PARP inhibitors in ovarian cancer

BACKGROUND: Slow progress in improving the outcome of ovarian cancer with chemotherapy over the last decade has stimulated research into molecularly targeted therapy. Poly(ADP-ribose) polymerase (PARP) inhibitors target DNA repair and are specifically active in cells that have impaired repair of DNA by the homologous recombination (HR) pathway. Cells with mutated BRCA function have HR deficiency (HRD), which is also present in a significant proportion of non-BRCA-mutated ovarian cancer. DESIGN: In the last decade, olaparib, the first and most-investigated oral PARP inhibitor, has undergone phase I-III trials as a single agent, in comparison with and in addition to chemotherapy, and as a maintenance therapy following chemotherapy. RESULTS: The greatest benefit to-date has been in the maintenance setting, prolonging the progression-free survival of high-grade serous ovarian cancer with a BRCA1/2 mutation. In this group of patients, olaparib has received approval as maintenance following chemotherapy from the EMA, and accelerated approval as a single agent in women who have had three or more lines of therapy. Olaparib can be given for a prolonged period with few significant side-effects in most patients. Similar trials with other PARP inhibitors (rucaparib, niraparib and veliparib) are in progress and include non-BRCA-mutated ovarian cancer. Second-generation studies are exploring the combination of PARP inhibitors with anti-angiogenic drugs. CONCLUSIONS: PARP inhibitors represent a step change in the management of ovarian cancer. BRCA mutations are the first genotypic predictive markers in ovarian cancer and can be used to select patients who will most likely benefit from PARP inhibitors. BRCA testing is now becoming a routine part of the evaluation of women with ovarian cancer, and tests for HRD are being used to evaluate PARP inhibitors in an extended population of non-BRCA-mutated ovarian cancer

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

Boltzmann Collision Term

We derive the Boltzmann equation for scalar fields using the Schwinger-Keldysh formalism. The focus lies on the derivation of the collision term. We show that the relevant self-energy diagrams have a factorization property. The collision term assumes the Boltzmann-like form of scattering probability times statistical factors for those self-energy diagrams which correspond to tree level scattering processes. Our proof covers scattering processes with any number of external particles, which come from self-energy diagrams with any number of loops.Comment: 17 pages, 4 figure

Exact Moment Simulation using Random Orthogonal Matrices

This paper introduces a method for simulating multivariate samples that have exact means, covariances, skewness and kurtosis. A new class of rectangular orthogonal matrices is fundamental to the methodology, and these ``L-matrices'' can be deterministic, parametric or data specific in nature. The target moments determine an L-matrix, then infinitely many random samples with the same exact moments may be generated by multiplying the L-matrix by arbitrary random orthogonal matrices. The methodology is thus termed ``ROM simulation''. We discuss certain classes of random orthogonal matrices and show how each class produces samples with different characteristics. ROM simulation has applications to many problems that are resolved using standard Monte Carlo methods. But since no parametric assumptions are required there is no sampling error caused by the discrete approximation of a continuous distribution, which is a major source of error in standard Monte Carlo simulations. For illustration, we apply ROM simulation to determine the value-at-risk of a stock portfolio.simulation, L-matrices, multivariate moments, value-at-risk

Targeted Therapies for Ovarian Cancer

Epithelial ovarian cancer has the highest mortality rate of all gynaecological malignancies. Most women present with advanced disease and develop a recurrence after radical surgery and chemotherapy. Improving the results of first- or subsequent-line chemotherapy has been slow, and novel approaches to systemic treatment are needed. Ovarian cancer is a heterogeneous disease with complex molecular and genetic changes. Understanding these better will provide information on the mechanisms of resistance and opportunities to target therapy more rationally, exploiting specific changes in the tumour. Here we reviewed targeted approaches to therapy, focussing on targeting angiogenesis and inhibition of DNA repair, 2 areas that show promising activity. Additionally, we reviewed studies that are underway, targeting the cell cycle, signalling pathways and immunotherapeutic strategies. Many of these innovative approaches already demonstrate promising activity in ovarian cancer and have the potential to improve the outcome in women with ovarian cancer

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

Generalized wordlength patterns and strength

Xu and Wu (2001) defined the \emph{generalized wordlength pattern} $(A_1, ..., A_k)$ of an arbitrary fractional factorial design (or orthogonal array) on $k$ factors. They gave a coding-theoretic proof of the property that the design has strength $t$ if and only if $A_1 = ... = A_t = 0$. The quantities $A_i$ are defined in terms of characters of cyclic groups, and so one might seek a direct character-theoretic proof of this result. We give such a proof, in which the specific group structure (such as cyclicity) plays essentially no role. Nonabelian groups can be used if the counting function of the design satisfies one assumption, as illustrated by a couple of examples