Neutrino Trapping and Out-of-Equilibrium Effects in Binary Neutron-Star Merger Remnants.

We study out-of-thermodynamic-equilibrium effects in neutron-star mergers with 3D general-relativistic neutrino-radiation large-eddy simulations. During mergers, the cores of the neutron stars remain cold (T∼ a few MeV) and out of thermodynamic equilibrium with trapped neutrinos originating from the hot collisional interface between the stars. However, within ∼2 to 3 ms matter and neutrinos reach equilibrium everywhere in the remnant massive neutron star. Our results show that dissipative effects, such as bulk viscosity, if present, are only active for a short window of time after the merger.

Black-Hole Remnants from Black-Hole-Neutron-Star Mergers.

Observations of gravitational waves and their electromagnetic counterparts may soon uncover the existence of coalescing compact binary systems formed by a stellar-mass black hole and a neutron star. These mergers result in a remnant black hole, possibly surrounded by an accretion disk. The mass and spin of the remnant black hole depend on the properties of the coalescing binary. We construct a map from the binary components to the remnant black hole using a sample of numerical-relativity simulations of different mass ratios q, (anti)aligned dimensionless spins of the black hole a_{BH}, and several neutron star equations of state. Given the binary total mass, the mass and spin of the remnant black hole can therefore be determined from the three parameters (q,a_{BH},Λ), where Λ is the tidal deformability of the neutron star. Our models also incorporate the binary black hole and test-mass limit cases and we discuss a simple extension for generic black-hole spins. We combine the remnant characterization with recent population synthesis simulations for various metallicities of the progenitor stars that generated the binary system. We predict that black-hole-neutron-star mergers produce a population of remnant black holes with masses distributed around 7 M_{⊙} and 9 M_{⊙}. For isotropic spin distributions, nonmassive accretion disks are favored: no bright electromagnetic counterparts are expected in such mergers.

Gravitational-Wave Luminosity of Binary Neutron Stars Mergers.

We study the gravitational-wave peak luminosity and radiated energy of quasicircular neutron star mergers using a large sample of numerical relativity simulations with different binary parameters and input physics. The peak luminosity for all the binaries can be described in terms of the mass ratio and of the leading-order post-Newtonian tidal parameter solely. The mergers resulting in a prompt collapse to black hole have the largest peak luminosities. However, the largest amount of energy per unit mass is radiated by mergers that produce a hypermassive neutron star or a massive neutron star remnant. We quantify the gravitational-wave luminosity of binary neutron star merger events, and set upper limits on the radiated energy and the remnant angular momentum from these events. We find that there is an empirical universal relation connecting the total gravitational radiation and the angular momentum of the remnant. Our results constrain the final spin of the remnant black hole and also indicate that stable neutron star remnant forms with super-Keplerian angular momentum.

24h-gene variation effect of combined bevacizumab/erlotinib in advanced non-squamous non-small cell lung cancer using exon array blood profiling.

BACKGROUND: The SAKK 19/05 trial investigated the safety and efficacy of the combined targeted therapy bevacizumab and erlotinib (BE) in unselected patients with advanced non-squamous non-small cell lung cancer (NSCLC). Although activating EGFR mutations were the strongest predictors of the response to BE, some patients not harboring driver mutations could benefit from the combined therapy. The identification of predictive biomarkers before or short after initiation of therapy is therefore paramount for proper patient selection, especially among EGFR wild-types. The first aim of this study was to investigate the early change in blood gene expression in unselected patients with advanced non-squamous NSCLC treated by BE. The second aim was to assess the predictive value of blood gene expression levels at baseline and 24h after BE therapy. METHODS: Blood samples from 43 advanced non-squamous NSCLC patients taken at baseline and 24h after initiation of therapy were profiled using Affymetrix' exon arrays. The 24h gene dysregulation was investigated in the light of gene functional annotations using gene set enrichment analysis. The predictive value of blood gene expression levels was assessed and validated using an independent dataset. RESULTS: Significant gene dysregulations associated with the 24h-effect of BE were detected from blood-based whole-genome profiling. BE had a direct effect on "Pathways in cancer", by significantly down-regulating genes involved in cytokine-cytokine receptor interaction, MAPK signaling pathway and mTOR signaling pathway. These pathways contribute to phenomena of evasion of apoptosis, proliferation and sustained angiogenesis. Other signaling pathways specifically reflecting the mechanisms of action of erlotinib and the anti-angiogenesis effect of bevacizumab were activated. The magnitude of change of the most dysregulated genes at 24h did not have a predictive value regarding the patients' response to BE. However, predictive markers were identified from the gene expression levels at 24h regarding time to progression under BE. CONCLUSIONS: The 24h-effect of the combined targeted therapy BE could be accurately monitored in advanced non-squamous NSCLC blood samples using whole-genome exon arrays. Putative predictive markers at 24h could reflect patients' response to BE after adjusting for their mutational status. Trial registration ClinicalTrials.gov: NCT00354549.

