Citations

Abstract Description A subset of follicular lymphoma patients has an early relapse with a poor outcome. We showed that this unfavorable group displays increased expression of IRF4, dysregulated immune signaling and an immunosuppressive microenvironment. However, little is known on the molecular mechanisms whereby IRF4 controls the crosstalk between B and T cells. To this aim, we leveraged Cγ1cre;irf4fl/fl mice that yield conditional deletion of irf4 (cKO) in germinal center B cells (GCB). After 10 days of immunization, cKO GCB showed significant increase of HLA-DR and CD40 expression, a skewed LZ:DZ ratio towards increased DZ, and suppression of plasma cells compared to WT. Upon irf4 deletion, we also found a significant increase of total CD4 and TFH cells and a decrease in Treg cells. To test if this effect was antigen-dependent, we cocultured sorted GCB from NP-OVA-immunized cKO and WT mice with CSFE-labeled OVA-specific OT-II CD4 T cells at a ratio of 2:1 for 5 days. We observed increased antigen specific proliferation of CD4 T cells with cKO GCB compared to WT. We then performed seahorse assay and mass spectrometry of the same GCB to define if IRF4-dependent B cell metabolic reprogramming influences immune responses. GCB cKO had lower glycolytic ECAR and increased intracellular glucose and non-essential amino acids than WT cells, suggesting a metabolic shift from glycolysis to the TCA cycle. Thus, IRF4 controls immune and metabolic signaling with functional effects on the B-T cell crosstalk. Funding Sources NCI K08CA279652, LRF Clinical Investigator Award (CDA 1020588), the Gerstner Family Career Development Award, the ASH Junior Faculty Scholar Award. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Abstract Description Broad spectrum antibiotics are being increasingly used in obstetric patients without long term follow up on neonatal risks. Previous data have suggested antibiotics for preterm premature rupture of membranes increases neonatal late onset sepsis and nectrozing enterocolitis (NEC), but the mechanism is unknown. We analyzed samples from the Mechanisms of Maternal Immunoglobulin A control over the neonatal microbiota and the development of NEC (MAMI) trial. MAMI enrolled infants born under 32 weeks and collected maternal-infant biospecimens. We performed a detailed chart review for maternal antibiotic exposure and analyzed breast milk samples collected 10-45 days post delivery by ELISA. Data were compared by t test and one way ANOVA. Breast milk IgA was higher than IgG and IgM (p < 0.0001, p < 0.005). When compared by antibiotic exposure, IgA and IgM were decreased with any antibiotic exposure (p = 0.02, p = 0.01). IgA was decreased by length of antibiotic exposure (p = 0.02). We stratified by the antibiotic spectrum of activity into narrow (penicillin, ampicillin) and broad (2nd and 3rd generation cephalosporin, gentamicin, etc) and found that the spectrum of antimicrobial activity was associated with a decrease in maternal IgA with broad spectrum antibiotics with the least amount of IgA (p < 0.004). Our data demonstrate mammary IgA and IgM are decreased with antenatal antimicrobial exposure. These data suggest a mechanism by which antenatal antibiotics may lead to neonatal sepsis and NEC. Topic Categories Mucosal and Regional Immunology (MUC)

PURPOSE The ECOG-ACRIN E3311 phase II trial demonstrated outstanding disease control (90.6% 54-month progression-free survival) after transoral surgery (TOS) with de-escalated, risk-based postoperative management in resectable human papillomavirus–associated oropharyngeal cancer. The goal of de-escalation was functional preservation. The objective of this work was to evaluate clinician-graded modified barium swallow (MBS) studies from E3311 over time and across arms for (1) aspiration and high-grade pharyngeal residue rates, (2) differences in swallow safety and efficiency, and (3) accuracy of site clinicians reporting against central MBS review. METHODS Eight hundred eighty-five MBS studies were performed on 314 patients from 50 of 59 sites at baseline, post-TOS, and 6 and 24 months postradiotherapy (RT). Swallow outcomes (aspiration, high-grade residue) were recorded by site clinicians. A subset of 414 MBS studies was centrally graded using penetration-aspiration scale scores and the Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) scale. RESULTS Aspiration, residue, and dysphagia rates significantly increased from baseline to post-TOS ( P < .01) and then decreased modestly at 6 and 24 months. At 6 months, swallow outcomes favored the 50- versus 60-Gy arm, with significantly lower aspiration and high-grade dysphagia rates, but this difference was not maintained at 24 months. MBS results reported by site clinicians demonstrated substantial agreement with those assessed by the central laboratory (PABAK, 0.75-0.84; P < .01). CONCLUSION Swallowing worsened after TOS but improved by 6 and 24 months despite adjuvant therapy. De-escalated adjuvant RT at 50 Gy reduced acute aspiration. Site-reported MBS metrics strongly aligned with DIGEST, showing potential as an accessible metric in cooperative group settings.

