Faculty Bibliography

BACKGROUND:cisplatin regimens. METHODS:From 2011 to 2016, 163 patients received concurrent cisplatin and intensity-modulated radiotherapy for locally advanced HNSCC. Primary endpoints were overall survival (OS) and progression-free survival. RESULTS:(P = 0.04) regimens. CONCLUSION/CONCLUSIONS:chemotherapy regimens.

OBJECTIVES/OBJECTIVE:Many clinics are faced with the difficulty of evaluating performance in patients who speak a language for which there are no validated tests. It would be desirable to have a nonlinguistic method of evaluating these patients. Spectral ripple tests are nonlinguistic and highly correlated with speech identification performance. However, they are generally not amenable to clinical environments as they typically require the use of computers which are often not found in clinic sound booths. In this study, we evaluate the Spectral-temporally Modulated Ripple Test (SMRT) Lite for computeRless Measurement (SLRM), which is a new variant of the adaptive SMRT that can be implemented via a CD player. DESIGN/METHODS:SMRT and SLRM were measured for 10 normal hearing and 10 cochlear implant participants. RESULTS:Performance on the two tests was highly correlated (r = 0.97). CONCLUSIONS:The results suggest that SLRM can be used interchangeably with SMRT but can be implemented without a computer.

Neurofibromatosis type 2 (NF2) is an autosomal-dominant disorder characterized by the development of bilateral vestibular schwannomas. The NF2 gene encodes the tumor suppressor merlin, and loss of merlin activity promotes tumorigenesis and causes NF2. Cellular redox signaling has been implicated in different stages of tumor development. Among reactive nitrogen species, peroxynitrite is the most powerful oxidant produced by cells. We recently showed that peroxynitrite-mediated tyrosine nitration down-regulates mitochondrial metabolism in tumor cells. However, whether peroxynitrite supports a metabolic shift that could be exploited for therapeutic development is unknown. Here, we show that vestibular schwannomas from NF2 patients and human, merlin-deficient (MD) Schwann cells have high levels of endogenous tyrosine nitration, indicating production of peroxynitrite. Further, scavenging or inhibiting peroxynitrite formation significantly and selectively decreased survival of human and mouse MD-Schwann cells. Using multiple complementary methods, we also found that merlin deficiency leads to a reprogramming of energy metabolism characterized by a peroxynitrite-dependent decrease of oxidative phosphorylation and increased glycolysis and glutaminolysis. In MD Schwann cells, scavenging of peroxynitrite increased mitochondrial oxygen consumption and membrane potential, mediated by the up-regulation of the levels and activity of mitochondrial complex IV. This increase in mitochondrial activity correlated with a decrease in the glycolytic rate and glutamine dependency. This is the first demonstration of a peroxynitrite-dependent reprogramming of energy metabolism in tumor cells. Oxidized proteins constitute a novel target for therapeutic development not only for the treatment of NF2 schwannomas but also other tumors in which peroxynitrite plays a regulatory role.

BACKGROUND/UNASSIGNED:Improved player safety is an important goal of professional baseball. Prevention of mild traumatic brain injury (concussion) is an area of emphasis because of the potential for long-term as well as short-term sequelae. HYPOTHESIS/UNASSIGNED:A rule change can lower the incidence of concussions and other injuries in professional baseball. STUDY DESIGN/UNASSIGNED:Cohort study; Level of evidence, 3. METHODS/UNASSIGNED:This study included a retrospective review of data entered concurrently into professional baseball's electronic medical record system. All minor and major league teams are required to use this system. All injuries are captured by creation of a new record in the system at the time of the injury. All active minor and major league players from 2011 to 2017 were included. The 30 major league clubs have 1200 roster players and play 162 games per season. The approximately 200 minor league clubs have about 7500 active players and play 56 to 144 games annually that combine for approximately 330,000 athlete-exposures per season. Before the 2014 season, Major League Baseball, in conjunction with its players association, instituted a rule limiting home plate collisions between base runners and catchers that applied to both Major League Baseball and Minor League Baseball. All concussions and other injuries at home plate from 2011 to 2017 were analyzed by mechanism and player position. RESULTS/UNASSIGNED:= .0001). CONCLUSION/UNASSIGNED:This rule change was associated with significant reductions in the numbers of concussions and other injuries caused by collisions at home plate as well as significant decreases in time lost from play.