EGFR and KRAS Mutations in ALK-Positive Lung Adenocarcinomas: Biological and Clinical Effect.

INTRODUCTION: In lung adenocarcinoma (ADC), anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangements are mutually exclusive with epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. However, the existence of double-positive (DP) patients have been sporadically described. We identified DP cases in therapy-naive ALK-rearranged ADC and characterized the biology of these tumors to better understand the clinical response to tyrosine kinase inhibitors (TKIs). MATERIALS AND METHODS: We selected 42 ALK-positive ADCs from a multicentric series of 301 cases of ADCs. A mutational analysis was performed using Sanger and/or pyrosequencing to address exons 18-21 of EGFR and codons 12-13 of the KRAS gene. In addition, the KRAS and EGFR copy number was investigated using fluorescent in situ hybridization. DP patients were treated with TKIs, and their response was evaluated according to the Response Evaluation Criteria in Solid Tumors criteria. RESULTS: Eight of 42 ALK-positive ADCs (19%) demonstrated a concomitant mutation in the EGFR (3 cases) or KRAS (5 cases) genes and were classified as DP. All DP cases displayed copy number gains in the EGFR or KRAS gene because of polysomy or gene amplification. In the latter cases, a mutant allele-specific imbalance was observed. Four patients were treated with TKIs. The 2 EGFR-mutant DP patients demonstrated a better response to crizotinib compared with erlotinib. The 2 KRAS-mutant DP patients experienced opposite responses to crizotinib. CONCLUSION: The incidence of DP ADC is not negligible. Patients with ALK/EGFR might benefit more from crizotinib compared with erlotinib administration, although the efficacy of TKIs in patients with ALK/KRAS remains unclear. An integrated targeted therapy should be considered for patients with DP ADC.

Target Therapy in Lung Cancer.

Lung cancer is an extremely heterogeneous disease, with well over 50 different histological variants recognized under the fourth revision of the World Health Organization (WHO) typing system. Because these variants have differing genetic and biological properties correct classification of lung cancer is necessary to assure that lung cancer patients receive optimum management. Due to the recent understanding that histologic typing and EGFR mutation status are important for target the therapy in lung adenocarcinoma patients there was a great need for a new classification that addresses diagnostic issues and strategic management to allow for molecular testing in small biopsy and cytology specimens. For this reason and in order to address advances in lung cancer treatment an international multidisciplinary classification was proposed by the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS), further increasing the histological heterogeneity and improving the existing WHO-classification. Is now the beginning of personalized therapy era that is ideally finalized to treat each individual case of lung cancer in different way.

High-throughput alternative splicing detection using dually constrained correspondence analysis (DCCA).

