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Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET—a phase I, single-arm study
BackgroundDostarlimab is a humanized monoclonal antibody that binds with high affinity to PD-1, resulting in inhibition of binding to PD-L1 and PD-L2. We report interim data from patients with endometrial cancer (EC) participating in a phase I trial of single-agent dostarlimab.MethodsGARNET, an ongoing, single-arm, open-label, phase I trial of intravenous dostarlimab in advanced solid tumors, is being undertaken at 123 sites. Two cohorts of patients with EC were recruited: those with dMMR/MSI-H disease (cohort A1) and those with proficient/stable (MMRp/MSS) disease (cohort A2). Patients received dostarlimab 500 mg every 3 weeks for 4 cycles, then dostarlimab 1000 mg every 6 weeks until disease progression. The primary endpoints were objective response rate (ORR) and duration of response (DOR) per RECIST V.1.1, as assessed by blinded independent central review.ResultsScreening began on April 10, 2017, and 129 and 161 patients with advanced EC were enrolled in cohorts A1 and A2, respectively. The median follow-up duration was 16.3 months (IQR 9.5–22.1) for cohort A1 and 11.5 months (IQR 11.0–25.1) for cohort A2. In cohort A1, ORR was 43.5% (95% CI 34.0% to 53.4%) with 11 complete responses and 36 partial responses. In cohort A2, ORR was 14.1% (95% CI 9.1% to 20.6%) with three complete responses and 19 partial responses. Median DOR was not reached in either cohort. In the combined cohorts, the majority of treatment-related adverse events (TRAEs) were grade 1–2 (75.5%), most commonly fatigue (17.6%), diarrhea (13.8%), and nausea (13.8%). Grade≥3 TRAEs occurred in 16.6% of patients, and 5.5% discontinued dostarlimab because of TRAEs. No deaths were attributable to dostarlimab.ConclusionDostarlimab demonstrated durable antitumor activity in both dMMR/MSI-H (ORR 43.5%) and MMRp/MSS EC (ORR 14.1%) with a manageable safety profile.Trial registration numberNCT02715284.
Journal Article
Outcome of Robotic Surgery for Endometrial Cancer as a Function of Patient Age
ObjectiveThis study aimed to evaluate and compare robot-assisted surgical staging on clinical outcomes, including quality of life and survival, as a function of patient age.MethodsEvaluation and comparison of perioperative morbidity, survival, and postoperative quality of life after prospective accumulation of clinical information including outcome measures for patients with endometrial cancer during the first 5 years of a robotic program, based on the following 3 age categories: women older than 80 years, women between 70 and 80 years, and women younger than 70 years.ResultsAll consecutive patients with endometrial cancer undergoing robotic surgery (n = 303) were included, with 197 women younger than 70 years, 75 women between 70 and 80 years, and 31 women older than 80 years. There were significantly more patients with advanced stage (stage II to IV in 17%, 34%, and 35%, P = 0.02) and grade 3 disease (26%, 43%, and 58%, P = 0.002) with increasing age. The perioperative data showed similar grade I or II complications (Clavien-Dindo classification) between the groups, but significantly more grade III and IV complications for women older than 80 years compared with women 80 years or younger (10% vs 1%, P = 0.004). The time needed to resume chore activities was significantly shorter for patients 70 years or older than patients younger than 70 years [8.9 (8.7) vs 18.8 (25.5) days, P = 0.048]. Overall, all patients irrespective of age were highly satisfied with the procedure. There was no difference between young and elderly patients for disease-free survival (P = 0.99).ConclusionsPatient’s age did not influence minor postoperative morbidity or overall satisfaction after robotic assisted surgery for endometrial cancer. Elderly patients had more major postoperative morbidity but resumed activities quicker than younger patients.
Journal Article
Vaginal Vault Dehiscence After Robotic Hysterectomy for Gynecologic Cancers: Search for Risk Factors and Literature Review
INTRODUCTIONVaginal vault dehiscence following robotic-assisted hysterectomy for gynecologic cancer may be attributed to surgical techniques and postoperative therapeutic interventions. We searched for risk factors in patients with gynecologic cancers and complemented this with a literature review.
METHODSEvaluation of prospectively gathered information on all consecutive robotic surgeries for gynecologic cancers was performed in a tertiary academic cancer center between December 2007 and March 2012. The literature was reviewed for articles relevant to “gynecologic oncology” and “robotics” with “vaginal cuff dehiscence” in the English and French languages. Respective authors were contacted to complete relevant information.
RESULTSSeven dehiscences were identified of 441 cases with established gynecologic cancers. The closures in these 7 were performed using interrupted 1-Vicryl (Ethicon Inc) (3/167; 1.8%), combination of interrupted 1-Vicryl and 1-Biosyn (Covidien Inc) (3/156, 1.9%), and V-Loc (Covidien Inc) (1/118, 0.8%) sutures. Associated risk factors included adjuvant chemotherapy and/or brachytherapy, early resumption of sexual activity, and low body mass index (mean, 23 ± 3.23 kg/m). Dehiscences occurred regardless of suturing by staff or trainees. Review of operative videos did not reveal a detectable etiologic factor, such as excessive cautery damage to the vaginal cuff or shallow tissue sutured. All 7 colporrhexis repairs were performed through a vaginal approach without the need of laparoscopy or laparotomy.
