Citations

119 Background: Radiotherapy (RT) interruptions have a negative impact on outcomes in many epithelial malignancies treated with definitive RT. The purpose of this study was to analyze the impact of RT duration on outcomes in patients (pts) with esophageal cancer treated with definitive chemoradiotherapy (CRT). Methods: Pts treated with definitive CRT on RTOG trials 8501 and 9405 were included. Separate analyses were performed in pts receiving standard dose (SD-CRT; 50 Gy + 5FU + cisplatin) and high dose (HD-CRT; 64.8 Gy + 5FU + cisplatin) CRT. Local (LF) and regional (RF) failure were estimated by the cumulative incidence method. Disease-free (DFS) and overall (OS) survival were estimated by the Kaplan-Meier method. Univariate (UVA) and multivariate (MVA) Cox proportional hazards models were utilized to examine for correlation between RT duration (< vs. ≥ median) with LF, RF, DFS and OS. Results: In the SD-CRT cohort (n=235), 96 pts (41%) had ≥ 1 RT interruption for a median of 3 (IQR 1-6) days. The median RT duration was 39 (IQR 37-43) days. In UVA and MVA, RT duration was not associated with LF, RF, DFS, or OS. Estimated outcome rates are in the table. In the HD-CRT cohort (n=107), 64 pts (60%) had ≥ 1 RT interruption for a median of 3.5 (IQR 2-7.5) days. The median RT duration was 52 (IQR 50-57) days. In UVA, RT duration ≥ 52 days was associated with a 33% reduction in risk of DFS failure (HR=0.66, 95% CI [0.44-0.98], p=0.039) and a 29% reduction in risk of death (HR=0.71, 95% CI [0.48-1.06], p=0.09). When excluding the 25 pts with RT dose < 64.8 Gy, RT duration was not associated with DFS or OS. Conclusions: In pts with esophageal cancer receiving definitive SD-CRT, an association between RT duration and outcomes was not observed. In pts receiving HD-CRT, longer RT duration was associated with improved DFS, which may have been due to a significant number of deaths at RT dose < 64.8 Gy. Supported by NCI U10 grants CA21661, CA180868, CA180822, CA37422. Clinical trial information: NCT00002631. [Table: see text]

Context: Fewer athletic injuries and lower anterior cruciate ligament injury incidence rates were noted in studies of neuromuscular-training (NMT) interventions that had high compliance rates. However, several groups have demonstrated that preventive NMT interventions were limited by low compliance rates. Objective: To descriptively analyze coach and athlete compliance with preventive NMT and compare the compliance between study arms as well as among school levels and sports. Design: Randomized, controlled clinical trial. Setting: Middle and high school athletic programs. Participants or Other Participants: A total of 52 teams, comprising 547 female athletes, were randomly assigned to the experimental or control group and followed for 1 athletic season. Intervention(s): The experimental group (n = 30 teams [301 athletes]: 12 basketball teams [125 athletes], 6 soccer teams [74 athletes], and 12 volleyball teams [102 athletes]) participated in an NMT program aimed at reducing traumatic knee injuries through a trunk-stabilization and hip-strengthening program. The control group (n = 22 teams [246 athletes]: 11 basketball teams [116 athletes], 5 soccer teams [68 athletes], and 6 volleyball teams [62 athletes]) performed a resistive rubber-band running program. Main Outcome Measure(s): Compliance with the assigned intervention protocols (3 times per week during the preseason [mean = 3.4 weeks] and 2 times per week in-season [mean = 11.9 weeks] of coaches [coach compliance] and athletes [athlete compliance]) was measured descriptively. Using an independent t test, we compared coach and athlete compliance between the study arms. A 2-way analysis of variance was calculated to compare differences between coach and athlete compliance by school level (middle and high schools) and sport (basketball, soccer, and volleyball). Results: The protocols were completed at a mean rate of 1.3 ± 1.1 times per week during the preseason and 1.2 ± 0.5 times per week in-season. A total of 88.4% of athletes completed 2/3 of the intervention sessions. Coach compliance was greater in the experimental group than in the control group (P = .014). Coach compliance did not differ by sport but was greater at the high school than the middle school (P = .001) level. Athlete compliance did not differ by study arm, sport, or school level. Conclusions: Athletes received instruction in about 50% of each protocol. Nearly 90% of athletes performed more than 2/3 of the assigned NMT interventions. The assigned intervention was performed more often in the experimental arm compared with the control arm. Coaches at the high school level complied with the given protocol more than middle school coaches did. Athletes complied well with the protocol, but coaches did not, especially at the middle school level.

