Influence of genomic landscape on cancer immunotherapy for newly diagnosed ovarian cancer: Biomarker analyses from the IMagyn050 randomized clinical trial

PURPOSE: To explore whether patients with BRCA1/2-mutated or homologous recombination deficient (HRD) ovarian cancers benefitted from atezolizumab in the phase III IMagyn050 (NCT03038100) trial. PATIENTS AND METHODS: Patients with newly diagnosed ovarian cancer were randomized to either atezolizumab or placebo with standard chemotherapy and bevacizumab. Programmed death-ligand 1 (PD-L1) status of tumor-infiltrating immune cells (IC) was determined centrally (VENTANA SP142 assay). Genomic alterations, including deleterious BRCA1/2 alterations, genomic loss of heterozygosity (gLOH), tumor mutation burden (TMB), and microsatellite instability (MSI), were evaluated using the FoundationOne assay. HRD was defined as gLOH ≥ 16%, regardless of BRCA1/2 mutation status. Potential associations between progression-free survival (PFS) and genomic biomarkers were evaluated using standard correlation analyses and log-rank of Kaplan-Meier estimates. RESULTS: Among biomarker-evaluable samples, 22% (234/1,050) harbored BRCA1/2 mutations and 46% (446/980) were HRD. Median TMB was low irrespective of BRCA1/2 or HRD. Only 3% (29/1,024) had TMB ≥10 mut/Mb, and 0.3% (3/1,022) were MSI-high. PFS was better in BRCA2-mutated versus BRCA2-non-mutated tumors and in HRD versus proficient tumors. PD-L1 positivity (≥1% expression on ICs) was associated with HRD but not BRCA1/2 mutations. PFS was not improved by adding atezolizumab in BRCA2-mutated or HRD tumors; there was a trend toward enhanced PFS with atezolizumab in BRCA1-mutated tumors. CONCLUSIONS: Most ovarian tumors have low TMB despite BRCA1/2 mutations or HRD. Neither BRCA1/2 mutation nor HRD predicted enhanced benefit from atezolizumab. This is the first randomized double-blind trial in ovarian cancer demonstrating that genomic instability triggered by BRCA1/2 mutation or HRD is not associated with improved sensitivity to immune checkpoint inhibitors. See related commentary by Al-Rawi et al., p. 1645

Pulsed Laser-Based X-Ray Sources for Rapid-Cool DT Layer Characterization

Ignition targets for the National Ignition Facility (NIF) will contain a cryogenically cooled {approx} 75 {micro}m-thick deuterium/tritium (DT) ice layer surrounded by a {approx} 150 {micro}m-thick beryllium (Be) shell [1]. Ignition target design optimization depends sensitively on the achievable inner surface quality of the ice layer and on the pressure of the DT gas inside the ice, which is determined by the temperature of the ice. The inner ice layer surface is smoothest at temperatures just below the DT ice/liquid/gas triple point (3T), but current ignition target designs require central gas pressures of 0.3 mg/cm3, corresponding to an ice layer temperature 1.5 K below the triple point (3T-1.5). At these lower temperatures, the ice layer quality degrades due to the formation of cracks and other features

Soft x-ray detection with diamond photoconductive detectors

Photoconductive detectors fabricated from natural lla diamonds have been used to measure the x-ray power emitted from laser produced plasmas. The detector was operated without any absorbing filters to distort the x-ray power measurement. The 5.5 eV bandgap of the detector material practically eliminates its sensitivity to scattered laser radiation thus permitting filterless operation. The detector response time or carrier life time was 90 ps. Excellent agreement was achieved between a diamond PCD and a multichannel photoemissive diode array in the measurement of radiated x-ray power and energy. 4 figs

Joint analysis of psychiatric disorders increases accuracy of risk prediction for schizophrenia, bipolar disorder, and major depressive disorder

Genetic risk prediction has several potential applications in medical research and clinical practice and could be used, for example, to stratify a heterogeneous population of patients by their predicted genetic risk. However, for polygenic traits, such as psychiatric disorders, the accuracy of risk prediction is low. Here we use a multivariate linear mixed model and apply multi-trait genomic best linear unbiased prediction for genetic risk prediction. This method exploits correlations between disorders and simultaneously evaluates individual risk for each disorder. We show that the multivariate approach significantly increases the prediction accuracy for schizophrenia, bipolar disorder, and major depressive disorder in the discovery as well as in independent validation datasets. By grouping SNPs based on genome annotation and fitting multiple random effects, we show that the prediction accuracy could be further improved. The gain in prediction accuracy of the multivariate approach is equivalent to an increase in sample size of 34% for schizophrenia, 68% for bipolar disorder, and 76% for major depressive disorders using single trait models. Because our approach can be readily applied to any number of GWAS datasets of correlated traits, it is a flexible and powerful tool to maximize prediction accuracy. With current sample size, risk predictors are not useful in a clinical setting but already are a valuable research tool, for example in experimental designs comparing cases with high and low polygenic risk