CONCLUSIONSPostoperative chemotherapy, brachytherapy, and early resumption of sexual activities are risk factors for vaginal vault dehiscence. Surgical technique, particularly the use of delayed absorbable sutures, deserves further evaluation
Journal Article
Microparticles From Ovarian Carcinomas Are Shed Into Ascites and Promote Cell Migration
ObjectiveMicroparticles are cellular-derived vesicles (0.5–1.0 μm) composed of cell membrane components, which are actively shed from the surface of various cells, including epithelial cells. We compared microparticles in ascites between women with ovarian carcinoma and women with benign ovarian pathology, and isolated tumor-derived (epithelial cell adhesion molecule [EpCAM]-positive) microparticles for functional analysis and proteomics.Materials and MethodsCases included 8 patients with benign ovarian neoplasms and 41 with ovarian carcinoma. Ascites from a high-grade stage III serous carcinoma was used for functional and proteomic analysis. Cancer cells were isolated using EpCAM-coated beads, microparticles were isolated by ultracentrifugation/flow cytometry, and sorting was achieved using markers (eg, EpCAM). Binding and migrations assays were performed with 3 ovarian cancer cell lines. Proteomic analysis of EpCAM-positive microparticles and ascites cancer cells was performed by mass spectrometry.ResultsMicroparticles in benign pelvic fluid were similar to early and advanced-stage ascites (2.4 vs 2.8 vs 2.0 × 106 microparticles/mL). Advanced stage had a greater proportion of EpCAM-positive microparticles than early or benign disease (13.3% vs 2.5% vs 2.1%; P = 0.001), and serous histology had more than endometrioid (13.2% vs 1.8%; P = 0.01). Microparticles bound to the surface of 3 cultured cell lines, and were internalized into the EpCAM-positive microparticles, resulting in more cell migration than buffer alone or EpCAM-negative microparticles (P = 0.007). A dose-dependent increase was seen with increasing numbers of EpCAM-positive microparticles. Proteomics revealed that most proteins in EPCAM-positive microparticles were shared with cancer cells, and many are associated with cell motility and invasion, such as fibronectin, filamin A, vimentin, myosin-9, and fibrinogen.ConclusionsAscites from advanced-stage and serous ovarian carcinomas contain large numbers of tumor-derived microparticles. In vitro, these microparticles bind to cancer cells and stimulate migration. Tumor-derived microparticles in ascites could mediate the predilection for peritoneal spread in serous ovarian carcinomas.
Journal Article
Virtual reality robotic surgery simulation curriculum to teach robotic suturing: a randomized controlled trial
The objective of this randomized, controlled trial was to assess whether voluntary participation in a proctored, proficiency-based, virtual reality robotic suturing curriculum using the da Vinci
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Skills Simulator™ improves robotic suturing performance. Residents and attending surgeons were randomized to participation or non-participation during a 5 week training curriculum. Robotic suturing skills were evaluated before and after training using an inanimate vaginal cuff model, which participants sutured for 10 min using the da Vinci
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Surgical System. Performances were videotaped, anonymized, and subsequently graded independently by three robotic surgeons. 27 participants were randomized. 23 of the 27 completed both the pre- and post-test, 13 in the training group and 10 in the control group. Mean training time in the intervention group was 238 ± 136 min (SD) over the 5 weeks. The primary outcome (improvement in GOALS+ score) and the secondary outcomes (improvement in GEARS, total knots, satisfactory knots, and the virtual reality suture sponge 1 task) were significantly greater in the training group than the control group in unadjusted analysis. After adjusting for lower baseline scores in the training group, improvement in the suture sponge 1 task remained significantly greater in the training group and a trend was demonstrated to greater improvement in the training group for the GOALS+ score, GEARS score, total knots, and satisfactory knots.
Journal Article
Martinez dominant as Cards top AstrosPitcher takes no-hitter to sixth; Hazelbaker, Moss add home runs
\"Every day I go out on the hill focused on my work and ready to go through nine innings hopefully,\" [Carlos Martinez] said. \"Some days there's bad days, some days there's good days like today. I stayed focused and I felt really good. I feel like it's just part of the game and I went out and did the best I could.\" \"It's good we're just having good approaches and obviously we're having success at the plate,\" [Jeremy Hazelbaker] said. \"It comes from preparation and just knowing what we're capable of and just being prepared every at-bat.\" \"The rollercoaster ride that we've been on is no fun when we're in this portion of it,\" Astros manager A.J. Hinch said. \"This game will test your character, it'll test your resolve, it'll test your ability to come back from adversity and this is another test for us. We've got the better part of six weeks left in the regular season, and we need to compile some wins.\"
Newspaper Article
