Citations

Abstract Pancreatic adenocarcinoma (PDA) has poor response to chemotherapy with a strong likelihood of cancer recurrence. While previous studies have examined patient samples collected before and after chemotherapy, few have analyzed matched samples from the same patients that allow us to deconvolute interpatient heterogeneity, a large limitation to PDA studies. Here, we study the effects of chemotherapy on tumor cells and their surrounding microenvironment using scRNA sequencing of matched pre- and post- treatment tissue biopsies from 5 patients. We utilized the Seurat v4 pipeline to observe transcriptomic differences and corresponding putative cellular interactions in both treatment states. Unsurprisingly, we found insufficient tumor epithelial cells post-treatment due to the intended cytotoxic effects of chemotherapy, leading us to focus on the tumor microenvironment where we had sufficient cells to analyze. We identified that immune cells in the TME are heterogeneously affected by chemotherapy treatment with patient specific differences, but we did identify a unanimous increase in CXCR4 in CD4 and CD8 positive T cells after treatment. Analysis of CAFs revealed that a subset of fibroblasts lose myofibroblastic features and increasingly acquire 'neural'-like features after treatment. This suggests that chemotherapy-altered fibroblasts may contribute to a pro-tumor microenvironment that facilitates recurrence through neuron–CAF–tumor interactions. Through inferred ligand-receptor pairs identified with the CellChat v2 pipeline, we observed that increased CXCL12 in these neural CAFs interacts with the increased CXCR4 on T-cells. We validated the expression of these genes in patients by staining human patient PDAC tissues (both treated and treatment naïve tissues) for neural genes that were highly enriched post-treatment in our single cell sequencing dataset. We have also begun inhibiting these genes of interest in CAFs and are exploring the effects of these ‘neural’-CAFs on patient-derived tumor organoids in culture. Citation Format: Aylin Z. Henstridge, Padma Kadiyala, Ahmed Elhoissiny, Jianhua Liu, Georgina Branch, Nandini Arya, Vaibhav Sahai, Nicole Peterson, Jorge Machicado, Richard Kwon, Allison Schulman, Erik Wamsteker, George Phillips, Martin Fernandez-Zapico, Mark Truty, Timothy Frankel, Fillip Bednar, Marina Pasca di Magliano, Costas Lyssiotis, Eileen S. Carpenter. An increase in neural cancer associated fibroblasts following exposure to chemotherapy in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B079.

Abstract Hepatocellular carcinoma (HCC) mortality is increasing globally, partly due to the growing prevalence of nonviral liver diseases. Genome‐wide association studies (GWAS) have identified genetic variants associated with HCC development. Leveraging GWAS summary statistics and linkage disequilibrium score regression (LDSR), we investigated disease co‐development with hepatitis C virus‐negative (HCV‐negative) HCC to provide unique insights into HCC etiology and prioritize relationships for further causal inquiry. We utilized the LDSR statistical framework to estimate the genetic correlation and heritability between HCV‐negative HCC with 901 epidemiologic, behavioral, and clinical traits from the United Kingdom Biobank (UKBB). First, we set the threshold for observed scale heritability of each trait at 0.02 to ensure reliable inferences with adequate study power. Next, we observed significant positive genetic correlations between HCV‐negative HCC and blood‐based biomarkers of liver injury (ALT, GGT) and allostatic load (including glycated hemoglobin, blood pressure, and total albumin). We also identified a positive genetic correlation between HCV‐negative HCC and diseases associated with metabolic dysfunction‐associated steatotic liver disease (MASLD), including diabetes, hypertension, chronic ischemic heart disease, and others. Taken together, our results help to identify polygenic and pleiotropic signals related to different phenotypic traits associated with HCC and support further exploration of the predictive power of blood‐based biomarkers identified in this study for inferring HCC development among HCV‐negative individuals.

