Citations

Abstract Purpose: The burden of esophageal cancer continues to rise, and noninvasive screening tools are needed. Methylated DNA markers (MDM) assayed from plasma show promise in detection of other cancers. For esophageal cancer detection, we aimed to discover and validate MDMs in tissue, and determine their feasibility when assayed from plasma. Experimental Design: Whole-methylome sequencing was performed on DNA extracted from 37 tissues (28 EC; 9 normal esophagus) and 8 buffy coat samples. Top MDMs were validated by methylation specific PCR on tissue from 76 EC (41 adeno, 35 squamous cell) and 17 normal esophagus. Quantitative allele-specific real-time target and signal amplification was used to assay MDMs in plasma from 183 patients (85 EC, 98 controls). Recursive partitioning (rPART) identified MDM combinations predictive of esophageal cancer. Validation was performed in silico by bootstrapping. Results: From discovery, 23 candidate MDMs were selected for independent tissue validation; median area under the receiver operating curve (AUC) for individual MDMs was 0.93. Among 12 MDMs advanced to plasma testing, rPART modeling selected a 5 MDM panel (FER1L4, ZNF671, ST8SIA1, TBX15, ARHGEF4) which achieved an AUC of 0.93 (95% CI, 0.89–0.96) on best-fit and 0.81 (95% CI, 0.75–0.88) on cross-validation. At 91% specificity, the panel detected 74% of esophageal cancer overall, and 43%, 64%, 77%, and 92% of stages I, II, III, and IV, respectively. Discrimination was not affected by age, sex, smoking, or body mass index. Conclusions: Novel MDMs assayed from plasma detect esophageal cancer with moderate accuracy. Further optimization and clinical testing are warranted.

Background: National Collegiate Athletic Association (NCAA) football players are at a high risk of injuries. Elbow injuries are uncommon, but there are insufficient data specifically on elbow injuries sustained in NCAA football players. Purpose: To define the epidemiology of elbow injuries in NCAA football players during the 2009-2010 to 2013-2014 seasons using data from the NCAA Injury Surveillance Program (NCAA-ISP). Study Design: Descriptive epidemiology study. Methods: Using the NCAA-ISP database, a convenience sample of NCAA football athletes was reviewed to determine the types, rates, and trends in elbow injuries. Several factors were examined, including the diagnosis, injury setting, time lost from sport, surgical necessity, and injury recurrence. Raw injury data were obtained as well as weighted totals from the NCAA-ISP to generate national estimates and adjust for underreporting. Injury rates were calculated by dividing the number of injuries by the total number of athlete-exposures (AEs). The rate ratios of injuries during competition versus practice were compared, as were the rate ratios of preseason, regular-season, and postseason injuries by type. Results: We identified 4874 total elbow injuries from the 2009-2010 to 2013-2014 seasons. The rate of injuries overall was 1.892 per 10,000 AEs. The rate for competition was 9.053 per 10,000 AEs and 1.121 per 10,000 AEs for practice. The rate ratio between competition and practice was 8.08 (95% CI, 6.04-10.80). Injury rates for the preseason, regular season, and postseason were 1.851, 1.936, and 1.406 per 10,000 AEs, respectively. Acute elbow instability was the most common injury type (65.43%). The most common mechanism was a contact injury (86.77%); 96.82% of injuries did not require surgery, and most elbow injuries required less than 24 hours of participation restriction (67.33%). Conclusion: Although elbow injuries in NCAA football players are uncommon, it is important to recognize and treat these injuries appropriately. Dislocations and ulnar collateral ligament injuries caused athletes to miss extended periods of play. Fortunately, a majority of injuries resulted in less than 24 hours of participation restriction. Particular attention should be given to preventing elbow injuries, especially ulnar collateral ligament strains, hyperextension injuries, and acute instability.

Study Design. Descriptive epidemiology study. Objective. The purpose of this study was to describe the epidemiology of neck and cervical spine injuries in collegiate athletes over a 5-year period. Summary of Background Data. The incidence and etiology of neck and cervical spine injuries in National Collegiate Athletic Association (NCAA) athletes has not been well defined in recent years. Methods. The incidence and characteristics of neck and cervical spine injuries were identified utilizing the NCAA Injury Surveillance Program database. Rates of injury were calculated as the number of injuries divided by the total number of athlete-exposures (AEs). AEs were defined as any student participation in one NCAA-sanctioned practice or competition. Results. Nationally, there were an estimated 11,510 neck and cervical spine injuries over the 5-year period. These occurred at a rate of 7.05 per 100,000 athlete-exposures (AEs). The rate of neck and cervical spine injuries in men was 2.66 per 100,000 AEs, while women suffered injuries at a rate of 1.95 per 100,000 AEs. In sex-comparable sports, men were 1.36 times more likely to suffer a neck or cervical spine injury compared with women. Men's football (29.09 per 100,000 AEs) and women's field hockey (11.51 per 100,000 AEs) were the sports with the highest rates of injuries. These injuries were 3.94 times more likely to occur during competition compared with practice. In-season injury rates were the highest, at 8.18 per 100,000 AEs. Conclusion. The vast majority of neck and cervical spine injuries in NCAA athletes are minor and uncommon. Across all sports in both sexes, the majority of injuries were new, and occurred during in-season competitions. Most athletes returned to play within 24 hours of injury. These data can inform players, parents, coaches, athletic trainers, and physicians regarding the prevalence and rates of these injuries and potentially inform decision-making regarding injury prevention, treatment, and rehabilitation. Level of Evidence: 4

