The Clinical Utility of Next Generation Sequencing Results in a Community-Based Hereditary Cancer Risk Program.

Since the 2013 Supreme Court ruling on BRCA1/BRCA2 patenting, hereditary cancer gene panels now include BRCA1 and BRCA2, making these panels an option for first-tier testing. However, questions remain about the clinical utility and implications of these panels for medical management with inclusion of genes of unknown to moderate penetrance. To better understand how use of these panels affected our practice, we reviewed patients who underwent testing in our clinic from July 1, 2013 through May 23, 2014. Indications for testing included personal and/or family history of breast and/or ovarian cancer. A total of 136 patients underwent panel testing via a single commercial laboratory; 12 (8.8 %) patients were positive for a pathogenic or likely pathogenic mutation (four BRCA2 mutations, two TP53 mutations, one CDH1 mutation, two ATM mutations, and one patient each with a CHEK2, NBN, or PALB2 mutation). Of these positive patients, 100 % met the National Comprehensive Cancer Network (NCCN) guidelines for Hereditary Breast and Ovarian Cancer genetic testing (2.2014). Mutations in seven of twelve (58 %) patients led to changes in medical management; three of seven (43 %) had a non-BRCA1 or BRCA2 gene mutation. Our findings suggest that there is clinical utility of panels that include genes of unknown to moderate penetrance.

Pharmacodynamics and effectiveness of topical nitroglycerin at lowering blood pressure during autonomic dysreflexia.

STUDY DESIGN: Secondary analysis of prospectively collected observational data assessing the safety of an autonomic dysreflexia (AD) management protocol. OBJECTIVES: To estimate the time to onset of action, time to full clinical effect (sustained systolic blood pressure (SBP) <160 mm Hg) and effectiveness of nitroglycerin ointment at lowering blood pressure for patients with spinal cord injuries experiencing AD. SETTING: US Veterans Affairs inpatient spinal cord injury (SCI) unit. METHODS: Episodes of AD recalcitrant to nonpharmacologic interventions that were given one to two inches of 2% topical nitroglycerin ointment were recorded. Pharmacodynamics as above and predictive characteristics (through a mixed multivariate logistic regression model) were calculated. RESULTS: A total of 260 episodes of pharmacologically managed AD were recorded in 56 individuals. Time to onset of action for nitroglycerin ointment was 9-11 min. Time to full clinical effect was 14-20 min. Topical nitroglycerin controlled SBP <160 mm Hg in 77.3% of pharmacologically treated AD episodes with the remainder requiring additional antihypertensive medications. A multivariate logistic regression model was unable to identify statistically significant factors to predict which patients would respond to nitroglycerin ointment (odds ratios 95% confidence intervals 0.29-4.93). The adverse event rate, entirely attributed to hypotension, was 3.6% with seven of the eight events resolving with close observation alone and one episode requiring normal saline. CONCLUSIONS: Nitroglycerin ointment has a rapid onset of action and time to full clinical effect with high efficacy and relatively low adverse event rate for patients with SCI experiencing AD.

Functional outcomes and survival after total glossectomy with laryngectomy: a systematic review.

Total glossectomy with laryngectomy (TGL) is a procedure with high morbidity/mortality risks reserved for cases of advanced tongue cancer with laryngeal invasion. This technique is controversial as there are significant impacts on quality of life, including loss of functional speech and swallowing. A systematic review was performed following the PRISMA guidelines with the primary goal of quantifying the functional outcomes and overall survival of patients undergoing TGL. The initial search resulted in 748 studies; seven of these met the inclusion criteria. Five studies evaluated functional speech postoperatively, and 12.1% (8/66) of patients in these studies achieved a form of functional speech. Most studies did not refer to the use of specific postoperative voice rehabilitation. Regarding swallowing function, 53.3% (32/60) of patients in five studies regained their ability to swallow. In six studies reporting gastrostomy tube dependence, 37.7% (29/77) of patients were tube-dependent. Recurrence within 1-year was reported in three studies; 52% (26/50) of the patients had recurrence within 1 year, and the 1-year disease-free survival rate was 48%. TGL is a highly invasive surgery; postoperatively, most patients do not regain the ability to speak, while only half are able to swallow. Despite these extreme efforts and sacrifices by the patient, approximately half of patients have a recurrence within the first year. The decision to perform a TGL should be made only in select and motivated patients after carefully explaining and weighing the oncological and quality of life risks and benefits.

Self-inflicted craniomaxillofacial gunshot wounds: management, reconstruction, and outcomes.

Suicide by firearm remains one of the leading causes of violence-related injury death in the United States each year. The mortality rate from these injuries is high, resulting in a paucity of outcome data in the literature regarding injuries to the maxillofacial region. This has largely been attributed to a lack of funding for research in this area compared to other leading causes of mortality in the United States. The aim of this study was to detail the authors' experience and approach to complex maxillofacial reconstruction using both local reconstructive methods and microvascular free tissue transfer. A retrospective cohort study was designed, including patients who sustained self-inflicted gunshot wounds to the maxillofacial region between January 1, 2012 and May 1, 2020. Forty-one patients met the inclusion criteria. The majority of the patients were male (87.8%). Mean patient age was 44.2 ± 16.6 years. Alcohol or drugs, and a psychiatric history were present in a majority of the cases. The most involved anatomical region was the midface (75.6% of cases). Seven patients required free tissue transfer for reconstruction, with many needing multiple flaps. Self-inflicted gunshot wounds represent challenging reconstruction scenarios, often in the setting of severe psychological trauma, and require a multidisciplinary team to ensure the optimal outcome.

