Citations

Abstract Background: Results from epidemiologic studies examining polyunsaturated fatty acids (PUFA) and colorectal cancer risk are inconsistent. Mendelian randomization may strengthen causal inference from observational studies. Given their shared metabolic pathway, examining the combined effects of aspirin/NSAID use with PUFAs could help elucidate an association between PUFAs and colorectal cancer risk. Methods: Information was leveraged from genome-wide association studies (GWAS) regarding PUFA-associated SNPs to create weighted genetic scores (wGS) representing genetically predicted circulating blood PUFAs for 11,016 non-Hispanic white colorectal cancer cases and 13,732 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations per SD increase in the wGS were estimated using unconditional logistic regression. Interactions between PUFA wGSs and aspirin/NSAID use on colorectal cancer risk were also examined. Results: Modest colorectal cancer risk reductions were observed per SD increase in circulating linoleic acid [ORLA = 0.96; 95% confidence interval (CI) = 0.93–0.98; P = 5.2 × 10−4] and α-linolenic acid (ORALA = 0.95; 95% CI = 0.92–0.97; P = 5.4 × 10−5), whereas modest increased risks were observed for arachidonic (ORAA = 1.06; 95% CI = 1.03–1.08; P = 3.3 × 10−5), eicosapentaenoic (OREPA = 1.04; 95% CI = 1.01–1.07; P = 2.5 × 10−3), and docosapentaenoic acids (ORDPA = 1.03; 95% CI = 1.01–1.06; P = 1.2 × 10−2). Each of these effects was stronger among aspirin/NSAID nonusers in the stratified analyses. Conclusions: Our study suggests that higher circulating shorter-chain PUFAs (i.e., LA and ALA) were associated with reduced colorectal cancer risk, whereas longer-chain PUFAs (i.e., AA, EPA, and DPA) were associated with an increased colorectal cancer risk. Impact: The interaction of PUFAs with aspirin/NSAID use indicates a shared colorectal cancer inflammatory pathway. Future research should continue to improve PUFA genetic instruments to elucidate the independent effects of PUFAs on colorectal cancer.

Background: Lateral epicondylitis, or tennis elbow, is a painful degenerative disorder that commonly occurs in adults between 40 and 60 years of age. Normal saline (NS) injections have been used as placebo through a large number of randomized controlled trials (RCTs) focused on the treatment of lateral epicondylitis. Purpose: This meta-analysis of RCTs aimed to assess the therapeutic effect of NS injections on lateral epicondylitis symptoms and compare results with established minimal clinically important difference criteria. Study Design: Systematic review and meta-analysis. Methods: MEDLINE, Embase, Web of Science, and Scopus databases were searched for clinical trials reporting pain and joint function with the visual analog scale, Patient-Rated Tennis Elbow Evaluation, and Disabilities of the Arm, Shoulder and Hand in patients with lateral epicondylitis. The meta-analysis was conducted with a random effects model and generic inverse variance method. Heterogeneity was tested with the I 2 statistic index. Results: A total of 15 RCTs included in this meta-analysis revealed a significant improvement in pain (mean difference, 3.61 cm [95% CI, 2.29-4.92 cm]; P < .00001; I 2 = 88%; visual analog scale) and function (mean difference, 25.65 [95% CI, 13.30-37.99]; P < .0001; I 2 = 82%; Patient-Rated Tennis Elbow Evaluation / Disabilities of the Arm, Shoulder and Hand) after NS injection (≥6 months). Conclusion: NS injections yielded a statistically significant and clinically meaningful improvement in pain and functional outcomes in patients with lateral epicondylitis. New research should focus on better methods to diminish the potential confounders that could lead to this effect because NS injections could mask the real effect of an active therapeutic intervention in RCT. Registration: CRD42019127547 (PROSPERO).

