A phase II evaluation of cediranib in the treatment of recurrent or persistent endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study

PURPOSE: Cediranib is a multi-tyrosine kinase inhibitor targeting vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) receptors. This phase II study was conducted to assess activity and tolerability of single-agent cediranib in recurrent/persistent endometrial cancer. PATIENTS AND METHODS: Eligible patients had recurrent or persistent endometrial cancer after receiving one or two prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group (GOG) performance status of ≤2 (≤1 if two prior cytotoxic regimens given). Cediranib 30mg orally daily for a 28daycycle was administered until disease progression or prohibitive toxicity. Microvessel density (MVD) was measured in tumor tissue from initial hysterectomy specimens and correlated with clinical outcome. Primary endpoints were tumor response and surviving progression-free for six months without subsequent therapy (6-month event-free survival [EFS]). RESULTS: Of 53 patients enrolled, 48 were evaluable for cediranib efficacy and toxicity. Median age was 65.5 years, 52% of patients had received prior radiation, and 73% of patients received only one prior chemotherapy regimen. A partial response was observed in 12.5%. Fourteen patients (29%) had six-month EFS. Median progression-free survival (PFS) was 3.65 months and median overall survival (OS) 12.5 months. No grade 4 or 5 toxicities were observed. A trend towards improved PFS was found in patients whose tumors expressed high MVD. CONCLUSION: Cediranib as a monotherapy treatment for recurrent or persistent endometrial cancer is well tolerated and met protocol set objectives for sufficient activity to warrant further investigation. MVD may be a useful biomarker for activity

Communication, Collaboration and Enhancing the Learning Experience: Developing a Collaborative Virtual Enquiry Service in University Libraries in the North of England

This paper uses the case study of developing a collaborative ‘out of hours’ virtual enquiry service by members of the Northern Collaboration Group of academic libraries in the north of England to explore the importance of communication and collaboration between academic library services in enhancing student learning. Set within the context of a rapidly changing UK higher education sector the paper considers the benefits and challenges of collaboration and the contribution of library services to the student experience. The project demonstrated clear benefits to student learning and evidence of value for money to individual institutions as well as showing commitment to national shared services agendas. Effective communication with students, with colleagues and stakeholders in our own and other Northern Collaboration member institutions, and with OCLC, our partner organisation, was a critical success factor in the development, promotion and uptake of the new service

A Randomized Phase II/III Study of Paclitaxel/Carboplatin/Metformin Versus Paclitaxel/Carboplatin/Placebo as Initial Therapy for Measurable Stage III or IVA, stage IVB, or Recurrent Endometrial Cancer: An NRG Oncology/GOG Study

INTRODUCTION: We evaluated the efficacy of the addition of the anti-diabetic drug metformin to standard-of-care paclitaxel and carboplatin (PC) in patients with advanced and recurrent endometrial cancer (EC). METHODS: In this phase II/III trial, EC patients with chemotherapy-naïve stage III/IVA (with measurable disease) and stage IVB or recurrent (with or without measurable disease) disease were randomly assigned to PC/metformin (850 mg BID) versus PC/placebo. Metformin or placebo was continued as maintenance therapy after completion of PC until disease progression. The primary endpoint of phase II was progression-free survival (PFS). The primary endpoint of phase III was overall survival (OS). Secondary endpoints were objective response, duration of response, and toxicity. RESULTS: From 3/17/2014 to 12/22/2017, 448 patients were randomized to phase II/III studies, and the data were frozen for interim analysis. The phase II study deemed metformin worthy of further investigation in the phase III study. The interim phase III analysis stopped accrual for futility on 2/1/2018. The addition of metformin to PC had a slightly higher hazard of death compared to the PC regimen (HR = 1.088; 90% CI 0.803 to 1.475), which was sufficient to close the study early. The PFS had (HR = 0.814; 90% CI 0.635 to 1.043). At a median follow-up of 10 months and 121 deaths, median OS was not determined and 28 months, on PC/placebo and PC/metformin, respectively. CONCLUSION: The hazard ratios for PFS and OS endpoints was not sufficiently decreased with the addition of metformin to PC to justify continuing the trial

HDAC2 Facilitates Pancreatic Cancer Metastasis

The mortality of patients with pancreatic ductal adenocarcinoma (PDAC) is strongly associated with metastasis, a multistep process that is incompletely understood in this disease. Although genetic drivers of PDAC metastasis have not been defined, transcriptional and epigenetic rewiring can contribute to the metastatic process. The epigenetic eraser histone deacetylase 2 (HDAC2) has been connected to less differentiated PDAC, but the function of HDAC2 in PDAC has not been comprehensively evaluated. Using genetically defined models, we show that HDAC2 is a cellular fitness factor that controls cell cycle in vitro and metastasis in vivo, particularly in undifferentiated, mesenchymal PDAC cells. Unbiased expression profiling detected a core set of HDAC2-regulated genes. HDAC2 controlled expression of several prosurvival receptor tyrosine kinases connected to mesenchymal PDAC, including PDGFRa, PDGFRβ, and EGFR. The HDAC2-maintained program disabled the tumor-suppressive arm of the TGFβ pathway, explaining impaired metastasis formation of HDAC2-deficient PDAC. These data identify HDAC2 as a tractable player in the PDAC metastatic cascade. The complexity of the function of epigenetic regulators like HDAC2 implicates that an increased understanding of these proteins is needed for implementation of effective epigenetic therapies. Significance: HDAC2 has a context-specific role in undifferentiated PDAC and the capacity to disseminate systemically, implicating HDAC2 as targetable protein to prevent metastasis

