Citations

AbstractBackgroundCholelithiasis is a frequent complication in pediatric sickle cell disease (SCD). Though it is standard practice to perform a cholecystectomy in pediatric SCD patients with symptoms of cholelithiasis, the use of elective cholecystectomy for asymptomatic patients remains controversial.ProcedureRecords of 191 pediatric sickle cell patients with cholelithiasis who underwent cholecystectomy were retrospectively reviewed. Patients classified as follows: (i) elective—no preoperative symptoms, cholelithiasis on screening ultrasound, comprehensive preoperative plan; (ii) symptomatic—preoperative symptoms of cholelithiasis on diagnostic ultrasound, comprehensive preoperative plan; or (iii) emergent—hospitalization for acute cholecystitis symptoms, cholelithiasis on diagnostic ultrasound, limited preoperative preparation. We compared the morbidity of cholecystectomy by examining pre‐ and post‐cholecystectomy hospital admission days, length of stay for cholecystectomy, and surgical complications.ResultsPatients with SCD underwent a total of 191 cholecystectomies over a 10‐year period: 51 elective, 110 symptomatic, and 30 emergent. Patients who required emergent cholecystectomy had a longer postoperative hospitalization time than elective or symptomatic cholecystectomy (7.3 vs 4.3, P < 0.001). Baseline values for total bilirubin and aspartate aminotransferase (AST) were significantly elevated (P < 0.02 and P < 0.07, respectively) in patients requiring emergent cholecystectomy.ConclusionsThis represents the largest reported retrospective review of pediatric cholelithiasis and cholecystectomy in SCD to date. These data strongly suggest that elective cholecystectomy decreases morbidity associated with emergent cholecystectomy. The overall outcomes for symptomatic and elective patients are favorable. However, our study indicates the need for prospective studies to identify clinical indicators for those emergent patients.

The newest iteration of the Diagnostic and Statistical Manual–fifth edition (DSM-5), is the first to include the diagnosis of disruptive mood dysregulation disorder (DMDD). The assessment and diagnosis of psychopathology in children are complicated, particularly for mood disorders. Practice can be guided by the use of well-validated instruments. However, as this is a new diagnosis existing instruments have not yet been evaluated for the diagnosis of DMDD. This study seeks to provide a method for using existing structured interview instruments to assess for this contemporary diagnosis. The Children’s Interview for Psychiatric Syndromes (ChIPS) and the Mini-International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) are reviewed and existing items consistent with a diagnosis of DMDD are identified. Finally, a case is presented using both measures and applying the theoretical items identified to illustrate how one might use these measures to assess DMDD. Limitations and future directions are discussed.

Abstract Nontuberculous mycobacteria (NTM) cause an increasingly important chronic and debilitating lung disease in older adults. Diagnosis is often delayed, although awareness among clinicians and patients is increasing. When necessary, treatment often lasts 18–24 months and consists of three or four antibiotics that can have serious side effects. Relapses are common and commonly require resumption of prolonged therapy. Given the need for improved diagnostic techniques and clinical trials to identify new therapies or to improve existing therapies, a group of North American clinicians and researchers formed the NTM Research Consortium (NTMRC) in 2014. The NTMRC recognized the importance of including the patient voice in determining research priorities for NTM. In November 2015, patients, caregivers, patient advocates, clinical experts, and researchers gathered for a 1-day meeting in Portland, Oregon funded by the Patient-Centered Outcomes Research Institute. The meeting goal was to define patient-centered research priorities for NTM lung infections. Patients expressed frustration with the number of people who have endured years of missed diagnoses or inadequate treatment of NTM. Participants identified as top research priorities the prevention of NTM infection; approval of more effective treatments with fewer side effects and easier administration; understanding the best chest physiotherapy methods; validating and using tools to measure quality of life; and developing a disease-specific activity and severity assessment tool. Workshop participants agreed that two complementary objectives are critical to ensure the best achievable outcomes for patients: (1) additional clinician education to improve screening and diagnosis of NTM infections; and (2) development of a geographically distributed network of experts in NTM disease to offer consultation or direct therapy after a diagnosis is made.