Contrasting opioid use for pain management in microvascular head and neck reconstruction: an international study.

Opioids are often the mainstay of postoperative pain management, despite strong evidence of their ill effects and potential for long-term addiction. The goal of this study was to quantify opioid use and contrast pain management strategies of multiple international institutions performing fibula free flap reconstruction. A retrospective multicenter cohort study was designed, including five international centers. For inclusion, the patients had to have undergone a primary fibula free flap reconstruction of the mandible. A total of 185 patients were included. The median opioid use across all centers at 72 hours was 133 oral morphine equivalents. The highest utilization was in the USA (P < 0.001), which was approximately six times that of Italy, four times that of Argentina, and twice that of India, despite all centers performing a similar procedure. Based on this study there are clear differences in prescribing practices and ideologies among surgeons from different countries.

Accuracy of virtual planned surgery versus conventional free-hand surgery for reconstruction of the mandible with osteocutaneous free flaps.

Virtual surgical planning (VSP) promises higher accuracy, efficiency, and superior patient outcomes, helping normalize outcomes from surgeons of different experience levels. A systematic review was conducted in agreement with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The objective was to evaluate the accuracy and secondarily efficiency of VSP compared with free-hand surgery, for mandibular reconstruction with free flaps. Six studies met inclusion criteria and had quantitative data suitable for meta-analysis. Intercondylar distance and gonion angle were used to assess accuracy, evaluated by mean change from preoperative VSP and postoperative imaging. The mean weighted difference in VSP intercondylar distance was 2.0 mm, compared with 3.9 mm for free hand (P=0.101) and mean change in gonion angle for VSP was 3.6°, compared with 7.7° for free hand (P<0.05). Efficiency assessed by mean ischemia time, was 73.8min and 109.9min, for VSP and free hand, respectively (P=0.203), and by total operative time, which was 391.8 min and 457.6 min in the VSP and free hand, respectively (P=0.340). VSP is consistently proven to be more accurate and efficient than traditional free-hand surgery; however, a standardized method for accuracy and efficiency measurements is still missing, causing heterogeneity among the scientific reports.

An analysis of unplanned readmissions after head and neck microvascular reconstructive surgery.

The 30-day readmission rate is a highly scrutinized metric of quality surgical care, because readmission is costly and perceived to be avoidable with planning and patient education. Head and neck surgery patients generally have multiple risk factors for readmission, as readmitted patients are generally older, with more co-morbidities, lower socio-economic status, and a history of multiple emergency department visits and readmissions. A retrospective cohort study was implemented to determine the incidence and etiology of 30-day readmission after microvascular head and neck reconstructive surgery, focusing on social risk factors. Data were analyzed by χ2 test, analysis of variance, t-test, and logistic regression, with statistical significance set at P<0.05. Of 209 patients included in this study, 35 (16.7%) had a 30-day readmission. Increased needs at discharge were associated with increased readmission, while other social risk factors were less significant for a readmission in this study.

Head and neck surgery is a risk factor for atrial fibrillation: incidence and outcomes.

Atrial fibrillation (AF) is the most common postoperative arrhythmia and can cause increased length of stay, costs, morbidity, and mortality. Little information exists about postoperative AF after major head and neck surgery, but it is thought to occur more frequently than after surgery at other extra-thoracic sites. A retrospective cohort study was implemented, including patients who had undergone major head and neck surgery and who had follow-up records covering a minimum of 60 days postoperative. The main outcome was the incidence of new onset postoperative AF after major head and neck surgery; secondary outcomes were the incidence of any AF, the role of cardiology, predictors of AF postoperatively, and clinical outcomes. A total 337 patients were included. Twenty-four patients experienced AF postoperatively (7.1%), of whom 12 (3.6%) had new onset AF. New onset AF was associated with advanced age of ≥65 years (odds ratio 11.6, P=0.027) and having a laryngectomy (odds ratio 9.9, P=0.003). Postoperative AF following major head and neck surgery is not a rare phenomenon and can be associated with considerable morbidity and costs due to the need for intensive care, specialty consultations, additional testing and laboratory studies, and cardiology follow-up.

A modest glucokinase overexpression in the liver promotes fed expression levels of glycolytic and lipogenic enzyme genes in the fasted state without altering SREBP-1c expression.

Hepatic genes crucial for carbohydrate and lipid homeostasis are regulated by insulin and glucose metabolism. However, the relative contributions of insulin and glucose to the regulation of metabolic gene expression are poorly defined in vivo. To address this issue, adenovirus-mediated hepatic overexpression of glucokinase was used to determine the effects of increased hepatic glucose metabolism on gene expression in fasted or ad libitum fed rats. In the fasted state, a 3 fold glucokinase overexpression was sufficient to mimic feeding-induced increases in pyruvate kinase and acetyl CoA carboxylase mRNA levels, demonstrating a primary role for glucose metabolism in the regulation of these genes in vivo. Conversely, glucokinase overexpression was unable to mimic feeding-induced alterations of fatty acid synthase, glucose-6-phosphate dehydrogenase, carnitine palmitoyl transferase I or PEPCK mRNAs, indicating insulin as the primary regulator of these genes. Interestingly, glucose-6-phosphatase mRNA was increased by glucokinase overexpression in both the fasted and fed states, providing evidence, under these conditions, for the dominance of glucose over insulin signaling for this gene in vivo. Importantly, glucokinase overexpression did not alter sterol regulatory element binding protein 1-c mRNA levels in vivo and glucose signaling did not alter the expression of this gene in primary hepatocytes. We conclude that a modest hepatic overexpression of glucokinase is sufficient to alter expression of metabolic genes without changing the expression of SREBP-1c.