Lohse, Christine M.

Abstract The intrinsic and acquired resistance to PD-1/PD-L1 immune checkpoint blockade is an important challenge for patients and clinicians because no reliable tool has been developed to predict individualized response to immunotherapy. In this study, we demonstrate the translational relevance of an ex vivo functional assay that measures the tumor cell killing ability of patient-derived CD8 T and NK cells (referred to as “cytotoxic lymphocytes,” or CLs) isolated from the peripheral blood of patients with renal cell carcinoma. Patient-derived PBMCs were isolated before and after nephrectomy from patients with renal cell carcinoma. We compared the efficacy of U.S. Food and Drug Administration (FDA)-approved PD-1/PD-L1 inhibitors (pembrolizumab, nivolumab, atezolizumab) and a newly developed PD-L1 inhibitor (H1A Ab) in eliciting cytotoxic function. CL activity was improved at 3 mo after radical nephrectomy compared with baseline, and it was associated with higher circulating levels of tumor-reactive effector CD8 T cells (CD11ahighCX3CR1+GZMB+). Treatment of PBMCs with FDA-approved PD-1/PD-L1 inhibitors enhanced tumor cell killing activity of CLs, but a differential response was observed at the individual-patient level. H1A demonstrated superior efficacy in promoting CL activity compared with FDA-approved PD-1/PD-L1 inhibitors. PBMC immunophenotyping by mass cytometry revealed enrichment of effector CD8 T and NK cells in H1A-treated PBMCs and immunosuppressive regulatory T cells in atezolizumab-treated samples. Our study lays the ground for future investigation of the therapeutic value of H1A as a next-generation immune checkpoint inhibitor and the potential of measuring CTL activity in PBMCs as a tool to predict individual response to immune checkpoint inhibitors in patients with advanced renal cell carcinoma.

Purpose: This study aimed to describe the relationship between changes in pre and post self-perceived dizziness handicap, scores on the patient health questionnaire, and perceptions of patient's value of being evaluated and managed by a multidisciplinary team. Method: Seventy-eight patients completed the Dizziness Handicap Inventory (DHI) and Patient Health Questionnaire–Fourth Edition (PHQ-4) questionnaires post multidisciplinary clinical consultations and testing for the chief complaints of dizziness, unsteadiness, vertigo, or balance problems. The diagnoses of each patient were recorded from the clinical reports of each specialty consultation and were classified as structural, functional, or psychiatric. They were contacted by phone at least 6 months after their visit to obtain feedback regarding their symptoms and overall patient experience. Results: The change in DHI total score did not differ significantly by diagnosis ( p = .56), indicating that patients experienced an improvement in DHI total score regardless of diagnosis. PHQ-4 anxiety scores worsened by a mean of 0.7 points for those with structural diagnoses ( p = .04), improved by a mean of 0.7 points for psychiatric diagnoses ( p = .16), and improved by a mean of 0.3 points for functional diagnoses ( p = .39). Only seven patients would not recommend the team to a family or friend; these patients tended to report worsening DHI total scores ( p = .27) compared to the significant improvement in DHI total scores for patients who would make such a recommendation ( p < .001). Similarly, only 13 patients did not feel the information they received had a positive impact; these patients tended to report worsening DHI total scores ( p = .18) compared to the significant improvement in DHI total scores for patients who did feel the information had a positive impact ( p < .001). Discussion: The assessment and management of patients with chronic dizziness is challenging due to symptoms arising from multiple etiologies. Our finding of a vast difference between high satisfaction and relatively unchanged dizziness handicap suggests that there is value in seeing a multidisciplinary team where consultations are unhurried, care is coordinated, and expectations regarding treatment can be managed.

