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ImportanceThere is a lack of reliable, patient-reported quality-of-life (QOL) instruments to address the multidimensional nature of patient-centered outcomes for patients undergoing parotidectomy. The Parotidectomy Quality of Life Index is a new 35-item validated patient-reported outcome instrument specific to recovery after parotidectomy.ObjectiveTo establish and validate a comprehensive English-language patient-reported QOL instrument specific to parotidectomy.Design, Setting, and ParticipantsThis survey study was conducted in 2 phases: first, in a single-institution cohort (October 12, 2021, to March 7, 2022), and second, as an anonymous web-based survey enrolled via printed promotional brochures and social media platforms (March 13 to July 31, 2023). Inclusion criteria were age at least 18 years and parotidectomy within the last year. For test-retest reliability, a subset of phase II participants volunteered to answer the survey a second time within 2 weeks. Data were analyzed from March 8, 2022, to November 3, 2023.Main Outcomes and MeasuresItem rankings from phase I participants were used to narrow the original 61-item survey down to 45 items in the phase II survey. To assess construct validity, an exploratory factor analysis was performed. Cronbach α and pairwise Pearson correlation coefficients were used to measure internal consistency, reliability, and redundancy. Test-retest reliability was evaluated using intraclass correlation coefficients.ResultsPhase I enrolled 38 individuals, of whom 30 completed the survey (15 women [60%]; 21 participants [84%] aged >40 years). Phase II enrolled 342 participants, of whom 317 completed the survey (305 women [89%]; 284 participants [83%] aged >40 years). A total of 42 items across 7 domains were selected based on exploratory factor analysis. After Cronbach α and pairwise correlation analysis, 33 items across 6 multi-item domains and 2 standalone items were incorporated into the final QOL instrument. Cronbach αs for each of the final 6 domains were at least 0.77, suggesting excellent internal validity. Pairwise correlations did not show strong correlations (ie, none ≥0.80), suggesting minimal redundancy between domains. Younger age was significantly associated with a lower global score. Participants with malignant tumors scored lower on 4 of the 6 multi-item domains. Test-retest reliability coefficients for the domains ranged from 0.82 to 0.93, indicating very good reproducibility over a 2-week interval.Conclusions and RelevanceThese findings suggest the Parotidectomy Quality of Life Index demonstrated excellent internal validity and test-retest reliability. With further external validation, this instrument may provide opportunity for quality improvement in clinical practice and has potential as a key patient-reported outcome in future parotidectomy clinical trials.

AbstractAlthough endoscopic submucosal dissection (ESD) is associated with higher en-bloc and R0 resection rates than cap-assisted endoscopic mucosal resection (cEMR), its comparative impact on achieving complete remission of dysplasia (CRD) and intestinal metaplasia (CRIM) in BE endoscopic eradication therapy (EET) is not well defined. We aimed to compare the journey of patients from initial endoscopic resection (ER) with ESD and cEMR to achieving CRD and CRIM.Patients undergoing ESD or cEMR followed by ablation for BE neoplasia at two academic institutions in the United States were included. Primary outcomes included CRD and CRIM rates following ER in the two groups. Secondary outcomes included the number of resection/ablative procedures from initial ER to achieving CRD and CRIM. Inverse probability treatment weighting (IPTW) was used to balance confounding variables between groups.A total of 801 patients (606 cEMR, 195 ESD) were included. ESD group patients had higher en-bloc resection rates (ESD 94.4%, cEMR 44.7%). Higher rates of CRD were observed in patients undergoing initial ESD (HR 1.53, P < 0.01). With time-to-event and IPTW analyses, rates of achieving CRD and CRIM were comparable between the groups. There were no significant differences in mean number of endoscopic resection or ablative procedures among patients undergoing initial cEMR resection compared with those treated with initial ESD.Despite larger lesion sizes and more cancers in patients undergoing ESD, the EET journey to achieving CRD and CRIM was comparable to that in patients receiving cEMR. Prospective studies are required to further study differences between these two treatment approaches.

