Critical number of lymph node involvement in esophageal and gastric cancer and its impact on long-term survival-A single-center 8-year study.

BACKGROUND: Nodal disease in esophageal and gastric cancer is associated with poor survival. OBJECTIVES: To determine the critical level of lymph node involvement where survival becomes significantly compromised. METHODS: Survival analyses using multivariable Cox regression and receiver operator characteristics (ROC) were undertaken to determine what number of positive lymph nodes were most sensitive and specific in predicting survival. RESULTS: A total of 317 patients underwent esophagectomy (n = 190, 59.9%) and gastrectomy (n = 127, 40.1%) for adenocarcinoma. At multivariable analyses, four nodes positivity (irrespective of T-category) was associated with nearly a fivefold increased risk of mortality when compared to node-negative patients (hazard ratio [HR], 4.9; interquartile range 2.0-11.5; P < .001). A positive ratio of up to 50.0% was not associated with worse survival than having four nodes positive (HR, 4.6; 95% confidence interval, 2.6-8.1; P < .001). ROC analysis demonstrated four lymph nodes positive to have a sensitivity of 80.5%, a specificity of 60.1%, and an accuracy of 77.8 (P < .001). CONCLUSION: The absolute number of nodes positive for cancer is more important than the proportion of positive nodes in predicting survival in esophageal/gastric cancer. Four positive lymph nodes are associated with a fivefold increase in mortality. Beyond this, increasing numbers of positive lymph nodes make no appreciable difference to survival.

Author Correction: Abnormal contractility in human heart myofibrils from patients with dilated cardiomyopathy due to mutations in TTN and contractile protein genes.

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Abnormal contractility in human heart myofibrils from patients with dilated cardiomyopathy due to mutations in TTN and contractile protein genes.

Dilated cardiomyopathy (DCM) is an important cause of heart failure. Single gene mutations in at least 50 genes have been proposed to account for 25-50% of DCM cases and up to 25% of inherited DCM has been attributed to truncating mutations in the sarcomeric structural protein titin (TTNtv). Whilst the primary molecular mechanism of some DCM-associated mutations in the contractile apparatus has been studied in vitro and in transgenic mice, the contractile defect in human heart muscle has not been studied. In this study we isolated cardiac myofibrils from 3 TTNtv mutants, and 3 with contractile protein mutations (TNNI3 K36Q, TNNC1 G159D and MYH7 E1426K) and measured their contractility and passive stiffness in comparison with donor heart muscle as a control. We found that the three contractile protein mutations but not the TTNtv mutations had faster relaxation kinetics. Passive stiffness was reduced about 38% in all the DCM mutant samples. However, there was no change in maximum force or the titin N2BA/N2B isoform ratio and there was no titin haploinsufficiency. The decrease in myofibril passive stiffness was a common feature in all hearts with DCM-associated mutations and may be causative of DCM.

"Young at heart": Regenerative potential linked to immature cardiac phenotypes.

The adult human myocardium is incapable of regeneration; yet, the zebrafish (Danio rerio) can regenerate damaged myocardium. Similar to the zebrafish heart, hearts of neonatal, but not adult mice are capable of myocardial regeneration. We performed a proteomics analysis of adult zebrafish hearts and compared their protein expression profile to hearts from neonatal and adult mice. Using difference in-gel electrophoresis (DIGE), there was little overlap between the proteome from adult mouse (>8weeks old) and adult zebrafish (18months old) hearts. Similarly, there was a significant degree of mismatch between the protein expression in neonatal and adult mouse hearts. Enrichment analysis of the selected proteins revealed over-expression of DNA synthesis-related proteins in the cardiac proteome of the adult zebrafish heart similar to neonatal and 4days old mice, whereas in hearts of adult mice there was a mitochondria-related predominance in protein expression. Importantly, we noted pronounced differences in the myofilament composition: the adult zebrafish heart lacks many of the myofilament proteins of differentiated adult cardiomyocytes such as the ventricular isoforms of myosin light chains and nebulette. Instead, troponin I and myozenin 1 were expressed as skeletal isoforms rather than cardiac isoforms. The relative immaturity of the adult zebrafish heart was further supported by cardiac microRNA data. Our assessment of zebrafish and mammalian hearts challenges the assertions on the translational potential of cardiac regeneration in the zebrafish model. The immature myofilament composition of the fish heart may explain why adult mouse and human cardiomyocytes lack this endogenous repair mechanism.

Pharmacological adjuncts for chronic venous ulcer healing: a systematic review.

