Citations

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.

Objectives Pancreatic ductal adenocarcinoma (PDAC) is often accompanied by weight loss. We sought to characterize factors associated with weight loss and observed nutritional interventions, as well as define the effect of weight loss on survival. Methods Consecutive subjects diagnosed with PDAC (N = 123) were retrospectively evaluated. Univariate analysis was used to compare subjects with and without substantial (>5%) weight loss. Multivariate logistic regression was performed to identify factors associated with weight loss, and survival analyses were performed using Kaplan-Meier curves and Cox survival models. Results Substantial weight loss at diagnosis was present in 71.5% of subjects and was independently associated with higher baseline body mass index, longer symptom duration, and increased tumor size. Recommendations for nutrition consultation and pancreatic enzyme replacement therapy occurred in 27.6% and 36.9% of subjects, respectively. Weight loss (>5%) was not associated with worse survival on multivariate analysis (hazard ratio, 1.32; 95% confidence interval, 0.76–2.30), unless a higher threshold (>10%) was used (hazard ratio, 1.77; 95% confidence interval, 1.09–2.87). Conclusions Despite the high prevalence of weight loss at PDAC diagnosis, there are low observed rates of nutritional interventions. Weight loss based on current criteria for cancer cachexia is not associated with poor survival in PDAC.

Individualized medicine enables better diagnoses and treatment decisions for patients and promotes research in understanding the molecular underpinnings of disease. Linking individual patient’s genomic and molecular information with their clinical phenotypes is crucial to these efforts. To address this need, the Center for Individualized Medicine at Mayo Clinic has implemented a genomic data warehouse and a workflow management system to bring data from institutional electronic health records and genomic sequencing data from both clinical and research bioinformatics sources into the warehouse. The system is the foundation for Mayo Clinic to build a suite of tools and interfaces to support various clinical and research use cases. The genomic data warehouse is positioned to play a key role in enhancing the research capabilities and advancing individualized patient care at Mayo Clinic.

Abstract A better understanding of gene-specific risks for development of breast cancer will lead to improved screening, prevention, and therapeutic strategies for individuals identified to carry germline mutations. We performed targeted massively-parallel sequencing to identify mutations and large genomic rearrangements in 26 known or proposed breast cancer susceptibility genes in 2134 BRCA-negative women with familial breast cancer (FBC). A case-control analysis was performed comparing the frequency of internally classified mutations identified in FBC cases to that in non-Finnish European controls from the Exome Aggregation Consortium (ExAC) excluding samples from The Cancer Genome Atlas. Including large genomic rearrangements, mutations were identified in 8.2% of FBC cases compared to 6.2% of ExAC controls, including mutations in high-penetrance genes (0.6% in cases vs. 0.1% in controls), moderate-penetrance genes (3.7% vs 1.7%), and seven cases with two mutations (0.3%). The remainder of FBC cases and ExAC controls had mutations in proposed breast cancer genes (1.6% of cases vs 2.4% of controls), Lynch syndrome genes (0.5% vs. 0.5%) or were heterozygous MUTYH carriers (1.5% vs. 1.5%). Case-control analysis demonstrated significant associations with FBC for ATM, PALB2, and TP53 mutations (OR&gt;3.0, p&lt;10-4), BARD1 mutations (OR=3.2, p=0.012), and CHEK2 truncating mutations (OR=1.6, p=0.041). Our results therefore demonstrate that only approximately 4% of BRCA1/2 negative FBC patients have mutations in genes definitively associated with breast cancer at this time. Large case-control studies are needed to fully evaluate the breast cancer risks associated with moderate penetrance and proposed breast cancer susceptibility genes. Citation Format: Kara N. Maxwell, Thomas Paul Slavin, Jenna M. Lilyquist, Joseph Vijai, Susan L. Neuhausen, Steven N. Hart, Vignesh Ravichandran, Tinu Thomas, Ann Maria, Kasmintan A. Schrader, Raymond Moore, Chunling Hu, Brad Wubbenhorst, Brandon M. Wenz, Kurt D'Andrea, Susan M. Domchek, Mark E. Robson, Paulo Peterlongo, Paolo Radice, James M. Ford, Judy E. Garber, Csilla Szabo, Kenneth Offit, Katherine L. Nathanson, Fergus J. Couch, Jeffrey N. Weitzel. Risks of familial breast cancer associated with known and proposed breast cancer susceptibility genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4265. doi:10.1158/1538-7445.AM2017-4265