Abstract Background DNA methylation profiling can be used to robustly predict postsurgical outcomes and response to radiotherapy (RT) for meningioma patients. To allow for seamless integration of these complementary models into clinical practice, a practical framework is needed. Methods We leveraged a cohort of nearly 2000 surgically-treated meningiomas with DNA methylation profiling and clinical outcomes data. Existing methylation-based prediction models were dichotomized to yield four risk groups: low and high recurrent risk, each with RT sensitive and resistant subgroups. Risk groups were correlated with progression-free survival in the context of existing biomarkers including extent of resection and WHO grade. Results We first demonstrated that all risk groups benefit from gross total resection. All “high-risk, RT sensitive” tumors (n = 306, 15.7%) also benefited from adjuvant RT: after GTR, median PFS increased from 4.68 (4.13-9.48) years to not reached (P = .003); after subtotal resection (STR), from 2.12 (1.59-3.02) to 4.09 (3.41-not reached) years (P = .004). “Low-risk, RT sensitive cases” (n = 1207, 61.8%) also benefited from RT after STR (median PFS 7.39 (6.66-12.8) vs. 16.53 (10.35-not reached) years, P = .03), suggesting that RT be considered in these patients. Neither “low-risk RT resistant” (n = 84, 4.3%) nor “high-risk RT resistant” (n = 356, 18.2%) cases benefited from RT, and the latter group was associated with universally poor outcomes. Conclusions We identify methylation-defined risk groups of meningioma for which additional benefit is gained from adjuvant RT, leading to a clinical decision-making framework for straightforward integration of molecular models into clinical practice.

Objective: The Complete Cochlear Implant Care (CCIC) model is a highly coordinated care delivery model reducing and condensing in-person visits for cochlear implant (CI) patients, leveraging telehealth and remote programming. Clinical, quality-of-life, implementation, patient experience, and financial outcomes of the clinical trial are reported. Study design: Prospective, nonrandomized, 2-arm clinical trial Setting: Tertiary referral CI center Patients: Adult CI candidates Interventions: Cochlear implantation Main outcome measures: Speech perception, quality of life, implementation, patient experience, and financial outcomes for both CCIC and traditional care delivery models. Results: Patients participating in the traditional and CCIC delivery models demonstrated 12-month postoperative speech perception scores comparable to nationally reported outcomes (CNC 61% and 72% and AzBio in quiet 75% and 87% for traditional and CCIC cohorts, respectively). Quality-of-life evaluation using the CIQOL-10 demonstrated similar 12-month postoperative scores between groups (52 and 54 for traditional and CCIC cohorts, respectively). The CI Patient Experience Survey demonstrated high satisfaction outcomes in ease of communication, preparedness for surgery, and overall care in both cohorts. Implementation analysis of the CCIC model revealed perceived benefits from staff and clinicians; however, support for expansion of the program was contingent upon the availability of app-based or web-based remote programming technology. Finally, financial analysis revealed decreased out-of-pocket costs for CCIC patients. Conclusion: The CCIC model has the potential to dramatically streamline hearing health care delivery and reduce out-of-pocket costs for CI recipients. Clinical outcomes between cohorts were comparable in this feasibility study; however, a sufficiently powered trial is required to definitively comment on clinical outcomes with the new care delivery model.

