Citations

OBJECTIVE Despite the use of multiple glucose-lowering medications, glycemic targets are not met in a significant fraction of people with type 2 diabetes. In this prospective, observational study we assessed the prevalence of hypercortisolism, a potential contributing factor to inadequate glucose control. RESEARCH DESIGN AND METHODS Individuals with type 2 diabetes and HbA1c 7.5%–11.5% (58–102 mmol/mol) on two or more glucose-lowering medications with or without micro-/macrovascular complications or taking multiple blood pressure–lowering medications were screened with a 1-mg dexamethasone suppression test. Common causes of false-positive DSTs were excluded. The primary end point was the prevalence of hypercortisolism, defined as post-DST cortisol >1.8 μg/dL (50 nmol/L). Characteristics associated with hypercortisolism were assessed with multiple logistic regression. The percentage and characteristics of participants with hypercortisolism and adrenal imaging abnormalities were also assessed. RESULTS Post-DST cortisol was unsuppressed in 252 of 1,057 participants (prevalence 23.8%; 95% CI 21.3, 26.5). Hypercortisolism prevalence was 33.3% among participants with cardiac disorders and 36.6% among those taking three or more blood pressure–lowering medications. Adrenal imaging abnormalities were reported in 34.7% of participants with hypercortisolism. Use of sodium–glucose cotransporter 2 inhibitors (odds ratio 1.558), maximum-dose glucagon-like peptide 1 receptor agonists (1.544), tirzepatide (1.981), or a higher number of blood pressure–lowering medications (1.390); older age (1.316); BMI <30 kg/m2 (1.639); non-Latino/Hispanic ethnicity (3.718); and use of fibrates (2.676) or analgesics (1.457) were associated with higher prevalence (all P < 0.03). CONCLUSIONS Hypercortisolism was associated with hyperglycemia in approximately one-quarter of individuals with inadequately controlled type 2 diabetes despite multiple medications.

PURPOSE The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. METHODS Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m 2 once daily; days 1 and 2) and rituximab (375 mg/m 2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points. RESULTS In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. CONCLUSION The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

Abstract There are limited prospective data on whether established risk factors modify breast cancer risk in women with pathogenic variants (PV) in BRCA1/2 and virtually no risk modification data for ATM, CHEK2, or PALB2. We conducted a nested case–control study in the Women’s Health Initiative (WHI), randomly selecting women with and without breast cancer for DNA sequencing. We evaluated breast cancer odds associated with obesity, family cancer history, smoking, alcohol, parity, breastfeeding, oophorectomy, tubal ligation, neighborhood socioeconomic status, and menopausal hormone therapy (MHT) with estrogen and progestin or estrogen only in PV carriers and noncarriers. In exploratory analyses, we grouped genes by established predisposition for estrogen receptor (ER)-positive (ATM and CHEK2) or ER-negative (BRCA1 and PALB2) disease. Multivariable models with interaction terms were used to assess differential risk modification by PVs. Among 12,957 WHI participants, 287 carried PVs. Breastfeeding was modestly associated with reduced risk for PALB2 [OR = 0.08; 95% confidence interval (CI), 0.00–0.92; P value = 0.042]. With one-sided 95% CI, power was sufficient to exclude OR ≥2.0 with obesity for ATM and BRCA2; smoking and alcohol for CHEK2; no breastfeeding for ATM; no oophorectomy for BRCA2 and CHEK2; no tubal ligation for CHEK2; and neighborhood socioeconomic status for all genes. Estrogen + progestin MHT was modestly associated with increased risk for ER-positive PVs (OR = 7.31; 95% CI, 1.14–64.20; P = 0.036). PVs did not modify risk (interaction P ≥ 0.05). BRCA1/2, ATM, CHEK2, and PALB2 PV carriers do not have breast cancer OR ≥2.0 with many established risk factors. However, MHT warrants additional study in PV carriers. Significance: There is limited information on whether established risk factors increase breast cancer risk from PVs. In the WHI, PV carriers had no substantial (≥2-fold) increase with most risk factors, except potentially MHT in ATM or CHEK2 carriers. The results may inform counseling and research on MHT.