Alternative splicing is an important component of tumorigenesis. Recent advent of exon array technology enables the detection of alternative splicing at a genome-wide scale. The analysis of high-throughput alternative splicing is not yet standard and methodological developments are still needed. We propose a novel statistical approach-Dually Constrained Correspondence Analysis-for the detection of splicing changes in exon array data. Using this methodology, we investigated the genome-wide alteration of alternative splicing in patients with non-small cell lung cancer treated by bevacizumab/erlotinib. Splicing candidates reveal a series of genes related to carcinogenesis (SFTPB), cell adhesion (STAB2, PCDH15, HABP2), tumor aggressiveness (ARNTL2), apoptosis, proliferation and differentiation (PDE4D, FLT3, IL1R2), cell invasion (ETV1), as well as tumor growth (OLFM4, FGF14), tumor necrosis (AFF3) or tumor suppression (TUSC3, CSMD1, RHOBTB2, SERPINB5), with indication of known alternative splicing in a majority of genes. DCCA facilitates the identification of putative biologically relevant alternative splicing events in high-throughput exon array data.

Gene Expression Signatures Predictive of Bevacizumab/Erlotinib Therapeutic Benefit in Advanced Nonsquamous Non-Small Cell Lung Cancer Patients (SAKK 19/05 trial).

PURPOSE: We aimed to identify gene expression signatures associated with angiogenesis and hypoxia pathways with predictive value for treatment response to bevacizumab/erlotinib (BE) of nonsquamous advanced non-small cell lung cancer (NSCLC) patients. EXPERIMENTAL DESIGN: Whole-genome gene expression profiling was performed on 42 biopsy samples (from SAKK 19/05 trial) using Affymetrix exon arrays, and associations with the following endpoints: time-to-progression (TTP) under therapy, tumor-shrinkage (TS), and overall survival (OS) were investigated. Next, we performed gene set enrichment analyses using genes associated with the angiogenic process and hypoxia response to evaluate their predictive value for patients' outcome. RESULTS: Our analysis revealed that both the angiogenic and hypoxia response signatures were enriched within the genes predictive of BE response, TS, and OS. Higher gene expression levels (GEL) of the 10-gene angiogenesis-associated signature and lower levels of the 10-gene hypoxia response signature predicted improved TTP under BE, 7.1 months versus 2.1 months for low versus high-risk patients (P = 0.005), and median TTP 6.9 months versus 2.9 months (P = 0.016), respectively. The hypoxia response signature associated with higher TS at 12 weeks and improved OS (17.8 months vs. 9.9 months for low vs. high-risk patients, P = 0.001). CONCLUSIONS: We were able to identify gene expression signatures derived from the angiogenesis and hypoxia response pathways with predictive value for clinical outcome in advanced nonsquamous NSCLC patients. This could lead to the identification of clinically relevant biomarkers, which will allow for selecting the subset of patients who benefit from the treatment and predict drug response.

EGFR exon-level biomarkers of the response to bevacizumab/erlotinib in non-small cell lung cancer.

Activating epidermal growth factor receptor (EGFR) mutations are recognized biomarkers for patients with metastatic non-small cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (TKIs). EGFR TKIs can also have activity against NSCLC without EGFR mutations, requiring the identification of additional relevant biomarkers. Previous studies on tumor EGFR protein levels and EGFR gene copy number revealed inconsistent results. The aim of the study was to identify novel biomarkers of the response to TKIs in NSCLC by investigating whole genome expression at the exon-level. We used exon arrays and clinical samples from a previous trial (SAKK19/05) to investigate the expression variations at the exon-level of 3 genes potentially playing a key role in modulating treatment response: EGFR, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and vascular endothelial growth factor (VEGFA). We identified the expression of EGFR exon 18 as a new predictive marker for patients with untreated metastatic NSCLC treated with bevacizumab and erlotinib in the first line setting. The overexpression of EGFR exon 18 in tumor was significantly associated with tumor shrinkage, independently of EGFR mutation status. A similar significant association could be found in blood samples. In conclusion, exonic EGFR expression particularly in exon 18 was found to be a relevant predictive biomarker for response to bevacizumab and erlotinib. Based on these results, we propose a new model of EGFR testing in tumor and blood.

VeriStrat® has a prognostic value for patients with advanced non-small cell lung cancer treated with erlotinib and bevacizumab in the first line: pooled analysis of SAKK19/05 and NTR528.

