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Abstract Background and study aims Despite the clinical efficacy of peroral endoscopic myotomy (POEM), postoperative symptomatic gastroesophageal reflux disease (GERD) remains a major concern. While it is known that length of the gastric myotomy affects postoperative GERD, the clinical relevance of variation in esophageal myotomy length is not well known. We performed a systematic review and meta-analysis of studies comparing outcomes of short versus standard myotomy length in patients with achalasia. Patients and methods We searched multiple databases from inception through November 2020 to identify studies that reported on outcomes of achalasia patients who underwent short compared with standard esophageal myotomy. Meta-analysis was performed to determine pooled odds ratio (OR) of clinical success, GERD outcomes, and adverse events with the two techniques. Results 5 studies with 474 patients were included in the final analysis (short myotomy group 214, standard myotomy group 260). There was no difference in clinical success (OR 1.17, 95 % confidence interval [CI] 0.54–2.52; I2 0 %; P = 0.69), postoperative symptomatic GERD (OR 0.87, 95 %CI 0.44–1.74; I2 29 %; P = 0.70), and overall adverse events (OR 0.52, 95 %CI 0.19–1.38; I2 40 %; P = 0.19), between the two groups. Incidence of postoperative erosive esophagitis as determined by endoscopy was lower in the short myotomy group (OR 0.50, 95 %CI 0.24–1.03; I2 0 %; P = 0.06). Conclusion Our analysis showed that performing POEM with short esophageal myotomy in achalasia was as safe and effective as standard myotomy, with lower incidence of postoperative erosive esophagitis.

The NCCN Guidelines for Wilms Tumor focus on the screening, diagnosis, staging, treatment, and management of Wilms tumor (WT, also known as nephroblastoma). WT is the most common primary renal tumor in children. Five-year survival is more than 90% for children with all stages of favorable histology WT who receive appropriate treatment. All patients with WT should be managed by a multidisciplinary team with experience in managing renal tumors; consulting a pediatric oncologist is strongly encouraged. Treatment of WT includes surgery, neoadjuvant or adjuvant chemotherapy, and radiation therapy (RT) if needed. Careful use of available therapies is necessary to maximize cure and minimize long-term toxicities. This article discusses the NCCN Guidelines recommendations for favorable histology WT.

Objectives To analyse the amount, reporting and handling of missing data, approach to intention-to-treat (ITT) principle application and sensitivity analysis utilisation in randomised clinical trials (RCTs) of rheumatoid arthritis (RA). To assess the trend in such reporting 10 years apart (2006 and 2016). Methods Parallel group drug therapy RA RCTs with a clinical primary endpoint. Results 176 studies enrolling a median of 160 (IQR 62–339) patients were eligible. In terms of actual analysis: 81 (46%) RCTs conducted ITT, 42 (23.9%) conducted modified ITT while 53 (30.1%) conducted non-ITT analysis. Only 58 of 97 (59.8%) RCTs reporting an ITT analysis actually performed it. The median (IQR) numbers of participants completing the trial and included in analysis for primary outcome were 86% (74%–91%) and 100% (97.1%–100%), respectively. 53 (32.7%) and 65 (40.1%) RCTs had >20% and 10%–20% missing primary outcome data, respectively. Missing data handling was unreported by 58 of 171 (33.9%) RCTs. When reported, vast majority used simple imputation methods. No significant trend towards improved reporting was seen between 2006 and 2016. Sensitivity analysis numerically improved from 2006 to 2016 (14.7% vs 21.4%). Conclusions There is significant discrepancy in the reported and the actual performed analysis in RA drug therapy RCTs. Nearly one-third of RCTs had >20% missing data. The reporting and methods of missing data handling remain inadequate with high usage of non-preferred simple imputation methods. Sensitivity analysis utilisation was low. No trend towards better missing data reporting and handling was seen.