Immunohistochemical staining of radixin and moesin in prostatic adenocarcinoma

<p>Abstract</p> <p>Background</p> <p>Some members of the Protein 4.1 superfamily are believed to be involved in cell proliferation and growth, or in the regulation of these processes. While the expression levels of two members of this family, radixin and moesin, have been studied in many tumor types, to our knowledge they have not been investigated in prostate cancer.</p> <p>Methods</p> <p>Tissue microarrays were immunohistochemically stained for either radixin or moesin, with the staining intensities subsequently quantified and statistically analyzed using One-Way ANOVA or nonparametric equivalent with subsequent Student-Newman-Keuls tests for multiple comparisons. There were 11 cases of normal donor prostates (NDP), 14 cases of benign prostatic hyperplasia (BPH), 23 cases of high-grade prostatic intraepithelial neoplasia (HGPIN), 88 cases of prostatic adenocarcinoma (PCa), and 25 cases of normal tissue adjacent to adenocarcinoma (NAC) analyzed in the microarrays.</p> <p>Results</p> <p>NDP, BPH, and HGPIN had higher absolute staining scores for radixin than PCa and NAC, but with a significant difference observed between only HGPIN and PCa (p = < 0.001) and HGPIN and NAC (p = 0.001). In the moesin-stained specimens, PCa, NAC, HGPIN, and BPH all received absolute higher staining scores than NDP, but the differences were not significant. Stage 4 moesin-stained PCa had a significantly reduced staining intensity compared to Stage 2 (p = 0.003).</p> <p>Conclusions</p> <p>To our knowledge, these studies represent the first reports on the expression profiles of radixin and moesin in prostatic adenocarcinoma. The current study has shown that there were statistically significant differences observed between HGPIN and PCa and HGPIN and NAC in terms of radixin expression. The differences in the moesin profiles by tissue type were not statistically significant. Additional larger studies with these markers may further elucidate their potential roles in prostatic neoplasia progression.</p

Circulating cell-free DNA assessment in biofluids from children with neuroblastoma demonstrates feasibility and potential for minimally invasive molecular diagnostics

Liquid biopsy strategies in pediatric patients are challenging due to low body weight. This study investigated cfDNA size distribution and concentration in blood, bone marrow, cerebrospinal fluid, and urine from 84 patients with neuroblastoma classified as low (n = 28), intermediate (n = 6), or high risk (n = 50) to provide key data for liquid biopsy biobanking strategies. The average volume of blood and bone marrow plasma provided ranged between 1 and 2 mL. Analysis of 637 DNA electropherograms obtained by Agilent TapeStation measurement revealed five different major profiles and characteristic DNA size distribution patterns for each of the biofluids. The proportion of samples containing primarily cfDNA was, at 85.5%, the highest for blood plasma. The median cfDNA concentration amounted to 6.28 ng/mL (blood plasma), 58.2 ng/mL (bone marrow plasma), 0.08 ng/mL (cerebrospinal fluid), and 0.49 ng/mL (urine) in samples. Meta-analysis of the dataset demonstrated that multiple cfDNA-based assays employing the same biofluid sample optimally require sampling volumes of 1 mL for blood and bone marrow plasma, 2 mL for cerebrospinal fluid, and as large as possible for urine samples. A favorable response to treatment was associated with a rapid decrease in blood-based cfDNA concentration in patients with high-risk neuroblastoma. Blood-based cfDNA concentration was not sufficient as a single parameter to indicate high-risk disease recurrence. We provide proof of concept that monitoring neuroblastoma-specific markers in very small blood volumes from infants is feasible

Endogenous ownership structure:factors affecting the post-privatisation equity in largest Hungarian firms

Using a data set for the 162 largest Hungarian firms during the period of 1994-1999, this paper explores the determinants of equity shares held by both foreign investors and Hungarian corporations. Evidence is found for a post-privatisation evolution towards more homogeneous equity structures, where dominant categories of Hungarian and foreign owners aim at achieving controlling stakes. In addition, focusing on firm-level characteristics we find that exporting firms attract foreign owners who acquire controlling equity stakes. Similarly, firm-size measurements are positively associated with the presence of foreign investors. However, they are negatively associated with 100% foreign ownership, possibly because the marginal costs of acquiring additional equity are growing with the size of the assets. The results are interpreted within the framework of the existing theory. In particular, following Demsetz and Lehn (1985) and Demsetz and Villalonga (2001) we argue that equity should not be treated as an exogenous variable. As for specific determinants of equity levels, we focus on informational asymmetries and (unobserved) ownership-specific characteristics of foreign investors and Hungarian investors