Anticoagulation in Cirrhosis: Evidence for the Treatment of Portal Vein Thrombosis and Applications for Prophylactic Therapy.

The clinical utility of anticoagulation for patients with cirrhosis and asymptomatic portal vein thrombosis (PVT) is widely debated. Complex hemostatic derangements in cirrhosis that increase risk of both bleeding and thrombosis, as well as a lack of randomized controlled data, limit conclusive assessments regarding optimal management of anticoagulation in this setting. In this review, we summarize the relevant literature pertaining to PVT in cirrhosis, including the effect of untreated PVT on the natural progression of liver disease and the overall impact of anticoagulation on clot burden and other relevant clinical outcomes. Apart from patients who are symptomatic or listed for liver transplantation, data supporting anticoagulation for the treatment of PVT is limited and without clear consensus guidelines. In patients with cirrhosis without PVT, emerging evidence for the role of prophylactic anticoagulation to mitigate the progression of fibrosis suggests an optimal risk-benefit tradeoff with decreased rates of liver decompensation and mortality, without a heightened risk of bleeding. In summation, as our understanding of the role of both prophylactic and therapeutic anticoagulation in cirrhosis continues to evolve, ongoing risk stratification of patients with asymptomatic PVT demands further attention.

Chronic liver disease, thrombocytopenia and procedural bleeding risk; are novel thrombopoietin mimetics the solution?

Chronic liver disease (CLD) alters normal hemostatic and thrombotic systems via multiple mechanisms including reduced platelet function and number, leading to challenging peri-operative planning. Hepatic thrombopoietin (TPO) synthesis is reduced in CLD, leading to several recent randomized, placebo-controlled trials examining the utility of TPO-mimetics to increase platelet counts prior to surgery. While these trials do suggest that TPO-mimetics are efficacious at increasing platelet counts in patients with CLD and have led to several recent drug approvals in this space by the U.S. Food & Drug Administration, it remains unclear whether these results translate to the relevant clinical endpoint of reduced perioperative bleeding rate and severity. In this article, we review several recently-published, phase 3 trials on the TPO-mimetics eltrombopag, avatrombopag and lusutrombopag, and discuss the clinical significance of their results.

Factors that Predict Failure to Meet Merit-Based Incentive Payment System Quality Measures for Asymptomatic Carotid Endarterectomy.

BACKGROUND: The Physician Quality Reporting System (PQRS) created by the Centers for Medicare and Medicaid Services financially penalizes providers who fail to meet expected quality of care measures. The purpose of this study is to evaluate the factors that predict failure to meet PQRS measures for carotid endarterectomy (CEA). METHODS: PQRS measure 260 (discharge by postoperative day 2 following CEA in asymptomatic patients) and 346 (rate of postoperative stroke or death following CEA in asymptomatic patients) were evaluated using hospital records from the state of Florida from 2008 to 2012. The impact of demographics, comorbidities, hospital factors, admission variables, and individual practitioner data upon timely discharge, and postoperative stroke and death. Odds ratios, 95% confidence intervals, and significance (P < 0.05) were determined through the development of a logistic regression model. Surgeons were identified by national provider identifier number, and practitioner data obtained from the American Medical Association Physician Masterfile. RESULTS: A total of 34,235 patient records and 701 providers were identified over the 5-year period. Significant negative predictors for PQRS measure 260 included weekend admission (odds ratio [OR], 2.9), Medicaid (OR, 2.4), surgeon historical postoperative stroke rate >2.0% (OR, 1.7), African-American race (OR, 2.0), and female gender (OR, 1.3). The presence of any of these factors was associated with a 13.5% rate of failure. The most significant negative predictor for PQRS measure 346 was surgeon postoperative stroke rate >2.0% (OR, 6.2 for stroke and OR, 29.0 for death). Surgeons in this underperforming group had worse outcomes compared to their peers despite having patients with fewer risk factors for poor outcomes. Surgeon specialty, board certification, and case volume do not impact either PQRS measures. CONCLUSIONS: Selected groups of patients and surgeons with a disproportionately high rate of postoperative stroke are at risk of failing to meet PQRS pay for performance quality measures. Awareness of these risk factors may help mitigate and minimize the risk of adversely impacting the value stream. Further evaluation of the causative factors that lead to surgeon underperformance could help to improve the quality of care.

Treatment of Stress Velopharyngeal Incompetence With Injection of Hyaluronic Acid.

Stress velopharyngeal incompetence (VPI) is a challenging clinical entity that can be managed by a variety of surgical and nonsurgical approaches. We describe the case of a clarinetist who presented with nasal air escape while playing. She had successful improvement in her symptoms after targeted injection of a hyaluronic acid compound to her posterior pharyngeal wall. Our objective is to describe the safety and efficacy of this technique, to emphasize the multidisciplinary management of patients with stress VPI, and to review the importance of both nasopharyngoscopy and videofluoroscopy in their evaluation.

Progressive shortfall in open aneurysm experience for vascular surgery trainees with the impact of fenestrated and branched endovascular technology.

