Citations

Objective Hyperinsulinemia elicits an increase sympathetic nervous system activity directed toward skeletal muscle (muscle sympathetic nerve activity, MSNA). The insulin‐mediated increase in MSNA is primarily attributed to its effect within the central nervous system. In addition to direct central effects, insulin also elicits peripheral vasodilation, which may further increase MSNA via arterial baroreflex‐mediated mechanisms in order to maintain blood pressure (BP). Herein we examined the contribution of insulin‐induced peripheral vasodilation and role for the arterial baroreflex in the MSNA response to hyperinsulinemia. We hypothesized that rescuing peripheral resistance with co‐infusion of the vasoconstrictor phenylephrine would attenuate the MSNA response to hyperinsulinemia. We further hypothesized the insulin‐mediated increase in MSNA would be recapitulated with another vasodilator (sodium nitroprusside, SNP). Methods In 33 healthy adults (28M/5F, 28±1 yrs, BMI 25.0±0.5 kg/m 2 ) MSNA (microneurography) and BP (Finometer/brachial catheter) were measured, and total peripheral resistance (TPR, ModelFlow) was calculated at rest and during intravenous insulin (n=20) or SNP (n=13) infusion. A subset of participants receiving insulin (n=7) were co‐infused with phenylephrine. Spontaneous arterial baroreflex sensitivity was determined over 5‐min at baseline and during pharmacological intervention(s). Results Insulin infusion increased MSNA (p=0.05) and decreased TPR (p<0.05), with no effects on arterial baroreflex sensitivity or BP (p>0.05). Co‐infusion with phenylephrine returned MSNA and TPR to baseline, with no effect on baroreflex sensitivity (p>0.05). Similar to insulin, SNP increased MSNA (p<0.01) and decreased TPR (p<0.05), with no effect on baroreflex sensitivity (p>0.05). Conclusions Present findings reveal that acute hyperinsulinemia increases MSNA without a change in arterial baroreflex sensitivity in healthy men and women. Insulin‐mediated increases in MSNA are lost with co‐infusion of phenylephrine and can be recapitulated with infusion of SNP. Results support a dynamic interplay between central and peripheral mechanisms during hyperinsulinemia to increase MSNA and maintain BP.

Abstract Background The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk. Methods We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2– or 3–degree-of-freedom joint test. A set-based score test was applied for rare genetic variants. Results The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2–degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P &lt; 1.2 × 10−4). Conclusion Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.

Abstract Background: Currently known associations between common genetic variants and colorectal cancer explain less than half of its heritability of 25%. As alcohol consumption has a J-shape association with colorectal cancer risk, nondrinking and heavy drinking are both risk factors for colorectal cancer. Methods: Individual-level data was pooled from the Colon Cancer Family Registry, Colorectal Transdisciplinary Study, and Genetics and Epidemiology of Colorectal Cancer Consortium to compare nondrinkers (≤1 g/day) and heavy drinkers (&gt;28 g/day) with light-to-moderate drinkers (1–28 g/day) in GxE analyses. To improve power, we implemented joint 2df and 3df tests and a novel two-step method that modifies the weighted hypothesis testing framework. We prioritized putative causal variants by predicting allelic effects using support vector machine models. Results: For nondrinking as compared with light-to-moderate drinking, the hybrid two-step approach identified 13 significant SNPs with pairwise r2 &gt; 0.9 in the 10q24.2/COX15 region. When stratified by alcohol intake, the A allele of lead SNP rs2300985 has a dose–response increase in risk of colorectal cancer as compared with the G allele in light-to-moderate drinkers [OR for GA genotype = 1.11; 95% confidence interval (CI), 1.06–1.17; OR for AA genotype = 1.22; 95% CI, 1.14–1.31], but not in nondrinkers or heavy drinkers. Among the correlated candidate SNPs in the 10q24.2/COX15 region, rs1318920 was predicted to disrupt an HNF4 transcription factor binding motif. Conclusions: Our study suggests that the association with colorectal cancer in 10q24.2/COX15 observed in genome-wide association study is strongest in nondrinkers. We also identified rs1318920 as the putative causal regulatory variant for the region. Impact: The study identifies multifaceted evidence of a possible functional effect for rs1318920.

