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Valle L.,Catalan Institute of Nanoscience and Nanotechnology | Hernandez-Illan E.,University of Alicante | Bellido F.,Catalan Institute of Nanoscience and Nanotechnology | Aiza G.,Catalan Institute of Nanoscience and Nanotechnology | And 22 more authors.
Human Molecular Genetics | Year: 2014

Germline mutations in DNA polymerase ε (POLE) and δ (POLD1) have been recently identified in families with multiple colorectal adenomas and colorectal cancer (CRC). All reported cases carried POLE c.1270C>G (p.Leu424Val) or POLD1 c.1433G>A (p.Ser478Asn) mutations. Due to the scarcity of cases reported so far, an accurate clinical phenotype has not been defined. We aimed to assess the prevalence of these recurrent mutations in unexplained familial and early-onsetCRC and polyposis, and to add additional information to define the clinical characteristics of mutated cases. A total of 858 familial/early onset CRC and polyposis patients were studied: 581 familial and early-onset CRC cases without mismatch repair (MMR) deficiency, 86 cases with MMR deficiency and 191 polyposis cases. Mutation screening was performed by KASPar genotyping assays and/or Sanger sequencing of the involved exons. POLE p.L424V was identified in a 28-year-old polyposis and CRC patient, as a de novo mutation. None of the 858 cases studied carried POLD1 p.S478N. A new mutation, POLD1 c.1421T>C (p.Leu474Pro), was identified in amismatch repair proficient Amsterdam II family. Its pathogenicity was supported by cosegregation in the family, in silico predictions, and previously published yeast assays.POLE and POLD1 mutations explain a fraction of familial CRC and polyposis. Sequencing the proofreading domains of POLE and POLD1 should be considered in routine genetic diagnostics. Until additional evidence is gathered, POLE and POLD1 genetic testing should not be restricted to polyposis cases, and the presence of de novo mutations, considered. © The Author 2014.The Author 2014. Published by Oxford University Press. All rights reserved.

Minig L.,Valencian Institute of Oncology | Minig L.,University of San Pablo - CEU | Chuang L.,Mount Sinai School of Medicine | Patrono M.G.,University of San Pablo - CEU | And 2 more authors.
Journal of Minimally Invasive Gynecology | Year: 2015

Study Objective: To compare the surgical outcome and short-term postoperative complications in premenopausal women who had undergone hysterectomies for benign indication with or without prophylactic bilateral salpingectomy. Design: A cohort of consecutive women who had undergone hysterectomy plus bilateral salpingectomy between May 2012 and July 2014 (group A) were compared with the same number of consecutive premenopausal patients who had undergone simple hysterectomy operated on before May 2012 (group B). Inclusion criteria included premenopausal women and benign indication for surgery (Canadian Task Force classification III). Setting: tertiary care hospital. Intervention: Salpingectomy versus no salpingectomy at the time of benign hysterectomy. Measurements and Main Results: A total of 97 and 71 patients were included in groups A and B, respectively. No differences between the 2 groups were observed regarding patient characteristics. The average operative time, estimated blood loss, uterine size, and intraoperative complications were similar between groups. The mean (standard deviation) length of hospitalization time was 43.7 (22.4) hours in group A and 53.9 (83.5) hours in group B (p = .008). There were no significant differences in terms of the incidence of postoperative complications, emergency visits after readmission, and hospital readmission between both groups of patients. Conclusion: Prophylactic salpingectomy at the time of benign hysterectomy in premenopausal women is safe and feasible and does not worsen surgical outcomes or the incidence of intraoperative and postoperative complications. © 2015 AAGL.

Martin M.,Complutense University of Madrid | Morales S.,Hospital Arnau de Vilanova de Lerida | Martinez N.,University Hospital Ramon jal | Guerrero A.,Valencian Institute of Oncology | And 6 more authors.
Journal of Clinical Oncology | Year: 2015

