Citations

601 Background: EOP is an I-SPY2 neoadjuvant sub-study designed to test the tolerability and impact of novel endocrine-based strategies in stage 2/3 BC pts predicted to have lower benefit from chemotherapy. Amcenestrant (A) is an oral selective estrogen receptor degrader (SERD) with activity in hormone receptor positive (HR+) HER2- metastatic BC. Methods: EOP eligibility included pts screened for the main I-SPY2 trial with HR+ HER2-, MammaPrint (MP) low risk Stage 2/3 BC. Pts with MP High risk tumor signatures were eligible if clinically node-negative (cN-). Pts were stratified by SET index and menopausal status. Pts were randomized to 3 arms: A 200 mg qd (A), A + abemaciclib 150 mg bid (AA), A + letrozole 2.5 mg qd (AL). Premenopausal pts received concurrent ovarian function suppression. Treatment was for 6 mos followed by surgery. Baseline (BL) and 3-wk biopsies were performed. Breast MRIs were conducted at BL (T0), 3 wks (T1), 12 wks (T2), 6 mos (T3). The primary endpoint was feasibility, defined as >75% of pts completing >75% study therapy. Results: Between May 2021 and Aug 2022, 74 pts were randomized: 31 A, 21 AA, 22 AL. Median age 50 years, 54% premenopausal, 38% clinically node-positive (cN+). 41% pts had ductal, 38% lobular, 11% mixed ductal/lobular histology. Mean BL tumor Ki67 (central testing) was 16.9%, 88% MP low, 76% SET index Hi. Pt and tumor characteristics were balanced across the 3 arms. Treatment in all 3 arms was feasible with 95% of pts completing >75% study therapy. Most common AEs include grade 1-2 hot flashes (69%) and fatigue (66%). Grade 3 AEs include neutropenia (2 pts) and diarrhea (1 pt) in AA. Table summarizes key response endpoints, which were similar between pre- and postmenopausal pts. Of 28 cN+ pts, 2 (7%) were pathologically node-negative (pN-). Mean MRI Functional Tumor Volume (cc) change between T0->T1, T1->T2, T2->T3, T0->T3 was -6.06 (-34.2%), -3.55 (-29.2%), -0.829 (-20.1%), -11.3 (-68.4%), respectively, similar across arms (p=0.396).ctDNA was detected in 10/59 (17%) pts at T0. ctDNA became undetectable in 6 pts, decreased in 4 pts, and went from ctDNA undetectable at baseline to detectable at T3 in 2 pts. Conclusions: Six months of neoadjuvant endocrine therapy (NET) with the oral SERD amcenestrant is feasible, well-tolerated, and demonstrates anti-proliferative and anti-tumor activity in pre- and postmenopausal pts. NET provides a rich platform for biomarker discovery and investigating response to endocrine therapy. Clinical trial information: NCT01042379 . [Table: see text]

Abstract T-cell/histiocyte–rich large B-cell lymphoma (THRLBCL) is a rare histologic variant of LBCL. Limited data regarding CD19–directed chimeric antigen receptor T-cell (CART) therapy in relapsed/refractory (R/R) THRLBCL suggest poor efficacy. We investigated CART outcomes for R/R THRLBCL through the Center for International Blood and Marrow Transplant Research registry. A total of 58 adult patients with R/R THRLBCL who received commercial CD19-CART therapy between 2018 and 2022 were identified. Most patients (67%) had early relapse of disease (45% primary refractory) with a median of 3 (range, 1-7) prior therapies and were treated with axicabtagene ciloleucel (69%). At median follow-up of 23 months after CART therapy, 2-year overall and progression-free survival were 42% (95% confidence interval [CI], 27-57) and 29% (95% CI, 17-43), respectively. In univariable analysis, poor performance status before CART therapy was associated with higher mortality (hazard ratio, 2.35; 95%CI, 1.02-5.5). The 2-year cumulative incidences of relapse/progression and nonrelapse mortality were 69% and 2%, respectively. Grade ≥3 cytokine release syndrome and immune effector cell–associated neurologic syndrome occurred in 7% and 15% of patients, respectively. In this largest analysis of CD19-CART therapy for R/R THRLBCL, ∼30% of patients were alive and progression free 2 years after CART therapy. Despite a high incidence of progression (69% at 2 years), these results suggest a subset of patients with R/R THRLBCL may have durable responses with CARTs.

