Citations

Purpose We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, ≤ 4 mL × 10 6 plaque-forming units/mL; after 3 weeks, ≤ 4 mL × 10 8 plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. Results One hundred ninety-eight patients were randomly assigned to talimogene laherparepvec plus ipilimumab (n = 98), or ipilimumab alone (n = 100). Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response (odds ratio, 2.9; 95% CI, 1.5 to 5.5; P = .002). Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; ipilimumab alone, 42%), chills (combination, 53%; ipilimumab alone, 3%), and diarrhea (combination, 42%; ipilimumab alone, 35%). Incidence of grade ≥ 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. Conclusion The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab.

Background: Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology. Objective: We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS. Methods: Cases with onset <18 years ( n = 569) and controls ( n = 16,251) were included from the United States and Sweden. Adjusted logistic regression and meta-analyses were performed for individual risk variants and a weighted genetic risk score (wGRS) for non-MHC variants. Results were compared to adult MS cases ( n = 7588). Results: HLA–DRB1*15:01 was strongly associated with POMS (odds ratio (OR) meta = 2.95, p < 2.0 × 10 −16 ). Furthermore, 28 of 104 non-MHC variants studied (23%) were associated ( p < 0.05); POMS cases carried, on average, a higher burden of these 28 variants compared to adults (OR avg = 1.24 vs 1.13, respectively), though the difference was not significant. The wGRS was strongly associated with POMS (OR meta = 2.77, 95% confidence interval: 2.33, 3.32, p < 2.0 × 10 −16 ) and higher, on average, when compared to adult cases. Additional class III risk variants in the MHC region associated with POMS were revealed after accounting for HLA–DRB1*15:01 and HLA–A*02. Conclusion: Pediatric and adult MS share many genetic variants suggesting similar biological processes are present. MHC variants beyond HLA–DRB1*15:01 and HLA–A*02 are also associated with POMS.

AbstractPurposeTo determine the relationship between the number of missing natural teeth or remaining natural teeth and osteoporotic hip fracture in elderly patients and to determine the relationship between the number of missing teeth or remaining teeth and osteoporotic fracture risk assessment (FRAX) probability.Materials and MethodsNumber of missing teeth was determined by clinical oral exam on a total of 100 subjects, 50 with hip fractures and 50 without. Ten‐year fracture risk and hip fracture risk probabilities were calculated using the FRAX tool. Statistical analyses were performed to determine strength of associations between number of missing natural teeth and likelihood of experiencing a fracture. Degree of correlation between number of missing natural teeth and FRAX probabilities were calculated.ResultsThere appears to be an association between the number of missing natural teeth and hip fractures. For every 5‐tooth increase in the number of missing teeth, the likelihood of being a subject in the hip fracture group increased by 26%. Number of missing natural teeth was positively correlated with FRAX overall fracture and hip fracture probability.ConclusionsNumber of missing natural teeth may be a valuable tool to assist members of medical and dental teams in identifying patients with higher FRAX scores and higher likelihood of experiencing a hip fracture. Additional research is necessary to validate these findings.

Objective The aim of this study was to compare outcomes of vaginal hysterectomy between patients with and without the following perceived contraindications to vaginal surgery: uterine weight greater than 280 g, prior cesarean delivery, no vaginal parity, and obesity. Methods Retrospective cohort of benign vaginal hysterectomies between 2009 and 2013 was obtained. Outcomes included uterine debulking, transfusion, intraoperative complications, length of stay, and Accordion grade 2+ postoperative complications. For each outcome, the association between the presence of each contraindication and the outcome was evaluated using univariate and multivariate logistic regression models. Results Among 692 vaginal hysterectomies, 11% (76/691) had a uterine weight greater than 280 g, 11.3% (78/690) had no vaginal parity, 14.9% (103/690) had a history of cesarean delivery, and 37.7% (248/657) had a body mass index of 30 kg/m2 or greater; 110 (15.9%) had 2 or more contraindications. Uterine debulking occurred in 146 women (21.1%), and both uterine weight greater 280 g (adjusted odds ratio, 39.2; 95% confidence interval, 18.4–83.5) and prior cesarean delivery (adjusted odds ratio, 2.1; 95% confidence interval, 1.2–3.7) were significantly associated with an increased likelihood of uterine debulking after adjusting for age, hematologic disease, and preoperative diagnosis. None of the contraindications were significantly associated with need for a blood transfusion, presence of an intraoperative complication, length of stay greater than 2 days, or presence of an Accordion grade 2+ postoperative complication, which occurred in 2.7%, 2.5%, 14.0%, and 6.9% of all women, respectively. Conclusions Vaginal hysterectomy can be safely performed with favorable outcomes, even in women with a uterus greater than 280 g, prior cesarean delivery, no vaginal parity, and obesity. Our findings challenge several perceived contraindications to vaginal hysterectomy.

Polymorphisms in the promoter of the BRM gene, a critical subunit of the chromatin remodeling SWI/SNF complex, have previously been implicated in risk and prognosis in Caucasian‐predominant lung, head and neck, esophageal, and pancreatic cancers, and in hepatocellular cancers in Asians. We investigated the role of these polymorphisms in hepatocellular carcinoma (HCC) risk and prognosis. HCC cases were recruited in a comprehensive cancer center while the matched controls were recruited from family practice units from the same catchment area. For risk analyses, unconditional logistic regression analyses were performed in HCC patients and matched healthy controls. Overall survival analyses were performed using Cox proportional hazard models, Kaplan‐Meier curves, and log‐rank tests. In 266 HCC cases and 536 controls, no association between either BRM promoter polymorphism (BRM‐741 or BRM‐1321) and risk of HCC was identified (P > 0.10 for all comparisons). There was significant worsening of overall survival as the number of variant alleles increased: BRM‐741 per variant allele adjusted hazards ratio (aHR) 5.77, 95% confidence interval (CI) 2.89‐11.54 and BRM‐1321 per variant allele aHR 4.09, 95%CI 2.22‐7.51. The effects of these two polymorphisms were at least additive, where individuals who were double homozygotes for the variant alleles had a 45‐fold increase in risk of death when compared to those who were double wild‐type for the two polymorphisms. Two BRM promoter polymorphisms were strongly associated with HCC prognosis but were not associated with increased HCC susceptibility. The association was strongest in double homozygotes for the allele variants.