Efficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS)

Càncer de bufeta; Rucaparib; Carcinoma urotelialCáncer de vejiga; Rucaparib; Carcinoma urotelialBladder cancer; Rucaparib; Urothelial carcinomaBackground ATLAS evaluated the efficacy and safety of the PARP inhibitor rucaparib in patients with previously treated locally advanced/unresectable or metastatic urothelial carcinoma (UC). Methods Patients with UC were enrolled independent of tumor homologous recombination deficiency (HRD) status and received rucaparib 600 mg BID. The primary endpoint was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (loss of genome-wide heterozygosity ≥10%) populations. Key secondary endpoints were progression-free survival (PFS) and safety. Disease control rate (DCR) was defined post-hoc as the proportion of patients with a confirmed complete or partial response (PR), or stable disease lasting ≥16 weeks. Results Of 97 enrolled patients, 20 (20.6%) were HRD-positive, 30 (30.9%) HRD-negative, and 47 (48.5%) HRD-indeterminate. Among 95 evaluable patients, there were no confirmed responses. However, reductions in the sum of target lesions were observed, including 6 (6.3%) patients with unconfirmed PR. DCR was 11.6%; median PFS was 1.8 months (95% CI, 1.6–1.9). No relationship was observed between HRD status and efficacy endpoints. Median treatment duration was 1.8 months (range, 0.1–10.1). Most frequent any-grade treatment-emergent adverse events were asthenia/fatigue (57.7%), nausea (42.3%), and anemia (36.1%). Of 64 patients with data from tumor tissue samples, 10 (15.6%) had a deleterious alteration in a DNA damage repair pathway gene, including four with a deleterious BRCA1 or BRCA2 alteration. Conclusions Rucaparib did not show significant activity in unselected patients with advanced UC regardless of HRD status. The safety profile was consistent with that observed in patients with ovarian or prostate cancer.The work was supported by Clovis Oncology (no grant number) and was designed by the sponsor, P. Grivas, and S. Chowdhury

Higher-order Kerr terms allow ionization-free filamentation in gases

We show that higher-order nonlinear indices ($n_4$, $n_6$, $n_8$, $n_{10}$) provide the main defocusing contribution to self-channeling of ultrashort laser pulses in air and Argon at 800 nm, in contrast with the previously accepted mechanism of filamentation where plasma was considered as the dominant defocusing process. Their consideration allows to reproduce experimentally observed intensities and plasma densities in self-guided filaments.Comment: 11 pages, 6 figures (11 panels

Spectral dependence of purely-Kerr driven filamentation in air and argon

Based on numerical simulations, we show that higher-order nonlinear indices (up to $n_8$ and $n_{10}$, respectively) of air and argon have a dominant contribution to both focusing and defocusing in the self-guiding of ultrashort laser pulses over most of the spectrum. Plasma generation and filamentation are therefore decoupled. As a consequence, ultraviolet wavelength may not be the optimal wavelengths for applications requiring to maximize ionization.Comment: 14 pages, 4 figures (14 panels

On negative higher-order Kerr effect and filamentation

As a contribution to the ongoing controversy about the role of higher-order Kerr effect (HOKE) in laser filamentation, we first provide thorough details about the protocol that has been employed to infer the HOKE indices from the experiment. Next, we discuss potential sources of artifact in the experimental measurements of these terms and show that neither the value of the observed birefringence, nor its inversion, nor the intensity at which it is observed, appear to be flawed. Furthermore, we argue that, independently on our values, the principle of including HOKE is straightforward. Due to the different temporal and spectral dynamics, the respective efficiency of defocusing by the plasma and by the HOKE is expected to depend substantially on both incident wavelength and pulse duration. The discussion should therefore focus on defining the conditions where each filamentation regime dominates.Comment: 22 pages, 11 figures. Submitted to Laser physics as proceedings of the Laser Physics 2010 conferenc

Identification of IMDC intermediate-risk subgroups in patients with metastatic clear-cell renal cell carcinoma (ccRCC).

e16577Background: Majority of patients (pts) with ccRCC at first line (1L) treatment are classified in the IR subgroup according to International Metastatic Renal Cell Carcinoma Database Consortium..

New Prognostic factors for second-line targeted therapy (TT) in metastatic renal cell carcinoma (mRCC).