Abstract INTRODUCTION Although frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominance has been recognized, a uniform description of the syndrome is still missing. This multicenter study aims to establish a cohesive clinical phenotype. METHODS Retrospective clinical data from 18 centers across 12 countries yielded 360 FTD patients with predominant RATL atrophy through initial neuroimaging assessments. RESULTS Common symptoms included mental rigidity/preoccupations (78%), disinhibition/socially inappropriate behavior (74%), naming/word‐finding difficulties (70%), memory deficits (67%), apathy (65%), loss of empathy (65%), and face‐recognition deficits (60%). Real‐life examples unveiled impairments regarding landmarks, smells, sounds, tastes, and bodily sensations (74%). Cognitive test scores indicated deficits in emotion, people, social interactions, and visual semantics however, lacked objective assessments for mental rigidity and preoccupations. DISCUSSION This study cumulates the largest RATL cohort unveiling unique RATL symptoms subdued in prior diagnostic guidelines. Our novel approach, combining real‐life examples with cognitive tests, offers clinicians a comprehensive toolkit for managing these patients. Highlights This project is the first international collaboration and largest reported cohort. Further efforts are warranted for precise nomenclature reflecting neural mechanisms. Our results will serve as a clinical guideline for early and accurate diagnoses.

Objective: To describe the epidemiology of body checking injuries in the National Collegiate Athletic Association (NCAA) Men's Ice Hockey. Design: Secondary data analysis of historical cohort data. Setting: A convenience sample of injuries in NCAA Men's Ice Hockey during the 2009/10 to 2019/20 academic years. Patients (or Participants) NCAA student-athletes. Independent Variables: Event type, season, time loss, body part, diagnosis, player position, and mechanism. Main Outcome Measures: This study examined injuries that occurred during practice or competition, regardless of time loss, reported to the NCAA Injury Surveillance Program. Injury counts, rates, and proportions were used. The injury rate and proportion ratios with 95% confidence intervals were also constructed. Three independent logistic regression models were constructed to examine differential odds of time loss (≥1 day; TL) injury and the 2 most common injuries, between body checking injuries and all other injuries. Results: Overall, 1290 body checking injuries (rate = 1.59/1000 athlete-exposures) were reported during the study period. Most were attributed to the upper extremity (42%) or head/neck (27%). The competition injury rate generally decreased after 2012/13. After adjusting for covariates, odds of (1) a TL injury was lower and (2) an acromioclavicular sprain was higher among body checking injuries as compared with injuries attributed to all other activities. Odds of concussion was not associated with body checking injuries. Conclusions: Body checking injuries were frequently attributed to the head/neck and upper extremities, and the rate of these injuries during competition appeared to be decreasing. Still, improvements in helmet and shoulder pad technology may further improve health and safety.

Abstract Acute graft-versus-host disease (GVHD) grading systems that use only clinical symptoms at treatment initiation such as the Minnesota risk identify standard and high-risk categories but lack a low-risk category suitable to minimize immunosuppressive strategies. We developed a new grading system that includes a low-risk stratum based on clinical symptoms alone and determined whether the incorporation of biomarkers would improve the model’s prognostic accuracy. We randomly divided 1863 patients in the Mount Sinai Acute GVHD International Consortium (MAGIC) who were treated for GVHD into training and validation cohorts. Patients in the training cohort were divided into 14 groups based on similarity of clinical symptoms and similar nonrelapse mortality (NRM); we used a classification and regression tree (CART) algorithm to create three Manhattan risk groups that produced a significantly higher area under the receiver operating characteristic curve (AUC) for 6-month NRM than the Minnesota risk classification (0.69 vs 0.64, P = .009) in the validation cohort. We integrated serum GVHD biomarker scores with Manhattan risk using patients with available serum samples and again used a CART algorithm to establish 3 MAGIC composite scores that significantly improved prediction of NRM compared to Manhattan risk (AUC, 0.76 vs 0.70, P = .010). Each increase in MAGIC composite score also corresponded to a significant decrease in day 28 treatment response (80% vs 63% vs 30%, P < .001). We conclude that the MAGIC composite score more accurately predicts response to therapy and long-term outcomes than systems based on clinical symptoms alone and may help guide clinical decisions and trial design.

Brachial Plexus Injuries are a catastrophic situation that affects patients on many levels. While many treatment options are discussed in the literature, general treatment principles should be applied, especially in the acute phase. In addition to the surgeon's expert knowledge of anatomy and injury characteristics, education of the patient concerning the ramifications of their injury and providing clear expectations of realistic outcomes are imperative for both the surgeon and the patient. A review of the principles of acute surgical treatment will be presented.