Abstract Herein, we present the long-term follow-up of the randomized E1912 trial comparing the long-term efficacy of ibrutinib–rituximab (IR) therapy to fludarabine, cyclophosphamide, and rituximab (FCR) and describe the tolerability of continuous ibrutinib. The E1912 trial enrolled 529 treatment-naïve patients aged ≤70 years with chronic lymphocytic leukemia (CLL). Patients were randomly assigned (2:1 ratio) to receive IR or 6 cycles of FCR. With a median follow-up of 5.8 years, median progression-free survival (PFS) is superior for IR (hazard ratio [HR], 0.37; P &lt; .001). IR improved PFS relative to FCR in patients with both immunoglobulin heavy chain variable region (IGHV) gene mutated CLL (HR: 0.27; P &lt; .001) and IGHV unmutated CLL (HR: 0.27; P &lt; .001). Among the 354 patients randomized to IR, 214 (60.5%) currently remain on ibrutinib. Among the 138 IR-treated patients who discontinued treatment, 37 (10.5% of patients who started IR) discontinued therapy due to disease progression or death, 77 (21.9% of patients who started IR) discontinued therapy for adverse events (AEs)/complications, and 24 (6.8% of patients who started IR) withdrew for other reasons. Progression was uncommon among patients able to remain on ibrutinib. The median time from ibrutinib discontinuation to disease progression or death among those who discontinued treatment for a reason other than progression was 25 months. Sustained improvement in overall survival (OS) was observed for patients in the IR arm (HR, 0.47; P = .018). In conclusion, IR therapy offers superior PFS relative to FCR in patients with IGHV mutated or unmutated CLL, as well as superior OS. Continuous ibrutinib therapy is tolerated beyond 5 years in the majority of CLL patients. This trial was registered at www.clinicaltrials.gov as #NCT02048813.

Hodgkin lymphoma (HL) is an uncommon malignancy of B-cell origin. Classical HL (cHL) and nodular lymphocyte–predominant HL are the 2 main types of HL. The cure rates for HL have increased so markedly with the advent of modern treatment options that overriding treatment considerations often relate to long-term toxicity. These NCCN Guidelines Insights discuss the recent updates to the NCCN Guidelines for HL focusing on (1) radiation therapy dose constraints in the management of patients with HL, and (2) the management of advanced-stage and relapsed or refractory cHL.

Background. There is a paucity of data on the impact of cytomegalovirus (CMV) serostatus and CMV infection on outcomes in facial vascularized composite allotransplantation. Methods. This international, multicenter, retrospective cohort study presents data on CMV and basic transplant-related demographics, including pretransplant viral D/R serostatus, and duration of antiviral prophylaxis. CMV-related complications (viremia, disease), allograft-related complications (rejection episodes, loss), and mortality were analyzed. Results. We included 19 patients, 4 of whom received CMV high-risk transplants (D+/R−). CMV viremia was noted in 6 patients (all 4 D+/R− patients and 2 D−/R+), mostly within the first-year posttransplant, shortly after discontinuation of antiviral prophylaxis (median 2 mo). CMV disease occurred in 2 D+/R− patients. The high-risk group experienced relatively more rejection episodes per month follow-up. None of D+/R− patients suffered allograft loss due to rejection (longest follow-up: 121 mo). Conclusions. D+/R− patients were at increased risk of CMV-related complications. Although a higher number of rejections was noted in this group, none of the D+/R− patients lost their allograft or died because of CMV or rejection. Thus, CMV D+/R− face transplantation can likely be safely performed with prophylaxis, active surveillance, and prompt treatment.

