Faculty Bibliography

OBJECTIVE/UNASSIGNED:We sought to consolidate the anatomical findings from radiologic research and prior surgical literature to develop a stepwise surgical approach utilizing cadaveric specimens which can serve to improve the accuracy and scalability of surgical apical cochleostomies in the future. METHODS/UNASSIGNED:Cadaveric temporal bone dissections, with subsequent image documentation and distance measurements to confirm surgical accuracy. RESULTS/UNASSIGNED:All four temporal bones (100%) that were drilled utilizing the newly developed surgical approach had an accurately placed apical cochleostomy. No inadvertent entry into the middle turn of the cochlea occurred. There was no violation of the labyrinthine facial nerve, or carotid artery. CONCLUSIONS/UNASSIGNED:Preliminary findings are promising for the described steps to achieve a substantial improvement in apical cochleostomy accuracy, with reduced trauma compared to historically taught techniques.

PURPOSE/OBJECTIVE:This prospective, non-randomized phase II single-arm pilot trial aimed to explore favorable mid-treatment nodal response (FMNR) through CT imaging to guide de-escalated chemoradiation therapy (CRT) in patients with favorable risk, node-positive HPV-associated oropharyngeal cancer (OPC). MATERIALS AND METHODS/METHODS:. At week 4, CT imaging evaluated nodal response: ≥40% reduction warranted de-escalation to 60 Gy, while <40% reduction continued standard CRT. Primary endpoint was 2-year PFS from initiation of dose de-escalated CRT. Tissue tumor modified viral (TTMV) HPV DNA samples and DW-MRI were collected at baseline and week 4. MDADI questionnaires were collected at baseline, 1, 3, 6, 12, and 24 months. RESULTS:Of 39 patients, 26 had FMNR and underwent de-escalated treatment. 13 pts had slow mid-treatment nodal shrinkage and received standard dose. At a median follow-up of 47.4 months, the 2-year PFS was 92.1% (95% CI: 0.72-0.98) for the deescalated dose group and 92.3% for the standard dose patients (95% CI: 0.57-0.99), p=0.96. With a median survival follow up of 48.9 months (range: 16.7-77.8 months), there were no deaths or distant failures. FMNR was associated with rapid TTMV HPV DNA clearance, reduced TTMV HPV DNA flare, lower baseline and week 4 MRI diffusivity, and higher baseline and week 4 MRI diffusional kurtosis. No differences in acute or late maximum grade 3-4 toxicity by patient were noted. MDADI composite scores showed minimal clinical important difference (MCID) in the de-escalated group at 1-month post-treatment while the standard group had MCID up to 1-year post-treatment. No patients required feeding tube placement. CONCLUSIONS:De-escalated CRT using CT-based mid-treatment nodal response in favorable risk, node-positive HPV-associated OPC achieved excellent 2-year PFS and OS rates and represents a potential approach in better selecting patients for treatment de-escalation.

BACKGROUND:Pituitary neuroendocrine tumors (PitNETs) are the most common intracranial neuroendocrine tumors. PitNETs can be challenging to classify, and current recommendations include a large immunohistochemical panel to differentiate among 14 WHO-recognized categories. METHODS:In this study, we analyzed clinical, immunohistochemical and DNA methylation data of 118 PitNETs to develop a clinico-molecular approach to classifying PitNETs and identify epigenetic classes. RESULTS:CNS DNA methylation classifier has an excellent performance in recognizing PitNETs and distinguishing the three lineages when the calibrated score is ≥0.3. Unsupervised DNA methylation analysis separated PitNETs into two major clusters. The first was composed of silent gonadotrophs, which form a biologically distinct group of PitNETs characterized by clinical silencing, weak hormonal expression on immunohistochemistry, and simple copy number profile. The second major cluster was composed of corticotrophs and Pit1 lineage PitNETs, which could be further classified using DNA methylation into distinct subclusters that corresponded to clinically functioning and silent tumors and are consistent with transcription factor expression. Analysis of promoter methylation patterns correlated with lineage for corticotrophs and Pit1 lineage subtypes. However, the gonadotrophic genes did not show a distinct promoter methylation pattern in gonadotroph tumors compared to other lineages. Promoter of the NR5A1 gene, which encodes SF1, was hypermethylated across all PitNETs clinical and molecular subtypes including gonadotrophs with strong SF1 protein expression indicating alternative epigenetic regulation. CONCLUSION/CONCLUSIONS:Our findings suggest that classification of PitNETs may benefit from DNA methylation for clinicopathological stratification.