Abstract INTRODUCTION Sex differences are apparent in neurodegenerative diseases but have not been comprehensively characterized in frontotemporal dementia (FTD). METHODS Participants included 337 adults with autosomal dominant FTD enrolled in the ALLFTD Consortium. Clinical assessments and plasma were collected annually for up to 6 years. Linear mixed‐effects models investigated how sex and disease stage are associated with longitudinal trajectories of cognition, function, and neurofilament light chain (NfL). RESULTS While sex differences were not apparent at asymptomatic stages, females showed more rapid declines across all outcomes in symptomatic stages compared to males. In asymptomatic participants, the association between baseline NfL and clinical trajectories was weaker in females versus males, a difference that was not present in symptomatic participants. DISCUSSION In genetic FTD, females show cognitive resilience in early disease stages followed by steeper clinical declines later in the disease. Baseline NfL may be a less sensitive prognostic tool for clinical progression in females with FTD‐causing mutations. Highlights Females with genetic FTD exhibit overall steeper increases in plasma neurofilament light chain (NfL) than males. Females with genetic FTD outperform NfL levels in asymptomatic stages compared to males. Once symptomatic, females with genetic FTD decline more rapidly than males. Plasma NfL is a stronger prognostic marker in asymptomatic males than females.

Abstract Multiple myeloma (MM) is the second most common hematologic malignancy among US adults, characterized by high rates of relapse and refractory disease. Anti-Myeloma T cell immunotherapies, such as chimeric antigen receptors (CAR-Ts) and bispecific T cell engagers (BiTEs), have been able to induce deep responses in the clinic and extending survival for many. However, even these responses are not durable and majority of patients still relapse. MM cell signaling in response to cytokines released by these T cells, such as Tumor Necrosis Factor (TNF) Alpha, and Interferon gamma (IFNγ), may offer additional insight into mechanisms of relapse and resistance as well as avenues of therapeutic manipulation. To evaluate the effects of TNF and IFNγ on MM cell death and proliferation, we obtained human MM cell lines (MMCLs) and stably transduced them with a GFP-NLS reporter. We then monitored these cell lines in the presence of TNF, IFNγ, or TNF+IFNγ and tracked their cell death and growth kinetics over time using DiYO-3 incorporation and GFP count, respectively, via IncuCyteS3 live cell imaging. We next utilized Teclistamab, a B cell maturation antigen (BCMA)-directed BiTE, to co-culture MMCLs with healthy donor derived T cells at various effector to target (E:T) ratios and monitored for T cell mediated death again via IncuCyteS3 live cell imaging. While all MMCLs were able to be killed at high E:T ratios (1:1), only cytokine-sensitive lines remained susceptible to T cell killing at lower E:T ratios (1:10). The addition of TNF and/or IFNγ blocking antibodies confirmed that the increased sensitivity of these lines to T cell killing was indeed mediated by the two cytokines. In summary, were able to show an in vitro model of differential MM cell response to Teclistamab mediated T cell killing, and that this difference in response was predicated on the MM cells’ baseline sensitivity to cytokine mediated cell death via TNF and IFNγ. Thus, further dissecting mechanisms underlying resistance or sensitivity of MM cells to cytokine induced death could suggest therapeutic targets with the potential to enhance the efficacy of anti-MM T cell immunotherapies. Citation Format: Allison Carr, Adrian Ting. Role of cytokine-induced cell death on efficacy of teclistamab-mediated T cell killing of multiple myeloma cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1380.

Abstract Background: Pancreatic cancer is a frequently fatal disease that is often diagnosed at a late stage associated with a poor prognosis and an increasing impact on cancer related mortality. Despite advances, chemotherapy remains the mainstem of therapeutic interventions for this disease and most of the currently identified molecular alterations are not currently targetable. Therefore, novel biomarkers and strategies are necessary to impact patient outcomes. Claudin-18.2 (CLDN18.2) is a splice variant of the Claudin 18 family and is a component of tight junctions, which seal the paracellular spaces of epithelial and endothelial cells. CLDN18.2 is frequently retained in malignant gastric tissue and overexpressed in pancreatic and gastroesophageal adenocarcinomas. CLDN18.2 overexpression at the message and protein levels has been observed in pre-clinical studies involving pancreatic cancer cell lines and in tumors from pancreatic cancer patients. The goal of this study was to obtain a deeper understanding of CLDN18.2 positivity and CLDN18.2 expression and the associated clinical prevalence, prognostic implications, patient clinical characteristics and relationship with other biomarkers in pancreatic ductal adenocarcinoma (PDAC) patient samples. Design: This was a single institution/reference laboratory based retrospective study including as many as 320 patients, in which CLDN18.2 positivity as defined by ≥ 75% of the tumor cells expressing moderate to strong membranous staining was examined. The goals were to evaluate CLDN18.2 in tumor samples by immunohistochemistry for prevalence in pancreatic adenocarcinoma patients. Claudin 18.2 expression was assessed by the Ventana (43-14A) Class I IVD that was purchased from Ventana/Roche Diagnostics. In addition to prevalence, CLDN18.2 was evaluated with respect to the clinicopathological features of patients, patient prognosis, adjusted for clinical covariables, response to treatments and relationship to patient demographics, tumor grade and disease status. Patient information has been obtained from electronic medical records and research database to establish clinical course (survival status, metastatic sites, etc.) along with patient demographics. Conclusions: CLDN18.2 is a novel potentially actionable biomarker in patients with advanced and metastatic pancreatic adenocarcinoma. This study provides important clinical information regarding CLDN18.2 expression in these patients that is important to consider when evaluating biomarkers in these patients. Funding for the study was provided by Astellas Pharma Global Development, Inc. Citation Format: Allison Kerper, Robert H. Getzenberg, Rondell P. Graham. Real world clinical characteristics of claudin 18.2 expression in patients with pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5915.

