Summary Background First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and ...high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 PD-L1) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients. Methods For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecified subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov , number NCT02108652. Findings Between June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17·2 months' median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2·7 months (2·1 to 4·2). Median overall survival was 15·9 months (10·4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 30% patients), diarrhoea (14 12% patients), and pruritus (13 11% patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients. Interpretation Atezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer. Funding F Hoffmann-La Roche, Genentech.
Electron avalanches in liquid argon mixtures Kim, J.G.; Dardin, S.M.; Kadel, R.W. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
12/2004, Letnik:
534, Številka:
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Journal Article
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We have observed stable avalanche gain in liquid argon when mixed with small amounts of xenon (xe) in the high electric field (
>
7
MV/cm) near the point of a chemically etched needle in a ...point–plane geometry. We identify two gain mechanisms, one pressure dependent, and the other independent of the applied pressure. We conclude that the pressure-dependent signals are from avalanche gain in gas bubbles at the tip of the needle, while the pressure-independent pulses are from avalanche gain in liquid. We measure the decay time spectra of photons from both types of avalanches. The decay times from the pressure-dependent pulses decrease (increase) with the applied pressure (high voltage), while the decay times from the pressure-independent pulses are approximately independent of pressure or high voltage. For our operating conditions, the collected charge distribution from avalanches is similar for 60 or 122
keV photon sources. With krypton additives, instead of Xe, we measure behavior consistent with only the pressure-dependent pulses. Neon and TMS were also investigated as additives, and designs for practical detectors were tested.
Atezolizumab anti-programmed death-ligand 1 (anti-PD-L1) is well tolerated and efficacious in multiple cancers, but has not been previously evaluated in metastatic castration-resistant prostate ...cancer (mCRPC). This study examined the safety, efficacy, and biomarkers of atezolizumab monotherapy for mCRPC.
This phase Ia, open-label, dose-escalation and dose-expansion study (PCD4989g) enrolled patients with mCRPC who had progressed on sipuleucel-T or enzalutamide. Atezolizumab was given intravenously every 3 weeks until confirmed disease progression or loss of clinical benefit. Prespecified endpoints included safety, efficacy, biomarker analyses, and radiographic assessments.
All 35 evaluable patients median age, 68 years (range, 45-83 years) received atezolizumab after ≥1 prior line of therapy; 62.9% of patients had received ≥3 prior lines. Treatment-related adverse events occurred in 21 patients (60.0%), with no deaths. One patient had a confirmed partial response (PR) per RECIST 1.1, and 1 patient had a PR per immune-related response criteria. The confirmed 50% PSA response rate was 8.6% (3 patients). Median overall survival (OS) was 14.7 months 95% confidence interval (CI): 5.9-not evaluable, with a 1-year OS rate of 52.3% (95% CI: 34-70); 2-year OS was 35.9% (95% CI: 13-59). Median follow-up was 13.0 months (range, 1.2-28.1 months). Biomarker analyses showed that atezolizumab activated immune responses; however, a composite biomarker failed to reveal consistent correlations with efficacy.
Atezolizumab was generally well tolerated in patients with mCRPC, with a safety profile consistent with other tumor types. In heavily pretreated patients, atezolizumab monotherapy demonstrated evidence of disease control; however, its limited efficacy suggests a combination approach may be needed.
Electron avalanching in liquid argon is being studied as a function of voltage, pressure, radiation intensity, and the concentrations of certain additives, especially xenon. The avalanches produced ...in an intense electric field at the tip of a tungsten needle are initiated by ionization from a movable americium (/sup 241/Am) gamma-ray source. Photons from xenon excimers are detected as photomultiplier signals in coincidence with the current pulse from the needle. In pure liquid argon, the avalanche behavior is erratic, but the addition of even a small amount of xenon (/spl les/100 ppm) stabilizes the performance. Similar attempts with neon (30%) as an additive to argon have been unsuccessful. Tests with higher energy gamma-rays (/sup 57/Co) yield spectra and other performance characteristics quite similar to those using the /sup 241/Am source. Two types of signal pulses are commonly observed: a set of pulses that are sensitive to ambient pressure and a set of somewhat smaller pulses that are not pressure dependent.