BACKGROUND:Inferring risk for malignant transformation (MT) in patients with lesions diagnosed as mild or moderate oral epithelial dysplasia (low-grade OED) remains challenging. We developed two models assessing the risk of progression to high-grade OED (severe dysplasia or carcinoma in situ) or OSCC in patients with low-grade OED lesions. METHODS:We included demographic, risk habit and clinical data from participants with low-grade OED lesions enrolled in the BC Oral Cancer Prevention Program's Oral Cancer Prediction Longitudinal study. Cox proportional hazard models were fit to estimate the effects of anatomic site and toluidine blue findings and adjusted for confounders, as both are associated with MT in the literature but without a North American-specific cohort analysis. Our primary model included both variables of interest. A secondary model included only anatomic site since toluidine blue is not in widespread use. RESULTS:Five hundred and thirty-four participants with 605 lesions met final inclusion criteria, with 339 mild and 266 moderate OED at baseline. In the primary model, lesions at a high-risk anatomic site or with positive toluidine blue staining were associated with a 2.6 and 2.4-fold increased risk of progression, respectively. In the second model that did not incorporate toluidine blue, high-risk anatomic site remained a highly associated risk factor (2.7-fold increased risk of progression). CONCLUSION/CONCLUSIONS:Lesion anatomic site is associated with higher risk of MT for the general practitioner, while a specialist with access to toluidine blue results can assume additional risk associated with positive staining. These models may inform decisions for surveillance and intervention for OED.

By improving the delivery and tumor retention of chemotherapeutics, nanomedicines hold potential for cancer treatment. The usefulness of nanoparticle (NP)-encapsulated analgesics for the cancer pain treatment is comparatively unexplored. We investigated whether NPs encapsulating olcegepant (OCP), an antagonist of the calcitonin receptor-like receptor (CLR) for the calcitonin gene-related peptide (CGRP), effectively relieved oral cancer pain in mice. Because persistent endosomal CLR signaling in Schwann cells mediates craniofacial pain, we reasoned that the predisposition of NPs to accumulate in endosomes could be leveraged to effectively relieve oral cancer pain. By expressing biosensors for activated CLR, Gα proteins and β-arrestins in HEK293T and Schwann cells, we found that CGRP activates CLR signaling first at the plasma membrane and then in early, late and recycling endosomes and the cis- and trans-Golgi apparatus. We synthesized biocompatible NPs encapsulating OCP and fluorophores by integrating hydrophobic ion pairing nanoformulation with Flash NanoPrecipitation. NPs slowly released OCP and accumulated in early endosomes, leading to sustained inhibition of endosomal CLR signaling in HEK293T and Schwann cells. Oral cancers were established in mice, which led to heightened pain-like responses. After intra-tumoral injection, NPs were retained in tumors for at least one week. OCP-loaded NPs almost completely reversed allodynia and hyperalgesia for a prolonged period, whereas unencapsulated OCP had small and transient effects. The NP accumulation in endosomal sites of pain signaling, the sustained release of antagonist, and the retention of NPs in tumors explain their beneficial actions. Thus, NP-encapsulation holds promise for the relief of painful cancers that are inadequately treated by opioids.

IMPORTANCE/UNASSIGNED:Stage I squamous cell carcinoma (SCC) of the glottic larynx carries a favorable prognosis after treatment with endoscopic surgery or radiation therapy (RT). In addition to tumor control, goals of therapy include preservation of voice quality, swallow function, and breathing. Multidisciplinary consensus guidelines are needed to assist clinicians in treatment selection and the appropriate use of both surgical and radiation-based techniques. OBSERVATIONS/UNASSIGNED:Treatment of clinical T1N0 glottic SCC has evolved over time, with advances in both transoral laser microsurgery and RT designed to become more targeted and reduce the overall treatment burden for patients. When selecting a treatment option, consideration should be given to patient-specific factors, including tumor position/extent, age, and medical and psychosocial factors. This 16-member multidisciplinary American Radium Society (ARS) Head and Neck Cancer Appropriate Use Criteria (AUC) expert panel performed a review of the English-language medical literature from 2000 to 2022 to inform consensus guidelines. Clinical case variants were developed to represent commonly encountered clinical scenarios, and the RAND/UCLA appropriateness method was used to rate the appropriate use of various treatments. The modified Delphi method was used to reach consensus recommendations, which were approved by the ARS Executive Committee and subject to public comment per established ARS procedures. CONCLUSIONS AND RELEVANCE/UNASSIGNED:Given the range of treatment options available, early glottic SCC management should be done in a multidisciplinary fashion including otolaryngologists and radiation oncologists. The ARS Head and Neck AUC expert panel created an appropriate-use consensus document by performing a literature review of the current treatment strategies for stage I glottic SCC, providing recommendations regarding the appropriateness of surgery or RT for various clinical scenarios and highlighting areas of controversy and uncertainty.

