The status of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors in ovarian cancer, part 2: extending the scope beyond olaparib and BRCA1/2 mutations

Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have shown clinical activity in epithelial ovarian cancer, leading both the US Food and Drug Administration (FDA) and the European Medicines Agency to approve olaparib for tumors characterized by BRCA1 and BRCA2 mutations. However, it is becoming increasingly evident that tumors that share molecular features with BRCA-mutant tumors-a concept known as BRCAness-also may exhibit defective homologous recombination DNA repair, and therefore will respond to PARP inhibition. A number of strategies have been proposed to identify BRCAness, including identifying defects in other genes that modulate homologous recombination and characterizing the mutational and transcriptional signatures of BRCAness. In addition to olaparib, a number of other PARP inhibitors are in clinical development. This article reviews the development of PARP inhibitors other than olaparib, and discusses the evidence for PARP inhibitors beyond BRCA1/2-mutant ovarian cancer

The status of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors in ovarian cancer, part 1: olaparib

Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have shown promising clinical activity in epithelial ovarian cancer. Following the observation in vitro that PARP inhibition is synthetically lethal in tumors with BRCA mutations, PARP inhibition has become the first genotype-directed therapy for BRCA1- and BRCA2-associated ovarian cancer. However, it is becoming clear that PARP inhibition also may have clinical utility in cancers associated with defects or aberrations in DNA repair that are unrelated to BRCA mutations. Deficient DNA repair mechanisms are present in approximately 30% to 50% of high-grade serous ovarian cancers, the most common histologic subtype. Olaparib is the best-studied PARP inhibitor to date, and a number of phase 3 trials with this agent are underway. This article reviews the development of olaparib for ovarian cancer and discusses the current evidence for its use, ongoing studies, future research directions, and the challenges ahead

The European Society for Medical Oncology (ESMO) Congress 2016: Highlights and summary of selected abstracts in gynecologic cancers

The 2016 ESMO Congress held in Copenhagen, Denmark (07–11th October 2016) brought together over 20,000 attendees from 127 countries. The highlight of the meeting for the gynecological track was the presentation at a Presidential session of the ENGOT-OV16/NOVA niraparib maintenance study. Other sessions included the following: 4 oral abstract presentations, 6 poster-discussion presentations and 45 general posters; an educational session on difficult decisions in gynecological oncology and a special symposium on personalized medicine in gynecological oncology. This report discusses the oral abstract sessions and selected poster presentations from the conference

Cow evaluation in North America

International audienc

The structure of the infinite models in integer programming

The infinite models in integer programming can be described as the convex hull of some points or as the intersection of halfspaces derived from valid functions. In this paper we study the relationships between these two descriptions. Our results have implications for corner polyhedra. One consequence is that nonnegative, continuous valid functions suffice to describe corner polyhedra (with or without rational data)

Co-constructing a new framework for evaluating social innovation in marginalized rural areas

The EU funded H2020 project \u2018Social Innovation in Marginalised Rural Areas\u2019 (SIMRA; www.simra-h2020.eu) has the overall objective of advancing the state-of-the-art in social innovation. This paper outlines the process for co- developing an evaluation framework with stakeholders, drawn from across Europe and the Mediterranean area, in the fields of agriculture, forestry and rural development. Preliminary results show the importance of integrating process and outcome-oriented evaluations, and implementing participatory approaches in evaluation practice. They also raise critical issues related to the comparability of primary data in diverse regional contexts and highlight the need for mixed methods approaches in evaluation

Role of Poly (ADP-Ribose) Polymerase inhibitors beyond BReast CAncer Gene-mutated ovarian tumours: definition of homologous recombination deficiency?

Purpose of review: PARP inhibitors have transformed the management of BRCA mutant (BRCAmut) high-grade serous and endometroid ovarian cancer (HGOC). However, it is clear that the benefit can be extended beyond this subgroup, particularly to those cancers with homologous recombination repair deficiency (HRD). We review emerging molecular and clinical data to support the use of PARP inhibitors in HRD HGOC and discuss the advantages and disadvantages of different HRD assays. Recent findings: Several phase 3 trials support the use of PARP inhibitor maintenance therapy beyond those patients with BRCAmut in the first-line and platinum-sensitive relapse setting. Many of these studies included HRD testing and it is clear, regardless of the assay used, that an incremental reduction in benefit is observed from BRCAmut tumours to HRD to homologous recombination proficient tumours. However, although currently available HRD assays predict the magnitude of benefit from PARP inhibitors, they consistently fail to identify a subgroup of patients who do not benefit. Summary: Clinical data support the use of PARP inhibitor maintenance therapy beyond BRCAmut patients. Current HRD tests lack negative predictive value and more research is required to develop a composite HRD assay that provides a dynamic readout of HRD status

Antibiotic Cycling and Antibiotic Mixing: which one best mitigates antibiotic resistance?

Published onlineJournal ArticleThis is the final version of the article. Available from Oxford University Press via the DOI in this record.Can we exploit our burgeoning understanding of molecular evolution to slow the progress of drug resistance? One role of an infection clinician is exactly that: to foresee trajectories to resistance during antibiotic treatment and to hinder that evolutionary course. But can this be done at a hospital-wide scale? Clinicians and theoreticians tried to when they proposed two conicting behavioural strategies that are expected to curb resistance evolution in the clinic, these are known as 'antibiotic cycling' and 'antibiotic mixing'. However, the accumulated data from clinical trials, now approaching 4 million patient days of treatment, is too variable for cycling or mixing to be deemed successful. The former implements the restriction and prioritisation of di_erent antibiotics at di_erent times in hospitals in a manner said to 'cycle' between them. In antibiotic mixing, appropriate antibiotics are allocated to patients but randomly.Mixing results in no correlation, in time or across patients, in the drugs used for treatment which is why theorists saw this as an optimal behavioural strategy. So while cycling and mixing were proposed as ways of controlling evolution, we show there is good reason why clinical datasets cannot choose between them: by re-examining the theoretical literature we show prior support for the theoretical optimality of mixing was misplaced. Our analysis is consistent with a pattern emerging in data: neither cycling or mixing is a priori better than the other at mitigating selection for antibiotic resistance in the clinic.REB was funded during this work by an MRC Discipline Hopping Fellowship G0802611, RPM was funded by a Conacyt PhD award, all authors were supported by EPSRC grant EP/I00503X/1 (grant holder REB)