BACKGROUND: The aim of this study was to systematically review the current evidence and determine whether there is a clinical benefit for using pharmacological agents as adjunctive treatment for chronic venous ulcers. METHOD: A systematic review of the MEDLINE and EMBASE (from 1 January 1947 through 15 August 2013) and Cochrane databases (from inception through 15 August 2013) was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Inclusion criteria were all randomised controlled trials investigating pharmacological adjuncts for the treatment of venous ulcers with a minimum sample size of 20 patients for each treatment arm. RESULTS: Ten relevant articles were identified; one pilot randomised controlled trial and four Cochrane reviews were included. Pentoxifylline, aspirin, sulodexide, mesoglycan, flavonoids, thromboxane A2 antagonist (ifetroban), zinc, prostaglandin and prostacyclin analogues were the drugs reviewed. Pentoxifylline was found to be more effective than placebo in terms of complete ulcer healing or in causing a significant improvement (greater than 60% reduction in ulcer size) (RR 1.70, 95% CI 1.30 to 2.24). Aspirin and flavonoids show potential to be effective adjuncts but methodological shortcomings and issues with bias limit the validity of results from trials involving each of these drugs, respectively. There was no significant difference between placebo and Ifetroban and likewise pooled results from trials investigating sulodexide and zinc showed no benefit in comparison to placebo. CONCLUSION: Many systemic pharmacological agents have been investigated as adjuncts to venous ulcer healing; however, pentoxifylline (400 mg, three times a day) is currently the only drug that has promising evidence to support its use. Other compounds are in early stage research.

OBSCN Mutations Associated with Dilated Cardiomyopathy and Haploinsufficiency.

BACKGROUND: Studies of the functional consequences of DCM-causing mutations have been limited to a few cases where patients with known mutations had heart transplants. To increase the number of potential tissue samples for direct investigation we performed whole exon sequencing of explanted heart muscle samples from 30 patients that had a diagnosis of familial dilated cardiomyopathy and screened for potentially disease-causing mutations in 58 HCM or DCM-related genes. RESULTS: We identified 5 potentially disease-causing OBSCN mutations in 4 samples; one sample had two OBSCN mutations and one mutation was judged to be not disease-related. Also identified were 6 truncating mutations in TTN, 3 mutations in MYH7, 2 in DSP and one each in TNNC1, TNNI3, MYOM1, VCL, GLA, PLB, TCAP, PKP2 and LAMA4. The mean level of obscurin mRNA was significantly greater and more variable in healthy donor samples than the DCM samples but did not correlate with OBSCN mutations. A single obscurin protein band was observed in human heart myofibrils with apparent mass 960 ± 60 kDa. The three samples with OBSCN mutations had significantly lower levels of obscurin immunoreactive material than DCM samples without OBSCN mutations (45±7, 48±3, and 72±6% of control level).Obscurin levels in DCM controls, donor heart and myectomy samples were the same. CONCLUSIONS: OBSCN mutations may result in the development of a DCM phenotype via haploinsufficiency. Mutations in the obscurin gene should be considered as a significant causal factor of DCM, alone or in concert with other mutations.

Temporal trends in safety of carotid endarterectomy in asymptomatic patients: systematic review.

OBJECTIVE: To systematically review temporal changes in perioperative safety of carotid endarterectomy (CEA) in asymptomatic individuals in trial and registry studies. METHODS: The MEDLINE and EMBASE databases were searched using the terms "carotid" and "endarterectomy" and "asymptomatic" from 1947 to August 23, 2014. Articles dealing with 50%-99% stenosis in asymptomatic individuals were included and low-volume studies were excluded. The primary endpoint was 30-day stroke or death and the secondary endpoint was 30-day all-cause mortality. Statistical analysis was performed using random-effects meta-regression for registry data and for trial data graphical interpretation alone was used. RESULTS: Six trials (n = 4,431 procedures) and 47 community registries (n = 204,622 procedures) reported data between 1983 and 2013. Registry data showed a significant decrease in postoperative stroke or death incidence over the period 1991-2010, equivalent to a 6% average proportional annual reduction (95% credible interval [CrI] 4%-7%; p < 0.001). Considering postoperative all-cause mortality, registry data showed a significant 5% average proportional annual reduction (95% CrI 3%-9%; p < 0.001). Trial data showed a similar visual trend. CONCLUSIONS: CEA is safer than ever before and high-volume registry results closely mirror the results of trials. New benchmarks for CEA are a stroke or death risk of 1.2% and a mortality risk of 0.4%. This information will prove useful for quality improvement programs, for health care funders, and for those re-examining the long-term benefits of asymptomatic revascularization in future trials.

Systematic review of perioperative outcomes following laparoscopic abdominal aortic aneurysm repair.

OBJECTIVE: To collate information available in the literature regarding perioperative outcomes following elective laparoscopic abdominal aortic aneurysm repair. MATERIALS AND METHODS: Electronic databases were searched and a systematic review was performed. In total, 1256 abstracts were screened, from which 10 studies were included for analysis. Perioperative and technical outcomes were analysed. RESULTS: In the totally laparoscopic repair of infra-renal aneurysms (n = 302), 30-day mortality ranged between 0% and 6% and in the laparoscopic-assisted cases (n = 547) ranged between 0% and 7%. Of the former group, 5-30% of cases were converted to open repair, with 6% reintervention rate, whereas there was a 5-10% conversion and 3% reintervention rate in the latter group. CONCLUSIONS: The outcomes from selected patients in selected centres demonstrate that elective laparoscopic repair of aortic aneurysms is feasible and comparable in safety to open repair; it remains unclear, however, whether there are substantial advantages of this method compared with open and endovascular repair.