Abstract Germline pathogenic variants in BRCA1 and BRCA2 account for 10% of ovarian cancer (OC), including ovarian, fallopian tube, and primary peritoneal carcinomas. Pathogenic variants in BRIP1, RAD51C, RAD51D, and other cancer predisposition genes have been observed in another 2% to 5% of OCs. However, the specific genes associated with OC and estimates of risk associated with pathogenic variants in the individual genes are not well defined. We sought to determine the relevance of multigene panel testing results for OC cases. The study was focused on 140,449 individuals, including 10,233 OC cases, receiving clinical panel testing of cancer predisposition genes. Standardized relative risks (SRR) for pathogenic variants in 18 cancer predisposition genes were estimated using reference controls from the Exome Aggregation Consortium (ExAC). The median (range) age at diagnosis of OC was 57 (21-90) years. OC cases were 76.2% Caucasian, 3.6% African American, 4.6% Asian, 4.7% Hispanic, and 10.9% unknown/other. Among the 10,233 OC cases, 1391 (13.6%) had pathogenic mutations, including 1032 pathogenic mutations among the 7793 Caucasian OC cases (13.2%). Using the non-Finnish European ExAC (excluding TCGA samples) reference controls, the allele frequency for all pathogenic variants in each gene was summed and compared to the frequency of mutations in the Caucasian OC cases. Pathogenic variants in the known OC predisposition genes: BRCA1, BRCA2, BRIP1, MSH2, MSH6, RAD51C, and RAD51D were associated with a high risk of OC (SRR&gt;4.0). Additionally, significant associations were observed for pathogenic variants in suspected OC risk genes ATM and PALB2 (SRR=2.06 and 2.78, respectively). This study identified several genes routinely screened on multigene panel testing that confer high or moderate risks of OC. Associations with known OC predisposition genes were confirmed. In addition, this study provides evidence that PALB2 is a moderate risk OC gene, and that ATM may confer lower to moderate risks of OC. If confirmed in future studies, these risks should be carefully considered in future screening and management of OC patients. In contrast, BARD1 and genes in the MRN complex were not associated with clinically relevant risks of OC. Citation Format: Jenna Lilyquist, Holly LaDuca, Eric Polley, Hermela Shimelis, Chunling Hu, Raymond Moore, Steven N. Hart, Fergus J. Couch, Jill Dolinsky, David E. Goldgar. Multigene panel testing and risk estimates in 10,233 ovarian cancer cases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1287. doi:10.1158/1538-7445.AM2017-1287

Background: The role of diet in multiple sclerosis (MS) is largely uncharacterized, particularly as it pertains to pediatric-onset disease. Objective: To determine the association between dietary factors and MS in children. Methods: Pediatric MS patients and controls were recruited from 16 US centers (MS or clinically isolated syndrome onset before age 18, <4 years from symptom onset and at least 2 silent lesions on magnetic resonance imaging). The validated Block Kids Food Screener questionnaire was administered 2011–2016. Chi-squared test compared categorical variables, Kruskal–Wallis test compared continuous variables, and multivariable logistic regression analysis was performed. Results: In total, 312 cases and 456 controls were included (mean ages 15.1 and 14.4 years). In unadjusted analyses, there was no difference in intake of fats, proteins, carbohydrates, sugars, fruits, or vegetables. Dietary iron was lower in cases ( p = 0.04), and cases were more likely to consume below recommended guidelines of iron (77.2% of cases vs 62.9% of controls, p < 0.001). In multivariable analysis, iron consumption below recommended guidelines was associated with MS (odds ratio = 1.80, p < 0.01). Conclusion: Pediatric MS cases may be less likely to consume sufficient iron compared to controls, and this warrants broader study to characterize a temporal relationship. No other significant difference in intake of most dietary factors was found.

AbstractObjectivesMultisource feedback (MSF) has potential value in learner assessment, but has not been broadly implemented nor studied in emergency medicine (EM). This study aimed to adapt existing MSF instruments for emergency department implementation, measure feasibility, and collect initial validity evidence to support score interpretation for learner assessment.MethodsResidents from eight U.S. EM residency programs completed a self‐assessment and were assessed by eight physicians, eight nonphysician colleagues, and 25 patients using unique instruments. Instruments included a five‐point rating scale to assess interpersonal and communication skills, professionalism, systems‐based practice, practice‐based learning and improvement, and patient care. MSF feasibility was measured by percentage of residents who collected the target number of instruments. To develop internal structure validity evidence, Cronbach's alpha was calculated as a measure of internal consistency.ResultsA total of 125 residents collected a mean of 7.0 physician assessments (n = 752), 6.7 nonphysician assessments (n = 775), and 17.8 patient assessments (n = 2,100) with respective response rates of 67.2, 75.2, and 77.5%. Cronbach's alpha values for physicians, nonphysicians, patients, and self were 0.97, 0.97, 0.96, and 0.96, respectively.ConclusionsThis study demonstrated that MSF implementation is feasible, although challenging. The tool and its scale demonstrated excellent internal consistency. EM educators may find the adaptation process and tools applicable to their learners.

