Synthesis, modeling, and biological evaluation of anti-tubulin indole-substituted furanones.

Due to the central role of tubulin in various cellular functions, it is a validated target for anti-cancer therapeutics. However, many of the current tubulin inhibitors are derived from complex natural products and suffer from multidrug resistance, low solubility, toxicity issues, and/or the lack of multi-cancer efficacy. As such, there is a continued need for the discovery and development of new anti-tubulin drugs to enter the pipeline. Herein we report on a group of indole-substituted furanones that were prepared and tested for anti-cancer activity. Molecular docking studies showed positive correlations between favorable binding in the colchicine binding site (CBS) of tubulin and anti-proliferative activity, and the most potent compound was found to inhibit tubulin polymerization. These compounds represent a promising new structural motif in the search for small heterocyclic CBS cancer inhibitors.

Initial presentation of human papillomavirus-related head and neck cancer: A retrospective review.

OBJECTIVE: Human papillomavirus (HPV) has been identified as a risk factor for oropharyngeal squamous cell carcinoma (OPSCC) and a cause of the recent dramatic rise in the incidence of this disease. HPV-positive OPSCC typically affects a younger population and has no validated screening test. This study aims to outline the common presenting signs of HPV-positive OPSCC. METHODS: We conducted a retrospective single-institution review on 370 patients who were treated at the Icahn School of Medicine at Mount Sinai, New York City, between April 2007 and November 2015 for OPSCC. We included patients with newly diagnosed OPSCC and sufficient history and physical data in the final analysis. Univariate analysis was used to compare HPV-positive and HPV-negative cohorts for demographics, tumor location, tumor staging, initial presentation and symptoms, and physical exam findings. RESULTS: Two hundred and seven patients met the inclusion criteria. The most common initial symptoms for OPSCC were neck mass (51.7%) and sore throat (13.0%). The HPV-positive cohort was more likely to present with a chief complaint of neck mass compared to the HPV-negative cohort (56.1% vs. 22.2%; P = 0.0015). A positive neck exam was associated with HPV-positive status (73.9% vs. 40.7%; P = 0.0012). CONCLUSION: HPV-positive OPSCC is an incipient epidemic, poised to surpass cervical cancer as the most common HPV-related cancer by 2020. Initial presenting signs may often be mistaken for benign processes. This study provides physicians with a better understanding of initial presentation of patients with HPV-positive OPSCC, leading to earlier diagnosis and improved outcomes. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:877-882, 2019.

Application of the Eighth Edition American Joint Committee on Cancer Staging System for HPV-Related Oropharyngeal Cancer Treated With Transoral Robotic Surgery.

OBJECTIVE: Analyze patients treated with transoral robotic surgery (TORS) in the context of the eighth edition of the American Joint Committee on Cancer (AJCC) staging system. METHODS: Retrospective cohort study including 110 human papillomavirus-related oropharyngeal cancer (HPV+OPC) patients with a minimum 1-year follow-up treated with TORS between 2007 to 2016. Kaplan-Meier methods were used to estimate 3-year disease-free survival and assess differences in recurrence. RESULTS: One hundred and ten patients with a median follow-up of 54 months were analyzed. Of those, 85% of patients were male, with a median age of 60. Twenty-two percent of patients received no adjuvant therapy; 43% received adjuvant radiation; and 35% underwent adjuvant chemoradiation. Extracapsular spread was identified in 24% of patients. Overall survival was 100%, with estimated 3-year disease-free survival (DFS) (95% confidence interval) of 87% (77, 93). Under the seventh edition of the AJCC, 5% of patients were stage I; 11% were stage II; 26% were stage III; and 57% were stage IVa. Twenty-seven patients (25%) were upstaged on final pathology, whereas 15 patients (14%) were downstaged. Under the eighth edition of the AJCC, 94% of patients were stage I for both clinical and pathologic staging systems. Six patients (6%) were upstaged on final pathology, whereas six patients (6%) were downstaged. No factors demonstrated statistical significance for DFS. Within pathologic stage I, Kaplan-Meier estimates for DFS did not reach statistical significance. CONCLUSION: The majority of patients undergoing TORS for HPV + OPC are stage I under the eighth edition of the AJCC staging system, with limited pathologic re-staging compared with the prior system. Oncologic outcomes are favorable for this group. No clinicopathologic features are significant for DFS within pathologic stage I. LEVEL OF EVIDENCE: 2b. Laryngoscope, 128:1133-1139, 2018.