674 Background: Metastasis directed therapy (MDT) is associated with improved cancer-specific survival and delay in use of systemic therapy for metastatic clear cell RCC (mccRCC). Although the benefits of MDT may differ based on organ site of metastasis due to differences in disease biology, survival based on site of metastasis remain underexplored. We aim to evaluate survival outcomes of patients who underwent MDT for solitary sites of mccRCC. Methods: The Mayo Clinic Nephrectomy Registry was queried to identify adults undergoing radical or partial nephrectomy for unilateral, sporadic ccRCC from 2000 to 2019 with a single site of metastasis treated with MDT including complete metastasectomy or radiation, in lieu of systemic therapy. Overall and cancer-specific survival were estimated using the Kaplan-Meier method, with the duration of follow-up calculated from the date of metastasis to the date of death or last follow-up. Associations with time to death from RCC were evaluated using Cox proportional hazards regression models and summarized with hazard ratios and 95% confidence intervals (CIs). Results: In this cohort of 207 mccRCC patients, 152 underwent complete metastasectomy and 55 underwent radiation. 133 died at a median of 2.7 years (IQR 1.2-4.7) following metastasis, including 105 who died from RCC at a median of 2.2 years (IQR 1.0-3.9). The median duration of follow-up for the 74 patients who were still alive at last follow-up was 8.1 years (IQR 3.7-12.1). Overall survival rates (95% CI) at 2, 4, 6, 8, and 10 years following metastasis were 73% (69-79), 54% (48-62), 45% (38-52), 37% (30-44), and 32% (26-40), respectively; cancer-specific survival rates were 75% (69-81), 56% (50-64), 47% (41-55), 44% (37-52), and 42% (35-50), respectively. Age, poor performance status, presence of synchronous metastasis and asynchronous metastasis <1 year from nephrectomy, tumor size, and bone metastasis were associated with death from RCC (table). Conclusions: These findings provide useful survival benchmarks to patients who are considering MDT as a therapeutic option. In addition, synchronous and asynchronous metastasis <1 year from nephrectomy, poor performance status, and bone metastasis are significantly associated with worse survival from mccRCC. [Table: see text]

AbstractObjectiveOtolaryngology residency is highly competitive, and applicant academic metrics are scrutinized. The predictive value of preresidency academic metrics on applicants’ future research productivity and career aspirations remains largely undefined.Study DesignRetrospective cohort studySettingAcademic otolaryngology department, 2014 to 2015.MethodsApplicant demographics, publication history, and United States Medical Licensing Examination (USMLE) scores were downloaded from Electronic Residency Application Service archives. Publications during residency were tallied from all PubMed articles indexed between July 1, 2015 and June 30, 2020. Postresidency career paths were examined by 2 investigators (D.J.C. and L.X.Y.) using Google searches with an emphasis on program websites, Doximity, and LinkedIn profiles. Associations with publication potential and postresidency positions were evaluated with Spearman rank correlation coefficients and Kruskal‐Wallis, Wilcoxon rank sum, and χ2 tests.ResultsOf 321 applicants, 226 (70%) matched, and 205 (64%) completed residency by June 2020. Matched residents published a median of 4 (range: 0‐41) manuscripts during residency. USMLE scores, Alpha Omega Alpha status, and the number of preresidency publications did not significantly correlate with publication potential during residency. The number of research experiences had a significant positive correlation with publications during residency (p < 0.001). Asian race (p = 0.002) and geographical region of residency (p < 0.001) also had significant associations with publication potential. Of the 205 graduates, 118 (58%) enrolled in fellowship. Age and female sex (74% vs 48%; p = 0.002) were the only factors significantly associated with pursuing a fellowship.ConclusionIn otolaryngology, not all preresidency academic metrics are associated with publication potential during residency or propensity for fellowship training. Programs should not use academic metrics alone to predict an applicant's future research productivity or career trajectory.

AbstractObjectiveTo assess the correlation between linear and volumetric changes in vestibular schwannomas (VS).Study DesignRetrospective imaging review was performed on patients diagnosed with sporadic VS from 2000 to 2019 who demonstrated linear growth on observation with serial magnetic resonance imaging (MRI).SettingTwo large tertiary care centers.MethodsChanges in diameter on serial MRI scans, measured by 1995 American Academy of Otolaryngology‐Head and Neck Surgery guidelines, were compared to changes in volume, calculated by segmentation.ResultsNinety‐two patients had VS confined to the internal auditory canal (IAC) with 236 MRIs analyzed, and 108 patients had VS involving the cerebellopontine angle (CPA) with 193 MRIs analyzed. The Spearman rank correlation coefficients between changes in diameter and volume for IAC and CPA tumors were 0.43 (p < .001) and 0.65 (p < .001), respectively. Linear diameter increases of 1 to <2 mm corresponded to a median volume change of 32% (interquartile range [IQR]: 6%‐86%) for IAC tumors, compared to 23% (IQR: 13%‐40%) for CPA tumors. Linear diameter increases of 2 to <3 mm (ie, the minimum linear diameter change classically considered “true growth”) corresponded to a median volume change of 42% (IQR: 23%‐100%) and 47% (IQR: 26%‐69%) for IAC and CPA tumors, respectively.ConclusionChanges in linear diameter significantly correlated with changes in volume for IAC and CPA tumors, although diameter changes that did not meet the definition of linear growth (<2 mm) had corresponding median volume changes in excess of 20% for both IAC and CPA tumors.

