OCT4 controls mitotic stability and inactivates the RB tumor suppressor pathway to enhance ovarian cancer aggressiveness.

OCT4 (Octamer-binding transcription factor 4) is essential for embryonic stem cell self-renewal. Here we show that OCT4 increases the aggressiveness of high-grade serous ovarian cancer (HG-SOC) by inactivating the Retinoblastoma tumor suppressor pathway and enhancing mitotic stability in cancer cells. OCT4 drives the expression of Nuclear Inhibitor of Protein Phosphatase type 1 (NIPP1) and Cyclin F (CCNF) that together inhibit Protein Phosphatase 1 (PP1). This results in pRB hyper-phosphorylation, accelerated cell proliferation and increased in vitro tumorigenicity of ovarian cancer cells. In parallel, OCT4 and NIPP1/CCNF drive the expression of the central Chromosomal Passenger Complex (CPC) components, Borealin, Survivin and the mitotic kinase Aurora B, promoting the clustering of supernumerary centrosomes to increase mitotic stability. Loss of OCT4 or NIPP1/CCNF results in severe mitotic defects, multipolar spindles and supernumerary centrosomes, finally leading to the induction of apoptosis. These phenotypes were recapitulated in different cancer models indicating general relevance for human cancer. Importantly, activation of these parallel pathways leads to dramatically reduced overall survival of HG-SOC patients. Altogether, our data highlights an unprecedented role for OCT4 as central regulator of mitotic fidelity and RB tumor suppressor pathway activity. Disrupting this pathway represents a promising strategy to target an aggressive subpopulation of HG-SOC cells.

Large solitary fibrous tumour of the retroperitoneum: a case report and review of the literature.

INTRODUCTION: This report describes an unusual case of a large solitary fibrous tumour (SFT) arising in the retroperitoneum. CASE PRESENTATION: A 53-year-old woman presented at the Emergency Department with urinary retention and lumbar pain. The urological examination was negative, whereas a presacral retroperitoneal mass was disclosed on ultrasound. The laboratory studies, including tumour markers, were negative. On laparotomy, it was not possible to remove the mass completely due to the difficulty of dissecting it free of the sacrum. Grossly, the fragment had a yellowish-white surface, with areas of necrosis and haemorrhage. On immunohistochemistry, tumour cells were positive for CD34, CD99 and Bcl-2 and negative for CD45, synaptophysin, chromogranin, S100, neuron-specific enolase, CK AE1-AE3, CK7, Wilms' tumour 1, smooth muscle actin, factor VIII, myogenin, epithelial membrane antigen, thyroid transcription factor-1 and CD117, leading to a diagnosis of SFT. Molecular investigation ruled out synovial sarcoma. CONCLUSION: Although SFT usually has a favourable prognosis, close follow-up is recommended due to the limited information on its long-term behaviour.

Apurinic apyrimidinic endonuclease/redox effector factor 1 immunoreactivity and grading in hepatocellular carcinoma risk of relapse after liver transplantation.

Apurinic apyrimidinic endonuclease (APE1)/redox effector factor 1 (Ref-1), which is a multifunction protein involved in both transcriptional regulation of gene expression during adaptive cellular responses to oxidative stress and in the base excision repair pathway of DNA lesions generated as a consequence of oxidant-induced base damage, contributes to the maintenance of genome stability. APE1/Ref-1 is normally localized in the nucleus; cytoplasmic localization observed in several tumors has been correlated with a poor prognosis. Hepatocellular carcinoma (HCC) grading is an essential tool to predict the risk of relapse and patient prognosis, particularly in patients undergoing liver transplantation (OLT). The aim of this study was to identify the role of APE1/Ref-1 in predicting a posttransplant HCC relapse. We studied 48 patients transplanted for HCC to define grading as well as nuclear and cytoplasmic APE1/Ref-1 expression within neoplastic versus nonneoplastic parenchyma. We defined a cutoff of 60% of cytoplasmic APE1/Ref-1 expression to identify positive cases. At a minimum of 1.5-year follow-up after transplantation, 32 patients are alive and 16 patients are deceased after HCC relapse. Among low-grade HCC (grades 1 and 2), 76% of cases are alive; only 34% showed cytoplasmic APE1/Ref-1 immunoreactivity. Among the high-grade cases (grades 3 and 4), 50% were alive with 64% showing cytoplasmic immunoreactivity. Nuclear reactivity was generally similar either in neoplastic or in cirrhotic livers, irrespective of the grade. These data seemed to support the hypothesis of a predictive role of APE1/Ref-1 for HCC risk of relapse, which together with tumor grade by analysis of a pretransplant needle biopsy should aid decision making for OLT.

Evaluation of prostate cancer staging in organ donors: intraoperative histology on periglandular soft tissues-a proposal.

An histopathologic screening method for prostate cancer assessment in organ donors is crucial because of the widening of the donor pool to older individuals. Evaluation of cancer grading with multiple biopsies is fundamental in the cases of abnormal prostate-specific antigen (PSA) values and suspect ultrasound findings. However, multiple biopsies may fail to represent the whole neoplasia, and grading may be difficult particularly because there may not be information about capsular penetration. Since October 2007, 20 prostate autopsy specimens were submitted to an histopathologic screening method of the entire prostate based on extemporary frozen section analysis (maximum 75 minutes) of shavings of samples of the lateral surfaces of the prostate gland: namely, approximately 5 samples or 7 in the case of a large gland. We produced 3-mm-thick step sections at three levels: the first was immediately taken at the cutting level, and then 30-microm sections were discarded. The following three levels of 5 microm intervals for 10 sections for each level were evaluated. There were 7 cases of undiagnosed prostate cancer, three of which were demonstrated on frozen sections with neoplastic foci of extraglandular infiltration within connective and adipose tissues outside the gland. No neoplasia was present in the other 13 cases. In all cases, the final diagnosis was confirmed by the extemporary analysis. Our goal was to confirm the optimal number of samples that were representative of the whole prostatic contour, to define time to diagnosis and to evaluate reproducibility of frozen-section histopathologic screening compared with paraffin sections. This novel approach should permit a more refined risk-benefit analysis.