Abstract Reducing antimicrobial exposure by limiting the duration of therapy is an effective antimicrobial stewardship strategy. In this article, we describe the impact of modification of the electronic health record to remove default durations of therapy on ambulatory antibiotic prescriptions issued from emergency departments in a large, multicenter health system.

Abstract Purpose: Tumor-infiltrating lymphocytes are associated with a decreased risk of recurrence in human papillomavirus–associated oropharyngeal squamous cell carcinoma. The composition and spatial distribution of tumor-infiltrating lymphocytes and tumor-infiltrating immune cells are not well characterized. Experimental Design: Formalin-fixed, paraffin-embedded primary and lymph node (LN) tumor tissues from 10 progressors (cases) and 10 matched nonprogressors (controls) were interrogated by imaging mass cytometry. Immune, stromal, and tumor cells were quantified from selected regions of interest using machine learning. Nearest neighbors, cell–cell interactions, and niche analyses were performed. Results: In primary regions of interest, immune cell, lymphocyte, T cell, CD8+ T cell, and innate cell prevalence was significantly greater in controls. High prevalence of immune cells, lymphocytes, innate cells, and CD4+ T cells in primary tissues was significantly associated with increased time to event (TTE). Although primary and LN prevalence of T cells, CD4+ T cells, CD8+ T cells, macrophages, and tumor cells were significantly correlated, differences in LNs were neither significant nor associated with TTE. Average distances between T cells and the nearest B cells and between lymphocytes and the nearest tumor cells were decreased in control primary tissues. Interactions between B and T cells were less organized in primary tissues from cases. A niche predominantly comprising lymphocytes was associated with longer TTE. Conclusions: In human papillomavirus–associated oropharyngeal squamous cell carcinoma, immune cell subset prevalence in primary tumors differs with outcome and is associated with TTE. Interactions between B cells and both T-cell subsets are associated with longer TTE, underscoring the importance of active intratumoral immune responses in outcomes.

Abstract Behavioral flexibility allows animals to adjust actions to changing environments. While the basal ganglia are critical for adaptation, the specific role of the external globus pallidus (GPe) is unclear. This study examined the contributions of two major GPe cell types—prototypic neurons projecting to the subthalamic nucleus (Proto GPe→STN neurons) and astrocytes—to behavioral flexibility. Using longitudinal operant conditioning with context reversals, we found that Proto GPe→STN neurons dynamically represent contextual information correlating with behavioral optimality. In contrast, GPe astrocytes exhibited gradual contextual encoding independent of performance. Deleting Proto GPe→STN neurons impaired adaptive responses to changing action-outcome contingencies without altering initial reward-seeking acquisition, highlighting their specific role in enabling behavioral flexibility. Furthermore, we discovered that Proto GPe→STN neurons integrate inhibitory striatal and excitatory subthalamic inputs, modulating downstream basal ganglia circuits to support flexible behavior. This research elucidates the complementary roles of Proto GPe→STN neurons and astrocytes in cellular mechanisms of flexible reward-seeking behavior.

Abstract Objective Margin distance is a significant prognosticator in oral cavity cancer but its role in HPV‐related oropharyngeal squamous cell carcinoma [HPV(+)OPSCC] remains unclear. Here, we investigate the impact of margin distance on locoregional recurrence in HPV(+)OPSCC. Study Design This is a retrospective cohort study of surgically treated HPV(+)OPSCC patients. Patients received either standard of care (at least 60 Gy with or without cisplatin) or de‐escalated adjuvant therapy (30‐36 Gy with concurrent docetaxel). Margin distance was measured in mm from the primary specimen or in combination with separately submitted margins. Kaplan‐Meier survival analysis with univariate and multivariable Cox regressions were conducted to determine the impact of margin distance on risk of local and locoregional recurrence. Setting Setting for this is 3 tertiary centers between January 2010 and February 2024. Results Among 1102 included patients, 33 (3.0%) had positive final margins. 374 patients had adequate margin distance data available. Margin distance was >3 mm in 73.4%, 1 to 3 mm in 24.5%, and <1 mm in 2.2% of patients. Positive final margins, pT4 disease, pN2 disease, and surgery alone as a treatment modality ( P < .02 for all) was associated with higher risk of 5‐year locoregional recurrence. Margin distance did not significantly impact risk of local or locoregional recurrence even after adjusting for de‐escalated adjuvant therapy ( P > .05). Conclusion Positive final margins after TORS without adjuvant radiotherapy for HPV(+)OPSCC carries a high risk of local recurrence. Margin distance does not appear to significantly impact risk of local or locoregional recurrence, even after de‐escalated adjuvant radiotherapy.

