Faculty Bibliography

OBJECTIVE:The effectiveness of µ-opioid receptor (MOPr) agonists for treatment of visceral pain is compromised by constipation, respiratory depression, sedation and addiction. We investigated whether a fentanyl analogue, (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NFEPP), which preferentially activates MOPr in acidified diseased tissues, would inhibit pain in a preclinical model of inflammatory bowel disease (IBD) without side effects in healthy tissues. DESIGN/METHODS:Antinociceptive actions of NFEPP and fentanyl were compared in control mice and mice with dextran sodium sulfate colitis by measuring visceromotor responses to colorectal distension. Patch clamp and extracellular recordings were used to assess nociceptor activation. Defecation, respiration and locomotion were assessed. Colonic migrating motor complexes were assessed by spatiotemporal mapping of isolated tissue. NFEPP-induced MOPr signalling and trafficking were studied in human embryonic kidney 293 cells. RESULTS:NFEPP inhibited visceromotor responses to colorectal distension in mice with colitis but not in control mice, consistent with acidification of the inflamed colon. Fentanyl inhibited responses in both groups. NFEPP inhibited the excitability of dorsal root ganglion neurons and suppressed mechanical sensitivity of colonic afferent fibres in acidified but not physiological conditions. Whereas fentanyl decreased defecation and caused respiratory depression and hyperactivity in mice with colitis, NFEPP was devoid of these effects. NFEPP did not affect colonic migrating motor complexes at physiological pH. NFEPP preferentially activated MOPr in acidified extracellular conditions to inhibit cAMP formation, recruit β-arrestins and evoke MOPr endocytosis. CONCLUSION/CONCLUSIONS:In a preclinical IBD model, NFEPP preferentially activates MOPr in acidified microenvironments of inflamed tissues to induce antinociception without causing respiratory depression, constipation and hyperactivity.

PURPOSE/UNASSIGNED:While sinusitis carries a seasonal variation, the temporal features of sinusitis-related orbital cellulitis (SRC) are unclear. This study analyzes the incidence, seasonality, management, and outcomes of SRC in northeastern New York. METHODS/UNASSIGNED:A retrospective review of 79 patients was performed from January 2008 - December 2018. Cases of orbital cellulitis without comitant sinusitis were excluded. Demographic, radiographic, clinical features, month at presentation, interventions (surgical and nonsurgical), microbiology, and hospitalization duration were recorded. Fisher-exact test, Mann-Whitney test, and Kruskal Wallis test statistical analyses were performed in consultation with our institution's statistician via a dedicated software package (vassarstats.net). RESULTS/UNASSIGNED:= .76). CONCLUSION/UNASSIGNED:Our findings suggest that cases requiring surgical management for SRC should undergo coinitial orbitotomy with FESS to reduce re-operation rates. Additionally, SRC incidence and severity did not correlate with season.

Squamous cell carcinoma of the head and neck (SCCHN) is a devastating disease that continues to have low cure rates despite the recent advances in therapies. Cisplatin is the most used chemotherapy agent, and treatment failure is largely driven by resistance to this drug. Amplification of chromosomal band 11q13 occurs in ∼30% of SCCHN tumors. This region harbors the ANO1 gene that encodes the TMEM16A ion channel, which is responsible for calcium-activated chloride transport in epithelial tissues. TMEM16A overexpression is associated with cisplatin resistance, and high TMEM16A levels correlate with decreased survival. However, the mechanistic underpinning of this effect remains unknown. Lysosomal biogenesis and exocytosis have been implicated in cancer because of their roles in the clearance of damaged organelles and exocytosis of chemotherapeutic drugs and toxins. Here, we show that TMEM16A overexpression promotes lysosomal biogenesis and exocytosis, which is consistent with the expulsion of intracellular cisplatin. Using a combination of genetic and pharmacologic approaches, we find that TMEM16A promotes lysosomal flux in a manner that requires reactive oxygen species, TRPML1, and the activation of the β-catenin–melanocyte-inducing transcription factor pathway. The lysosomal inhibitor hydroxychloroquine (HCQ) synergizes with cisplatin in killing SCCHN cells in vitro. Using a murine model of SCCHN, we show that HCQ and cisplatin retard the growth of cisplatin-resistant patient-derived xenografts in vivo. We propose that TMEM16A enables cell survival by the up-regulation of lysosomal sequestration and exocytosis of the cytotoxic drugs. These results uncover a model of treatment for resistance in cancer, its reversal, and a role for TMEM16A.

OBJECTIVE:Acinic cell carcinoma (AciCC) is a rare, usually low-grade salivary malignancy. Evidence on rates of lymph node metastases (LNMs) is limited in pediatric patients and varies significantly (4%-45%) in adults. We set out to determine and compare rates of LNMs in pediatric and adult AciCC and to analyze their impact on survival, using the National Cancer Database. STUDY DESIGN/METHODS:Historical cohort study. SETTING/METHODS:National Cancer Database. METHODS:All AciCCs of the major salivary glands with complete clinical and pathologic nodal staging were selected between 2010 and 2016. Patient demographics, tumor characteristics, treatment, and survival were analyzed. Univariable and multivariable regression were performed to determine factors associated with LNMs and survival. RESULTS:< .001) were associated with LNM in adult patients. CONCLUSION/CONCLUSIONS:LNMs in AciCC of the major salivary glands are rare in children and adults. However, high-grade and T3-T4 tumors are associated with an increased risk of LNM. LNM is associated with worse survival.

