Faculty Bibliography

Current immunotherapy paradigms aim to reinvigorate CD8⁺ T cells, but the contribution of humoral immunity to antitumor immunity remains understudied. Here, we demonstrate that in head and neck squamous cell carcinoma (HNSCC) caused by human papillomavirus infection (HPV⁺), patients have transcriptional signatures of germinal center (GC) tumor infiltrating B cells (TIL-Bs) and spatial organization of immune cells consistent with tertiary lymphoid structures (TLS) with GCs, both of which correlate with favorable outcome. GC TIL-Bs in HPV⁺ HNSCC are characterized by distinct waves of gene expression consistent with dark zone, light zone and a transitional state of GC B cells. Semaphorin 4a expression is enhanced on GC TIL-Bs present in TLS of HPV⁺ HNSCC and during the differentiation of TIL-Bs. Our study suggests that therapeutics to enhance TIL-B responses in HNSCC should be prioritized in future studies to determine if they can complement current T cell mediated immunotherapies.

Fibrosis of the vocal folds poses a substantive clinical challenge potentially underlying the rapid proliferation of direct steroid injections into the upper airway. The variable clinical response to glucocorticoids (GCs) in the vocal folds is likely related to diversity inherent to GCs and both patient-specific, and upstream, cell-specific responses to GCs. Broadly, we hypothesize the disparity in clinical outcomes are due to undesirable effects of GCs on resident fibroblasts. Transcriptome analysis identified significant GC-mediated modulation of Hippo signaling, a known regulator of fibrotic gene expression. Subsequent analysis confirmed GC-mediated YAP activation, a transcriptional co-factor in the Hippo signaling pathway. YAP inhibition attenuated ACTA2 expression in GC-treated human vocal fold fibroblasts. Nuclear localization and phosphorylation at Ser211, however, was not affected by YAP inhibition, suggesting nuclear translocation of YAP is indirectly driven by GR. RNA-seq analysis confirmed the influence of GCs on Wnt signaling, and canonical Wnt signaling target genes were upregulated by GCs. These data implicate YAP and its downstream targets as putative mediators of a pro-fibrotic response to GCs. Therapeutic YAP inhibition may ultimately be clinically relevant and warrants further consideration.

An increasing number of elderly patients are seeking hearing rehabilitation strategies, including cochlear implantation. Elderly patient who are frail or those with significant pre-existing comorbidities have a higher risk of perioperative morbidity after undergoing surgery with general anesthesia. Additionally, there is a growing concern that general anesthesia could increase the risk of dementia or postoperative cognitive decline. In patients who wish to avoid the perceived medical and cognitive risks attributed to general anesthesia or for those who are deemed medically unfit for general anesthesia, surgery under local anesthesia with conscious sedation may be offered. This article details the surgical technique of local anesthesia with conscious sedation and describes the modifications and technical nuances which may be employed for executing a successful surgery.

BACKGROUND: A frequent concern surrounding amplification with hearing aids for patients with sensorineural hearing loss is whether these devices negatively affect hearing ability. To date, there have been few studies examining the long-term effects of amplification on audiometric outcomes in adults. PURPOSE/OBJECTIVE: In the present study, we examined how hearing aids affect standard audiometric outcomes over long-term periods of follow-up. RESEARCH DESIGN/METHODS: We retrospectively collected audiometric data in adults with sensorineural hearing loss, constructing a model of long-term outcomes. STUDY SAMPLE/METHODS: This retrospective cohort study included 802 ears from 401 adult patients with bilateral sensorineural hearing loss eligible for amplification with hearing aids at a single institution. INTERVENTION/METHODS: Of the eligible patients, 88 were aided bilaterally, and 313 were unaided. DATA COLLECTION AND ANALYSIS/METHODS:), and word recognition score (WRS) per-ear at each encounter. We then modeled the association between the use of hearing aids for 5 years and these audiometric outcomes using targeted maximum likelihood estimation. RESULTS: < 0.001), adjusting for measured confounders. CONCLUSION/CONCLUSIONS:, and WRS, suggesting a greater decline in hearing ability in patients using hearing aids. Future studies are needed to examine these effects between treatment groups over longer periods of time and in more heterogeneous populations to improve clinical practice guidelines and safety of both prescriptive fitting nonprescriptive amplification.