Purpose To test whether combining bevacizumab, an anti-vascular endothelial growth factor treatment, with endocrine therapy (ET) could potentially delay the emergence of resistance to ET. Patients and Methods A multicenter, randomized, open-label, phase III, binational (Spain and Germany) study added bevacizumab (15 mg/kg every 3 weeks) to ET (ET-B; letrozole or fulvestrant) as first-line therapy in postmenopausal patients with human epidermal growth factor receptor 2 (HER2) -negative and hormone receptor-positive advanced breast cancer. We compared progression-free survival (PFS), overall survival (OS), overall esponse rate (ORR), response duration (RD), time to treatment failure (TTF), clinical benefit rate (CBR), and safety. Results From 380 patients recruited (2007 to 2011), 374 were analyzed by intent to-treat (184 patients on ET and 190 patients on ET-B). Median age was 65 years, 270 patients (72%) had Eastern Cooperative Oncology Group performance status of 0, 178 patients (48%) had visceral metastases, and 171 patients (46%) and 195 patients (52%) had received prior chemotherapy or ET, respectively. Median PFS was 14.4 months in the ET arm and 19.3 months in the ET-B arm (hazard ratio, 0.83; 95% CI, 0.65 to 1.06; P = .126). ORR, CBR, and RD with ET versus ET-B were 22% versus 41% (P< .001), 67% versus 77% (P = .041), and 13.3 months versus 17.6 months (P = .434), respectively. TTF and OS were comparable in both arms. Grade 3 to 4 hypertension, aminotransferase elevation, and proteinuria were significantly higher in the ET-B arm. Eight patients (4.2%) receiving ET-B died during study or within 30 days of end of treatment. Conclusion The addition of bevacizumab to ET in first-line treatment failed to produce a statistically significant increase in PFS or OS in women with HER2-negative/hormone receptor-positive advanced breast cancer. © 2015 American Society of Clinical Oncology. All rights reserved.

Poveda A.,Valencian Institute of Oncology | Vergote I.,University Hospital | Tjulandin S.,Russian Cancer Research Center | Kong B.,Shandong University | And 12 more authors.
Annals of Oncology | Year: 2011

Background: OVA-301 is a large randomized trial that showed superiority of trabectedin plus pegylated liposomal doxorubicin (PLD) over PLD alone in relapsed ovarian cancer. The optimal management of patients with partially platinum-sensitive relapse [6-12 months platinum-free interval (PFI)] is unclear. Patients and methods: Within OVA-301, we therefore now report on the outcomes for the 214 cases in this subgroup. Results: Trabectedin/PLD resulted in a 35% risk reduction of disease progression (DP) or death [hazard ratio (HR) = 0.65, 95% confidence interval (CI), 0.45-0.92; P = 0.0152; median progression-free survival (PFS) 7.4 versus 5.5 months], and a significant 41% decrease in the risk of death (HR = 0.59; 95% CI, 0.43-0.82; P = 0.0015; median survival 23.0 versus 17.1 months). The safety of trabectedin/PLD in this subset mimicked that of the overall population. Similar proportions of patients received subsequent therapy in each arm (76% versus 77%), although patients in the trabectedin/PLD arm had a slightly lower proportion of further platinum (49% versus 55%). Importantly, patients in the trabectedin/PLD arm survived significantly longer after subsequent platinum (HR = 0.63; P = 0.0357; median 13.3 versus 9.8 months). Conclusion: This hypothesis-generating analysis demonstrates that superior benefits with trabectedin/PLD in terms of PFS and survival in the overall population appear particularly enhanced in patients with partially sensitive disease (PFI 6-12 months). © The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Kaye S.B.,Institute of Cancer Research | Colombo N.,Italian National Cancer Institute | Monk B.J.,University of California at Irvine | Tjulandin S.,Russian Cancer Research Center | And 12 more authors.
Annals of Oncology | Year: 2011

Background: OVA-301 is a large randomized trial that showed superiority of trabectedin plus pegylated liposomal doxorubicin (PLD; CentoCor Ortho Biotech Products L.P., Raritan, NJ, USA). over single-agent PLD in 672 patients with relapsed ovarian cancer, particularly in the partially platinum-sensitive subgroup [platinum-free interval (PFI) of 6-12 months]. This superiority has been suggested to be due to the differential impact of subsequent (platinum) therapy. Patients and methods: A detailed analysis of subsequent therapies and survival outcomes in the overall population and in the subsets according to platinum sensitivity was therefore conducted. Results: Similar proportions of patients received subsequent therapy in each arm (76% versus 77%), including further platinum-based regimens (49% versus 55%). Patients in the trabectedin/PLD arm received subsequent chemotherapy at a later time (median delay 2.5 months versus PLD arm). Overall survival from subsequent platinum was significantly prolonged in the partially platinum-sensitive disease subset (hazard ratio = 0.63; P = 0.0357). Conclusion: The superiority of trabectedin/PLD over single-agent PLD in OVA-301 cannot be explained by differences in the extent or nature of subsequent therapies administered to these patients. On the other hand, these exploratory analyses support the hypothesis that the enhanced survival benefits in the partially platinum-sensitive subset might be due to an extended PFI leading to longer survival with subsequent platinum. © The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

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