Juvenile-onset systemic lupus erythematosus (JSLE) presents with an aggressive course and high morbidity associated with disease and treatment. JSLE patients have a poorer health-related quality of life (HRQoL) when compared with age-matched patients with other rheumatologic disorders. We aim to summarize the impact of current pharmacological therapies on the HRQoL of JSLE patients. Search strategies were developed across seven databases. Randomized clinical trials (RCTs) and cohort studies comparing interventions to standard therapy, placebo or pre-post cohort comparisons for more than 4 weeks were included. The outcome included self-reported scales compared at baseline and a therapeutic time point. Risk of bias was evaluated by using the Cochrane risk of bias tool and the Newcastle–Ottawa quality assessment scale. A total of 2812 articles were narrowed down to 309 for full-text screening. Four RCTs and one prospective cohort study, with a total of 634 JSLE patients, met the inclusion criteria. Four of the studies had a controlled intervention plus standard therapy compared with standard therapy alone or placebo. Multiple indices were used to evaluate HRQoL. These included the Pediatric Quality of Life Inventory, Childhood Health Assessment Questionnaire, Simple Measure of Impact of Lupus Erythematosus in Youngsters tool, Kids Fatigue Severity Scale and Child Depression Inventory. A single study reported a significant improvement while remaining studies reported no difference or failed to report the statistical analysis. Although HRQoL is significantly impaired in JSLE, evidence regarding its improvement is limited due to the small number of eligible studies, heterogeneity in scales, and HRQoL domains. A universal HRQoL questionnaire for JSLE needs to be established and used in both the research and clinical setting. All studies should adhere to reporting guidelines.

580 Background: Though studies indicate that the genomic profiles of ICC and ECC are distinct, the clinical features that differentiate them still remain to be well characterized. The purpose of this study was to further analyze these differences and patient treatment patterns in a multi-center cohort. Methods: A retrospective chart review was performed at 8 institutions on patients (pts) with ICC or ECC diagnosed after June 2009. Data on demographics, risk factors, treatments, pathology and overall survival (OS) were collected. Tumor genotyping results from CLIA-certified tissue assays were analyzed. Fisher’s exact, Wilcoxon rank sum and log-rank tests were used to compare sub-groups. Results: In a database of 737 pts with cholangiocarcinoma, 538(73%) had ICC and 199(27%) had ECC. Pts with ICC more often presented in later stages, had tumors > 5cm at resection (p < 0.0001) and had metastases to the liver, lymph nodes, lung and/or bone (p < 0.01). Pts with ICC more often received liver directed therapy, targeted therapy and multiple lines of systemic therapy and they more often enrolled in a clinical trial (all p < 0.01). Pts with ECC were more likely to be male, undergo surgery, receive adjuvant chemotherapy and/or chemoradiation (all p < 0.05). Mutation profiling performed in 381 (52%) pts (ICC/ECC = 301/80) showed that pts with ICC were more likely to have IDH1 mutations and FGFR2 fusions, whereas pts with ECC were more likely to have KRAS, APC, SMAD4, WNT, TGFb and TP53 mutations (all < 0.05). Factors that did not differ significantly between pts with ICC and ECC include race, rates of primary sclerosing cholangitis, median diagnosis CA19-9 levels and R1 resection rate. Median OS from diagnosis was 18.9 months in ICC and 17.3 months in ECC (p = 0.8471). Conclusions: While pts with ICC and ECC have some similarities in their clinical features, differences in metastases patterns and molecular profiling significantly impact their management such that pts with ICC receive more liver-directed therapy, targeted therapy and more lines of systemic therapy. Further prospective studies are needed as referral patterns to tertiary care centers may have impacted these results.

Abstract Background : Sex is recognized as a significant determinant of outcome among glioblastoma patients, but the relative prognostic importance of glioblastoma features has not been thoroughly explored for sex differences. Methods : Combining multi-modal MR images, biomathematical models, and patient clinical information, this investigation assesses which pretreatment variables have a sex-specific impact on the survival of glioblastoma patients (299 males and 195 females). Results : Among males, tumor (T1Gd) radius was a predictor of overall survival (HR=1.027, p=0.044). Among females, higher tumor cell net invasion rate was a significant detriment to overall survival (HR=1.011, p<0.001). Female extreme survivors had significantly smaller tumors (T1Gd) (p=0.010 t-test), but tumor size was not correlated with female overall survival (p=0.955 CPH). Both male and female extreme survivors had significantly lower tumor cell net proliferation rates than other patients (M p=0.004, F p=0.001, t-test). Conclusion : Despite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes.