Abstract Background: The gut metabolome may be associated with the incidence and progression of numerous diseases. The composition of the gut metabolome can be captured by measuring metabolite levels in the feces. However, there are little data describing the effect of fecal sample collection methods on metabolomic measures. Methods: We collected fecal samples from 18 volunteers using four methods: no solution, 95% ethanol, fecal occult blood test (FOBT) cards, and fecal immunochemical test (FIT). One set of samples was frozen after collection (day 0), and for 95% ethanol, FOBT, and FIT, a second set was frozen after 96 hours at room temperature. We evaluated (i) technical reproducibility within sample replicates, (ii) stability after 96 hours at room temperature for 95% ethanol, FOBT, and FIT, and (iii) concordance of metabolite measures with the putative “gold standard,” day 0 samples without solution. Results: Intraclass correlation coefficients (ICC) estimating technical reproducibility were high for replicate samples for each collection method. ICCs estimating stability at room temperature were high for 95% ethanol and FOBT (median ICC &gt; 0.87) but not FIT (median ICC = 0.52). Similarly, Spearman correlation coefficients (rs) estimating metabolite concordance with the “gold standard” were higher for 95% ethanol (median rs = 0.82) and FOBT (median rs = 0.70) than for FIT (median rs = 0.40). Conclusions: Metabolomic measurements appear reproducible and stable in fecal samples collected with 95% ethanol or FOBT. Concordance with the “gold standard” is highest with 95% ethanol and acceptable with FOBT. Impact: Future epidemiologic studies should collect feces using 95% ethanol or FOBT if interested in studying fecal metabolomics. Cancer Epidemiol Biomarkers Prev; 25(11); 1483–90. ©2016 AACR.

Background: Knee laxity in the setting of suspected anterior cruciate ligament (ACL) injury is frequently assessed through physical examination using the Lachman, pivot-shift, and anterior drawer tests. The degree of laxity noted on these examinations may influence treatment decisions and prognosis. Hypothesis: Increased preoperative knee laxity would be associated with increased risk of subsequent revision ACL reconstruction and worse patient-reported outcomes 2 years postoperatively. Study Design: Cohort study; Level of evidence, 2. Methods: From an ongoing prospective cohort study, 2333 patients who underwent primary isolated ACL reconstruction without collateral or posterior cruciate ligament injury were identified. Patients reported by the operating surgeons as having an International Knee Documentation Committee (IKDC) grade D for Lachman, anterior drawer, or pivot-shift examination were classified as having high-grade laxity. Multiple logistic regression modeling was used to evaluate whether having high-grade preoperative laxity was associated with increased odds of undergoing revision ACL reconstruction within 2 years of the index procedure, controlling for patient age, sex, Marx activity level, level of competition, and graft type. Multiple linear regression modeling was used to evaluate whether having high-grade preoperative laxity was associated with worse IKDC score or Knee injury and Osteoarthritis Outcome Score Knee-Related Quality of Life subscale (KOOS-QOL) scores at a minimum 2 years postoperatively, controlling for baseline score, patient age, ethnicity, sex, body mass index, marital status, smoking status, sport participation, competition level, Marx activity rating score, graft type, and articular cartilage and meniscus status. Results: Pre-reconstruction laxity data were available for 2325 patients (99.7%). Two-year revision data were available for 2259 patients (96.8%), and patient-reported outcomes were available for 1979 patients (84.8%). High-grade preoperative laxity was noted in 743 patients (31.9%). The mean postoperative IKDC score was 81.8 ± 15.9, and the mean KOOS-QOL score was 72.0 ± 22.0. The presence of high-grade pre-reconstruction laxity was associated with significantly increased odds of ACL graft revision (odds ratio [OR] = 1.87 [95% CI, 1.19-2.95]; P = .007). The presence of high-grade pre-reconstruction laxity was not associated with any difference in postoperative IKDC (β = −0.56, P = .44) or KOOS-QOL (β = 0.04, P = .97). Conclusion: The presence of high-grade pre-reconstruction knee laxity as assessed by manual physical examination under anesthesia is associated with significantly increased odds of revision ACL surgery but has no association with patient-reported outcome scores at 2 years after ACL reconstruction.