Abstract Background Recommended noninvasive strategies for average-risk colorectal cancer (CRC) screening include multitarget stool DNA and fecal immunochemical test from ages 45 to 75 years. With new clinical trials, performance data for next-generation multitarget stool DNA, multitarget stool RNA, and blood-based screening tests are now available. This decision analytical model study evaluated the estimated benefit-to-burden ratio by means of efficient frontiers for noninvasive established and emerging CRC screening strategies. Methods Outcomes were estimated using the Colorectal Cancer and Adenoma Incidence and Mortality microsimulation model for average-risk individuals in the United States. Screening strategies were next-generation multitarget stool DNA (an updated marker panel), fecal immunochemical tests, multitarget stool RNA, or blood-based tests every 1-3 years, over various age ranges. Test performance inputs were derived from recent large clinical trials. A strategy was deemed efficient if no other strategy provided more life-years gained with equivalent or fewer lifetime colonoscopies and near-efficient if within 3 days of life-years gained of the efficient frontier. Results All modeled screening strategies resulted in life-years gained vs no screening. No strategy using blood-based tests was efficient or near-efficient. Overall, 10 strategies were efficient (6 next-generation multitarget stool DNA and 4 fecal immunochemical tests), including 2 strategies among those ages 45-75 years (biennial and triennial next-generation multitarget stool DNA). Overall, 22 strategies were near-efficient, including 4 strategies among those ages 45-75 years (annual, biennial, or triennial fecal immunochemical test; annual next-generation multitarget stool DNA). Conclusion Based on this modeling study, next-generation multitarget stool DNA was the only noninvasive screening test at guideline-endorsed interval and age-recommended ranges that was deemed efficient. Blood-based and multitarget stool RNA strategies were deemed not efficient for primary screening.

PURPOSE Ziftomenib—a potent, highly selective, oral menin inhibitor—was well tolerated and demonstrated encouraging clinical activity as monotherapy for relapsed/refractory NPM1 -mutated ( NPM1 -m) and KMT2A -rearranged AML in the KOMET-001 phase I trial. METHODS In the registration-enabling phase II part of KOMET-001, patients with relapsed/refractory NPM1 -m AML received ziftomenib 600 mg once daily. The primary end point was the rate of complete remission with full hematologic recovery (CR)/CR with partial hematologic recovery (CRh). RESULTS From January 26, 2023, to May 13, 2024, 92 patients (median age, 69 years [range, 33-84]) were treated. The primary end point was met, with a CR/CRh rate of 22% (95% CI, 14 to 32; P = .0058); 61% were negative for measurable residual disease. Overall response rate was 33% (95% CI, 23 to 43), with a median duration of 4.6 months (95% CI, 2.8 to 7.4). Prespecified subgroup analyses showed comparable CR/CRh regardless of previous therapy, including venetoclax, or type of comutations. Median overall survival was 6.6 months (95% CI, 3.6 to 8.6). Common grade ≥3 treatment-emergent adverse events were febrile neutropenia (26%), anemia (20%), and thrombocytopenia (20%). Differentiation syndrome occurred in 25% of patients (15% grade 3; no grade 4-5) and was manageable with protocol-defined mitigation. Three patients (3%) discontinued treatment because of ziftomenib-related adverse events. CONCLUSION Ziftomenib demonstrated significant clinical benefit and deep responses in patients with heavily pretreated, relapsed/refractory NPM1 -m AML. Ziftomenib was well tolerated with a safety profile consistent with previous studies, including manageable differentiation syndrome, lack of clinically significant QTc prolongation, and low rates of myelosuppression.

Background Intracranial occlusions in embolic stroke of undetermined source are histopathologically similar to cardiac sources of embolism. Whether patients with embolic stroke of undetermined source and intracranial occlusion benefit from anticoagulation is unknown. Methods A multicenter retrospective cohort of adults with cryptogenic stroke was queried for patients with proximal or medium/distal vessel occlusion. The primary outcome was recurrent ischemic stroke, which was assessed in unadjusted and adjusted Cox proportional hazards models and repeated following 1:1 propensity score matching and biweight kernel density matching. Results Of the 2328 patients who were followed over a median of 1.31 years (interquartile range, 0.34–2.85), 999 (42.6%) had an intracranial occlusion. When compared with patients without an intracranial occlusion, those with an occlusion had fewer atherosclerotic vascular risk factors, more severe symptoms, and less severe cerebral microvascular disease. The rate of recurrent stroke was similar between patients with versus without an intracranial occlusion (6.8%/year [95% CI, 5.7–8.2] versus 7.0%/year [95% CI 6.0–8.1]; adjusted hazard ratio [HR], 1.09 [95% CI, 0.77–1.55]). There was no association between occlusion and recurrent stroke in the adjusted propensity score matching (HR, 1.01 [95% CI, 0.64–1.59]) or kernel density models (HR, 0.95 [95% CI, 0.62–1.45]). There was no interaction between occlusion and treatment with anticoagulation, sex, age, or high‐risk sources of embolism for the primary outcome in the unmatched and matched analyses. Conclusions Intracranial occlusion in patients with embolic stroke of undetermined source is not associated with a greater risk of recurrence when compared with patients without an intracranial occlusion. There was no difference in rate of recurrent stroke with anticoagulation when stratified by presence or absence of occlusion.