Abstract Background Ripretinib 150 mg once daily (QD) is indicated for advanced gastrointestinal stromal tumors (GISTs) as at least fourth-line therapy. In INVICTUS, ripretinib intrapatient dose escalation (IPDE) to 150 mg b.i.d. was allowed after progressive disease (PD) on 150 mg QD by blinded independent central review using modified RECIST 1.1. We report the efficacy and safety of ripretinib IPDE to 150 mg b.i.d. after PD among patients randomized to ripretinib 150 mg QD in the INVICTUS study. Materials and Methods Tumor imaging was performed every 28-day cycle for the first four cycles in the ripretinib 150 mg QD period and then every other cycle, including the 150 mg b.i.d. period. Among the ripretinib IPDE patients, progression-free survival (PFS)1 was the time from randomization until PD; PFS2 was the time from the first dose of ripretinib 150 mg b.i.d. to PD or death. Results Among 43 ripretinib IPDE patients, median PFS1 was 4.6 months (95% confidence interval [CI], 2.7–6.4) and median PFS2 was 3.7 months (95% CI, 3.1–5.3). Median overall survival was 18.4 months (95% CI, 14.5–not estimable). Ripretinib 150 mg b.i.d. (median duration of treatment 3.7 months) was well tolerated with new or worsening grade 3–4 treatment-emergent adverse events (TEAEs) of anemia in six (14%) and abdominal pain in three (7%) patients. Ripretinib 150 mg b.i.d. was discontinued because of TEAEs in seven (16%) patients. Conclusion Ripretinib 150 mg b.i.d. after PD on 150 mg QD may provide additional clinically meaningful benefit with an acceptable safety profile in patients with at least fourth-line GISTs. Implications for Practice Of the 85 patients with advanced gastrointestinal stromal tumor having received at least three prior anticancer therapies randomized to ripretinib 150 mg once daily (QD) in the phase III INVICTUS study, 43 underwent ripretinib intrapatient dose escalation (IPDE) to 150 mg b.i.d. after progressive disease (PD). Median progression-free survival was 4.6 months before and 3.7 months after ripretinib IPDE. The safety profile of ripretinib 150 mg b.i.d. was acceptable. These findings indicate ripretinib IPDE to 150 mg b.i.d. may provide additional clinical benefit in patients with PD on ripretinib 150 mg QD, for whom limited treatment options exist.

PURPOSE The prevalence of germline pathogenic variants (PVs) in established breast cancer predisposition genes in women in the general population over age 65 years is not well-defined. However, testing guidelines suggest that women diagnosed with breast cancer over age 65 years might have < 2.5% likelihood of a PV in a high-penetrance gene. This study aimed to establish the frequency of PVs and remaining risks of breast cancer for each gene in women over age 65 years. METHODS A total of 26,707 women over age 65 years from population-based studies (51.5% with breast cancer and 48.5% unaffected) were tested for PVs in germline predisposition gene. Frequencies of PVs and associations between PVs in each gene and breast cancer were assessed, and remaining lifetime breast cancer risks were estimated for non-Hispanic White women with PVs. RESULTS The frequency of PVs in predisposition genes was 3.18% for women with breast cancer and 1.48% for unaffected women over age 65 years. PVs in BRCA1, BRCA2, and PALB2 were found in 3.42% of women diagnosed with estrogen receptor (ER)–negative, 1.0% with ER-positive, and 3.01% with triple-negative breast cancer. Frequencies of PVs were lower among women with no first-degree relatives with breast cancer. PVs in CHEK2, PALB2, BRCA2, and BRCA1 were associated with increased risks (odds ratio = 2.9-4.0) of breast cancer. Remaining lifetime risks of breast cancer were ≥ 15% for those with PVs in BRCA1, BRCA2, and PALB2. CONCLUSION This study suggests that all women diagnosed with triple-negative breast cancer or ER-negative breast cancer should receive genetic testing and that women over age 65 years with BRCA1 and BRCA2 PVs and perhaps with PALB2 and CHEK2 PVs should be considered for magnetic resonance imaging screening.

Background In advanced pharyngoesophageal cancer patients, a critical event is represented by the failure of primary reconstruction with exposure of the carotid artery and partial or total defect of the cervical esophagus. For these high-risk patients, a partitioned pectoralis major musculocutaneous (PMMC) flap can prevent carotid blowout and provide skin for simultaneous esophageal reconstruction. Methods Twenty-six patients needing pharyngoesophageal reconstruction together with coverage of carotid artery exposure were included in this retrospective case series. The patients were treated with a partitioned PMMC flap, based on the branching pattern of the pectoral branch of the thoracoacromial artery and the perforators of the pectoralis major muscle, to simultaneously reconstruct the defect and provide coverage for the carotid artery. Results In 25 patients, the partitioned PMMC flap reconstructions resulted in complete wound healing without occurrence of carotid blowout syndrome or fistula formation. Minor complications as partial flap necrosis (7.7%) and strictures formation (7.7%) were recorded but did not compromise reconstruction. Twenty-two patients were able to adopt a semisolid diet, and 4 had recurrence of cancer. Conclusions The partitioned PMMC flap reconstruction represents a useful salvage solution to simultaneously restore the continuity of the alimentary tract and provide reliable coverage for the exposed carotid artery.