TPS4208 Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) carries a 5-year relative survival of 3%. Immune checkpoint inhibitors have thus far failed to improve outcomes due to an immunosuppressive tumor microenvironment (TME). Signaling through the C-X-C motif chemokine receptor 4 (CXCR4)/C-X-C motif chemokine ligand 12 (CXCL12) axis results in exclusion of anti-tumor immune cells in mouse PDAC models. Longitudinal survival studies testing combinations of CXCR4i, aPD-1, and gemcitabine in the KPC mouse model of PDAC demonstrated a survival benefit with the combination of all three agents. Results from a multicenter, investigator-initiated, single arm pilot study evaluating the preliminary safety and efficacy ofMotixafortide (CXCR4i), Cemiplimab (aPD1), Gemcitabine, and Nab-paclitaxel (MCGN) in 11 patients with treatment-naïve mPDAC were recently presented. Seven patients (64%) achieved a partial response, including 6 confirmed partial responses, and 10 patients (91%) had disease control, compared to historic partial response and disease control rates of 23% and 48%, respectively, with gemcitabine and nab-paclitaxel (GN). Preliminary median progression-free survival (PFS) was 9.6 months compared to historic median PFS of 5.5 months with GN. Analysis of paired pre- and on-treatment biopsy samples from demonstrated an increase in CD8+ T-cell density in tumors from all 11 patients treated with MCGN (p=0.007). Based on these promising results, the protocol was amended from a single arm expansion totaling 40 patients to a randomized phase 2 study. Methods: This is an open-label, multicenter, investigator-initiated phase 2 clinical trial. Patients are randomized 2:1 to receive MCGN or GNalone (N=108). The primary endpoint is progression free survival. The study has 80% power to detect an improvement in PFS from 6 to 9.2 months (HR 0.65) with a one-sided alpha of 0.20. One interim analysis for futility is planned when 50% of the PFS events are observed. Secondary objectives include response rate, disease control rate, duration of clinical benefit and overall survival. Patients will undergo optional paired biopsies which will be analyzed in conjunction with samples collected from the phase I pilot study. Exploratory studies include interrogation of the TME using quantitative multiplex immunofluorescence and single-cell RNA sequencing. The randomized phase 2 trial is open to enrollment and one patient has been randomized as of 1/29/2024. Clinical trial information: NCT04543071 .

e16286 Background: GEP-NET is a rare disease with variable tumor biology. An indolent disease course with subtle symptoms renders timely diagnosis difficult; 2/3 of patients (pts) are diagnosed at locally advanced or metastasized stage. In clinical decision-making, disease-specific factors, patient (pt) age and long-term disease control must be balanced against the aggressiveness of therapies. NCCN, NANETS and ENETS guidelines recognize the diversity of mGEP-NET by recommending individualized treatment approaches. We aimed to describe treatment (Tx) utilization patterns in mGEP-NET. Methods: Retrospective cohort study using MarketScan® Commercial and Medicare Databases spanning 07/01/2017-01/31/2023. Eligible were GEP-NET pts with ≥1 inpatient or ≥2 outpatient claims, a subsequent new diagnosis of metastatic disease (index), no secondary malignancy, and follow-up time of ≥12 months (m) after index. Results: Of 16218 GEP-NET pts, 2002 (mean age 60y; 50% female) met inclusion criteria. Mean follow-up time after index was 17m, with 49%, 27% and 15% followed up for ≥12, 24 and 36m, resp. Medical history (12m baseline before index) included mean Charlson Comorbidity Index of 2.62, with hypertension (HTN), type 2 diabetes (T2DM), chronic liver disease (CLD), asthma/COPD, cardiovascular disease (CVD), and chronic kidney disease (CKD) present in 56, 26, 22, 18, 17 and 10% of pts, resp.; 5% had carcinoid syndrome. In total, 949 pts (47.4%) received first-line (1L) systemic Tx: somatostatin analogs (SSA; 61.6%) of either very short or long duration (median 116d vs 775d), chemotherapy (38.8%), targeted therapies (3.4%) and PRRT (0.5%). Relative to NCCN cancer surveillance guidelines, 49.5% received more and 36.8% received fewer than 4 scans in the first year of treatment. Conversely, 1053 (52.6%) did not receive any 1L systemic Tx. With the exception of CLD, pts with vs without 1L Tx had similar proportions of medical conditions during the 12m baseline and during follow-up (HTN 72.4 vs 66.5%; T2DM 34.0 vs 30.3%; asthma/COPD 16.5 vs 19.3%; CVD 27.3 vs 36.9%; CKD 18.9 vs 17.9%; however, CLD 54.0 vs 36.7%). See Table comparing both cohorts on insurance, treatments, and health care utilization during follow-up. Conclusions: This claims analysis reveals treatment differences among mGEP-NET pts that cannot be explained by the parameters assessed herein. Further research should investigate factors influencing diagnosis and treatment decision-making, applying also pt-level health record data; and analyze economic barriers to diagnosis and treatment. [Table: see text]

Pityriasis rubra pilaris (PRP) is a rare inflammatory skin disease with a poorly understood pathogenesis. Through a molecularly driven precision medicine approach and an extensive mechanistic pathway analysis in PRP skin samples, compared to psoriasis, atopic dermatitis, healed PRP, and healthy controls, we identified IL-1β as a key mediator, orchestrating an NF-κB–mediated IL-1β–CCL20 axis, including activation of CARD14 and NOD2. Treatment of three patients with the IL-1 antagonists anakinra and canakinumab resulted in rapid clinical improvement and reversal of the PRP-associated molecular signature with a 50% improvement in skin lesions after 2 to 3 weeks. This transcriptional signature was consistent with in vitro stimulation of keratinocytes with IL-1β. With the central role of IL-1β underscoring its potential as a therapeutic target, our findings propose a redefinition of PRP as an autoinflammatory keratinization disorder. Further clinical trials are needed to validate the efficacy of IL-1β antagonists in PRP.