Previously, we showed how small admixtures of xenon (Xe) stabilize electron avalanches in liquid Argon (LAr). In the present work, we have measured the positive charge carrier mobility in LAr with ...small admixtures of Xe to be 6.4/spl times/10/sup -3/ cm/sup 2//Vs, in approximate agreement with the mobility measured in pure LAr and consistent with holes as charge carriers. We have measured the concentration of Xe actually dissolved in the liquid and compared the results with expectations based on the amount of Xe gas added to the LAr. We also have tested LAr doped with krypton to investigate the mechanism of avalanche stabilization.
The application of modeling and simulation techniques is increasingly common in the preclinical stages of the drug development process. GDC-0917 ...(S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N-(2-(oxazol-2-yl)-4-phenylthiazol-5-yl)pyrrolidine-2-carboxamide is a potent second-generation antagonist of inhibitor of apoptosis (IAP) proteins that is being developed for the treatment of various cancers. GDC-0917 has low to moderate clearance in the mouse (12.0 ml/min/kg), rat (27.0 ml/min/kg), and dog (15.3 ml/min/kg), and high clearance in the monkey (67.6 ml/min/kg). Accordingly, oral bioavailability was lowest in monkeys compared with other species. Based on our experience with a prototype molecule with similar structure, in vitro-in vivo extrapolation was used to predict a moderate clearance (11.5 ml/min/kg) in humans. The predicted human volume of distribution was estimated using simple allometry at 6.69 l/kg. Translational pharmacokinetic-pharmacodynamic (PK-PD) analysis using results from MDA-MB-231-X1.1 breast cancer xenograft studies and predicted human pharmacokinetics suggests that ED50 and ED90 targets can be achieved in humans using acceptable doses (72 mg and 660 mg, respectively) and under an acceptable time frame. The relationship between GDC-0917 concentrations and pharmacodynamic response (cIAP1 degradation) was characterized using an in vitro peripheral blood mononuclear cell immunoassay. Simulations of human GDC-0917 plasma concentration-time profile and cIAP1 degradation at the 5-mg starting dose in the phase 1 clinical trial agreed well with observations. This work shows the importance of leveraging information from prototype molecules and illustrates how modeling and simulation can be used to add value to preclinical studies in the early stages of the drug development process.
Background: Evaluating shoes during sport-related movements may provide a better assessment of plantar loads associated with repetitive
injury and provide more specific data for comparing shoe ...cushioning characteristics.
Hypothesis: Accelerating, cutting, and jumping pressures will be higher than in straight running, differentiating regional shoe cushioning
performance in sport-specific movements.
Study Design: Controlled laboratory study.
Materials and Methods: Peak pressures on seven anatomic regions of the foot were assessed in 10 male college athletes during running straight ahead,
accelerating, cutting left, cutting right, jump take-off, and jump landing wearing Speed TD and Air Pro Turf Low shoes (Nike,
Beaverton, Ore). Pedar insoles (Novel, Munich, Germany) were sampled at 99 Hz during the 6 movements.
Results: Cutting and jumping movements demonstrated more than double the pressure at the heel compared with running straight, regardless
of shoe type. The Air Pro Turf showed overall lower pressure for all movement types ( P <.0377). Cutting to the left, the Air Pro Turf shoe had lower heel pressures (36.6 ± 12.5 N/cm 2 ) than the Speed TD (50.3 ± 11.2 N/cm 2 ) ( P <.0001), and the Air Pro Turf had lower great toe pressures than the Speed TD (44.8 ± 8.1 N/cm 2 vs 54.4 ± 8.4 N/cm 2 ; P = .0002). The Air Pro Turf also had significantly lower pressures than the Speed TD at the central forefoot during acceleration
(38.2 ± 8.3 N/cm 2 vs 50.8 ± 7.4 N/cm 2 ; P <.0001).
Conclusion: Sport-related movements load the plantar surface of the foot more than running straight. Shoe cushioning characteristics
were more robustly assessed during sport-related movements (4 significant results detected) compared with running straight
(1 significant result detected).
Clinical Relevance: There is an interaction between shoe cushioning characteristics and sport-related movements that may influence plantar pressure
and repetitive stress injuries.
Keywords:
sports
shoes
performance
injury prevention
design
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