Citations

Background Blood pressure ( BP ) varies over time within individual patients and across different BP measurement techniques. The effect of different BP targets on concordance between BP measurements is unknown. The goals of this analysis are to evaluate concordance between (1) clinic and ambulatory BP , (2) clinic visit‐to‐visit variability and ambulatory BP variability, and (3) first and second ambulatory BP and to evaluate whether different clinic targets affect these relationships. Methods and Results The SPRINT (Systolic Blood Pressure Intervention Trial) ambulatory BP monitoring ancillary study obtained ambulatory BP readings in 897 participants at the 27‐month follow‐up visit and obtained a second reading in 203 participants 293±84 days afterward. There was considerable lack of agreement between clinic and daytime ambulatory systolic BP with wide limits of agreement in Bland‐Altman plots of −21 to 34 mm Hg in the intensive‐treatment group and −26 to 32 mm Hg in the standard‐treatment group. Overall, there was poor agreement between clinic visit‐to‐visit variability and ambulatory BP variability with correlation coefficients for systolic and diastolic BP all <0.16. We observed a high correlation between first and second ambulatory BP ; however, the limits of agreement were wide in both the intensive group (−27 to 21 mm Hg) and the standard group (−23 to 20 mm Hg). Conclusions We found low concordance in BP and BP variability between clinic and ambulatory BP and second ambulatory BP . Results did not differ by treatment arm. These results reinforce the need for multiple BP measurements before clinical decision making.

Abstract Aims Native T1 times from T1 mapping cardiac magnetic resonance (CMR) are associated with myocardial fibrosis in aortic stenosis (AS). We investigated whether changing patterns in native T1 predict clinical outcomes after aortic valve replacement (AVR) in severe AS patients. Methods and results Forty-three patients with severe AS (65.9 ± 8.1 years; 24 men) who underwent T1 mapping CMR at baseline and 1 year after AVR were prospectively enrolled. Upper limit of native T1 from healthy volunteers was used to define normal myocardium and diffuse fibrosis (native T1 &lt; 1208.4 and ≥1208.4 ms, respectively). Participants were categorized into Group 1 (pre- and post-AVR normal myocardium; n = 11), Group 2 (pre-AVR diffuse fibrosis and post-AVR normal myocardium; n = 18), and Group 3 (post-AVR diffuse fibrosis; n = 14). Native T1 significantly decreased 1 year after AVR (pre-AVR, 1233.8 ± 49.7 ms; post-AVR, 1189.1 ± 58.4 ms; P &lt; 0.001), which was associated with left ventricular (LV) mass regression (△native T1 vs. △LV mass index, r = 0.454, P = 0.010) and systolic function improvement (△native T1 vs. △LV ejection fraction, r = −0.379, P = 0.012). Group 2 showed greater functional improvements, whereas these benefits were blunted in Group 3. Group 3 had significantly worse outcomes than Group 1 [hazard ratio (HR), 9.479, 95% confidence interval (CI) 1.176–76.409; P = 0.035] and Group 2 (HR 3.551, 95% CI 1.178–10.704; P = 0.024). Conclusion AVR-induced changes in native T1 values are associated with LV systolic functional changes as well as prognosis in severe AS. Post-AVR T1 mapping CMR can be used as an imaging biomarker.

AbstractAccurate pathologic diagnoses and molecularly informed treatment decisions for a wide variety of cancers depend on robust clinical molecular testing that uses genomic, epigenomic, and transcriptomic-based tools. Nowhere is this more essential than in the workup of brain tumors, as emphasized by the incorporation of molecular criteria into the 2016 World Health Organization classification of central nervous system tumors and the updated official guidelines of the National Comprehensive Cancer Network. Despite the medical necessity of molecular testing in brain tumors, access to and utilization of molecular diagnostics is still highly variable across institutions, and a lack of reimbursement for such testing remains a significant obstacle. The objectives of this review are (i) to identify barriers to adoption of molecular testing in brain tumors, (ii) to describe the current molecular tools recommended for the clinical evaluation of brain tumors, and (iii) to summarize how molecular data are interpreted to guide clinical care, so as to improve understanding and justification for their coverage in the routine workup of adult and pediatric brain tumor cases.

Abstract Purpose: Protein kinases are known to play a prominent role in oncogenic progression across multiple cancer subtypes, yet their role in prostate cancer progression remains underexplored. The purpose of this study was to identify kinases that drive prostate cancer progression. Experimental Design: To discover kinases that drive prostate cancer progression, we investigated the association between gene expression of all known kinases and long-term clinical outcomes in tumor samples from 545 patients with high-risk disease. We evaluated the impact of genetic and pharmacologic inhibition of the most significant kinase associated with metastatic progression in vitro and in vivo. Results: DNA-dependent protein kinase (DNAPK) was identified as the most significant kinase associated with metastatic progression in high-risk prostate cancer. Inhibition of DNAPK suppressed the growth of both AR-dependent and AR-independent prostate cancer cells. Gene set enrichment analysis nominated Wnt as the top pathway associated with DNAPK. We found that DNAPK interacts with the Wnt transcription factor LEF1 and is critical for LEF1-mediated transcription. Conclusions: Our data show that DNAPK drives prostate cancer progression through transcriptional regulation of Wnt signaling and is an attractive therapeutic target in aggressive prostate cancer.