Objective: To characterize patient outcomes after primary stereotactic radiosurgery (SRS) for the management of sporadic facial nerve schwannoma. Study design: Retrospective cohort study. Setting: Six tertiary referral centers across the United States and United Kingdom. Patients: Adults undergoing SRS from 2000 through 2023 for sporadic facial nerve schwannoma along any segment of the facial nerve were included. Patients with NF2-related schwannomatosis were excluded. Intervention: Stereotactic radiosurgery. Main outcome measure: Long-term tumor control. Results: Among 60 patients meeting inclusion, the median age at SRS was 52 years (IQR: 41 to 64) with a median tumor size of 19.5 mm (IQR: 14.7 to 22.8). Tumors commonly involved the internal auditory canal (73%), cisternal (49%), geniculate/labyrinthine (47%), and tympanic segments (22%). Two patients experienced SRS failure and underwent salvage treatment; salvage-free survival rates (95% CI; number still at risk) at 1, 3, 5, and 10 years after SRS were 100% (100 to 100; 55), 100% (100 to 100; 36), 100% (100 to 100; 18), and 87% (72 to 100; 9), respectively. Among 31 (52%) patients with House-Brackmann (HB) grade I facial function at presentation, only 6 demonstrated worse facial function at a median of 3.2 years (IQR: 1.7 to 6.6) after SRS. Of 18 patients with serviceable hearing (AAO-HNS class A/B) at SRS, 13 maintained serviceable hearing at a median of 1.0 years (IQR: 0.5 to 4.9) of post-SRS audiometric follow-up. Conclusions: Durable tumor control after primary SRS for sporadic facial nerve schwannoma is achieved in most patients. Among those with HB grade I facial function at presentation, treatment with SRS harbors limited additional risk of facial paresis beyond observation alone.

Background: Fecal microbiota, live-jslm (RBL) is approved in the United States and Canada for prevention of recurrent Clostridioides difficile infection (rCDI) in adults following standard-of-care (SOC) antibiotic treatment. Objectives: Provide an updated integrated safety analysis, incorporating final safety data from Punch CD3-OLS. Design: Safety data were combined from five RBL trials: three phase II and two phase III trials. Methods: Adult participants had documented rCDI and completed SOC therapy before receiving one or two doses of RBL or placebo, rectally administered as one treatment course. Treatment-emergent adverse events (TEAEs) were recorded for ⩽6 months. Results: TEAEs were reported in 70.9% (845/1192) of RBL recipients; most TEAEs were mild to moderate and gastrointestinal in nature. Most serious TEAEs were related to preexisting conditions or CDI. There was no clustering of serious TEAEs. Most TEAEs leading to death were related to preexisting conditions. Conclusion: Overall, data demonstrate RBL has a favorable 6-month safety profile. Trial registration: ClinicalTrials.gov: NCT01925417; NCT02299570; NCT02589847; NCT03244644; NCT03931941.

Abstract BACKGROUND Gaseous hydrogen sulfide (H2S), a by-product of cysteine metabolism, inhibits cancer cell behavior and growth in glioblastoma (GBM) models. H2S production capacity (HPC) is decreased in human GBM specimens compared to non-tumor controls. Thus, boosting HPC is a novel strategy for GBM treatment. Suppression of thyroid hormone signaling increases production of H2S. Hypothesis: methimazole-induced hypothyroidism will increase tumor HPC to enhance chemotherapy efficacy in GBM. GOAL Proof of concept that methimazole, by reducing thyroid hormone signaling, can increase HPC in patients with recurrent/progressive GBM (rGBM). PRIMARY ENDPOINTS 10% increase in HPC and a 1.5-fold increase in peripheral blood sulfhydration signaling. METHODS This window of opportunity trial evaluates safety, HPC in plasma and tumor, and efficacy of methimazole + chemotherapy in patients with rGBM. rGBM patients planned for a resection begin methimazole 15 mg/d 5-7 days pre-op with investigator’s choice chemotherapy added 10-28 days post-op. Patients receive combination until progression. Pre- and post-op plasma and resected tumor tissue are assayed for HPC and proteins relevant to H2S production. Key eligibility: rGBM for whom a clinically-indicated resection is planned; normal thyroid function with no history of thyroid dysfunction. Patients may have received unlimited prior regimens including bevacizumab. RESULTS To date 15 patients (8 male), median age 56 years, enrolled. The trial was amended to increase methimazole to 25 mg/d; 3 patients have received this dose. Median TSH rose from 1.3 mU/ml to 20.5 at cycle 6. Free T3 and T4 did not fall significantly. Median plasma HPC rose 3-fold while tumor HPC did not rise significantly. No treatment-related grade 3-5 toxicities. Efficacy: PFS6 – 15% and OS12 – 21%. CONCLUSIONS Induction of subclinical hypothyroidism is feasible and safe in rGBM with significant increases in plasma but not tumor HPC. Further tumor correlative data for the dose-escalated methimazole will be presented.