AbstractObjectiveThe extent of parotidectomy for benign tumors has de‐escalated in the United States. We aim to define modern benchmarks for operative time and hospital length of stay (LOS) in parotidectomy and identify risk factors that may prolong these benchmarks.Study DesignThis is a retrospective cross‐sectional study of all adults who underwent parotidectomy for a primary parotid neoplasm between January 2011 and December 2021 using the American College of Surgeons National Surgical Quality Improvement Program database.MethodsThe extent of parotidectomy was defined using Current Procedural Terminology codes. Prolonged operative time and LOS were defined as above the 75th percentile (longer than 194 minutes and more than 1 day, respectively). Multivariable logistic regression was used to identify patient and surgical risk factors that predict prolonged operative time or LOS.ResultsBenign parotidectomies are mostly performed as outpatient procedures in the United States (average LOS <1 day). Prolonged operative time was independently associated with malignant tumors versus benign tumors (adjusted odds ratio [aOR]: 2.7, 95% confidence interval [CI]: 2.4‐3.0), total parotidectomy with facial nerve sacrifice versus lesser extent of parotidectomy (aOR: 2.3, 95% CI: 1.7‐3.0), and simultaneous reconstructive procedures versus none (P < .001 for all). These features were similarly independently associated with prolonged LOS (P < .001 for all). Complication rates were universally low.ConclusionThe majority of superficial parotidectomies in this country are performed as outpatient procedures requiring <3 hours of operative time, with low complication rates. Malignant tumors, greater extent of parotidectomy, and simultaneous procedures were independently associated with prolonged operative time and LOS. These national benchmarks can inform operating room and hospital bed resource assignments.

Introduction: GOLCA is a potential first-in-class CELMoDTM agent for the treatment of lymphoma, purposefully designed to target the proteins Ikaros/Aiolos to produce dual immunomodulatory and anti-tumor activity, with preferential distribution to lymphoid organs. Pharmacodynamic data in pts with R/R FL show that, combined with RTX, the immunomodulatory effects of GOLCA are significantly increased (Chavez et al, EHA 2024, #1132). GOLCA as monotherapy (mono) and + RTX has been shown to be well-tolerated and effective in pts with R/R DLBCL (Chavez et al, ASH 2023, #4496) and R/R FL (Chavez et al, EHA 2024, #1132). Here, we report 30 mo follow up of pts with R/R FL who received GOLCA mono, and updated safety/efficacy of GOLCA + RTX from the ongoing Phase 1/2 CC-99282-NHL-001 study (NCT03930953). Methods: Pts with R/R FL with ≥ 2 prior lines of therapy (L) received GOLCA mono at different dosing schedules during part A (dose exploration) and GOLCA ± RTX at 0.2 mg or 0.4 mg days (d) 1-14 every 28 d (q28d) in part B (dose expansion). Total treatment duration with GOLCA was up to 2 years or until progressive disease or unacceptable toxicity, whichever occurred first. The efficacy-evaluable population consisted of pts completing ≥ 1 cycle of GOLCA and having baseline tumor assessment and ≥ 1 post-baseline tumor