Association of Body Mass Index With Infectious Complications in Free Tissue Transfer for Head and Neck Reconstructive Surgery.

Importance: Elevated body mass index (BMI) has been proposed as a risk factor for morbidity and mortality among patients undergoing surgery. Conversely, an elevated BMI may confer a protective effect on perioperative morbidity. Objective: To examine whether an elevated BMI is an independent risk factor for perioperative and postoperative infectious complications after free tissue transfer in head and neck reconstructive surgery. Design, Setting, and Participants: This cohort study included patients undergoing major head and neck surgery requiring free tissue transfer at a tertiary care center. Data were collected for 415 patients treated from January 1, 2007, through December 31, 2014. Main Outcomes and Measures: The outcome of interest was postoperative infection and complications after head and neck surgery using free flaps. Covariates considered for adjustment in the statistical model included alcohol consumption (defined as >5 drinks per day [eg, 360 mL of beer, 150 mL of wine, or 45 mL of 80-proof spirits]), type 2 diabetes, prior radiotherapy, anesthesia time, hypothyroidism, smoking, American Society of Anesthesiologists classification, antibiotic regimen received (defined as a standard regimen of a first- or second-generation cephalosporin with or without metronidazole hydrochloride vs an alternative antibiotic regimen for patients allergic to penicillin), and primary surgeon. A multiple logistic regression model was developed for the incidence of the infection end point as a function of elevated BMI (>30.0). Results: Among the 415 patients included in this study (277 men [66.7%] and 138 women [33.2%]; mean [SD] age, 61.5 [13.9] years), type 2 diabetes and use of an alternative antibiotic regimen were found to be independently associated with increased infectious complications after free flap surgery of the head and neck, with estimated odds ratios of 2.78 (95% CI, 1.27-6.09) and 2.67 (95% CI, 1.14-6.25), respectively, in the multiple logistic regression model. However, a high BMI was not found to be statistically significant as an independent risk factor for postoperative infectious complication (estimated odds ratio, 1.19; 95% CI, 0.48-2.92). Conclusions and Relevance: Elevated BMI does not seem to play a role as an independent risk factor in postoperative complications in free tissue transfer in head and neck surgery.

CDH23 Related Hearing Loss: A New Genetic Risk Factor for Semicircular Canal Dehiscence?

OBJECTIVE: To investigate the prevalence and relative risk of semicircular canal dehiscence (SCD) in pediatric patients with CDH23 pathogenic variants (Usher syndrome or non-syndromic deafness) compared with age-matched controls. STUDY DESIGN: Retrospective cohort study. SETTING: Multi-institutional study. PATIENTS: Pediatric patients (ages 0-5 years) were compared based on the presence of biallelic pathogenic variants in CDH23 with pediatric controls who underwent computed tomography (CT) temporal bone scan for alternative purposes. INTERVENTIONS: Retrospective review of diagnostic high resolution CT temporal bone scans and magnetic resonance imaging (MRI) for evaluation of SCD. MAIN OUTCOME MEASURES: Superior and posterior semicircular canals were evaluated by a neuroradiologist for presence of SCD or abnormal development. RESULTS: Forty-two CT scans were reviewed for SCD. Eighty-six percent of the CDH23 variant group had abnormalities in at least one canal compared with only 12% in age-matched controls. In the CDH23 variant group there were four patients with superior SCD (57%, RR = 10.0) and three patients with posterior canal abnormalities (43%, RR = 7.5) compared with two, and two patients, respectively, in the control population. Four CDH23 variant children had bilateral abnormalities. One child had thinning or dehiscence in both the superior and posterior canals. Relative risk of SCD in children with CDH23 pathogenic variants is 7.5 (p < 0.001) compared with the pediatric control population. CONCLUSIONS: Children with a CDH23 pathogenic variants are at significantly increased risk of having SCD and this may be a contributing factor to the vestibular dysfunction in Usher syndrome type 1D patient population.

Facial Transplantation.

Reconstruction of severe facial deformities poses a unique surgical challenge: restoring the aesthetic form and function of the face. Facial transplantation has emerged over the last decade as an option for reconstruction of these defects in carefully selected patients. As the world experience with facial transplantation grows, debate remains regarding whether such a highly technical, resource-intensive procedure is warranted, all to improve quality of life but not necessarily prolong it. This article reviews the current state of facial transplantation with focus on the current controversies and challenges, with particular attention to issues of technique, immunology, and ethics.