Paraneoplastic thrombocytosis in ovarian cancer

<p>Background: The mechanisms of paraneoplastic thrombocytosis in ovarian cancer and the role that platelets play in abetting cancer growth are unclear.</p> <p>Methods: We analyzed clinical data on 619 patients with epithelial ovarian cancer to test associations between platelet counts and disease outcome. Human samples and mouse models of epithelial ovarian cancer were used to explore the underlying mechanisms of paraneoplastic thrombocytosis. The effects of platelets on tumor growth and angiogenesis were ascertained.</p> <p>Results: Thrombocytosis was significantly associated with advanced disease and shortened survival. Plasma levels of thrombopoietin and interleukin-6 were significantly elevated in patients who had thrombocytosis as compared with those who did not. In mouse models, increased hepatic thrombopoietin synthesis in response to tumor-derived interleukin-6 was an underlying mechanism of paraneoplastic thrombocytosis. Tumorderived interleukin-6 and hepatic thrombopoietin were also linked to thrombocytosis in patients. Silencing thrombopoietin and interleukin-6 abrogated thrombocytosis in tumor-bearing mice. Anti–interleukin-6 antibody treatment significantly reduced platelet counts in tumor-bearing mice and in patients with epithelial ovarian cancer. In addition, neutralizing interleukin-6 significantly enhanced the therapeutic efficacy of paclitaxel in mouse models of epithelial ovarian cancer. The use of an antiplatelet antibody to halve platelet counts in tumor-bearing mice significantly reduced tumor growth and angiogenesis.</p> <p>Conclusions: These findings support the existence of a paracrine circuit wherein increased production of thrombopoietic cytokines in tumor and host tissue leads to paraneoplastic thrombocytosis, which fuels tumor growth. We speculate that countering paraneoplastic thrombocytosis either directly or indirectly by targeting these cytokines may have therapeutic potential. </p&gt

Debris and Shrapnel Mitigation Procedure for NIF Experiments

All experiments at the National Ignition Facility (NIF) will produce debris and shrapnel from vaporized, melted, or fragmented target/diagnostics components. For some experiments mitigation is needed to reduce the impact of debris and shrapnel on optics and diagnostics. The final optics, e.g., wedge focus lens, are protected by two layers of debris shields. There are 192 relatively thin (1-3 mm) disposable debris shields (DDS's) located in front of an equal number of thicker (10 mm) main debris shields (MDS's). The rate of deposition of debris on DDS's affects their replacement rate and hence has an impact on operations. Shrapnel (molten and solid) can have an impact on both types of debris shields. There is a benefit to better understanding these impacts and appropriate mitigation. Our experiments on the Omega laser showed that shrapnel from Ta pinhole foils could be redirected by tilting the foils. Other mitigation steps include changing location or material of the component identified as the shrapnel source. Decisions on the best method to reduce the impact of debris and shrapnel are based on results from a number of advanced simulation codes. These codes are validated by a series of dedicated experiments. One of the 3D codes, NIF's ALE-AMR, is being developed with the primary focus being a predictive capability for debris/shrapnel generation. Target experiments are planned next year on NIF using 96 beams. Evaluations of debris and shrapnel for hohlraum and capsule campaigns are presented

High order reflectivity of graphite (HOPG) crystals for x ray energies up to 22 keV

We used Kr K{alpha} (12.6 keV) and Ag K{alpha} (22.1 keV) x-rays, produced by petawatt class laser pulses interacting with a Kr gas jet and a silver foil, to measure the integrated crystal reflectivity of flat Highly Oriented Pyrolytic Graphite (HOPG) up to fifth order. The reflectivity in fourth order is lower by a factor of 50 when compared to first order diffraction. In second order the integrated reflectivity decreases from 1.3 mrad at 12.6 keV to 0.5 mrad at 22.1 keV. The current study indicates that HOPG crystals are suitable for measuring scattering signals from high energy x ray sources (E {ge} 20 keV). These energies are required to penetrate through the high density plasma conditions encountered in inertial confinement fusion capsule implosions on the National Ignition Facility