Study Design: Retrospective cohort study of prospectively collected data. Objective: To examine the incidence of iatrogenic spinal cord injury following elective cervical spine surgery. Methods: A retrospective multicenter case series study involving 21 high-volume surgical centers from the AOSpine North America Clinical Research Network was conducted. Medical records for 17 625 patients who received cervical spine surgery (levels from C2 to C7) between January 1, 2005, and December 31, 2011, were reviewed to identify occurrence of iatrogenic spinal cord injury. Results: In total, 3 cases of iatrogenic spinal cord injury following cervical spine surgery were identified. Institutional incidence rates ranged from 0.0% to 0.24%. Of the 3 patients with quadriplegia, one underwent anterior-only surgery with 2-level cervical corpectomy, one underwent anterior surgery with corpectomy in addition to posterior surgery, and one underwent posterior decompression and fusion surgery alone. One patient had complete neurologic recovery, one partially recovered, and one did not recover motor function. Conclusion: Iatrogenic spinal cord injury following cervical spine surgery is a rare and devastating adverse event. No standard protocol exists that can guarantee prevention of this complication, and there is a lack of consensus regarding evaluation and treatment when it does occur. Emergent imaging with magnetic resonance imaging or computed tomography myelography to evaluate for compressive etiology or malpositioned instrumentation and avoidance of hypotension should be performed in cases of intraoperative and postoperative spinal cord injury.

Study Design: Retrospective multicenter case series study. Objective: Because cervical dural tears are rare, most surgeons have limited experience with this complication. A multicenter study was performed to better understand the presentation, treatment, and outcomes following cervical dural tears. Methods: Multiple surgeons from 23 institutions retrospectively identified 21 rare complications that occurred between 2005 and 2011, including unintentional cervical dural tears. Demographic data and surgical history were obtained. Clinical outcomes following surgery were assessed, and any reoperations were recorded. Neck Disability Index (NDI), modified Japanese Orthopaedic Association (mJOA), Nurick classification (NuC), and Short-Form 36 (SF36) scores were recorded at baseline and final follow-up at certain centers. All data were collected, collated, and analyzed by a private research organization. Results: There were 109 cases of cervical dural tears among 18 463 surgeries performed. In 101 cases (93%) there was no clinical sequelae following successful dural tear repair. There were statistical improvements ( P < .05) in mJOA and NuC scores, but not NDI or SF36 scores. No specific baseline or operative factors were found to be associated with the occurrence of dural tears. In most cases, no further postoperative treatments of the dural tear were required, while there were 13 patients (12%) that required subsequent treatment of cerebrospinal fluid drainage. Analysis of those requiring further treatments did not identify an optimum treatment strategy for cervical dural tears. Conclusions: In this multicenter study, we report our findings on the largest reported series (n = 109) of cervical dural tears. In a vast majority of cases, no subsequent interventions were required and no clinical sequelae were observed.

Study Design: A multicenter, retrospective case series. Objective: In the past several years, screw fixation of the cervical spine has become commonplace. For the most part, this is a safe, low-risk procedure. While rare, screw backout or misplaced screws can lead to morbidity and increased costs. We report our experiences with this uncommon complication. Methods: A multicenter, retrospective case series was undertaken at 23 institutions in the United States. Patients were included who underwent cervical spine surgery from January 1, 2005, to December 31, 2011, and had misplacement of screws requiring reoperation. Institutional review board approval was obtained at all participating institutions, and detailed records were sent to a central data center. Results: A total of 12 903 patients met the inclusion criteria and were analyzed. There were 11 instances of screw backout requiring reoperation, for an incidence of 0.085%. There were 7 posterior procedures. Importantly, there were no changes in the health-related quality-of-life metrics due to this complication. There were no new neurologic deficits; a patient most often presented with pain, and misplacement was diagnosed on plain X-ray or computed tomography scan. The most common location for screw backout was C6 (36%). Conclusions: This study represents the largest series to tabulate the incidence of misplacement of screws following cervical spine surgery, which led to revision procedures. The data suggest this is a rare event, despite the widespread use of cervical fixation. Patients suffering this complication can require revision, but do not usually suffer neurologic sequelae. These patients have increased cost of care. Meticulous technique and thorough knowledge of the relevant anatomy are the best means of preventing this complication.