VA Telemedicine: An Analysis of Cost and Time Savings.

INTRODUCTION: The Veterans Affairs (VA) healthcare system provides beneficiary travel reimbursement ("travel pay") to qualifying patients for traveling to appointments. Travel pay is a large expense for the VA and hence the U.S. Government, projected to cost nearly $1 billion in 2015. Telemedicine in the VA system has the potential to save money by reducing patient travel and thus the amount of travel pay disbursed. In this study, we quantify this savings and also report trends in VA telemedicine volumes over time. MATERIALS AND METHODS: All telemedicine visits based at the VA Hospital in White River Junction, VT between 2005 and 2013 were reviewed (5,695 visits). Travel distance and time saved as a result of telemedicine were calculated. Clinical volume in the mental health department, which has had the longest participation in telemedicine, was analyzed. RESULTS: Telemedicine resulted in an average travel savings of 145 miles and 142 min per visit. This led to an average travel payment savings of $18,555 per year. Telemedicine volume grew significantly over the study period such that by the final year the travel pay savings had increased to $63,804, or about 3.5% of the total travel pay disbursement for that year. The number of mental health telemedicine visits rose over the study period but remained small relative to the number of face-to-face visits. A higher proportion of telemedicine visits involved new patients. CONCLUSIONS: Telemedicine at the VA saves travel distance and time, although the reduction in travel payments remains modest at current telemedicine volumes.

Posterior semicircular canal dehiscence: CT prevalence and clinical symptoms.

OBJECTIVE: To estimate the prevalence of and symptoms associated with posterior semicircular canal dehiscence (PSCD) compared to superior semicircular canal dehiscence (SSCD) and nondehiscent semicircular canals (NDSC). STUDY DESIGN: Retrospective review. SETTING: Academic tertiary referral center. PATIENTS: Review of 412 temporal bone CT scans and associated patient records, excluding patients with prior mastoid or skull base surgery. INTERVENTION(S): CT images (0.625 mm thick) were reviewed in the planes of the semicircular canals. Patient demographics and symptoms were tabulated and analyzed. MAIN OUTCOME MEASURE(S): Prevalence of PSCD and SSCD; degree of hearing loss; presence or absence of aural fullness, autophony, tinnitus, pulsatile tinnitus, disequilibrium, vertigo, and Tullio phenomenon. RESULTS: Review of the 412 CT scans revealed 5 cases of PSCD (1.2%) and 20 cases of SSCD (4.9%). All patients with PSCD were male, aged 16 to 73 years. One patient with PSCD reported tinnitus, autophony, disequilibrium, vertigo, and Tullio phenomenon; 2 patients reported only tinnitus and aural fullness, and 1 patient had no symptoms. PSCD was commonly associated with SSCD. There were no significant differences in symptoms between PSCD patients and the other groups. There were, however, statistically significant differences between SSCD patients and NDSC patients in the rates of autophony, tinnitus, and disequilibrium. CONCLUSION: The prevalence of PSCD in patients undergoing temporal bone CT scans is considerably less than SSCD (1.2% versus 4.9%), and the 2 conditions commonly coexist. Given the small numbers in our study, we were not able to demonstrate any distinguishable clinical features for the PSCD patients.

Negligible effect of perioperative epidural analgesia among patients undergoing elective gastric and pancreatic resections.

BACKGROUND: There are conflicting data regarding improvements in postoperative outcomes with perioperative epidural analgesia. We sought to examine the effect of perioperative epidural analgesia vs. intravenous narcotic analgesia on perioperative outcomes including pain control, morbidity, and mortality in patients undergoing gastric and pancreatic resections. METHODS: We evaluated 169 patients from 2007 to 2011 who underwent open gastric and pancreatic resections for malignancy at a university medical center. Emergency, traumatic, pediatric, enucleations, and disseminated cancer cases were excluded. Clinicopathologic data were reviewed among epidural (E) and non-epidural (NE) patients for their association with perioperative endpoints. RESULTS: One hundred twenty patients (71 %) received an epidural and 49 (29 %) did not. There were no significant differences (P > 0.05) in mean pain scores at each of the four days (days 0-3) among the E (3.2 ± 2.7, 3.2 ± 2.3, 2.3 ± 1.9, and 2.1 ± 1.9, respectively) and NE patients (3.7 ± 2.7, 3.4 ± 1.9, 2.9 ± 2.1, and 2.4 ± 1.9, respectively). Within each of the E and NE patient groups, there were significant differences (P < 0.0001) in mean pain scores from day 0 to day 3 (P < 0.0001). Of the E patients, 69 % also received intravenous patient-controlled analgesia (PCA). Ileus (13 % E vs. 8 % NE), pneumonia (12 % E vs. 8 % NE), venous thromboembolism (6 % E vs. 4 % NE), length of stay [11.0 ± 12.1 (8, 4-107) E vs. 12.2 ± 10.7 (7, 3-54) NE], overall morbidity (36 % E vs. 39 % NE), and mortality (4 % E vs. 2 % NE) were not significantly different. CONCLUSIONS: Routine use of epidurals in this group of patients does not appear to be superior to PCA.