Oral cancer patients report sensitivity to spicy foods and liquids. The mechanism responsible for chemosensitivity induced by oral cancer is not known. We simulate oral cancer-induced chemosensitivity in a xenograft oral cancer mouse model using two-bottle choice drinking and conditioned place aversion assays. An anatomic basis of chemosensitivity is shown in increased expression of TRPV1 in anatomically relevant trigeminal ganglion (TG) neurons in both the xenograft and a carcinogen (4-nitroquinoline 1-oxide)-induced oral cancer mouse models. The percent of retrograde labeled TG neurons that respond to TRPV1 agonist, capsaicin, is increased along with the magnitude of response as measured by calcium influx, in neurons from the cancer models. To address the possible mechanism of TRPV1 sensitivity in tongue afferents, we study the role of PAR₂, which can sensitize the TRPV1 channel. We show co-expression of TRPV1 and PAR₂ on tongue afferents and using a conditioned place aversion assay, demonstrate that PAR₂ mediates oral cancer-induced, TRPV1-evoked sensitivity in an oral cancer mouse model. The findings provide insight into oral cancer-mediated chemosensitivity.

OBJECTIVES/UNASSIGNED:Removal of a cochlear implant and its intracochlear electrode array is sometimes necessary, potentially causing cochlear explant trauma. Explantation typically occurs years post-implantation by which time reactive tissue has formed around the electrode. We aimed to create an in-vitro electrode explant model to examine explant forces and intracochlear trauma across multiple electrode types and insertion depths. STUDY DESIGN/UNASSIGNED:An in-vitro model using gel to represent tissue surrounding the electrode was developed. Pre-curved electrodes and straight electrodes at different insertion depths (20mm, 25mm, 28mm) were explanted from the model. During explantation, explant force was measured, and high-definition videos were recorded to capture electrode exit path and gel disruption. RESULTS/UNASSIGNED:Explant force patterns varied based on electrode position in the scala tympani. Explant forces did not correlate with gel disruption, which represented explant trauma. The least gel disruption occurred with pre-curved electrodes and the under-inserted straight electrode. The greatest disruption occurred with the overly inserted straight electrode. CONCLUSION/UNASSIGNED:An in-vitro model using gel to mimic tissue surrounding the electrode may provide insights into potential electrode explant trauma. Explant force did not correlate with explant trauma in our model. Pre-curved electrodes and shallower insertion depth of a straight electrode resulted in the least amount of explant trauma.

BACKGROUND:Addressing operational inefficiencies in operating rooms (ORs) enhances patient access to care, reduces delays, and improves employee and patient satisfaction. The Comprehensive Unit-based Safety Program (CUSP) promotes patient safety through increased teamwork, empowerment of frontline staff, and utilization of science of safety principles. CUSP has demonstrated success in outpatient and inpatient settings to decrease complication rates and establish a culture of safety but has been used minimally in the perioperative setting. In this study, the CUSP methodology was utilized to improve perioperative efficiency in pediatric spine surgery, and preimplementation and postimplementation efficiency were compared, using the rate of first case on-time starts (FCOTS) as the primary metric. METHODS:A CUSP quality improvement workgroup including nurses, technicians, surgeons, anesthesiologists, and administrators sought feedback on opportunities for improvement and tracked key performance metrics in the OR from 2015 to 2020. Key interventions developed in response to feedback included standardizing and streamlining room setup and adjusting staffing models for greater efficiency. Univariate analysis was conducted to compare time periods pre-CUSP and post-CUSP implementation. RESULTS:First case on-time starts increased from 38% to a high of 81% after implementation. For more complex cases, the average patient in the room to anesthesia ready time improved by 31% with decreased variance over time, and average closure to patient out of room time improved by 45%. Improvements were sustained through Year 3, while CUSP remained a primary focus for the team. CONCLUSIONS:CUSP is effective in enhancing perioperative efficiency, demonstrating strong improvement in on-time starts over 5 years. The results indicate that process improvement in ORs requires consistent attention to sustain gains over time. Engaging frontline staff in quality improvement fosters collaboration and provides employee buy-in to promoting a culture of safety and improving value in patient care. LEVEL OF EVIDENCE/METHODS:Level III-retrospective comparative study.

Successful tracheal reconstruction remains a challenging task for the reconstructive surgeon. A variety of techniques have been previously employed, using both autografts and allografts. The authors present a novel method for tracheal reconstruction utilizing a prelaminated fascial flap in conjunction with a bioabsorbable scaffold. Laryngoscope, 2021.