Background: Little research has focused on the rates and patterns of elbow injuries in National Collegiate Athletic Association (NCAA) student-athletes. Purpose: To describe the epidemiological patterns of elbow injuries in NCAA athletes during 5 seasons over the academic years 2009 through 2014 using the NCAA Injury Surveillance Program (NCAA-ISP) database. Study Design: Descriptive epidemiology study. Methods: A voluntary convenience sample of NCAA varsity teams from 11 sports was examined to determine the rates and patterns of elbow injuries. Rates and distributions of elbow injuries were identified within the context of sport, event type, time in season, mechanism, time lost from sport, surgical treatment, and injury type. Rates of injury were calculated as the number of injuries divided by the total number of athlete-exposures (AEs). An AE was defined as any student participation in 1 NCAA-sanctioned practice or competition with an inherent risk of exposure to potential injury. Injury rate ratios (IRRs) and injury proportion ratios (IPRs) were then calculated to compare the rates within and between sports by event type, season, sex, mechanism, surgical treatment, and time lost from sport. Comparisons between sexes were made using only sports data that had both male and female samples. Results: Overall, 373 elbow injuries were reported in the NCAA-ISP data set during the 2009-2010 through 2013-2014 academic years among 11 varsity sports. The overall rate of injury was 1.76 per 10,000 AEs. The rate of elbow injuries in men was 0.74 per 10,000 AEs, while women experienced injuries at a rate of 0.63 per 10,000 AEs. In sex-comparable sports, men were 1.17 times more likely to experience an elbow injury compared with women. Men’s wrestling (6.00/10,000 AEs) and women’s tennis (1.86/10,000 AEs) were the sports with the highest rates of elbow injuries by sex, respectively. The top 3 highest injury rates overall occurred in men’s wrestling, baseball, and tennis. Elbow injuries were 3.5 times more likely to occur during competition compared with practice. Athletes were 0.76 times less likely to sustain an elbow injury during the preseason compared with in-season. Contact events were the most common mechanism of injury (67%). For sex-comparable sports, men were 2.41 times more likely than women to have contact as their injury mechanism (95% CI, 0.78-7.38). The majority of athletes missed less than 24 hours of participation time (67%), and only a minority (3%) of patients with elbow injuries went on to have surgical intervention. Elbow ulnar collateral ligament injuries were most common (26% of total injuries). Conclusion: Analysis of the study data demonstrated a significant rate of elbow injuries, 1.76 injuries per 10,000 AEs in NCAA collegiate athletes. Higher injury rates can be expected in males within sex-comparable sports. Elbow injuries are most common in the setting of competitions and most commonly occur secondary to contact-type mechanisms. Injuries were more likely to occur during in-season play. The majority of injuries required less than 24 hours of time away from sport and did not require surgical intervention.