assessment or clinical progression or disease-related death. Results: As of May 31, 2024, 63 pts with R/R FL have enrolled: GOLCA mono (n = 19) at various dosing schedules and GOLCA + RTX at 0.2 mg (n = 22) or 0.4 mg (n = 22) on d1-14 q28d schedule. The median time from diagnosis to first dose of GOLCA was 68 mo (range, 23-136) and 59 mo (range, 15-309) in GOLCA mono and + RTX cohorts, respectively. The median number of prior therapies received was 4 (range, 2-11), and 3 (range, 1-12) in GOLCA mono and + RTX cohorts, respectively. In the GOLCA mono and + RTX cohorts, 9/19 (47%) and 13/43 (30%) pts had received prior lenalidomide (len)-based therapy, with 5/9 and 7/13 having len-refractory disease, respectively. In the GOLCA + RTX cohort, 10/43 (23%) had prior CAR T cell therapy and 6/43 (14%) had prior anti-CD20xCD3 bispecific antibody with or without CAR T cell therapy. In the GOLCA + RTX-treated safety population (n = 43), the incidence of treatment emergent adverse events (TEAEs) was similar across 0.2 and 0.4 mg dose levels (DL). The most frequent grade (G) 3+ TEAEs were neutropenia (44%) and anemia (12%). The incidence of febrile neutropenia was 7%. Serious adverse events occurred in 30% of pts, with febrile neutropenia and pneumonia being the most common, in 2 pts (5%) each, as well as pulmonary embolism in 1 pt. Neutropenia led to GOLCA dose interruption in 4 pts (9%) and dose reduction in 1 pt (2%). No pts discontinued treatment because of GOLCA-related TEAEs. Non-hematological TEAEs (e.g., GI toxicity, rash, fatigue) were all low-grade (except 1 pt with G3 fatigue). There were no new safety signals identified for GOLCA mono (part A) at the 30-mo follow up period. In the efficacy-evaluable population, at a median follow up of 6 mo (range 3-18), the ORR and CRR in the GOLCA + RTX cohort (n = 29) were 57% and 29% at 0.2 mg dose (n = 14) and 93% and 67% at 0.4 mg dose (n = 15), respectively. The median time to response was 2 mo (first response assessment). At the 0.4 mg DL of GOLCA + RTX, consistent responses were seen in pts at 2L/3L and 4L+, including in those with prior exposure to len-based therapies and/or T-cell-redirecting therapy. At the 0.4 mg DL, 12/14 (86%) pts remained in response at the time of data cut-off. In pts receiving GOLCA mono across different dose schedules in part A (n = 12), ORR and CRR were 67% and 42%, respectively. Responses were durable, with median DOR of 22 mo (range, 2-51) at a median follow up of 30 mo. 33% of pts (4/12) have completed 2 yrs of protocol defined GOLCA treatment and remain in response at the 1 yr post-treatment follow-up period, without requiring any intervening treatment. Conclusions: GOLCA 0.4 mg + RTX was well tolerated and highly active in heavily pre-treated pts with R/R FL, including those with prior exposure to len-based therapies and/or T-cell-redirecting therapies. Treatment with fixed-duration GOLCA mono led to durable responses including a subset of pts remaining treatment free, without progression at extended follow up. These data further support development of GOLCA + RTX as a fixed-duration, chemotherapy-free, outpatient treatment option in pts with R/R FL, and also pts with newly diagnosed advanced stage FL (NCT06425302).

