Institute, Buffalo, New York.Using the Statistical Analysis for Genetic Epidemiology program, we carried out complex segregation analyses of ovarian cancer affection status by fitting different genetic hypothesis-based regressive multivariate logistic models. We evaluated the likelihood of sporadic, major gene, environmental, general, and six types of Mendelian models. Under each hypothesized model, we also estimated the susceptibility allele frequency, transmission probabilities for the susceptibility allele, baseline susceptibility and estimates of familial association. Comparisons between models were carried out using either maximum likelihood ratio test in the case of hierarchical models, or Akaike information criterion for non-nested models. When assessed against sporadic model without familial association, the model with both parent-offspring and sib-sib residual association could not be rejected. Likewise, the Mendelian dominant model that included familial residual association provided the best-fitting for the inheritance of ovarian cancer. The estimated disease allele frequency in the dominant model was 0.21.This report provides support for a genetic role in susceptibility to ovarian cancer with a major autosomal dominant component. This model does not preclude the possibility of polygenic inheritance of combined effects of multiple low penetrance susceptibility alleles segregating dominantly

Solução glicosada hipertônica no mesentério e no peritônio de ratos: estudo macroscópico e microscópico

PURPOSE: The objective of the experimental study is to detect the macroscopic and microscopic alterations of the mesenterium and parietal peritoneum when hypertonic glucose aqueous solution 10%-25% is administrated into the peritoneal cavity of the rat. METHODS: 90 Wistar females young rats adults were used weighin between 180-250 g, numbered 1 to 90, establishing unique group and divided in three groups (A, B, C) of 30 animals chosen aleatory manner. 0,9% saline solution was used called control group, or group A, 10% glucose solution named group B, and in the others 30 was used 25% glucose solution named group C, differing in the observation period, (06h, 24h and 48h), but with the same procedure. A midline abdominal wall laparotomy was made and in the animals of the control group was injected 2 ml of a 0,9% saline solution into the peritoneal cavity. After, we made a suture in mass without to include the peritoneum. For the others groups (B, C) the rats received 10% glucose solution and 25% glucose solution injected into the peritoneal cavity respectively. All groups were kept under observation and the results were submitted to statistical analysis by a longitudinal and transversal comparative study. RESULTS: A new surgery was done in 6h, 24h and 48h, and we observed in macroscopic evaluation, the presence of fluid, serous uniforme and rosy all over the cavity. Vascular congestion was present. We dried out 90 fragments of mesenterium and 90 fragments of parietal peritonium bilateral. In the microscopic study, necrosis was not present. For the mesenterium histological study we observed 16 cases (17,8%) unspecific chronic inflammation, 30 cases (33,4%) hiperplasic linfonod, 10 cases (11,1%) high vascular congestion, 6 cases (6,6%) reaction fibrosis and 28 cases (31,1%) no alteration. For the parietal peritonium histological study we observed 6 cases (3,3%) reaction fibrosis and 174 cases (96,7%) no alteration. Giant cell was not present. In the statistical analisys statistic there is no significance between the groups (p>0,05). CONCLUSION: Hypertonic glucose solution and NaCl 0,9% on the mesenterium and parietal peritonium do not produce tissue necrosis in a rat and the inflammation process has the same intensity.OBJETIVO: Investigar as alterações macroscópicas e microscópicas do mesentério e do peritônio parietal quando se administra a solução aquosa de glicose hipertônica a 10% e a 25% na cavidade peritoneal de rato. MÉTODOS: 90 ratos fêmeas (n=90), adultos, Wistar, jovens, com peso variando de 180 a 250 gramas foram divididos em 3 sub-grupos (A, B e C) contendo cada um 30 animais com procedimentos idênticos, diferindo apenas no período de observação. Os números de 1 a 30 constituem o grupo A ou grupo-controle (NaCl 0,9%), os números de 31 a 60 constituem o grupo B ou grupo-glicose a 10% e os números de 61 a 90 constituem o grupo C ou grupo- glicose a 25%. Realizando-se posteriormente laparotomia com incisão mediana longitudinal de pele a 2 cm abaixo do processo Xiphoideus sterni, estendendo-se por 3 cm caudalmente na linha média ventral. A escolha do procedimento a ser realizado para introdução na cavidade peritoneal de 2 ml de uma solução de cloreto de sódio 0,9% (controle), de glicose hipertônica a 10% e de glicose hipertônica a 25%. Em períodos correspondentes às 6h, 24h e 48h de pós-operatório, os animais de cada grupo foram reoperados, sendo realizada avaliação macroscópica e microscópica além dos registros das alterações histológicas do mesentério e peritônio parietal. RESULTADOS: Na microscopia do mesentério observou-se que 30 animais (33,4%) apresentaram linfonodos hiperplásicos; 6 animais (6,6%) com fibrose reacional; 10 animais (11,1%) com intensa congestão vascular; 16 animais (17,8%) com inflamação crônica inespecífica; 28 casos (31,1%) sem alteração. A microscopia do peritônio revelou 6 casos com fibrose reacional (3,3%) 174 casos (96,7%) sem alteração histológica. CONCLUSÃO: As soluções de glicose a 10% e a 25% não causam necrose tecidual quando introduzidas na cavidade peritoneal. O processo reacional inflamatório é de igual intensidade tecidual comparando-se ao uso da solução de NaCl a 0,9%.UNCISAL DepartmentUFAL Morphology Department and Human AnatomyUNIFESP-EPM Surgery DepartmentUNIFESP, EPM, Surgery DepartmentSciEL