OBJECTIVES/OBJECTIVE:) and PRO scores; (3) explore how changes across individual PROs align with changes in DIGEST pre- to six weeks post- surgery. METHODS:) pharyngeal total score and the DIGEST. PROs included the Bazaz Dysphagia Scale, the Eating Assessment Tool (EAT-10), the Swallowing Quality of Life Questionnaire (SWAL-QoL), and the Hospital for Special Surgery Dysphagia Index (HSS-DDI). RESULTS:Statistical models for all outcome measures revealed a significant effect of operative timepoint, indicating worse outcomes postoperatively. There were greater postoperative increases in point prevalence and incidence rates using PROs compared with DIGEST. Rates of clinically meaningful change were similar across PROs and DIGEST, but not consistently across the same individual cases. CONCLUSION/CONCLUSIONS:This study highlights the difference between physical function and patient experience, suggesting the presence or absence of dysphagia symptoms may not correspond with observed physical impairments after ACDF. LEVEL OF EVIDENCE/METHODS:Level III.

BACKGROUND:Mutations in DICER1 are uncommon, poorly understood, and infrequently found in thyroid nodules. METHODS:The objective of this study was to investigate category III/IV thyroid nodules according to The Bethesda System for Reporting Thyroid Cytopathology with DICER1 gene mutations detected in fine-needle aspiration cytology samples using ThyroSeq v3 molecular testing, with a focus on an exploration of the clinical and histopathologic outcomes of these nodules. In this multicenter study spanning more than 6 years, nodules were retrospectively analyzed for patient demographics, clinical course, cytologic features, and histopathology, where available. RESULTS:In total, 88 patients with somatic DICER1 mutations were included, with a mean age of 39.6 years and a female predominance. All mutations were in the somatic hotspot region, most commonly at the codon 5437 site. Most excised nodules showed benign histologic features (65.9%). Interestingly, the rate of malignancy was higher in this cohort compared with that in the national average. CONCLUSIONS:DICER1 mutations appear to confer a higher risk of malignancy, but are not associated with any specific cytological or histopathological distinguishing features.

Oropharyngeal dysphagia is an independent predictor of poor outcomes in many health conditions and can be targeted directly through swallowing therapy. This study aims to explore the outcomes of outpatient swallowing therapy in clinical practice across a diverse cohort of patients. This was a retrospective, single-site longitudinal cohort study. Patients 18 years or older with dysphagia who completed 7-8 weeks of outpatient swallowing therapy with a pre- and post-treatment videofluoroscopy were included. Therapy employed a progressive swallowing exercise regimen based on the Systematic Exercise for Treatment of Swallowing (SETS) protocol. Outcome measures included the pharyngeal components of the Modified Barium Swallow Impairment Profile, penetration-aspiration scale scores, and diet recommendations using the International Dysphagia Diet Standardization Initiative. 152 patients were included. Swallowing therapy improved all MBSImP component scores except 1, 7, and 13. Therapy improved total pharyngeal impairment scores by 2.66 points (p < .001) and total oral impairment score by 1.41 points (p < .001). Odds of elevated aspiration risk were reduced by 49% (p < .001). Patients were more likely to be on an unmodified food consistency after completion of therapy (OR 26, p = .004), but liquid consistency was not altered (OR 2.0, p = .57). Overall, 44% of patients in the cohort with an efficiency issue improved, and 50% of patients at risk for aspiration pre-therapy improved. Completing a 7-8 week course of exercise-based outpatient swallowing therapy is effective at improving multiple measures of swallowing physiology, safety and efficiency. It can also enable relaxation of diet consistency restrictions based on the IDDSI framework.

Analgesia by non-steroidal anti-inflammatory drugs (NSAIDs) is ascribed to inhibition of prostaglandin (PG) biosynthesis and ensuing inflammation. However, NSAIDs have life-threatening side effects, and inhibition of inflammation delays pain resolution. Decoupling the mechanisms underlying PG-evoked pain vs. protective inflammation would facilitate pain treatment. Herein, we reveal that selective silencing of the PGE₂ receptor 2 (EP2) in Schwann cells via adeno-associated viral vectors abrogates the indomethacin-sensitive component of pain-like responses in mice elicited by inflammatory stimuli without affecting inflammation. In human Schwann cells and in mice, EP2 activation and optogenetic stimulation of adenylyl cyclase evokes a plasma membrane-compartmentalized cyclic adenosine monophosphate (cAMP) signal that, via A-kinase anchor protein-associated protein kinase A, sustains inflammatory pain-like responses, but does not delay their resolution. Thus, an unforeseen and druggable EP2 receptor in Schwann cells, via specific cAMP nanodomains, encodes PGE₂-mediated persistent inflammatory pain but not PG-dependent protective inflammation.