Faculty Bibliography

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.

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.

OBJECTIVE:Given that financial considerations play an increasingly prominent role in clinical decision-making, we sought (1) to determine the cost-effectiveness of in-office biopsy for the patient, the provider, and the health-care system, and (2) to determine the diagnostic accuracy of in-office biopsy. STUDY DESIGN/METHODS:Retrospective, financial analyses were performed. METHODS:Patients who underwent in-office (Current Procedural Terminology Code 31576) or operative biopsy (CPT Code 31535) for laryngopharyngeal lesions were included. Two financial analyses were performed: (1) the average cost of operating room (OR) versus in-office biopsy was calculated, and (2) a break-even analysis was calculated to determine the cost-effectiveness of in-office biopsy for the provider. In addition, the diagnostic accuracy of in-office biopsies and need for additional biopsies or procedures was recorded. RESULTS:Of the 48 patients included in the current study, 28 underwent in-office biopsy. A pathologic sample was obtained in 26 of 28 (92.9%) biopsies performed in the office. Of these patients, 16 avoided subsequent OR procedures. The average per patient cost was $7000 and $11,000 for in-office and OR biopsy, respectively. Break-even analysis demonstrated that the provider could achieve a profit 2 years after purchase of the necessary equipment. CONCLUSION/CONCLUSIONS:In-office laryngopharyngeal biopsies are accurate and, overall, more cost-effective than OR biopsies. Purchase of the channeled, distal chip laryngoscope and biopsy forceps to perform in-office biopsies can be profitable for a provider with a videolaryngoscopy tower. In-office biopsy should be considered the initial diagnostic tool for suspected laryngopharyngeal malignancies noted on videolaryngoscopy.

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.

Pain is rated by oral cancer patients as the worst symptom and significantly impairs a patient's ability to eat, talk, and drink. Mediators, secreted from oral cancer microenvironment, excite primary afferent neurons, which in turn generate pain. Oral cancer cells release TNFalpha which induces acute inflammation and nociception in mice. We hypothesize that TNFalpha activates Schwann cells to amplify pain signals. First, we confirmed the involvement of TNFalpha in oral cancer pain in patients and animal models. We found that oral cancer tissues collected from patients have higher TNFalpha concentration compared to anatomically matched normal tissues. Differences in TNFalpha concentration between the tumor and anatomically matched normal tissues correlate positively with total pain scores. In a Nitroquinoline 1-oxide (4NQO) mouse oral cancer model we demonstrated reduced mechanical hypersensitivity (P<0.05, N=8) with the dolognawmeter gnawing assay when TNFalpha was neutralized with C-87. Using a non-contact co-culture model, we found that HSC-3 cells induced a more activated human primary Schwann cells phenotype with increased proliferation (P<0.05) and migration (P<0.05); introduction of C-87 in the co-culture reduced Schwann cell proliferation (P<0.05) and migration (P<0.05) induced by HSC-3 cells. After removal of the co-cultured cancer cells, cancer-activated Schwann cells secrete greater amounts of TNFalpha and nerve growth factor (NGF), another known nociceptive mediator in the oral cancer microenvironment, compared to Schwann cells initially co-cultured with DOK (P<0.05) or naive Schwann cells (P<0.05). To determine whether activated Schwann cells mediate oral cancer pain, we cultured Schwann cells in hypoxic conditions - a known cancer stimulus that induces robust Schwann cell activation. Schwann cell supernatant was then collected and injected into the mouse cheek. Supernatant from hypoxia-activated Schwann cells induced greater facial allodynia (measured with von Frey filaments) in mice (P<0.05, N=7), compared to supernatant from Schwann cells cultured in normoxic conditions (N=5). C-87 significantly reduced facial allodynia caused by hypoxiaactivated Schwann cells (P<0.05, N=5). We infer from our results that TNFalpha plays a role in the activation of Schwann cells and that cancer-activated Schwann cells are a source of nociceptive mediators in the cancer microenvironment. Inhibition of Schwann cell activation might be clinically useful for alleviating oral cancer pain

BACKGROUND:Radiation-associated-dysphagia is a serious side effect of radiotherapy (RT) for head and neck cancer (HNC). METHODS:Seventy-six patients had a weekly prospective follow-up from baseline until one week post-RT. Combined mixed model analysis (n = 43) determined the evolution of self-perceived swallowing function, isometric tongue strength (MIP), tongue strength (TS) during swallowing (Pswal), and quality of life (QoL) in these patients during RT. RESULTS:Swallowing deteriorated from the third week on, resulting in an increase of tube dependency from 10% at baseline toward 31% post-RT. Both MIP and Pswal are reduced, with anterior MIP decreasing in 29% of patients and posterior MIP in 17%. Pswal decreases for saliva and a bolus swallow. All QoL subscales except "sleep" were affected during RT. CONCLUSIONS:Self-perceived swallowing function, TS and QoL decrease during RT for HNC. Current findings highlight the need for early monitoring of these parameters.

BACKGROUND:Injection medialization is performed to improve glottic closure, thereby airway protection. Overall objective to determine if unilateral injection medialization changes glottal area with concomitant adjustments in penetration/aspiration scale (PAS) scores and pharyngeal high-resolution manometry (HRM) parameters. METHODS:Enrolled 17 adults with unilateral vocal fold paralysis/paresis and aspiration/penetration. Fiberoptic endoscopic evaluation of swallowing and pharyngeal HRM completed at (1) baseline (within 1 week before injection), (2) postinjection (within 1 week post injection), and (3) 1-month postinjection. Comparisons between time points for PAS scores, glottal area, pharyngeal pressure, and timing. RESULTS:No significant differences in normalized glottal area. No significant differences in PAS scores, for any consistency. Significantly increased rate of mesopharynx pressure rise and maximum pressure at 1 month postinjection (P = .01 and .02, respectively) compared to baseline. Significant decrease in mesopharynx integral from baseline to 1 week postoperative (P = .03). CONCLUSION/CONCLUSIONS:Findings suggest unilateral vocal fold injection medialization had limited effect on swallow function.