AbstractObjectiveWe aim to explore the prognostic value of tumor‐infiltrating lymphocytes (TILs) in the primary tumor and metastatic lymph nodes of patients with HPV(+)OPSCC. We hypothesize that TILS density at both sites is associated with disease‐free survival in HPV(+)OPSCC.Study DesignMatched case‐control study among HPV(+)OPSCC patients who underwent intent‐to‐cure surgery. Cases developed locoregional or distant recurrence. Controls were matched based on age, sex, pathologic T, N, and overall stage, year of surgery, type of adjuvant treatment received, and the Adult Comorbidity Evaluation‐27 (ACE‐27) score.SettingSingle tertiary care center, May 2007 to December 2016.MethodsTumoral TILs (tTILs) density was defined as % TILs; stromal TILs (sTILs) density was defined as absent/sparse or moderate/dense crowding. Associations between TILs and time to disease progression were assessed using Cox regression models.ResultsForty‐four case‐control pairs (N = 88) were included: 42 (48%) AJCC pStage I, 39 (44%) pStage II, and 7 (8%) pStage III. tTILs density ≥10% (hazard ratio [HR] 0.41, 95% confidence interval [CI] 0.17‐0.99, p = .048) and a moderate/dense sTILs density (HR 0.21, 95% CI 0.06‐0.75, p = .016) in the primary tumor were significantly associated with decreased risk of progression. TILs density in the lymph node was associated with decreased risk of progression but did not reach statistical significance. The tTILs and sTILs density correlated strongly between the primary tumor and lymph node. Concordance between the pathologists' was moderate (60%‐70%).ConclusionsIn HPV(+)OPSCC, a higher density of tumoral and stromal TILs in the primary tumor and possibly the lymph node may predict a lower risk of disease progression.

Objective To characterize the effect of the COVID-19 pandemic on national cochlear implantation utilization by age using inclusive cochlear implantation data from two manufacturers between 2015 and 2020. Study Design Analysis of prospectively registered consecutive patient data from two major cochlear implant (CI) manufacturers in the United States. Patients Children or adults who received CIs. Interventions Cochlear implantation. Main Outcome Measures Annual implantation utilization by age. Results A total of 46,804 patients received CIs from the two participating manufacturers between 2015 and 2020. The annual number of implant recipients increased significantly during the first 5 years of the study period for both children and adults, from a total of 6,203 in 2015 to 9,213 in 2019 (p < 0.001). During 2020, there was a 13.1% drop in national cochlear implantation utilization across all ages compared with 2019, including a drop of 2.2% for those ≤3 years old, 3.8% for those 4–17 years old, 10.1% for those 18–64 years old, 16.6% for those 65–79 years old, and 22.5% for those ≥80 years old. In a multivariable linear regression model, the percent drop in CIs differed significantly by age-group (p = 0.005). Conclusions Especially in light of the prepandemic projected CI counts for 2020, the COVID-19 pandemic reduced national cochlear implantation utilization by over 15% among Medicare-aged patients and by almost 25% among those ≥80 years old, resulting in more than a 3-year setback in total annual CIs. Children were less affected, with those ≤3 years old experiencing minimal interruption during 2020.

Objective Large vestibular aqueduct (LVA) is the most common inner ear dysplasia identified in patients with hearing loss. Our objective was to systematically quantify LVA morphologies and correlate imaging findings with established audiometric outcomes. Study Design Retrospective review. Setting Tertiary referral center. Patients Patients with large vestibular aqueduct identified radiographically, with or without hearing loss. Intervention(s) Diagnostic only. Main Outcome Measure(s) Vestibular aqueduct (VA) width at midpoint, width at external aperture, and length were measured on cross-sectional imaging. Morphology was classified as type I (borderline), type II (tubular), or type III (funneled). Audiometric endpoints included air/bone conduction, pure tone averages, and air-bone gaps at 250 and 500 Hz. Statistical associations were evaluated using linear regression models, adjusted for age at first audiogram and sex. Results One hundred seventeen patients (197 ears) were included, with mean age at first audiogram of 22.2 years (standard deviation, 21.7 yr). Imaging features associated with poor audiometric outcomes were increasing VA width at midpoint and external aperture, decreasing VA length, dilated extraosseous endolymphatic sac, cochleovestibular malformations, and increasing VA type (III > II > I). Conclusions Quantitative LVA measurements and a standardized morphologic classification system aid in prediction of early audiometric endpoints.