Comprehensive evaluation and efficient classification of BRCA1 RING domain missense substitutions.

BRCA1 is a high-risk susceptibility gene for breast and ovarian cancer. Pathogenic protein-truncating variants are scattered across the open reading frame, but all known missense substitutions that are pathogenic because of missense dysfunction are located in either the amino-terminal RING domain or the carboxy-terminal BRCT domain. Heterodimerization of the BRCA1 and BARD1 RING domains is a molecularly defined obligate activity. Hence, we tested every BRCA1 RING domain missense substitution that can be created by a single nucleotide change for heterodimerization with BARD1 in a mammalian two-hybrid assay. Downstream of the laboratory assay, we addressed three additional challenges: assay calibration, validation thereof, and integration of the calibrated results with other available data, such as computational evidence and patient/population observational data to achieve clinically applicable classification. Overall, we found that 15%-20% of BRCA1 RING domain missense substitutions are pathogenic. Using a Bayesian point system for data integration and variant classification, we achieved clinical classification of 89% of observed missense substitutions. Moreover, among missense substitutions not present in the human observational data used here, we find an additional 45 with concordant computational and functional assay evidence in favor of pathogenicity plus 223 with concordant evidence in favor of benignity; these are particularly likely to be classified as likely pathogenic and likely benign, respectively, once human observational data become available.

Atypical aortic thrombus: should nonoperative management be first line?

BACKGROUND: Aortic thrombus in the absence of atherosclerotic plaque or aneurysm is rare, and its optimal management remains unclear. Although atypical aortic thrombus (AAT) has been historically managed operatively, successful nonoperative strategies have been recently reported. Here, we report our experience in treating patients with AAT that has evolved from a primarily operative approach to a first-line, nonoperative strategy. METHODS: Records of patients treated for AAT between 2008 and 2011 at our institution were reviewed. RESULTS: Ten female and three male patients with ages ranging from 27 to 69 were identified. Seven were treated operatively and 6 nonoperatively. Initial presentation was variable and included limb thromboembolic events (n = 6), visceral ischemia (n = 5), and stroke (n = 1). Associated risk factors included hypercoagulability (76%; n = 10) and hyperlipidemia (38%, n = 5). In the nonoperative group, complete thrombus resolution was obtained via anticoagulation (n = 5) or systemic thrombolysis (n = 1). Complete thrombus extraction was achieved in all operative patients. There were 11 significant complications in 5 of the 7 patients (71%) in the operative group, including intraoperative lower extremity embolism, pericardial effusion, stroke, and 1 death. There was 1 complication in the patients treated nonoperatively. The median hospital length of stay was 9 days (range 3-49) for those treated nonoperatively and 30 days (range 4-115) for those undergoing operative thrombectomy. CONCLUSIONS: Although AAT has traditionally been treated operatively, nonoperative management of AAT with anticoagulation or thrombolysis is feasible in selected patients and may lessen morbidity and length of hospitalization in those patients for whom it is appropriate.

Incidence of and risk factors for iliocaval venous obstruction in patients with active or healed venous leg ulcers.

BACKGROUND: Iliocaval venous obstruction (ICVO) can be a significant contributor to venous hypertension in patients with advanced disease. The incidence of ICVO in patients with CEAP clinical class 5 and 6 disease has not been reported. In this study, we reviewed a series of patients with healed or active venous leg ulcers to determine the incidence of ICVO and the risk factors related to its occurrence. METHODS: Patients with CEAP clinical class 5 and 6 venous insufficiency underwent evaluation with duplex ultrasound scan to identify the presence of venous reflux in the deep and superficial systems and either computed tomography (CT) or magnetic resonance (MR) venography to identify ICVO. The venograms were evaluated by two separate examiners to calculate the percentage of obstruction in the iliocaval outflow tract. Demographics and risk factors related to venous disease were collected and examined for their association with severe ICVO. RESULTS: A total of 78 CEAP clinical class 5 and 6 patients evaluated with either a CT or MR venogram were retrospectively reviewed. The average patient age was 59.3 years and 53.4% were men. The ulcer affected the left lower extremity in 46% of cases and 50% of patients reported a medical history of deep vein thrombosis (DVT). Overall, 37% of imaging studies demonstrated ICVO of at least 50% and 23% had obstruction of >80%. Risk factors that were found to be independently associated with a significantly higher incidence of >80% ICVO included female gender (P = .023), a medical history of DVT (P = .035), and reflux in the deep venous system (P = .035). No limb with superficial venous reflux (SVR) alone was found to have ICVO >80%. CONCLUSIONS: ICVO is a frequent and underappreciated contributor to venous hypertension in patients with venous leg ulcers. Women and patients with a history of DVT or duplex scan-diagnosed deep venous reflux (DVR) have a higher incidence of outflow obstruction and should be routinely studied with CT or MR venography to allow correction in this high-risk group of patients.

Laparoscopic Total Gastrectomy with D2 Lymphadenectomy and Side-to-Side Stapled Esophagojejunostomy.

INTRODUCTION: An optimal method has yet to be established for laparoscopic total gastrectomy with intracorporeal anastomosis. METHODS: We aim to describe a simple technique for intracorporeal anastomoses. Technique of laparoscopic total gastrectomy with side-to-side stapled intracorporeal esophagojejunostomy anastomosis and Roux-en-Y jejunojejunostomy is performed on patients with gastric malignancy in an academic community tertiary care center. RESULTS: The anastomotic technique of laparoscopic total gastrectomy with side-to-side stapled esophagojejunostomy is described. CONCLUSION: Laparoscopic total gastrectomy with D2 lymphadenectomy and side-to-side esophagojejunostomy is safe to perform and has the advantage of a wide lumen with low chance for stricture. A laparoscopic total gastrectomy with stapled side-to-side esophagojejunostomy is feasible and safe in advanced gastric cancer.

Tissue-engineered vascular grafts: autologous off-the-shelf vascular access?

Dialysis grafts have provided reliable access for millions of patients in need of renal replacement therapy. However, regardless of the material used for artificial dialysis grafts their mean patency remains generally poor and infection rates are greater than native arteriovenous fistulas. The need for superior alternatives to conventional synthetic materials used for vascular access has been an area of investigation for more than 25 years and recently there has been a great deal of progress in the field of tissue-engineered vascular grafts. Many of these technologies are either commercially available or are now entering early phases of clinical trials. This review briefly covers the history, potential advantages, and disadvantages of these technologies, which are likely to create an impact in the field of vascular access surgery.

Efficacy and tolerability of laparoscopic-assisted radiofrequency ablation of hepatocellular carcinoma in patients above 60 years of age.

The purpose of this study was to evaluate the safety and efficacy of laparoscopic-assisted radiofrequency ablation (RFA) in patients with hepatocellular carcinoma above the age of 60 years. A single-center, retrospective study of a prospective dataset evaluated efficacy and morbidity of RFA in patients above 60 years of age. About 37% of patients had an intrahepatic recurrence 1 year after ablation. By multivariate analysis, only the number of lesions ablated was a predictor of recurrence (P=0.007). Overall mortality was 19% at 1 year and factors associated with mortality include elevated α-fetoprotein, number of lesions ablated, and platelet count. Complications occurred in 10% of our population with 1 death. RFA is well tolerated in patients of 60 years of age and above. The outcomes in this study validate a local ablative strategy for the treatment of hepatocellular carcinoma in the elderly and it is superior to no treatment alone.