Weekly platinum chemotherapy for recurrent ovarian cancer

British Journal of Cancer (2002) 86, 2–4. DOI: 10.1038/sj/bjc/6600062 www.bjcancer.co

Uterine papillary serous and clear cell carcinomas predict for poorer survival compared to grade 3 endometrioid corpus cancers

To compare the survival of women with uterine papillary serous carcinoma (UPSC) and clear cell carcinoma (CC) to those with grade 3 endometrioid uterine carcinoma (G3EC). Demographic, pathologic, treatment, and survival information were obtained from the Surveillance, Epidemiology, and End Results Program from 1988 to 2001. Data were analysed using Kaplan–Meier and Cox proportional hazards regression methods. Of 4180 women, 1473 had UPSC, 391 had CC, and 2316 had G3EC cancers. Uterine papillary serous carcinoma and CC patients were older (median age: 70 years and 68 vs 66 years, respectively; P<0.0001) and more likely to be black compared to G3EC (15 and 12% vs 7%; P<0.0001). A higher proportion of UPSC and CC patients had stage III–IV disease compared to G3EC patients (52 and 36% vs 29%; P<0.0001). Uterine papillary serous carcinoma, CC and G3EC patients represent 10, 3, and 15% of endometrial cancers but account for 39, 8, and 27% of cancer deaths, respectively. The 5-year disease-specific survivals for women with UPSC, CC and G3EC were 55, 68, and 77%, respectively (P<0.0001). The survival differences between UPSC, CC and G3EC persist after controlling for stage I–II (74, 82, and 86%; P<0.0001) and stage III–IV disease (33, 40, and 54; P<0.0001). On multivariate analysis, more favourable histology (G3EC), younger age, and earlier stage were independent predictors of improved survival. Women with UPSC and CC of the uterus have a significantly poorer prognosis compared to those with G3EC. These findings should be considered in the counselling, treating and designing of future trials for these high-risk patients

Sustained platelet-sparing effect of weekly low dose paclitaxel allows effective, tolerable delivery of extended dose dense weekly carboplatin in platinum resistant/refractory epithelial ovarian cancer

Background: Platinum agents have shown demonstrable activity in the treatment of patients with platinum resistant, recurrent ovarian cancer when delivered in a "dose-dense" fashion. However, the development of thrombocytopenia limits the weekly administration of carboplatin to no greater than AUC 2. Paclitaxel has a well-described platelet sparing effect however its use to explicitly provide thromboprotection in the context of dose dense carboplatin has not been explored. Methods: We treated seven patients with platinum resistant ovarian cancer who had previously received paclitaxel or who had developed significant peripheral neuropathy precluding the use of further full dose weekly paclitaxel. Results: We were able to deliver carboplatin AUC 3 and paclitaxel 20 mg/m(2) with no thrombocytopenia or worsening of neuropathic side-effects, and with good activity. Conclusions: We conclude that this regimen may be feasible and active, and could be formally developed as a "platinum-focussed dose-dense scaffold" into which targeted therapies that reverse platinum resistance can be incorporated, and merits further evaluation