PURPOSE Cytokine release syndrome (CRS) of any grade occurs in 56%-80% of bispecific antibodies (BsAbs) used in multiple myeloma (MM). Risk mitigation strategies are required to expedite escalation of care if toxicities develop. The rarity of grade 3 or 4 CRS compels protocolized outpatient management of BsAbs as outpatient practice may avoid hospital admissions and costly resource utilization without compromising safety. MATERIALS AND METHODS Patients with MM who received BsAb step-up dosing (SUD) from August 23, 2023, to March 29, 2024, were enrolled. Baseline demographics, patient outcomes, and CRS management were reviewed to assess the safety of outpatient practice. Resource utilization was also analyzed. RESULTS In this study, 34 patients received outpatient SUD of BsAbs (teclistamab n = 17, talequetamab n = 17) with 16 remaining outpatient throughout the entire SUD period. CRS occurred in seven patients who did not require hospitalization, demonstrating the safety of outpatient management of BsAb toxicity, regardless of low-grade CRS. CRS was observed in 24 patients (maximum grade 2) and immune effector cell–associated neurotoxicity syndrome in four patients (maximum grade 3). All patients with CRS received steroids, including 12 patients at home when instructed. Tocilizumab was given to 13 patients, accounting for 18 doses. If all doses of BsAbs and tocilizumab were given outpatient, the medication margin would be $115,004 in US dollars (USD). CONCLUSION An outpatient-based practice for BsAb administration demonstrated safety and cost savings. The description of our practice and results of this study provide valuable insights into the safety, feasibility, and resource stewardship of outpatient management of BsAbs. Future research should attempt to predict and stratify CRS risk to deliver a tailored supportive strategy and continued increase of outpatient management.

ABSTRACTAlthough recent studies have demonstrated the efficacy of chimeric antigen receptor T‐cell (CAR‐T) therapy in relapsed large B‐cell lymphoma (LBCL) with MYC rearrangement (R‐MYC), the data comparing CAR‐T to autologous hematopoietic cell transplant (auto‐HCT) in such patients who achieve a complete or partial response (CR/PR) after salvage therapies are limited. We compared the clinical outcomes of patients with R‐MYC LBCL (including double and triple hit lymphomas) who underwent CAR‐T or auto‐HCT after achieving a CR/PR with salvage therapies using the Center for International Blood & Marrow Transplant Research registry. Among the 252 patients (auto‐HCT = 98, CAR‐T = 154), relative to auto‐HCT, CAR‐T was associated with significantly lower overall survival (OS) (Hazard Ratio [HR] 2.09, 95% CI 1.38–3.15, p < 0.001) on multivariate analysis. There were no differences in progression‐free survival (PFS) (HR 1.21, 95% CI 0.81–1.8 p = 0.36), risk of relapse (HR 1.1, 95% CI 0.71–1.69 p = 0.68), nonrelapse mortality (NRM) (HR 1.74, 95% CI 0.64–4.7 p = 0.28) while the post‐relapse survival was longer in auto‐HCT relative to CAR‐T (HR 1.93, 95% CI 1.21–3.06 p = 0.01). On propensity score matched analysis accounting for differences in characteristics across the two cohorts, we detected no significant differences in OS (HR 1.72, 95% CI 0.92–3.21 p = 0.09), PFS (HR 1.04, 95% CI 0.64–1.68 p = 0.88), NRM (HR 1.22, 95% CI 0.35–4.2 p = 0.76), relapse (HR = 0.93, 95% CI 0.54–1.6 p = 0.8) and post‐relapse survival (HR 2.25, 95% CI 0.98–5.17, p = 0.06). These data, although retrospective, support consideration for auto‐HCT in patients with R‐MYC LBCL who achieve a CR/PR after salvage therapies, particularly in regions with no or limited access to CAR‐T.