BK channels, abundantly expressed in vascular smooth muscle cells (VSMCs), are the key determinant of vascular physiology. BK channel activity is tightly regulated by its accessory β 1 (BK-β 1 ) subunits. BK-β 1 protein expression is down-regulated in diabetic vessels, contributing to diabetic vascular complications including hypertension, stroke and coronary heart disease. However, BK-β 1 mRNA is not reduced in diabetic vessels suggesting increased BK-β 1 turnover. Since ubiquitin-proteasome system (UPS) accounts for 80~90% of intracellular protein degradations in mammalian cells, we hypothesize that muscle ring finger-1 (MuRF-1) protein, the muscle specific E3 ligase, accelerates vascular BK-β 1 degradation in diabetes mellitus. In this study, we found that BK-β 1 protein level was decreased by 1.95±0.14 fold, accompanied by a 2.83±0.16 fold increase of MuRF-1 expression in streptozotocin-induced diabetic mouse vessels (n=3, p<0.05 vs. control). Moreover, response of vascular BK channel activation by DHS-1 (a specific BK-β 1 activator) was absent in diabetic mouse vascular smooth muscle cells (VSMCs). Similar results were observed in human VSMCs cultured with 22 mM glucose (HG) compared to those cultured with 5 mM glucose. Knockdown of MuRF-1 by siRNA (100 nM) produced a 4.2-fold decrease of MuRF-1 protein level and a 1.8-fold increase in BK-β 1 expression in HG-cultured VSMCs. In addition, the total BK-β 1 expression was 2.58±0.04 fold lower but the ubiquitinated BK-β 1 protein was 5.18±0.04 fold higher in HEK293 cells 48-h after transfection with MuRF-1, compared to those with MuRF-1ΔR (an inactive mutant with the Ring structure deletion) transfection (n=3, p<0.05). Immunoprecipitation experiments confirmed that the N-terminus of BK-β 1 was physically associated with MuRF-1. Inhibition of UPS activity by 10 μM MG-132 (a proteasome inhibitor) enhanced BK-β 1 expression by 1.70±0.01 fold (n=3, p<0.05 vs. control). Our results indicate that MuRF-1 participated in ubiquitin-mediated vascular BK-β 1 protein proteasomal degradation and delineated a fundamental mechanism underlying vasculopathy in diabetes.

The Vitamin Intervention for Stroke Prevention (VISP) trial was a multi-center, controlled, double blinded clinical trial, designed to determine whether the daily intake of high dose folic acid, vitamins B6 and B12 reduced recurrent cerebral infarction. Baseline post-methionine load homocysteine levels were predictive of recurrent stroke risk in VISP. We have conducted a genome-wide association study (GWAS), investigating 2100 VISP stroke cases required to have homocysteine levels greater than the 25th percentile at enrolment. Using imputation with 1000 genomes and principal component analysis, we were able to detect an association of p≤6.70x10-17 for SNPs within, or flanking, the glycine N-methyltransferase (GNMT) gene and post-methionine load test homocysteine level. Change in homocysteine levels pre and post-methionine load test also resulted in significant GWAS scores in the chromosome 6 region (p = 2.54x10-23, rs7760250). GNMT catalyzes the conversion of S-adenosyl-L-methionine to S-adenosyl-L-homocysteine and sarcosine via the folate one-carbon metabolism pathway. In addition to being an essential component in the conversion of methionine to homocysteine, GNMT plays a significant role in the global epigenetic state as homocysteine is an important methyl donor. This region displays significant linkage disequilibrium, warranting close analysis of the entire GNMT locus in search of both rare and common variants. Cases who carry the minor allele haplotype at associated loci had a higher level of post-methionine load homocysteine (37.69µM/L) than those who carry the major allele haplotype (27.33µM/L), inferring functional differences due to GNMT variants. Taken together these data suggest a clear and important role for GNMT in post-methionine load test homocysteine level, epigenetic state and stroke risk.