Telomeres cap chromosome ends, protecting them from degradation, double‐strand breaks, and end‐to‐end fusions. Telomeres are maintained by telomerase, a reverse transcriptase encoded by TERT, and an RNA template encoded by TERC. Loci in the TERT and adjoining CLPTM1L region are associated with risk of multiple cancers. We therefore investigated associations between variants in 22 telomere structure and maintenance gene regions and colorectal, breast, prostate, ovarian, and lung cancer risk. We performed subset‐based meta‐analyses of 204,993 directly‐measured and imputed SNPs among 61,851 cancer cases and 74,457 controls of European descent. Independent associations for SNP minor alleles were identified using sequential conditional analysis (with gene‐level p value cutoffs ≤3.08 × 10−5). Of the thirteen independent SNPs observed to be associated with cancer risk, novel findings were observed for seven loci. Across the DCLRE1B region, rs974494 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Across the TERC region, rs75316749 was positively associated with colorectal, breast, ovarian, and lung cancers. Across the DCLRE1B region, rs974404 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Near POT1, rs116895242 was inversely associated with colorectal, ovarian, and lung cancers, and RTEL1 rs34978822 was inversely associated with prostate and lung cancers. The complex association patterns in telomere‐related genes across cancer types may provide insight into mechanisms through which telomere dysfunction in different tissues influences cancer risk.

Abstract Breast cancer is the most common type of cancer, and has a strong heritable component, with approximately 15 percent of new cases having family history of breast cancer. Genetic panel testing for patients with a family history of breast cancer has become a popular clinical resource. However, the risk of breast cancer associated with inactivating mutations in the predisposition genes is largely undefined, creating critical limitations in the interpretations of the results from panel testing and subsequent medical management. The Cancer Risk Estimates Related to Susceptibility Genes (CARRIERS) consortium was established to determine the risk of cancers associated with truncating mutations in the known predisposition genes and to extend these studies to the clinical classification of variants of uncertain significance (VUS) in the relevant genes. CARRIERS involves screening of approximately 30,000 population-based breast cancer cases and 30,000 study matched controls for mutations in 28 established or proposed breast cancer predisposition genes. Population-based risks for breast cancer associated with mutations in each gene will be estimated. In parallel, 10,000 breast cancer cases from moderate and high-risk breast cancer families will be similarly screened for mutations and the penetrance of the mutations in high-risk families will be estimated. Furthermore, VUS identified by mutation screening will be characterized by functional and family-based studies and models for classification of the clinical relevance of VUS in each gene will be developed. These data are expected to lead to improvements in cancer risk assessment and improved management of patients found to carry mutations or VUS in breast cancer predisposition. Citation Format: Jenna Lilyquist, Peter Kraft, Steven N. Hart, Emily J. Hallberg, Chunling Hu, Raymond Moore, Rohan Gnanaolivu, Susan M. Domchek, Jeffrey N. Weitzel, Katherine L. Nathanson, David E. Goldgar, Fergus J. Couch. The CARRIERS consortium: Establishing refined breast cancer risk estimates in known predisposition genes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 810.

Abstract Pancreatic adenocarcinoma generally presents with a poor prognosis and an extremely low response rate to first line therapies. There is a critical unmet need to discover and implement effective diagnostic panels to stratify outcomes and tailor treatment strategies to improve survival. The BERG Interrogative Biology® platform utilizes Artificial Intelligence to analyze and integrate multi-omic profiles with clinical annotation to define novel biomarkers and improve treatment interventions. Herein, we analyzed the serum proteome, signaling lipidome, structural lipidome, and metabolome of 163patients at multiple timepoints (pancreatic cancer: 115; pancreatitis: 15; and age-matched healthy controls: 33). Utilizing the power of the Bayesian Network learner, bAIcis™ (BERG Artificial Intelligence Clinical Information System), multi-omic profiles were aligned to the longitudinal clinical information and subjected to AI-algorithms to infer probabilistic cause-and-effect relationships among molecular and clinical variables explicitly explaining pancreatic cancer status, cancer progression, and survival, and defining the interconnectivity of molecular features with clinical phenotype. Network features linking into clinical endpoints and key network pressure points were identified as molecular drivers. The drivers of clinical endpoints were analyzed to rank potential biomarkers. Novel biomarkers were discovered that demonstrate diagnostic potential for pancreatic cancer detection, disease prognosis including metastatic disease progression, patient stratification associated with survival, and response to standard chemotherapy agents like Gemcitibine. A prospective study is underway to validate the biomarkers and discover additional diagnostic and therapeutic molecules to improve the outcomes for patients affected by adenocarcinoma of the pancreas. Citation Format: Niven R. Narain, A James Moser, Ramesh Ramanathan, John Crowley, Amy Stoll-D’Astice, Yezhou Sun, Leonardo O. Rodrigues, Eric M. Grund, Emily Chen, Vivek K. Vishnudas, Michael A. Kiebish, Viatcheslav R. Akmaev, Rangaprasad Sarangarajan. Project Survival: Interrogative Biology® platform mediated discovery of molecular markers for detection, stratification and outcomes in pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 786.