Head and neck squamous cell carcinomas (HNSCC) represent a group of epithelial neoplasms that exhibit considerable heterogeneity in clinical behavior. Here, we examined the stromal and vascular heterogeneity in a panel of patient-derived xenograft (PDX) models of HNSCC and the impact on therapeutic response. Tumor sections from established tumors were stained for p16 (surrogate for human papillomavirus (HPV) infection), stromal (Masson's trichrome) and vascular (CD31) markers. All PDX models retained the HPV/p16 status of the original patient tumor. Immunohistochemical evaluation revealed the presence of multiple vessel phenotypes (tumor, stromal or mixed) in the PDX panel. Vascular phenotypes identified in the PDX models were validated in a tissue microarray of human HNSCC. Treatment with a microtubule targeted vascular disrupting agent (VDA) resulted in a heterogeneous antivascular and antitumor response in PDX models. The PDX with the tumor vessel phenotype that exhibited higher CD31+ vessel counts and leaky vasculature on magnetic resonance imaging (MRI) was sensitive to VDA treatment while the PDX with the stromal vessel phenotype was resistant to therapy. Collectively, our results demonstrate the phenotypic and functional vascular heterogeneity in HNSCC and highlight the impact of this heterogeneity on response to antivascular therapy in PDX models of HNSCC.

Proteases sustain hyperexcitability and pain by cleaving protease-activated receptor-2 (PAR₂) on nociceptors through distinct mechanisms. Whereas trypsin induces PAR₂ coupling to Gα_q, Gα_s, and β-arrestins, cathepsin-S (CS) and neutrophil elastase (NE) cleave PAR₂ at distinct sites and activate it by biased mechanisms that induce coupling to Gα_s, but not to Gα_q or β-arrestins. Because proteases activate PAR₂ by irreversible cleavage, and activated PAR₂ is degraded in lysosomes, sustained extracellular protease-mediated signaling requires mobilization of intact PAR₂ from the Golgi apparatus or de novo synthesis of new receptors by incompletely understood mechanisms. We found here that trypsin, CS, and NE stimulate PAR₂-dependent activation of protein kinase D (PKD) in the Golgi of HEK293 cells, in which PKD regulates protein trafficking. The proteases stimulated translocation of the PKD activator Gβγ to the Golgi, coinciding with PAR₂ mobilization from the Golgi. Proteases also induced translocation of a photoconverted PAR₂-Kaede fusion protein from the Golgi to the plasma membrane of KNRK cells. After incubation of HEK293 cells and dorsal root ganglia neurons with CS, NE, or trypsin, PAR₂ responsiveness initially declined, consistent with PAR₂ cleavage and desensitization, and then gradually recovered. Inhibitors of PKD, Gβγ, and protein translation inhibited recovery of PAR₂ responsiveness. PKD and Gβγ inhibitors also attenuated protease-evoked mechanical allodynia in mice. We conclude that proteases that activate PAR₂ by canonical and biased mechanisms stimulate PKD in the Golgi; PAR₂ mobilization and de novo synthesis repopulate the cell surface with intact receptors and sustain nociceptive signaling by extracellular proteases.

Background: Abnormal blood glucose (BG) levels during hematopoietic cell transplantation (HCT) are associated with increased infections, delayed engraftment, and prolonged hospitalization, though little is known about these associations. Materials and Methods: We retrospectively evaluated mean BG levels in the week prior to HCT and subsequent outcomes for 852 HCTs at our hospital from 1/2009 - 12/2013 pertaining to 745 patients. Outcomes included infections (pneumonia, C. difficile, positive cultures, administration of antimicrobials, or neutropenic fever), time-to-engraftment (TTE), and quality indicators (30- and 90-day readmission rates [RR] and median length-of-stay [LOS]). Results: 404 patients met the criteria for involvement in this study. The population was 55% male and was racially and ethnically mixed (White 38%, African American 23%, Hispanic 6%, Asian 7%, Other 21%). Mean age was 57+14 years. Significantly more patients in Group 2 were diagnosed with pneumonia (19%) compared with the Group 1 (7%) and Group 3 (10%) [p=.0054]. Patients in Group 2 also had significantly longer median LOS: Group 1-23 days, Group 2-26 days, Group 3-22 days [p = .0157]. No significant differences were noted in terms of the other infectious complications or in time-to-engraftment or readmissions. Conclusion: Pre-HCT BG trends may be a prognostic biomarker for adverse outcomes, and thus can help improve quality of care for HCT patients.

