Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase III DUO-E Trial

PURPOSE Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)-deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease. METHODS This phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control. RESULTS Seven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; P = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; P < .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib v control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab v control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib v control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1-positive subgroups (HR [durvalumab v control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib v control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77 [95% CI, 0.56 to 1.07]; P = .120; durvalumab + olaparib v control: HR, 0.59 [95% CI, 0.42 to 0.83]; P = .003). The safety profiles of the experimental arms were generally consistent with individual agents. CONCLUSION Carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

The effects of flossing with a chlorhexidine solution on interproximal gingivitis : a randomized controlled trial

Background: Gingivitis, which is an inflammatory response of the gingival tissues to bacterial plaque, can be treated by brushing and flossing or using chlorhexidine (CHX). Objective: To determine whether floss presoaked in CHX would improve oral health relative to floss presoaked in placebo solution. Materials and methods: A 3 month, double-blinded, parallel, randomized control trial was conducted on 27 adults with a minimum of 10 bleeding sites, who were randomly assigned to dental floss with 0.12% CHX or a placebo solution (QS). Scaling, rubber cup prophylaxis, and flossing instructions were performed at Week -1. Subjects were assessed for probing depth (PD) with bleeding on probing (BOP), gingival index (GI), plaque index (PI), and stain index (SI) at Weeks 0, 6, and 12. Flossing compliance was monitored by self-reports and yards of dental floss used. Student t-tests, ANCOVA and Wilcoxon Signed-Rank were conducted. Results: Self-reported median flossing compliance was 100% for CHX and 93% for QS. A statistically significant reduction for PD in the CHX group at Week 6 (p = 0.029) and specifically, for the gingivitis sites at Week 6 (p = 0.006) and Week 12 (p = 0.005). Reductions in BOP were statistically significant for CHX group with moderate gingivitis (p = 0.0078). The CHX group had a statistically significant reduction in BOP in all areas of the oral cavity with the largest reductions occurring in the anterior areas (p = 0.011). All GI scores were statistically significant from Weeks 0 to 12 (p < 0.0001). Although not statistically significant, PI appeared to be constant for CHX group and increasing for QS group. The two groups did not differ significantly for SI. Conclusion: CHX applied via dental floss significantly reduced probing depths in shallow sulci and bleeding in subjects with moderate gingivitis. Further studies are suggested to determine the effects of CHX with different interdental aids, higher concentrations of CHX, and subjects with moderate to severe gingivitis. Funding: CFDHRE and BCDHA Key words: gingivitis, chlorhexidine, dental floss, RCT, bleeding on probing, gingival and plaque indices.Dentistry, Faculty ofGraduat

D: Comparison of interdental brush to dental floss for reduction of clinical parameters of periodontal disease: a systematic review

AbSTRACT background: Daily oral biofilm disruption by clients is recommended by oral health professionals to prevent oral diseases and to maintain optimal oral and overall health. since periodontal diseases and caries are prevalent interproximally, the adjunctive use of interdental aids is highly recommended. objectives: to evaluate the effectiveness of interdental brushing as an adjunct to toothbrushing for the primary outcome of interproximal gingival bleeding and a secondary outcome of interproximal plaque. Methods: only randomized controlled trials were included. studies were included irrespective of publication status and language. Hand searching was conducted in two peer reviewed journals, with references mined. Pharmaceutical companies that develop and manufacture interdental brushes were also contacted for unpublished or ongoing clinical trials. sixty-two studies were retrieved from the literature with seven studies meeting the inclusion/ exclusion criteria. forest plots and Chi-square tests were used to determine the presence of heterogeneity. random effects model, relative risk and 95% confidence intervals were used in the analysis. results: four studies were included in the meta analysis for bleeding outcome. although some heterogeneity was present among the studies, the interdental brush groups demonstrated statistical significance for reducing interproximal bleeding compared to the dental floss groups, p = 0.003. Plaque outcomes were analyzed using seven studies, with interdental brush demonstrating statistically significant differences to dental floss, p = 0.024. Conclusion: interdental brush is an effective alternative to dental floss for reducing interproximal bleeding and plaque in clients with filled or open embrasures