Abstract Context Dipeptidyl peptidase 4 (DPP4) inhibitors may increase the risk of heart failure. Decreased degradation of vasoactive peptides like substance P [also degraded by angiotensin-converting enzyme (ACE)] and Y1 agonists peptide YY (PYY 1-36) and neuropeptide Y (NPY 1-36) could contribute. Objective This study tested the hypothesis that there is an interactive effect of DPP4 inhibition and ACE inhibition (vs antihypertensive control subjects) on vasoactive peptides after a mixed meal. Participants and Design Fifty-three patients with type 2 diabetes and hypertension were randomized to double-blind treatment with ramipril, valsartan, or amlodipine for 15 weeks in parallel groups. During the 5th, 10th, and 15th weeks, participants also received placebo + placebo, sitagliptin 100 mg/d + placebo, and sitagliptin + aprepitant 80 mg/d in random order. On the last day of each crossover treatment, participants underwent a mixed-meal study. Results Sitagliptin increased postprandial glucagon-like peptide-1 and decreased glucose in all antihypertensive groups. Sitagliptin increased NPY 1-36 and decreased Y2 agonists NPY 3-36 and PYY 3-36 in all groups. During ramipril or valsartan, but not amlodipine, sitagliptin increased postprandial norepinephrine; substance P receptor blockade with aprepitant prevented this effect. Despite increased norepinephrine, sitagliptin decreased postprandial blood pressure during ACE inhibition. Conclusion DPP4 inhibition increases postprandial concentrations of the Y1 agonist NPY 1-36. During treatment with an ACE inhibitor or angiotensin receptor blocker, DPP4 inhibition increased postprandial norepinephrine through a substance P receptor–dependent mechanism. Increased NPY 1-36 and norepinephrine could increase risk of heart failure but did not result in higher postprandial blood pressure.

Favorable long-term functional outcomes after severe traumatic brain injury (TBI) may be underestimated. We analyzed 24-month functional outcomes from a consecutive series of severe TBI survivors. A prospective, observational database of severe TBI survivors from a single institution was analyzed. Glasgow Outcome Scale-Extended (GOS-E) scores were obtained at 3, 6, 12, and 24 months post-injury. GOS-E scores were dichotomized into unfavorable and favorable outcomes, and the proportion of survivors changing from unfavorable to favorable outcomes was calculated using Wilcoxon signed-rank tests. Surviving adults ( N = 304; mean age ± standard deviation = 35.06 ± 15.11; 80.92% male; mode of initial GCS = 7) were analyzed. A statistically significant mean increase in GOS-E was noted from 3 to 6, 6 to 12, 12 to 24, and 6 to 24 months after injury (0.65 [ p < 0.0001], 0.42 [ p < 0.0001], 0.23 [ p = 0.020], and 0.61 [ p < 0.0001], respectively). Moreover, 43% of survivors from 3 to 6 months, 36% from 6 to 12 months, 38% from 12 to 24 months, and 54% from 6 to 24 months progressed from an unfavorable to a favorable outcome. Two thirds of survivors in the unfavorable category at 3 months had favorable outcomes at 2 years. Overall, 74% of surviving adults with a documented GOS-E at 2 years after injury had a favorable outcome. Severe TBI survivors demonstrated significant improvement in functional outcomes from 3 to 24 months after injury. At 2 years, three fourths of survivors had a favorable outcome. Long-term prognosis in severe TBI is better than broadly appreciated.

Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p‐value = 3.5 × 10−6) and rs2189517 (in RAD51B) with rectal cancer risk (p‐value = 5.7 × 10−6). The results had statistical significance close to the Bonferroni corrected p‐value of 5.8 × 10−6. Ninety‐four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis‐eQTL suggesting possible mechanisms of carcinogenesis.

Diffuse large B-cell lymphomas (DLBCLs) and follicular lymphoma (FL) are the most common subtypes of B-cell non-Hodgkin’s lymphomas in adults. Histologic transformation of FL to DLBCL (TFL) occurs in approximately 15% of patients and is generally associated with a poor clinical outcome. Phosphatidylinositol 3-kinase (PI3K) inhibitors have shown promising results in the treatment of relapsed/refractory FL. CAR T-cell therapy (axicabtagene ciloleucel and tisagenlecleucel) has emerged as a novel treatment option for relapsed/refractory DLBCL and TFL. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines for B-Cell Lymphomas regarding the treatment of TFL and relapsed/refractory FL and DLBCL.