PURPOSE Given the extended survivorship of young adults with breast cancer, characterizing health care utilization and adherence to surveillance guidelines can inform gaps in care. PATIENTS AND METHODS Patients age 40 years and younger at diagnosis of stage 0-III breast cancer enrolled in a prospective cohort study completed a survey 7 years after diagnosis assessing receipt of care and surveillance. We evaluated factors associated with transition to a primary care provider (PCP) for cancer-related follow-up and adherence to mammography and bone density scans. RESULTS Among 660 women, 92% reported having a PCP, although for cancer-related follow-up, 57% saw only an oncology provider, 29% saw both a PCP and oncology provider. In the past 2 years, 68% reported getting a flu shot, 76% a pap test/pelvic examination, 56% cholesterol screening, and 42% (n = 232 endocrine therapy [ET] users) a bone density scan. Among women who had a unilateral mastectomy or lumpectomy (n = 356), 82% reported a mammogram in the past year. In multivariate analyses, those with stage 0 ( v I disease) were more likely to see a PCP for follow-up ( v PCP + oncology provider); ET users and those more concerned about recurrence were less likely. Patients with human epidermal growth factor receptor 2-positive (HER2) disease were more likely to adhere to mammography; those with a BRCA mutation and those with a unilateral mastectomy were less likely. Patients with a BRCA mutation and who had chemotherapy were more likely to report a bone density scan. CONCLUSION Although most have a PCP, over half of young survivors continue to see an oncology provider for follow-up in long-term survivorship. Mammography uptake was high; uptake of other health maintenance practices was lower. Identification of barriers/facilitators to receipt of guideline-concordant care may inform strategies to optimize survivorship.

Summary We investigated the outcomes of patients with advanced systemic mastocytosis (AdvSM) undergoing allogeneic haematopoietic cell therapy (alloHCT) in the US. Twenty‐seven adult (median age, 58 years) patients with AdvSM received alloHCT from 2014 to 2021. Most patients were white (93%), male (63%) and had systemic mastocytosis (SM) with associated haematological neoplasm (SM‐AHN, 70%), received peripheral blood grafts (89%) and non‐myeloablative regimens. KIT mutation was detected in 14 of the reported 16 patients (87.5%). Post‐transplantation cyclophosphamide (PTCy) was used in approximately 50% of the cohort. Approximately 1 year after alloHCT, median bone marrow mast cell burden decreased from 15% pre‐alloHCT to 1.5% (range 0–8) at 1 year post‐alloHCT. The median serum tryptase decreased from 55 ng/mL (range 3–400 ng/mL) pre‐alloHCT to 18 ng/mL (range 0–481 ng/mL) at 1 year post‐alloHCT. At 1 year, progression‐free survival (PFS) and overall survival (OS) were 59% (95% confidence interval [CI], 41%–77%) and 74% (95% CI, 56%–89%) respectively. In the subset of patients with SM‐AHN, 1‐year PFS and OS were 74% (52%–91%) and 79% (95% CI, 58%–94%) respectively. The cumulative incidence of relapse/progression for the entire population of patients with SM ( n = 27) was 4% (95% CI, 0–14) at 100 days and 15% (95% CI, 4–31) at 1 year. For the subset of patients with AHN, the cumulative incidence was 11% (95% CI, 1–28) at 100 days and 21% (95% CI, 6–42) at 1 year. Relapse/progression was the cause of death in six of 12 patients (5 died of AHN and 1 died of SM progression). Eighteen and nine patients received a KIT inhibitor before alloHCT and after alloHCT respectively. In addition, six patients received a KIT inhibitor for the treatment of relapse/progression of SM after alloHCT. Although it is difficult to delineate the exact effect of alloHCT and KIT inhibitors because of the size of the study in this era, the use of alloHCT and KIT inhibitors pre‐ and post‐ alloHCT is increasing. In the near future, larger studies are required to provide further insights into this subject.