General dentists (GDs) have the opportunity to examine their patients for oral premalignancy/malignancy. We estimated the annualized per dentist number of oral lesions suspicious for premalignancy/malignancy discovered by United States (U.S.) general dentists and the annualized per dentist number of histologically-confirmed cancers subsequently diagnosed. Eligible participants were licensed, clinically-active U.S. GDs who were members of the U.S. National Dental Practice-Based Research Network. An a priori sample size of 900 was determined; 2000 GDs were invited to participate; 1,073 completed the study. Self-reported, cross-sectional data were obtained via an online questionnaire during 4/12/2017-8/31/2017 and analyzed. The reported numbers of suspicious oral lesions and histologically-confirmed oral cancer cases diagnosed over the previous six months were quantified. Potential outcome predictors were evaluated as covariates in multivariable analyses. Crude and adjusted statistics were produced by regressing each outcome on each independent variable while assuming a Poisson distribution, log link and utilizing robust standard errors. Eighty-seven percent of dentists reported discovering 1+ lesion suspicious for oral premalignancy/malignancy during the preceding six months. The mean number of suspicious lesions/dentist/year was 9.5; adjusted mean: 9.6. Fifteen percent of participants reported discovering 1+ lesion confirmed as cancer during the same period, 213 confirmed cancer cases/6 months or 426/year. Crude and adjusted mean numbers of histologically-confirmed oral cancers were both 0.4 cancers/dentist/year. Our findings suggest that many U.S. general dentists are actively identifying oral lesions suspicious for premalignancy/malignancy, thereby aiding in the discovery of oral malignancies and representing an important component in the frontline against cancer.

OBJECTIVE:To describe and assess intraoperative and postoperative outcomes in the insertion of osseointegrated auditory implants with a newly designed surgical instrumentation set through a punch type technique. STUDY DESIGN/METHODS:Retrospective case series. METHODS:Patients who underwent bone anchored auditory implant surgery using the Minimally Invasive Ponto Surgery (Oticon Medical, Somerset, NJ) surgical set through a punch technique at nine neurotology tertiary referral based practices were identified. Demographic data, skin thickness at implant site, implant used, duration of surgery, adverse intraoperative events, and postoperative outcomes were recorded. RESULTS:Seventy-five patients comprised the study cohort (32 males, 43 females). Most patients (57. 3%) were aged 51 to 75 years while 30.7% of the cohort comprised those aged 18 to 50 years and 12% were over 75 years. All but two patients received 4 mm fixtured implants and 68% received the Oticon Medical BioHelix implant. Two patients received 3 mm fixture implants and 32% received the Oticon Medical Wide Ponto implant. Mean surgical time was 12.2 minutes (6-45 min, standard deviation of 6.88 min). In three instances, surgery was converted to a linear incision to control brisk bleeding. Skin condition was Holgers 0 to 1 in 91.8%, while 5.5% had Holgers 2, and 2.7% had Holgers 3 at the first postoperative visit. At second postoperative visit, 94.3% had Holgers 0 to 1, 4.3% had Holgers 2, and 1.4% had Holgers 3. All instances of adverse skin reactions were treated with topical or systemic antibiotics and/or local debridement. There were no instances of implant loss. One patient had his implant traumatically displaced to a 45-degree angle necessitating implant replacement at a second site. CONCLUSION/CONCLUSIONS:Punch technique placement of osseointegrated auditory implants using the Minimally Invasive Ponto Surgery surgical set represents a safe technique that further simplifies a progressively minimally invasive surgery.