BACKGROUND: VeriStrat(®) is a serum proteomic test used to determine whether patients with advanced non-small cell lung cancer (NSCLC) who have already received chemotherapy are likely to have good or poor outcomes from treatment with gefitinib or erlotinib. The main objective of our retrospective study was to evaluate the role of VS as a marker of overall survival (OS) in patients treated with erlotinib and bevacizumab in the first line. PATIENTS AND METHODS: Patients were pooled from two phase II trials (SAKK19/05 and NTR528). For survival analyses, a log-rank test was used to determine if there was a statistically significant difference between groups. The hazard ratio (HR) of any separation was assessed using Cox proportional hazards models. RESULTS: 117 patients were analyzed. VeriStrat classified patients into two groups which had a statistically significant difference in duration of OS (p = 0.0027, HR = 0.480, 95% confidence interval: 0.294-0.784). CONCLUSION: VeriStrat has a prognostic role in patients with advanced, nonsquamous NSCLC treated with erlotinib and bevacizumab in the first line. Further work is needed to study the predictive role of VeriStrat for erlotinib and bevacizumab in chemotherapy-untreated patients.

Bevacizumab and erlotinib (BE) first-line therapy in advanced non-squamous non-small-cell lung cancer (NSCLC) (stage IIIB/IV) followed by platinum-based chemotherapy (CT) at disease progression: a multicenter phase II trial (SAKK 19/05).

PURPOSE: This phase II trial aimed to evaluate feasibility and efficacy of a first-line combination of targeted therapies for advanced non-squamous NSCLC: bevacizumab (B) and erlotinib (E), followed by platinum-based CT at disease progression (PD). METHODS: 103 patients with advanced non-squamous NSCLC were treated with B (15 mg/kg day 1 of each 21-day cycle) and E (150 mg daily) until PD or unacceptable toxicity. Upon PD patients received 6 cycles of CT (cisplatin/carboplatin and gemcitabine). The primary endpoint was disease stabilization rate (DSR) after 12 weeks of BE treatment. RESULTS: 101 patients were evaluable. Under BE, DSR at week 12 was 54.5%. 73 patients had at least stable disease (SD), including 1 complete remission and 17 partial responses (PR). No unexpected toxicities were observed. Median time to progression (TTP) under BE was 4.1 months. 62 patients started CT; 35 received at least 4 cycles (6 PR, 32 SD). At a median follow-up of 36 months, median overall survival (OS) was 14.1 months. CONCLUSIONS: First-line BE treatment followed by a fixed CT regimen at PD is feasible with acceptable toxicity and activity. In a non-squamous NSCLC population unselected for EGFR status, we found OS rates similar to standard CT.

NAD(P)H: quinone oxidoreductase 1 expression in kidney podocytes.

NAD(P)H:quinone oxidoreductase 1 (NQO1; DT-diaphorase; DTD) is a cytosolic two-electron reductase, and compounds of the quinone family such as mitomycin C are efficiently bioactivated by this enzyme. The observation that DT-diaphorase is highly expressed in many cancerous tissues compared to normal tissues has provided us with a potentially selective target that can be exploited in the design of novel anticancer agents. Because of the relative lack of information about the cell-specific expression of DT-diaphorase, the purpose of this study was to map the distribution of this enzyme in normal human tissues. Fifteen tissue samples from normal human kidney were analyzed for expression of DT-diaphorase by immunohistochemistry (two-step indirect method). We found a specific high expression of DT-diaphorase in glomerular visceral epithelial cells (podocytes). These results suggest that a high expression of DT-diaphorase in podocytes could play a major role in the pathogenesis of renal toxicity and mitomycin C-induced hemolytic uremic syndrome, in which injury to the glomerular filtration mechanism is the primary damage, leading to a cascade of deleterious events including microangiopathic hemolytic anemia and thrombocytopenia. This observation has potential therapeutic implications because the DT-diaphorase metabolic pathway is influenced by many agents, including drugs, diet, and environmental cell factors such as pH and oxygen tension.