Outcomes of > 1300 Nipple-Sparing Mastectomies with Immediate Reconstruction: The Impact of Expanding Indications on Complications

Annals of Surgical Oncology - The enhanced esthetics and demonstrated oncologic safety of nipple-sparing mastectomy (NSM) in selected patients have resulted in increased rates among patients with...     

Cep63 recruits Cdk1 to the centrosome: implications for regulation of mitotic entry, centrosome amplification, and genome maintenance

Centrosomes are central regulators of mitosis that are often amplified in cancer cells. Centrosomes function both as organizers of the mitotic spindle and as reaction centers to trigger activation of Cdk1 and G(2)/M transition in the cell cycle, but their functional organization remains incomplete. Recent proteomic studies have identified novel components of the human centrosome including Cep63, a protein of unknown function that Xenopus studies have implicated in mitotic spindle assembly and spindle inactivation after DNA damage. Here, we report that human Cep63 binds to and recruits Cdk1 to centrosomes, and thereby regulates mitotic entry. RNAi-mediated Cep63 depletion in U2OS cancer cells induced polyploidization through mitotic skipping. Elicitation of this phenotype was associated with downregulation of centrosomal Cdk1, mimicking the phenotype induced by direct depletion of Cdk1. In contrast, Cep63 overexpression induced de novo centrosome amplification during cell-cycle interphase. Induction of this phenotype was suppressible by cell treatment with the Cdk inhibitor roscovitine. In a survey of 244 neuroblastoma cases, Cep63 mRNA overexpression was associated with MYCN oncogene amplification and poor prognosis. In cultured cells, Cep63 overexpression was associated with an enhancement in replication-induced DNA breakage. Together, our findings define human Cep63 as a centrosomal recruitment factor for Cdk1 that is essential for mitotic entry, providing a physical link between the centrosome and the cell-cycle machinery.     

Cerebral tissue oxygenation measured by two different probes: challenges and interpretation

Purpose  

Cerebral tissue oxygenation (PbrO₂) is most frequently monitored using a Licox CC1.SB system (LX, Integra Neuroscience, France) but recently a new probe—the Neurovent-PTO (NV)—was introduced by a different manufacturer (Raumedic, Germany). There are no prospective data on how these probes compare in clinical routine. We therefore compared both probes in comatose patients suffering from traumatic brain injury (TBI) or subarachnoid haemorrhage (SAH) during dynamic changes of inspirational oxygen fraction (FiO₂) and mean arterial pressure (MAP).     

Cytotoxic T lymphocytes simultaneously targeting multiple tumor-associated antigens to treat EBV negative lymphoma

Although immunotherapy with Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) can treat EBV-associated Hodgkin and non-Hodgkin lymphoma (HL/NHL), more than 50% of such tumors are EBV negative. We now describe an approach that allows us to consistently generate, in a single line, CTLs that recognize a wide spectrum of nonviral tumor-associated antigens (TAAs) expressed by human HL/NHL, including Survivin, MAGE-A4, Synovial sarcoma X (SSX2), preferentially expressed antigen in melanoma (PRAME) and NY-ESO-1. We could generate these CTLs from nine of nine healthy donors and five of eight lymphoma patients, irrespective of human leukocyte antigen (HLA) type. We reactivated TAA-directed T cells ex vivo, by stimulation with dendritic cells (DCs) pulsed with overlapping peptide libraries spanning the chosen antigens in the presence of an optimized Th1-polarizing, prosurvival/proliferative and Treg inhibitory cytokine combination. The resultant lines of CD4(+) and CD8(+), polycytokine-producing T cells are directed against a multiplicity of epitopes expressed on the selected TAAs, with cytolytic activity against autologous tumor cells. Infusion of such multispecific monocultures may extend the benefits of CTL therapy to treatment even of EBV negative HL and NHL.     

A prognostic gene expression index in ovarian cancer—validation across different independent data sets

Ovarian carcinoma has the highest mortality rate among gynaecological malignancies. In this project, we investigated the hypothesis that molecular markers are able to predict outcome of ovarian cancer independently of classical clinical predictors, and that these molecular markers can be validated using independent data sets. We applied a semi‐supervised method for prediction of patient survival. Microarrays from a cohort of 80 ovarian carcinomas (TOC cohort) were used for the development of a predictive model, which was then evaluated in an entirely independent cohort of 118 carcinomas (Duke cohort). A 300‐gene ovarian prognostic index (OPI) was generated and validated in a leave‐one‐out approach in the TOC cohort (Kaplan‐Meier analysis, p = 0.0087). In a second validation step, the prognostic power of the OPI was confirmed in an independent data set (Duke cohort, p = 0.0063). In multivariate analysis, the OPI was independent of the post‐operative residual tumour, the main clinico‐pathological prognostic parameter with an adjusted hazard ratio of 6.4 (TOC cohort, CI 1.8–23.5, p = 0.0049) and 1.9 (Duke cohort, CI 1.2–3.0, p = 0.0068). We constructed a combined score of molecular data (OPI) and clinical parameters (residual tumour), which was able to define patient groups with highly significant differences in survival. The integrated analysis of gene expression data as well as residual tumour can be used for optimized assessment of the prognosis of platinum‐taxol‐treated ovarian cancer. As traditional treatment options are limited, this analysis may be able to optimize clinical management and to identify those patients who would be candidates for new therapeutic strategies. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.