OBJECTIVE:To identify novel heterozygous LPIN2 mutations in a patient with Majeed syndrome and characterize the pathomechanisms that lead to the development of sterile osteomyelitis. METHODS:Targeted genetic analysis and functional studies assessing monocyte responses, macrophage differentiation, and osteoclastogenesis were conducted to compare the pathogenesis of Majeed syndrome to interleukin-1 (IL-1)-mediated diseases including neonatal-onset multisystem inflammatory disease (NOMID) and deficiency of the IL-1 receptor antagonist (DIRA). RESULTS:A 4-year-old girl of mixed ethnic background presented with sterile osteomyelitis and elevated acute-phase reactants. She had a 17.8-kb deletion on the maternal LPIN2 allele and a splice site mutation, p.R517H, that variably spliced out exons 10 and 11 on the paternal LPIN2 allele. The patient achieved long-lasting remission receiving IL-1 blockade with canakinumab. Compared to controls, monocytes and monocyte-derived M1-like macrophages from the patient with Majeed syndrome and those with NOMID or DIRA had elevated caspase 1 activity and IL-1β secretion. In contrast, lipopolysaccharide-stimulated, monocyte-derived, M2-like macrophages from the patient with Majeed syndrome released higher levels of osteoclastogenic mediators (IL-8, IL-6, tumor necrosis factor, CCL2, macrophage inflammatory protein 1α/β, CXCL8, and CXCL1) compared to NOMID patients and healthy controls. Accelerated osteoclastogenesis in the patient with Majeed syndrome was associated with higher NFATc1 levels, enhanced JNK/MAPK, and reduced Src kinase activation, and partially responded to JNK inhibition and IL-1 (but not IL-6) blockade. CONCLUSION/CONCLUSIONS:We report 2 novel compound heterozygous disease-causing mutations in LPIN2 in an American patient with Majeed syndrome. LPIN2 deficiency drives differentiation of proinflammatory M2-like macrophages and enhances intrinsic osteoclastogenesis. This provides a model for the pathogenesis of sterile osteomyelitis which differentiates Majeed syndrome from other IL-1-mediated autoinflammatory diseases.

Introduction Photobiomodulation therapy has been shown to be an effective treatment for reducing the incidence and severity of oral mucositis (OM). The objective of this study is to determine the range of effective PBM dose, and review the adequacy of reporting irradiation parameters. Methods Online databases were searched to compare efficacy of PBM versus controls for preventing or treating cancer therapy-induced OM. Irradiation parameters were reviewed for accuracy. Results A total of 53 clinical trials were identified and 29 papers were excluded, leaving 24 papers for review. Only 1 study reported all parameters accurately. Seven studies reported a difference in OMgrade >= 3 (WHO) between the placebo and PBM groups greater than 40% when PBM was used prophylactically with greater irradiation parameters (mean energy dose 50%, beam area 58%, irradiance 246%, and treatment time per point 290% greater than the overall mean values).Aplot of effect size (%) vs. total energy per session was created using studies that reported adequate information to determine both total energy per session and the difference in the percent of patients with OMgrade >= 3 between the study group and placebo group. These data points were fit with a quadratic curve to evaluate if the data may resemble the parabolic relationship observed in previous studies. Conclusions This review has reconfirmed the lack of accurate reporting of PBM parameters. Total energy per session may be used to guide PBM dose parameters

OBJECTIVES/HYPOTHESIS:The purpose of this study is to develop consensus on key points that would support the use of systemic bevacizumab for the treatment of recurrent respiratory papillomatosis (RRP), and to provide preliminary guidance surrounding the use of this treatment modality. STUDY DESIGN:Delphi method-based survey series. METHODS:A multidisciplinary, multi-institutional panel of physicians with experience using systemic bevacizumab for the treatment of RRP was established. The Delphi method was used to identify and obtain consensus on characteristics associated with systemic bevacizumab use across five domains: 1) patient characteristics; 2) disease characteristics; 3) treating center characteristics; 4) prior treatment characteristics; and 5) prior work-up. RESULTS:The international panel was composed of 70 experts from 12 countries, representing pediatric and adult otolaryngology, hematology/oncology, infectious diseases, pediatric surgery, family medicine, and epidemiology. A total of 189 items were identified, of which consensus was achieved on Patient Characteristics (9), Disease Characteristics (10), Treatment Center Characteristics (22), and Prior Workup Characteristics (18). CONCLUSION:This consensus statement provides a useful starting point for clinicians and centers hoping to offer systemic bevacizumab for RRP and may serve as a framework to assess the components of practices and centers currently using this therapy. We hope to provide a strategy to offer the treatment and also to provide a springboard for bevacizumab's use in combination with other RRP treatment protocols. Standardized delivery systems may facilitate research efforts and provide dosing regimens to help shape best-practice applications of systemic bevacizumab for patients with early-onset or less-severe disease phenotypes. LEVEL OF EVIDENCE:5 Laryngoscope, 131:E1941-E1949, 2021.