The legacy of human-Neandertal interbreeding Non-African humans are estimated to have inherited on average 1.5 to 4% of their genomes from Neandertals. However, how this genetic legacy affects human traits is unknown. Simonti et al. combined genotyping data with electronic health records. Individual Neandertal alleles were correlated with clinically relevant phenotypes in individuals of European descent. These archaic genetic variants were associated with medical conditions affecting the skin, the blood, and the risk of depression. Science , this issue p. 737

Genetic variation can affect drug response in multiple ways, although it remains unclear how rare genetic variants affect drug response. The electronic Medical Records and Genomics (eMERGE) Network, collaborating with the Pharmacogenomics Research Network, began eMERGE‐PGx, a targeted sequencing study to assess genetic variation in 82 pharmacogenes critical for implementation of “precision medicine.” The February 2015 eMERGE‐PGx data release includes sequence‐derived data from ∼5,000 clinical subjects. We present the variant frequency spectrum categorized by variant type, ancestry, and predicted function. We found 95.12% of genes have variants with a scaled Combined Annotation‐Dependent Depletion score above 20, and 96.19% of all samples had one or more Clinical Pharmacogenetics Implementation Consortium Level A actionable variants. These data highlight the distribution and scope of genetic variation in relevant pharmacogenes, identifying challenges associated with implementing clinical sequencing for drug treatment at a broader level, underscoring the importance for multifaceted research in the execution of precision medicine.

Many basic, mechanistic studies of how sex steroids alter vascular function proceeded from Dr. Bush's seminal epidemiologic observations that noncontraceptive use of estrogen reduced all-cause and cardiovascular mortality. However, translating findings from these basic science studies into clinical trials and clinical guidelines has been controversial. This commentary reviews the development of sex steroid vascular research, identifies mechanisms by which sex steroids affect vascular function, reviews findings from recent clinical hormone trials, and identifies challenges and the need for continued funding of such investigations.

Objective Genome-wide association studies have identified a large number of single nucleotide polymorphisms (SNPs) associated with a wide array of cancer sites. Several of these variants demonstrate associations with multiple cancers, suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesised that SNPs previously associated with other cancers may additionally be associated with colorectal cancer. In a large-scale study, we examined 171 SNPs previously associated with 18 different cancers for their associations with colorectal cancer. Design We examined 13 338 colorectal cancer cases and 40 967 controls from three consortia: Population Architecture using Genomics and Epidemiology (PAGE), Genetic Epidemiology of Colorectal Cancer (GECCO), and the Colon Cancer Family Registry (CCFR). Study-specific logistic regression results, adjusted for age, sex, principal components of genetic ancestry, and/or study specific factors (as relevant) were combined using fixed-effect meta-analyses to evaluate the association between each SNP and colorectal cancer risk. A Bonferroni-corrected p value of 2.92×10 −4 was used to determine statistical significance of the associations. Results Two correlated SNPs—rs10090154 and rs4242382—in Region 1 of chromosome 8q24, a prostate cancer susceptibility region, demonstrated statistically significant associations with colorectal cancer risk. The most significant association was observed with rs4242382 (meta-analysis OR=1.12; 95% CI 1.07 to 1.18; p=1.74×10 −5 ), which also demonstrated similar associations across racial/ethnic populations and anatomical sub-sites. Conclusions This is the first study to clearly demonstrate Region 1 of chromosome 8q24 as a susceptibility locus for colorectal cancer; thus, adding colorectal cancer to the list of cancer sites linked to this particular multicancer risk region at 8q24.