Negligible effect of selective preoperative biliary drainage on perioperative resuscitation, morbidity, and mortality in patients undergoing pancreaticoduodenectomy.

OBJECTIVE: To examine the effect of selective preoperative biliary drainage (BD) on perioperative resuscitation, morbidity, and mortality in patients undergoing pancreaticoduodenectomy. Biliary drainage prior to pancreaticoduodenectomy remains controversial. Proponents argue that it facilitates referral to high-volume tertiary centers, while detractors maintain that it increases surgical morbidity and mortality. DESIGN: Retrospective analysis of single-institution tumor registry database. SETTING: University medical center. PATIENTS: From October 1, 2003, to May 31, 2008, 90 patients underwent pancreaticoduodenectomy for periampullary mass lesions. MAIN OUTCOME MEASURES: Clinicopathologic data were reviewed and analyzed among patients who did and did not receive BD for their association with perioperative outcomes. chi(2) Analysis, independent-samples t tests, and Mann-Whitney U tests were used as appropriate. RESULTS: Fifty-six patients (62%) underwent BD, and 34 (38%) did not. Intraoperative bile cultures were positive for 1 or more species of microorganisms in 88% of stented patients (35 of 40). There were no significant differences in fluid requirements, transfusion requirements, or surgery duration between patients who did and did not undergo BD. Estimated blood loss was increased in patients who received BD (625 mL vs 525 mL in patients who did not undergo BD; P = .03), while reoperation was significantly more common in nonstented patients (4% vs 15% in patients who did not undergo BD; P = .02). Intensive care unit stay, overall length of stay, pancreatic leak/abscess/fistula, infectious complications, postoperative percutaneous drainage, hospital readmission, and 30- and 90-day mortality were not significantly different between the 2 groups. CONCLUSIONS: Although preoperative biliary stents may complicate the intraoperative management and lessen the postoperative complications of patients undergoing pancreaticoduodenectomy, only estimated blood loss and reoperation were significantly different in this cohort. Further study may reveal patient subgroups who may specifically benefit or suffer from preoperative biliary stenting. Currently, selective preoperative BD appears appropriate in the multidisciplinary management of patients with periampullary lesions.

In vitro characterization of a compliant biodegradable scaffold with a novel bioreactor system.

The influence of scaffold compliance on blood vessel tissue engineering remains unclear and compliance mismatch issues are important to an in vivo tissue-engineering approach. We have designed and constructed a modular bioreactor system that is capable of imparting pulsatile fluid flow while simultaneously measuring vessel distension with fluid pressure changes in real time. The setup uses a pneumatic PID control system to generate variable fluid pressure profiles via LabVIEW and an LED micrometer to monitor vessel distension to an accuracy of +/-2 microm. The bioreactor was used to measure the compliance of elastomeric poly(1,8-octanediol citrate) (POC) scaffolds over physiologically relevant pressure ranges. The compliance of POC scaffolds could be adjusted by changing polymerization conditions resulting in scaffolds with compliance values that ranged from 3.8 +/- 0.2 to 15.6 +/- 4.6%/mmHg x 10(-2), depending on the distension pressures applied. Furthermore, scaffolds that were incubated in phosphate-buffered saline for 4 weeks exhibited a linear increase in compliance (2.6 +/- 0.9 to 7.7 +/- 1.2%/mmHg x 10(-2)) and were able to withstand normal physiological blood pressure without bursting. The ability to tailor scaffold compliance and easily measure vessel compliance in real time in vitro will improve our understanding of the role of scaffold compliance on vascular cell processes.