No abstract availabl

Phase-ordering dynamics of the Gay-Berne nematic liquid crystal

Phase-ordering dynamics in nematic liquid crystals has been the subject of much active investigation in recent years in theory, experiments and simulations. With a rapid quench from the isotropic to nematic phase a large number of topological defects are formed and dominate the subsequent equilibration process. We present here the results of a molecular dynamics simulation of the Gay-Berne model of liquid crystals after such a quench in a system with 65536 molecules. Twist disclination lines as well as type-1 lines and monopoles were observed. Evidence of dynamical scaling was found in the behavior of the spatial correlation function and the density of disclination lines. However, the behavior of the structure factor provides a more sensitive measure of scaling, and we observed a crossover from a defect dominated regime at small values of the wavevector to a thermal fluctuation dominated regime at large wavevector.Comment: 18 pages, 16 figures, animations available at http://www.physics.brown.edu/Users/faculty/pelcovits/lc/coarsening.htm

Abiraterone Alone or in Combination With Enzalutamide in Metastatic Castration-Resistant Prostate Cancer With Rising Prostate-Specific Antigen During Enzalutamide Treatment

Purpose Enzalutamide resistance could result from raised androgens and be overcome by combination with abiraterone acetate. PLATO (ClinicalTrials.gov identifier: NCT01995513) interrogated this hypothesis using a randomized, double-blind, placebo-controlled design. Patients and Methods In period one, men with chemotherapy-na¨ıve metastatic castration-resistant prostate cancer received open-label enzalutamide 160 mg daily. Men with no prostate-specific antigen (PSA) increase at weeks 13 and 21 were treated until PSA progression ($25$ 2 ng/mL above nadir), then randomly assigned at a one-to-one ratio in period two to abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily with either enzalutamide or placebo (combination or control group, respectively) until disease progression as defined by the primary end point: progression-free survival (radiographic or unequivocal clinical progression or death during study). Secondary end points included time to PSA progression and PSA response in period two. Results Of 509 patients enrolled in period one, 251 were randomly assigned in period two. Median progression-free survival was 5.7 months in the combination group and 5.6 months in the control group (hazard ratio, 0.83; 95% CI, 0.61 to 1.12; P = .22). There was no difference in the secondary end points. Grade 3 hypertension (10% v 2%) and increased ALT (6% v 2%) or AST (2% v 0%) were more frequent in the combination than the control group. Conclusion Combining enzalutamide with abiraterone acetate and prednisone is not indicated after PSA progression during treatment with enzalutamide alone; hypertension and elevated liver enzymes are more frequent with combination therapy

Tumor Heterogeneity of Fibroblast Growth Factor Receptor 3 (FGFR3) Mutations in Invasive Bladder Cancer: Implications for Peri-Operative anti-FGFR3 Treatment

Background: Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer. Preclinical studies show that anti-FGFR3 treatment slows down tumor growth, suggesting that this tyrosine kinase receptor is a candidate for personalized bladder cancer treatment, particularly in patients with mutated FGFR3. We addressed tumor heterogeneity in a large multicenter, multi-laboratory study, as this may have significant impact on therapeutic response. Patients: and methods We evaluated possible FGFR3 heterogeneity by the PCR-SNaPshot method in the superficial and deep compartments of tumors obtained by transurethral resection (TUR, n = 61) and in radical cystectomy (RC, n = 614) specimens and corresponding cancer-positive lymph nodes (LN+, n = 201).Results: We found FGFR3 mutations in 13/34 (38%) T1 and 8/27 (30%) ≥T2-TUR samples, with 100% concordance between superficial and deeper parts in T1-TUR samples. Of eight FGFR3 mutant ≥T2-TUR samples, only 4 (50%) displayed the mutation in the deeper part. We found 67/614 (11%) FGFR3 mutations in RC specimens. FGFR3 mutation was associated with pN0 (P < 0.001) at RC. In 10/201 (5%) LN+, an FGFR3 mutation was found, all concordant with the corresponding RC specimen. In the remaining 191 cases, RC and LN+ were both wild type.Conclusions: FGFR3 mutation status seems promising to guide decision-making on adjuvant anti-FGFR3 therapy as it appeared homogeneous in RC and LN+. Based on the results of TUR, the deep part of the tumor needs to be assessed if neoadjuvant anti-FGFR3 treatment is considered. We conclude that studies on the heterogeneity of actionable molecular targets should precede clinical trials with these drugs in the perioperative setting