BACKGROUND: In 2014, we published a series of articles in the Journal of Vascular Surgery that detailed the decrease in volume of open aneurysm repair (OAR) completed for abdominal aortic aneurysm (AAA) by vascular surgery trainees. At that time, only data points from 2000 through 2011 were available, and reliable predictions could only be made through 2015. Lack of data on endovascular aneurysm repair (EVAR) using fenestrated (FEVAR) and branched (BrEVAR) endografts also affected our findings. Despite these limitations, our predictions for OAR completed by vascular trainees were accurate for 2012 to 2014. This report uses updated data points through 2014 in conjunction with data on FEVAR and BrEVAR obtained from industry to predict trends in OAR and how it will affect vascular surgery training through 2020. METHODS: An S-curve modified logistic function was used to model the effect of introducing new technologies (EVAR, FEVAR, BrEVAR) on the standard management of AAA with OAR starting in the year 2000, similar to the technique that we have previously described. Weighted samples and data from the United States Census Bureau were used in conjunction with volume estimates derived from the National Inpatient Sample, State Inpatient Databases, and industry sources to determine trends in OAR and EVAR. The number of cases completed at teaching hospitals was calculated using the National Inpatient Sample, and Accreditation Council for Graduate Medical Education case logs were used to forecast the number of cases completed by vascular surgery trainees through 2020. Sensitivity analysis and trend analysis were completed. RESULTS: Approximately 45,000 AAA repairs are completed annually in the United States, but only 15% of these are now completed using OAR compared with >50% just a decade ago. Further, with the accelerating adoption of FEVAR and BrEVAR, and expanding indications for standard EVAR, our model predicts that <3000 OARs will be completed annually by 2020. Because only a subset of these cases are completed at teaching institutions, our model predicts that a vascular surgery trainee in a fellowship program will complete only one to two OARs, whereas trainees in a 0+5 program may complete two to three OARs. CONCLUSIONS: Our initial prediction in the 2014 report was that vascular trainees would complete approximately five OARs by 2020. After incorporating new data on BrEVAR, FEVAR, and the accelerating pace of EVAR use between 2012 and 2014, it now appears that vascular trainees will complete one to three OARs during their training.

Curcumin-mediated regulation of Notch1/hairy and enhancer of split-1/survivin: molecular targeting in cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is highly malignant and characterized by poor prognosis with chemotherapeutic resistance. Therefore, continued development of novel, effective approaches are needed. Notch expression is markedly upregulated in CCA, but the utility of Notch1 inhibition is not defined. Based on recent findings, we hypothesized that curcumin, a polyphenolic phytochemical, suppresses CCA growth in vitro via inhibition of Notch1 signaling. METHODS: Established CCA cell lines CCLP-1 and SG-231 were treated with varying concentrations of curcumin (0-20 µM). Viability was assessed through 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide and clonogenic assays. Evaluation of apoptosis was determined via Western analysis for apoptotic markers and Caspase-Glo 3/7 assay. Cell lysates were further analyzed via Western blotting for Notch1/HES-1/survivin pathway expression, cell cycle progression, and survival. RESULTS: Curcumin-treated CCA cells exhibited reduced viability compared with control treatment. Statistically significant reductions in cell viability were observed with curcumin treatment at concentrations of 7.5, 10, and 15 µM by approximately 10%, 48%, and 56% for CCLP-1 and 13%, 25%, and 50% for SG-231, respectively. On Western analysis, concentrations of ≥10 µM showed reductions in Notch1, HES-1, and survivin. Apoptosis was evidenced by an increase in expression of cleaved poly [ADP] ribose polymerase and an increase in caspase activity. Cyclin D1 (cell cycle progression) expression levels were also reduced with treatment. CONCLUSIONS: Curcumin effectively induces CCA (CCLP-1 and SG-231) growth suppression and apoptosis at relatively low treatment concentrations when compared with the previous research. A concomitant reduction of Notch1, HES-1, and survivin expression in CCA cell lines provides novel evidence for a potential antitumorigenic mechanism-of-action. To our knowledge, this is the first report showing reduction in HES-1 expression via protein analysis after treatment with curcumin. Such findings merit further investigation of curcumin-mediated inhibition of Notch signaling in CCA either alone or in combination with chemotherapeutic agents.

Potential Molecular Targeted Therapeutics: Role of PI3-K/Akt/mTOR Inhibition in Cancer.

Primary liver cancer is one of the most commonly occurring cancers worldwide. Hepatocellular carcinoma (HCC) represents the majority of primary liver cancer and is the 3rd most common cause of cancer-related deaths globally. Survival rates of patients with HCC are dependent upon early detection as concomitant liver dysfunction and advanced disease limits traditional therapeutic options such as resection or ablation. Unfortunately, at the time of diagnosis, most patients are not eligible for curative surgery and have a five-year relative survival rate less than 20%, leading to systemic therapy as the only option. Currently, sorafenib is the only approved systemic therapy; however, it has a limited survival advantage and low efficacy prompting alternative strategies. The inception of sorafenib for HCC systemic therapy and the understanding involved of cancer therapy have led to an enhanced focus of the PI3-k/Akt/mTOR pathway as a potential area of targeting including pan and isoform-specific PI3-K inhibitors, Akt blockade, and mTOR suppression. The multitude, expanding roles, and varying clinical trials of these inhibitors have led to an increase in knowledge and availability for current and future studies. In this review, we provide a review of the literature with the aim to focus on potential targets for HCC therapies as well as an in depth focus on Akt inhibition.