Lymphovascular invasion quantification could improve risk prediction of lymph node metastases in patients with submucosal (T1b) esophageal adenocarcinoma

AIM: To quantify lymphovascular invasion (LVI) and to assess the prognostic value in patients with pT1b esophageal adenocarcinoma. METHODS: In this nationwide, retrospective cohort study, patients were included if they were treated with surgery or endoscopic resection for pT1b esophageal adenocarcinoma. Primary endpoint was the presence of metastases, lymph node metastases, or distant metastases, in surgical resection specimens or during follow‐up. A prediction model to identify risk factors for metastases was developed and internally validated. RESULTS: 248 patients were included. LVI was distributed as follows: no LVI (n = 196; 79.0%), 1 LVI focus (n = 16; 6.5%), 2–3 LVI foci (n = 21; 8.5%) and ≥4 LVI foci (n = 15; 6.0%). Seventy‐eight patients had metastases. The risk of metastases was increased for tumors with 2–3 LVI foci [subdistribution hazard ratio (SHR) 3.39, 95% confidence interval (CI) 2.10–5.47] and ≥4 LVI foci (SHR 3.81, 95% CI 2.37–6.10). The prediction model demonstrated a good discriminative ability (c‐statistic 0.81). CONCLUSION: The risk of metastases is higher when more LVI foci are present. Quantification of LVI could be useful for a more precise risk estimation of metastases. This model needs to be externally validated before implementation into clinical practice

Preoperative endoscopic versus percutaneous transhepatic biliary drainage in potentially resectable perihilar cholangiocarcinoma (DRAINAGE trial): Design and rationale of a randomized controlled trial

Background: Liver surgery in perihilar cholangiocarcinoma (PHC) is associated with high postoperative morbidity because the tumor typically causes biliary obstruction. Preoperative biliary drainage is used to create a safer environment prior to liver surgery, but biliary drainage may be harmful when severe drainage-related complications deteriorate the patients' condition or increase the risk of postoperative morbidity. Biliary drainage can cause cholangitis/cholecystitis, pancreatitis, hemorrhage, portal vein thrombosis, bowel wall perforation, or dehydration. Two methods of preoperative biliary drainage are mostly applied: endoscopic biliary drainage, which is currently used in most regional centers before referring patients for surgical treatment, and percutaneous transhepatic biliary drainage. Both methods are associated with severe drainage-related complications, but two small retrospective series found a lower incidence in the number of preoperative complications after percutaneous drainage compared to endoscopic drainage (18-25% versus 38-60%, respectively). The present study randomizes patients with potentially resectable PHC and biliary obstruction between preoperative endoscopic or percutaneous transhepatic biliary drainage. Methods/Design: The study is a multi-center trial with an "all-comers" design, randomizing patients between endoscopic or percutaneous transhepatic biliary drainage. All patients selected to potentially undergo a major liver resection for presumed PHC are eligible for inclusion in the study provided that the biliary system in the future liver remnant is obstructed (even if they underwent previous inadequate endoscopic drainage). Primary outcome measure is the total number of severe preoperative complications between randomization and exploratory laparotomy. The study is designed to detect superiority of percutaneous drainage: a provisional sample size of 106 patients is required to detect a relative decrease of 50% in the number of severe preoperative complications (alpha = 0.95; beta = 0.8). Interim analysis after inclusion of 53 patients (50%) will provide the definitive sample size. Secondary outcome measures encompass the success of biliary drainage, quality of life, and postoperative morbidity and mortality. Discussion: The DRAINAGE trial is designed to identify a difference in the number of severe drainage-related complications after endoscopic and percutaneous transhepatic biliary drainage in patients selected to undergo a major liver resection for perihilar cholangiocarcinoma. Trial registration: Netherlands Trial Register [, 11 October 2013]

Reasons for Discontinuing Active Surveillance : Assessment of 21 Centres in 12 Countries in the Movember GAP3 Consortium

Background: Careful assessment of the reasons for discontinuation of active surveillance (AS) is required for men with prostate cancer (PCa). Objective: Using Movember's Global Action Plan Prostate Cancer Active Surveillance initiative (GAP3) database, we report on reasons for AS discontinuation. Design, setting, and participants: We compared data from 10 296 men on AS from 21 centres across 12 countries. Outcome measurements and statistical analysis: Cumulative incidence methods were used to estimate the cumulative incidence rates of AS discontinuation. Results and limitations: During 5-yr follow-up, 27.5% (95% confidence interval [CI]: 26.4-28.6%) men showed signs of disease progression, 12.8% (95% CI: 12.0-13.6%) converted to active treatment without evidence of progression, 1.7% (95% CI: 1.5-2.0%) continued to watchful waiting, and 1.7% (95% CI: 1.4-2.1%) died from other causes. Of the 7049 men who remained on AS, 2339 had follow-up for >5 yr, 4561 had follow-up for Conclusions: Our descriptive analyses of current AS practices worldwide showed that 43.6% of men drop out of AS during 5-yr follow-up, mainly due to signs of disease progression. Improvements in selection tools for AS are thus needed to correctly allocate men with PCa to AS, which will also reduce discontinuation due to conversion to active treatment without evidence of disease progression. Patient summary: Our assessment of a worldwide database of men with prostate cancer (PCa) on active surveillance (AS) shows that 43.6% drop out of AS within 5 yr, mainly due to signs of disease progression. Better tools are needed to select and monitor men with PCa as part of AS. (C) 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.Peer reviewe