AbstractDiabetes is an established risk factor for colorectal cancer. However, colorectal cancer is a heterogeneous disease and it is not well understood whether diabetes is more strongly associated with some tumor molecular subtypes than others. A better understanding of the association between diabetes and colorectal cancer according to molecular subtypes could provide important insights into the biology of this association. We used data on lifestyle and clinical characteristics from the Colorectal Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), including 9756 colorectal cancer cases (with tumor marker data) and 9985 controls, to evaluate associations between reported diabetes and risk of colorectal cancer according to molecular subtypes. Tumor markers included BRAF and KRAS mutations, microsatellite instability and CpG island methylator phenotype. In the multinomial logistic regression model, comparing colorectal cancer cases to cancer‐free controls, diabetes was positively associated with colorectal cancer regardless of subtype. The highest OR estimate was found for BRAF‐mutated colorectal cancer, n = 1086 (ORfully adj: 1.67, 95% confidence intervals [CI]: 1.36‐2.05), with an attenuated association observed between diabetes and colorectal cancer without BRAF‐mutations, n = 7959 (ORfully adj: 1.33, 95% CI: 1.19‐1.48). In the case only analysis, BRAF‐mutation was differentially associated with diabetes (Pdifference = .03). For the other markers, associations with diabetes were similar across tumor subtypes. In conclusion, our study confirms the established association between diabetes and colorectal cancer risk, and suggests that it particularly increases the risk of BRAF‐mutated tumors.

Introduction: Takotsubo cardiomyopathy (TTC) is diagnosed in 1-2% of the patients presenting with troponin positive suspected acute coronary syndromes(ACS). Rising trends of adverse events in patients with TTC, makes it imperative to explore causes and predictors of readmission in this patient population. Methods: National Readmission Data (NRD) 2013-14 was utilized to select study cohort. International Classification of Diseases, 9th Revision (ICD-9-CM) diagnostic code 429.83 was used to identify takotsubo cardiomyopathy. Admissions within 90 day of index admission were considered as early readmissions. Readmission etiologies were identified by ICD-9-CM code in primary diagnosis field of readmissions. Hierarchical multivariate models were used to evaluate predictors of early readmission. Results: A total of 12255 patients were identified during study period out of which 23.92% (n=2932 with 4224 readmissions) patients were readmitted within 90 days of discharge following index admission. Most common etiologies for readmission were cardiac (18.56%), respiratory (17.20%), GI renal (9.10%), infections (13.12%) and neurological complications (5.88%). Among cardiac complications acute heart failure was the most common etiology (7.48%). Highest number of readmissions happened on first day after discharge (n=125) and within 33 days after discharge, >50% of readmissions took place (n=2136). Conclusions: Patients with TTC are highly likely to be readmitted with first month after discharge, most likely secondary to cardiac or respiratory complications. These findings warrant close post discharge transition to reduce morbidity and improve health care outcomes.

Introduction: Catheter ablation is widely accepted intervention for atrial fibrillation (AF), but data is limited on contemporary trends in major complications and mortality due to the procedure. Methods: HCUP’s Nationwide inpatient sample (NIS) database was utilized from 2011-14 to identify the AF patients treated with Catheter Ablation using ICD-9- CM codes. χ 2 test was utilized to compare categorical variables, the student’s t-test for continuous variables and hierarchical mixed-effects logistic regression models for multivariate predictors of post-procedural complications. Results: In total 50,969 patients were identified undergoing AF ablation during the study period (37.6% female, 51.4 age ≥ 65). Overall complication rate was 5.5% with relative increase over study period (+56.4%, p < 0.001). In subgroup analysis of complication trends significant relative increase seen in respiratory (+352.7%, p < 0.001), neurological (+43.9%, p = 0.003) and vascular (+38.7%, p = 0.003) complications. While cardiac complications (+9.1%, p = 0.323) and In-hospital mortality (+ 60%, p = 0.173) showed insignificant change. On multivariate analysis of mortality and complication significant increased risk was associated with female gender (OR, 95% CI, p-value) (1.40, 1.17-1.68, p < 0.001), as well as higher comorbidity burden (CCI ≥ 1). While higher hospital volume (≥ 50 procedures) was associated with significantly decreased complication rates. Conclusions: Patients undergoing AF ablation showed an insignificant change in mortality, with increase trends of complication. Which was likely related to higher comorbidity burden over study period.