AbstractIntroduction Vestibular schwannomas (VS) are slow growing tumors. Although there are a wide variety of available treatment options, these tumors are often initially observed. We aimed to establish the presenting symptoms and outcomes of patients treated with initial observation at our institution.Methods The medical records of patients with radiographically diagnosed VS were reviewed from 1989 to 2018. Actuarial estimates of radiographic tumor control and freedom of local therapy were calculated and compared using Cox regression analyses.Results A total of 360 patients were diagnosed with VS at our institution from 1989 through 2018 with a median age of 59.9 years. After radiographic diagnosis, 243 patients (67.5%) opted for initial observation. Local control at 1, 5, and 10 years was 91, 67, and 58%, respectively. On multivariable analysis, factors associated with shorter time to radiographic tumor progression included younger patient age (p = 0.016) and tumors with an extracanalicular component (p = 0.032). Regarding time until definitive treatment only larger baseline American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) tumor size predicted for earlier initiation of therapy (p < 0.001), although this was restricted to tumors with an extracanalicular component (p = 0.004), as opposed to purely internal auditory canal tumors (p = 0.839).Conclusion Many patients who were initially observed continued to have satisfactory local control rates at 10 years. In patients with extracanalicular tumors, larger AAO-HNS tumor measurements were associated with earlier radiographic tumor progression and shorter time to local therapy, with 7 mm serving as a potential threshold value for extracanalicular tumors. Younger patients and tumors with primarily an extracanalicular portion may warrant closer observation.

Abstract Persons of African ancestry (AA) have a twofold higher risk for multiple myeloma (MM) compared with persons of European ancestry (EA). Genome-wide association studies (GWASs) support a genetic contribution to MM etiology in individuals of EA. Little is known about genetic risk factors for MM in individuals of AA. We performed a meta-analysis of 2 GWASs of MM in 1813 cases and 8871 controls and conducted an admixture mapping scan to identify risk alleles. We fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. In GWAS meta-analysis, we identified 2 suggestive novel loci located at 9p24.3 and 9p13.1 at P &lt; 1 × 10−6; however, no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. Of the 23 known EA risk variants, 20 showed directional consistency, and 9 replicated at P &lt; .05 in AA individuals. In 8 regions, we identified markers that better capture MM risk in persons with AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95% confidence interval, 1.56-2.11) increased MM risk compared with those with average risk (25%-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P = 5.1 × 10−12). Our study shows that common genetic variation contributes to MM risk in individuals with AA.

Abstract Background : Sex is recognized as a significant determinant of outcome among glioblastoma patients, but the relative prognostic importance of glioblastoma features has not been thoroughly explored for sex differences. Methods : Combining multi-modal MR images, biomathematical models, and patient clinical information, this investigation assesses which pretreatment variables have a sex-specific impact on the survival of glioblastoma patients (299 males and 195 females). Results : Among males, tumor (T1Gd) radius was a predictor of overall survival (HR=1.027, p=0.044). Among females, higher tumor cell net invasion rate was a significant detriment to overall survival (HR=1.011, p<0.001). Female extreme survivors had significantly smaller tumors (T1Gd) (p=0.010 t-test), but tumor size was not correlated with female overall survival (p=0.955 CPH). Both male and female extreme survivors had significantly lower tumor cell net proliferation rates than other patients (M p=0.004, F p=0.001, t-test). Conclusion : Despite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes.

PURPOSETo estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized.METHODSWe analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes.RESULTSWe found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10−76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10−3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10−3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10−2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age ( P for trend = 2.0 × 10−3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies ( P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer.CONCLUSIONThese results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.