Background: In heart failure with preserved ejection fraction (HFpEF), left ventricular (LV) systolic elastance (Ees) increases in tandem with increases in arterial elastance (Ea), which maintains ejection fraction but limits systolic reserve and precipitates volume sensitivity. The left atrium (LA) lies in series with the LV and contributes to LV stroke volume. We hypothesized that HFpEF is associated with increased LA systolic elastance (E LA ) and deranged atrioventricular (AV) coupling which may additionally compromise cardiac performance. Methods: HFpEF was modeled by experimental hypertension (bilateral renal wrap + DOCA) in elderly dogs (n=9). LA and LV structure, function (echo, MRI) and invasively assessed pressure-volume relationships (PVR, open-chest; pericardiotomy; admittance catheter) were compared to sham-operated young dogs (control; n=13). Results: As compared to controls, HFpEF dogs displayed concentric remodeling, with increased diastolic stiffness, Ea and Ees (p<0.05 for all) and reduced Ea/Ees (p=0.03). LA maximum volume (28±3 vs 23±3mL, p=0.007), LA stroke volume (4±1 vs2±1mL, p=0.006), LA active emptying fraction (18±6 vs 12±2%, p=0.03) and LA ejection rate (51±14 vs 30±16mL/s) were higher in HFpEF versus controls, suggesting increased LA stroke work and inotropy. At matched heart rate and LA pressure, E LA was steeper in HFpEF than control (2.7±0.9 vs 1.5±0.6mmHg/mL, p=0.01) and positively correlated with Ees (r=0.6, p=0.005) and Ea (r=0.66, p=0.002). However AV mismatch occurred as increases in E LA were not proportionate to increases in Ees (Ees/E LA 1.3±0.4 HFpEF vs 0.8±0.4 control, p<0.05). On linear regression, worse AV coupling (i.e. higher Ees/E LA ) was associated with lower LV stroke volume ( Figure ). Conclusion: In experimental HFpEF, despite enhanced LA contractility, AV coupling was deranged. Worse AV coupling may further contribute to reserve dysfunction, LA pressure rise, and susceptibility to pulmonary edema in HFpEF.

Background: Reduced left atrial (LA) compliance (LAC) contributes to pulmonary venous hypertension in heart failure with preserved ejection fraction (HFpEF); however the underlying mechanisms are poorly defined. We hypothesized that microvascular inflammation with rarefaction and impaired nitric oxide (NO) signaling, LA titin hypophosphorylation and fibrosis may each contribute to reduced LAC in HFpEF. Methods: Invasive LA pressure-volume (PV) analyses (open-chest; pericardiotomy; admittance catheter) were performed in 9 aged dogs with experimental hypertension (bilateral renal wrap + DOCA; HFpEF) compared to 13 sham-operated young adult dogs (control). LAC was measured at end-LA reservoir during acute preload reduction (cava occlusion). LA tissue and LA microvascular function were analyzed. Results: Compared to controls, the curvilinear end-LA reservoir PV relationship ( Fig A ) was shifted upward/leftward in HFpEF (LA diastolic stiffness constant 0.08 vs 0.16 mmHg/mL in controls, p=0.005). LA microvascular density (MVD; CD31 stain) tended to be lower in HFpEF than controls (2154±578 vs 2650±523 vessels/mm 2 , p=0.07) and LA MVD negatively correlated with the LA diastolic stiffness constant (r=-0.66, p=0.006). LA microvessels from HFpEF dogs showed impaired endothelium-dependent shear stress-mediated dilation compared to controls, consistent with impaired NO signaling ( Fig B ). Titin isoform expression was similar between groups, but isoform N2B (stiffer) was (p=0.03) and N2BA (compliant) tended to be (p=0.09) hypophosphorylated in HFpEF LA appendage (LAA) tissue. Fibrosis (Picrosirius Red) was similar between groups in the LA free wall and LAA, but increased in areas adjacent to the pulmonary veins in HFpEF (27±12% vs controls 15±8%, p=0.01). Conclusion: In experimental HFpEF, LAC was reduced in association with evidence of LA microvascular rarefaction and impaired NO signaling, titin hypophosphorylation and regional increases in LA fibrosis.