Abstract Background: Immune checkpoint inhibitors (ICPIs) have led to dramatic improvement in outcome of several cancers. Program death ligand1 (PD-L1) staining and tumor mutational burden (TMB) have emerged as independent predictive biomarkers of ICPIs in lung cancer. Here we examine the landscape of TMB and PD-L1 expression in breast cancer and present a case of patient with high TMB and PD-L1 negative breast cancer with exceptional response to ICPIs. Methods: Hybrid-capture based comprehensive genomic profiling of 395 cancer related genes using the FoundationOne assay was performed on 14,867 breast carcinomas sequenced in the course of routine clinical care. Ventana (SP-263) PD-L1 status (n=1425) and hormone receptor status was available for a subset of patients. Subgroup analyses were performed based on histological type [invasive lobular carcinoma (ILC, n=740)], molecular subtypes [ER-positive (ER+; n= 1371), HER2-amplified (HER2+; n=1522), and TNBC (n=917)], patient age (≤45, 46-60, ≥61), and local vs. metastatic disease (n=5241 and 6710). Results: Consistent with previous reports, the rates of positive PD-L1 staining are highest in TNBC (14%) and lowest in HER2+, ILC, and ER+ disease (6.0%, 5.1%, 2.3%). Interestingly, the rate of PD-L1 positivity, defined as ≥1% tumor staining, was significantly lower in metastatic disease vs. local disease (6.3% vs. 11.1%; p = 0.005). The frequency of high TMB, defined as >10 mutations/mb, was greatest in ILC and HER2+ disease (13.6% and 9.9%) and lowest in TNBC and ER+ disease (7.0% and 6.9%). Rates of high TMB were associated with increased patient age (3.7%, 9.3%, and 12.8% frequency in patients ≤45, 46-60, and ≥61) and were significantly higher in metastatic vs. local disease (11.1% vs 5.3%; p<2E-23). PD-L1 positive and TMB high populations were not significantly co-occurrent (OR = 1.02, p = 0.87). Similar percentages of PD-L1 positivity were observed in both TMB low (9.3%) and TMB high (9.5%). However, among patients with very high TMB (>20 mut/mb), there was a significant association between TMB and PD-L1 positivity (OR = 2.6, p = 0.023). Nevertheless, even with high cutoff, 79% of the TMB high samples were PD-L1 negative. We also report on a stage IIIb (T4, N2, M0) ER+ HER2- breast cancer patient with high TMB (40muts/mb) and negative PD-L1 IHC who previously progressed on aromatase inhibitor with CDK4/6 inhibitor and chemotherapy but achieved durable complete response of > 1 year with nivolumab in combination with capecitabine. Conclusions: Predictive biomarkers for ICPIs are critical to identify a subset of breast cancer patients who may respond to immunotherapy. TMB high and PD-L1 positivity do not significantly co-occur and the majority of TMB high cases were PD-L1 negative. Nevertheless, this group of patients may still benefit with ICPIs. Further studies are needed to evaluate this subset of patients. Citation Format: Ethan Sokol, Lee Albacker, Aixa Soyano, Ricardo Parrondo, Brenda Ernst, Emmanuel Gabriel, Garrett Frampton, Jeffrey Ross, Siraj Ali, Jon Chung, Saranya Chumsri. Incidence of high tumor mutation burden (TMB) and PD-L1 positivity in breast cancers and potential response to immune checkpoint inhibitors (ICPIs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4894.

Abstract Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in United States with a 5-year survival rate of only 8%. Inherited predisposition plays an important role in PDAC risk. Rare, moderately to highly penetrant mutations in hereditary cancer and pancreatitis genes, identified in families with a high incidence of disease, account for a small fraction of cases. At the other end of the spectrum, common risk variants of low penetrance have been discovered through genome-wide association studies (GWAS). Currently, over 20 common PDAC risk signals have been identified through GWAS in populations of European ancestry. However, these loci explain only a small fraction of genetic heritability for PDAC, and the causal genes for the large majority of these are unknown. Most susceptibility alleles discovered through GWAS are located in noncoding regions of the genome and are likely to function through allele specific regulation of gene expression. Transcriptome-wide association studies integrate expression quantitative trait loci (eQTL) with GWAS data to discover genes whose cis-regulated expression is associated with complex traits. To identify novel susceptibility loci and likely causal genes, we applied this approach to PDAC. Firstly, we used two reference datasets generated from histologically normal pancreatic tissue samples from individuals of European ancestry, the DCEG/LTG (n=95) and Genotype-Tissue Expression (GTEx v7, n=174), to build robust predictors for gene expression (n=2,872-5,906; r2>0.01), using 5 different models (Top1, Lasso, Enet, Blup and Bslmm) in FUSION and PrediXcan. Gene expression predictors (n=2,043-21,422) were also generated by Enet in 48 different tissues (n=74-421 samples) from 608 individuals of European ancestry (GTEx). We then applied these predictor models to PDAC GWAS summary statistics from 9,040 PC cases and 12,496 controls. We discovered 24 genes whose genetically predicted expression is significantly associated with PDAC risk (FDR < 0.05), including 13 candidate genes at 10 novel loci (CELA3B, SMC2, SMC2-AS1, RP11-80H5.9, SMUG1, BTBD6, RCCD1, PNMT, CDK12, PGAP3, SUPT4H1, RP11-888D10.3 and PGPEP1) and 11 at 5 known risk loci (TERT, CLPTM1L, ZDHHC11B, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, BCAR1 and TMEM170A). Pathway enrichment analysis for genes differentially expressed in the top vs. bottom quartile of CELA3B expression highlighted higher expression of inflammatory and immune response genes in both the DCEG/LTG and GTEx pancreatic transcriptome datasets, indicating that low expression of this gene may be associated with an inflammatory state in the pancreas. Our findings showcase the utility of integrating multiple datasets to generate hypotheses and provide novel clues for the genetic mechanisms underlying pancreatic cancer risk. Citation Format: Jun Zhong, Ashley Jermusyk, Lang Wu, Jason W. Hoskins, Irene Collins, Mingfeng Zhang, Song Lei, Charles C. Chung, Tongwu Zhang, Wenming Xiao, Rachael Stolzenberg-Solomon, Alison P. Klein, Brian M. Wolpin, Xiao-Ou Shu, Stephen J. Chanock, Sara Olson, Nilanjan Chatterjee, Jill Smith, Jianxin Shi, Peter Kraft, Gloria M. Petersen, Wei Zheng, Laufey T. Amundadottir. Large-scale transcriptome-wide association study (TWAS) identifies novel candidate susceptibility genes for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1591.