8 research outputs found
Enforcing crash failure semantics in distributed systems with fine-grained object mobility
Migration is a powerful technique in distributed systems providing many benefits.
The granularity of migration ranges from the coarse-grained movement of whole
processes to the fine-grained mobility of individual objects which provides more
flexibility and control. One of the costs of fine-grained mobility is an increase in
the complexity of programming with respect to failures. Classic fault-tolerance
techniques for distributed systems cannot be applied in systems with fine-grained
object mobility due to the unacceptable overhead of applying these techniques to
many small objects. We discuss a group service that allows programmers to apply
classic distributed system fault-tolerance techniques to systems with fine-grained
object mobility. This service enforces the condition that all objects in a group are
either all available or all failed, and has been implemented in the Emerald language
and runtime environment. Examples using the group service include a fault-tolerant
name server and a fault-tolerant distributed system monitor.Science, Faculty ofComputer Science, Department ofGraduat
Abstract The Measured Access Characteristics of World-Wide-Web Client Proxy Caches
The growing popularity of the World Wide Web is placing tremendous demands on the Internet. A key strategy for scaling the Internet to meet these increasing demands is to cache data near clients and thus improve access latency and reduce network and server load. Unfortunately, research in this area has been hampered by a poor understanding of the locality and sharing characteristics of Web-client accesses. The recent popularity of Web proxy servers provides a unique opportunity to improve this understanding, because a small number of proxy servers see accesses from thousands of clients. This paper presents an analysis of access traces collected from seven proxy servers deployed in various locations throughout the Internet. The traces record a total of 47.4 million requests made by 23,700 clients over a twenty-one day period. We use a combination of static analysis and trace-driven cache simulation to characterize the locality and sharing properties of these accesses. Our analysis shows that a 2- to 10-GB second-level cache yields hit rates between 24 % and 45 % with 85 % of these hits due to sharing among different clients. Caches with more clients exhibit more sharing and thus higher hit rates. Between 2 % and 7 % of accesses are consistency misses to unmodified objects, using the Squid and CERN proxy cache coherence protocols. Sharing is bimodal. Requests for shared objects are divided evenly between objects that are narrowly shared and those that are shared by many clients; widely shared objects also tend to be shared by clients from unrelated traces.
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Niraparib and dostarlimab for the treatment of recurrent platinum-resistant ovarian cancer: results of a Phase II study (MOONSTONE/GOG-3032)
This study assessed the efficacy, safety, and health-related quality of life (HRQoL) of the treatment regimen of dostarlimab, a programmed death-1 inhibitor, combined with niraparib, a poly (ADP-ribose) polymerase inhibitor, in patients with BRCA wild type (BRCAwt) recurrent platinum-resistant ovarian cancer (PROC) who had previously received bevacizumab treatment.
This Phase II, open-label, single-arm, multicenter study, conducted in the USA, enrolled patients with recurrent PROC to receive niraparib and dostarlimab until disease progression or unacceptable toxicity (up to 3 years). A preplanned interim futility analysis was performed after the first 41 patients had undergone ≥1 radiographic evaluation (approximately 9 weeks from the first treatment).
The prespecified interim futility criterion was met and the study was therefore terminated. For the 41 patients assessed, the objective response rate (ORR) was 7.3% (95% confidence interval: 1.5–19.9); no patients achieved a complete response, 3 patients (7.3%) achieved a partial response (duration of response; 3.0, 3.8, and 9.2 months, respectively), and 9 patients (22.0%) had stable disease. In total, 39 patients (95.1%) experienced a treatment-related adverse event, but no new safety issues were observed. HRQoL, assessed using FOSI, or Functional Assessment of Cancer Therapy – Ovarian Symptom Index scores, worsened over time compared with baseline scores.
The study was terminated due to the observed ORR at the interim futility analysis. This highlights a need for effective therapies in treating patients with recurrent BRCAwt PROC.
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•Overall response rate did not improve with niraparib and dostarlimab in recurrent BRCAwt platinum-resistant ovarian cancer (124/125).•Low objective response rate versus standard of care triggered prespecified futility criteria and early study termination (122/125).•No new safety signals were reported for niraparib and dostarlimab combination therapy (87/125).•Health-related quality of life measures worsened over time from baseline, with no control group for comparison (112/125)
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MOONSTONE/GOG-3032: Interim analysis of a phase 2 study of niraparib + dostarlimab in patients (pts) with platinum-resistant ovarian cancer (PROC)
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Background: PROC is poorly responsive to anticancer therapy. PARP inhibitors such as niraparib may increase neoantigen load and synergize with anti-PD-1 agents. TOPACIO reported a preliminary objective response rate (ORR: 18%) and disease control rate (DCR: 65%) to niraparib + pembrolizumab in pts with OC of any BRCA status. MOONSTONE sought to determine efficacy in pts without BRCA mutation ( BRCAm). Methods: In this phase 2 open-label, single-arm study, eligible pts received 1–3 prior lines of therapy including platinum, taxane, and bevacizumab, had RECIST v1.1 radiographic progression within 6 mo of last platinum line and had no known germline BRCAm. Pts were treated with niraparib 300/200 mg PO daily (based on weight/platelets) and 500 mg dostarlimab IV Q3W (cycles 1–4) followed by 1000 mg Q6W until disease progression, toxicity or consent withdrawal. Programmed death-ligand 1 (PD-L1) positive status was determined by Ventana SP263 assay using visually-estimated combined positive score ≥5%. The primary endpoint was investigator-assessed ORR per RECIST v1.1. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), DCR, and safety. Futility was prespecified as ≤5 responses in the first 40 pts. Results: At interim analysis (data cutoff Oct 6, 2021), 41 pts were enrolled; median age was 65.0 y (range 35–77). At baseline, 8 (20%)/22 (54%)/11 (27%) pts had received 1/2/3 prior lines of therapy, respectively; 26 (63%) pts had primary resistance to platinum therapy and 15 (37%) were sensitive to first platinum treatment. Overall, tumors were PD-L1+/PD-L1–/unknown in 13 (32%)/25 (61%)/3 (7%), respectively. Efficacy results are shown in the Table. Treatment-related adverse events were reported in 95% of pts, most commonly nausea (56%), fatigue (34%), vomiting (32%), and anemia (29%). Conclusions: PROC remains difficult to treat; the ORR observed with niraparib + dostarlimab did not reach the threshold for 2nd-stage accrual in this cohort of pts with PROC, no known BRCAm, and prior bevacizumab treatment. PD-L1 status did not predict response; HRD testing is in process. Although DCR was 29%, futility was declared based on low ORR. The safety of the combination was similar to the safety profile of each monotherapy. Clinical trial information: NCT03955471. [Table: see text