Primary and secondary plan diagnosis

Diagnosis of plan failures is an important subject in both single- and multi-agent planning. Plan diagnosis may provide information that can improve the way the plan failures are dealt with in three ways: (i) it provides information necessary for the adjustment of the current plan or for the development of a new plan, (ii) it can be used to point out which equipment and/or agents should be repaired or adjusted so they will not further harm the plan execution, and (iii) it can identify the agents responsible for plan execution failures. We introduce two general types of plan diagnosis: primary plan diagnosis identifying the incorrect or failed execution of actions, and secondary plan diagnosis that identifies the underlying causes of the faulty actions. Furthermore, three special cases of secondary diagnosis are distinguished, namely equipment diagnosis, environment diagnosis and agent diagnosis.

Modeling the impact of scaffold architecture and mechanical loading on collagen turnover in engineered cardiovascular tissues

\u3cp\u3eThe anisotropic collagen architecture of an engineered cardiovascular tissue has a major impact on its in vivo mechanical performance. This evolving collagen architecture is determined by initial scaffold microstructure and mechanical loading. Here, we developed and validated a theoretical and computational microscale model to quantitatively understand the interplay between scaffold architecture and mechanical loading on collagen synthesis and degradation. Using input from experimental studies, we hypothesize that both the microstructure of the scaffold and the loading conditions influence collagen turnover. The evaluation of the mechanical and topological properties of in vitro engineered constructs reveals that the formation of extracellular matrix layers on top of the scaffold surface influences the mechanical anisotropy on the construct. Results show that the microscale model can successfully capture the collagen arrangement between the fibers of an electrospun scaffold under static and cyclic loading conditions. Contact guidance by the scaffold, and not applied load, dominates the collagen architecture. Therefore, when the collagen grows inside the pores of the scaffold, pronounced scaffold anisotropy guarantees the development of a construct that mimics the mechanical anisotropy of the native cardiovascular tissue.\u3c/p\u3

Functional Na(V)1.8 Channels in Intracardiac Neurons The Link Between SCN10A and Cardiac Electrophysiology

Rationale: The SCN10A gene encodes the neuronal sodium channel isoform Na(V)1.8. Several recent genome-wide association studies have linked SCN10A to PR interval and QRS duration, strongly suggesting an as-yet unknown role for Na(V)1.8 in cardiac electrophysiology. Objective: To demonstrate the functional presence of SCN10A/Nav1.8 in intracardiac neurons of the mouse heart. Methods and Results: Immunohistochemistry on mouse tissue sections showed intense Na(V)1.8 labeling in dorsal root ganglia and intracardiac ganglia and only modest Na(V)1.8 expression within the myocardium. Immunocytochemistry further revealed substantial Na(V)1.8 staining in isolated neurons from murine intracardiac ganglia but no Na(V)1.8 expression in isolated ventricular myocytes. Patch-clamp studies demonstrated that the Na(V)1.8 blocker A-803467 (0.5-2 mu mol/L) had no effect on either mean sodium current (I-Na) density or I-Na gating kinetics in isolated myocytes but significantly reduced I-Na density in intracardiac neurons. Furthermore, A-803467 accelerated the slow component of current decay and shifted voltage dependence of inactivation toward more negative voltages, as expected for blockade of Na(V)1.8-based I-Na. In line with these findings, A-803467 did not affect cardiomyocyte action potential upstroke velocity but markedly reduced action potential firing frequency in intracardiac neurons, confirming a functional role for Na(V)1.8 in cardiac neural activity. Conclusions: Our findings demonstrate the functional presence of SCN10A/Na(V)1.8 in intracardiac neurons, indicating a novel role for this neuronal sodium channel in regulation of cardiac electric activity. (Circ Res. 2012;111:333-343.

Gray matter volume and white matter lesions in chronic kidney disease: exploring the association with depressive symptoms

Objective: Chronic kidney disease (CKD) is associated with structural brain damage and with a high prevalence of depression. We therefore investigated structural brain alterations in both gray and white matter in CKD patients, focusing on depression-related (frontal-subcortical) regions. Method: This cross-sectional MRI study in 24 CKD patients and 24 age- and sex-matched controls first tested whether CKD was associated with regionally lower gray matter (GM) volumes and more severe white matter lesions (WMLs). In exploratory subanalyses, we examined whether differences were more pronounced in CKD patients with depressive symptoms. Results: CKD patients showed lower global GM volume (P=.04) and more severe WMLs (P=.04) compared to controls. In addition, we found substantial clusters of lower GM in the bilateral orbitofrontal-cortex for CKD patients, which were however nonsignificant after proper multiple-comparison correction. In exploratory analyses for depressed CKD patients, reduced GM clusters were mainly detected within the frontal lobe. WML severity was unrelated to depression. Conclusion: CKD was characterized by differences in brain structure. Although subthreshold, lower GM volumes were observed in depression-related brain areas and were more pronounced for depressed patients. There is a need for replication in larger and longitudinal studies to investigate whether WMLs and regional GM reductions may render CKD patients more susceptible for depression. (C) 2016 Elsevier Inc. All rights reserved