A phase 1 study of PARP-inhibitor ABT-767 in advanced solid tumors with BRCA1/2 mutations and high-grade serous ovarian, fallopian tube, or primary peritoneal cancer

Purpose This phase 1 study examined safety, pharmacokinetics (PK), and efficacy of the poly(ADP-ribose) polymerase (PARP) inhibitor ABT-767 in patients with advanced solid tumors and BRCA1/2 mutations or with high-grade serous ovarian, fallopian tube, or primary peritoneal cancer. Methods Patients received ABT-767 monotherapy orally until disease progression or unacceptable toxicity. Dose was escalated from 20 mg once daily to 500 mg twice daily (BID). Dose-limiting toxicities, recommended phase 2 dose (RP2D), food effect, objective response rate, and biomarkers predicting response were determined. Results Ninety-three patients were treated with ABT-767; 80 had a primary diagnosis of ovarian cancer. ABT-767 demonstrated dose-proportional PK up to 500 mg BID and half-life of ~2 h. Food had no effect on ABT-767 bioavailability. Most common grade 3/4 treatment-related adverse events were nausea, fatigue, decreased appetite, and anemia. Anemia showed dose-dependent increase. RP2D was 400 mg BID. Objective response rate by RECIST 1.1 was 21% (17/80) in all evaluable patients and 20% (14/71) in evaluable patients with ovarian cancer. Response rate by RECIST 1.1 and/or CA-125 was 30% (24/80) in patients with ovarian cancer. Mutations in BRCA1 or BRCA2, homologous recombination deficiency (HRD), and platinum sensitivity were associated with tumor response. Median progression-free survival was longer for HRD positive (6.7 months) versus HRD negative patients (1.8 months) with ovarian cancer. Conclusions ABT-767 had an acceptable safety profile up to the established RP2D of 400 mg BID and dose-proportional PK. Patients with BRCA1 or BRCA2 mutation, HRD positivity, and platinum sensitivity were more sensitive to ABT-767

Who Governs EU Cohesion Policy? Deconstructing the Reforms of the Structural Funds

This article re-assesses the multi-level governance debate and specifically the 'renationalization thesis', with respect to EU cohesion policy. It focuses on two of the principles of decision-making under the structural funds: concentration (decisions on where the money is spent) and programming (decisions on how it is spent). The analysis takes a longitudinal approach, examining each of the policy phases from 1988 until the recent debate on the 2007-13 period. The article concludes that the role of national governments (relative to the European Commission) in key decisions on the implementation of cohesion policy has been exaggerated in the literature and that important arguments underpinning the 'renationalization thesis' are flawed. Copyright (c) 2007 The Author(s); Journal compilation (c) 2007 Blackwell Publishing Ltd.

Is the European Commission a 'Hothouse' for Supranationalism? Exploring Actor-Level Supranationalism

The article explores actor-level supranationalism among seconded national experts (SNEs) in the European Commission. The transformative clout of the European Commission is assessed by the extent to which SNEs adopt a "supranational" role perception. The survey and interview data presented demonstrates that SNEs evoke multiple roles, notably departmental, epistemic and supranational roles. OLS regression analyses reveal that actor-level supranationalism among SNEs reflect (i) processes of re-socialization inside the Commission, (ii) the organizational composition of the Commission and (iii) organizational "in"compatibilities between the Commission and domestic government institutions. Copyright (c) 2007 The Author(s); Journal compilation (c) 2007 Blackwell Publishing Ltd.

A meta-analysis of Hodgkin lymphoma reveals 19p13.3 <i>TCF3</i> as a novel susceptibility locus

Recent genome-wide association studies (GWAS) of Hodgkin lymphoma (HL) have identified associations with genetic variation at both HLA and non-HLA loci; however, much of heritable HL susceptibility remains unexplained. Here we perform a meta-analysis of three HL GWAS totaling 1,816 cases and 7,877 controls followed by replication in an independent set of 1,281 cases and 3,218 controls to find novel risk loci. We identify a novel variant at 19p13.3 associated with HL (rs1860661; odds ratio (OR)=0.81, 95% confidence interval (95% CI)=0.76–0.86, &lt;i&gt;P&lt;/i&gt;&lt;sub&gt;combined&lt;/sub&gt;=3.5 × 10&lt;sup&gt;−10&lt;/sup&gt;), located in intron 2 of &lt;i&gt;TCF3&lt;/i&gt; (also known as &lt;i&gt;E2A&lt;/i&gt;), a regulator of B- and T-cell lineage commitment known to be involved in HL pathogenesis. This meta-analysis also notes associations between previously published loci at 2p16, 5q31, 6p31, 8q24 and 10p14 and HL subtypes. We conclude that our data suggest a link between the 19p13.3 locus, including &lt;i&gt;TCF3&lt;/i&gt;, and HL risk