Introduction Knowledge of epidemiologic risk factors, clonal changes associated with MDS development from precursor states, and evolution from one MDS state to another (lower- (LR) or higher-risk (HR) disease or leukemia (AML)) are largely limited to retrospective studies, which may not reflect the true MDS spectrum. The MDS NHS is an established prospective cohort of patients (pts) with suspected MDS enrolled at diverse US sites. Extensive clinical data and biospecimens are collected at baseline and throughout follow-up (F/U), in real time, as pts are followed for life. Here, we assess rates and potential predictors of progression providing a foundation for precise stratification across the MDS spectrum, which may ultimately guide intervention. Methods At baseline, all MDS NHS pts have central pathology review and those assigned to MDS, MDS/MPN overlap, AML&lt;30% blasts, or at-risk of MDS (AR-MDS: CCUS and other at-risk) are followed prospectively. We compared AR-MDS with LR-MDS (MDS and MDS/MPN overlap with IPSS-R ≤ 3.5) and HR-MDS (MDS and MDS/MPN overlap with IPSS-R &gt; 3.5). We defined disease progression as any F/U diagnosis of worsening disease or documented disease-related death. Rates of disease progression were compared between groups using survival analysis methods for cumulative incidence incorporating non-disease death as a competing risk. Associations between progression and predictor variables were explored using univariate tests of association and multivariable survival (Cox regression) models for time-to-progression and logistic models for probability of progression (yes/no). Results The MDS NHS enrolled 2051 pts during June 2016-February 2024, with 54% (1111, above categories) followed prospectively. Median F/U is 1.7 yrs (IQR: 0.8-3.1 yrs, max: 7.9 yrs). For the current analysis, 582 MDS and 505 AR-MDS pts were included. Compared to AR-MDS, MDS patients were more often male (70% v 61%, p&lt;0.01), older (median age: 75 v 72 years, p&lt;0.01), and had lower baseline hemoglobin (median: 10.1 v 11.9 g/dL, p&lt;0.001), platelets (median: 124 x109 v 146 x109 cells/L, p&lt;0.001), and absolute neutrophil counts (median: 1.9 x109 vs 2.8 x109 cells/L, p&lt;0.001). F/U time was similar among AR-MDS and MDS (median: 1.9 vs 1.6 yrs), with both groups having a 75th percentile of 3 yrs and maximum of 7 yrs. A total of 331 deaths were observed (30%), with 145 (44%) of these due to causes related to MDS (myeloid disease and/or cardiovascular disease). Overall, 18.5% had disease progression, with annual rates of 8% (MDS) and 2% (AR-MDS) (p&lt;0.01). Among HR-MDS, progression rates were greatest in the 1st year following diagnosis (33%) and declined thereafter, whereas progression rates remained between 5-8% for LR-MDS and 1-3% for AR-MDS over 5 yrs of F/U. AR-MDS had similar rates of progression within the first 3 yrs from diagnosis as MDS with the lowest IPSS-R category. Among AR-MDS, low hemoglobin (hazard ratio, HR [95% CI]=3.2 [1.4-7.3], p&lt;0.01) was significantly associated with progression. Among MDS, low hemoglobin (HR=4.0 [2.2-7.0], p&lt;0.001), low platelet count (HR=3.1 [1.7-5.6], p&lt;0.001) and higher numbers of mutations (HR=1.13 [1.0-1.2], p&lt;0.01) were significantly associated with progression. Due to the low rate of progression in AR-MDS, meaningful comparisons of mutations could not be completed. In MDS, univariate analyses showed that somatic mutation prevalence in gene pathways for transcription, cell cycle and RAS signaling, and in genes TP53, BCOR, SF3B1, DDX41, PTPN11, SETBP1, and JAK2 were significantly associated with the probability of progression (p&lt;0.05 in all). In multivariable models, adjusting for patient age, sex, and MDS risk level, the probability of progression (PP) was significantly higher among those with vs without somatic mutations in BCOR (PP=63% vs 29%, p=0.004), PTPN11 (PP=67% vs 29%, p=0.009), SETBP1 (PP=61% vs 30%, p=0.02), JAK2 (PP=59% vs 30%, p=0.02), DDX41 (PP=56% vs 30%, p=0.03) and TP53 (PP=43% vs 29%, p=0.04). Conclusions In this large prospective cohort of MDS and pts at risk for MDS, the annual rate of any disease progression was 8% among MDS and 2% among AR-MDS, lower than some retrospective series. Specific cytopenias and genetic factors associated with progression were identified. The MDS NHS provides an incomparable opportunity to address the critical clinical challenges of management and prevention of MDS progression across its spectrum.