Citations

Background: Tumor mutational burden (TMB) is an FDA-approved biomarker for immune checkpoint inhibitor (ICI) therapy. However, its predictive value varies among tumor types and molecular contexts. We investigated whether a very high TMB identifies a biologically distinct subset and whether a higher cutoff provides additional clinical insights beyond the conventional high TMB threshold. Methods: We analyzed 133 patients with advanced solid tumors and TMB ≥ 10 mutations/Mb (mut/Mb) who underwent tumor genomic profiling using a 523-gene DNA/RNA next-generation sequencing panel. Tumors were stratified into prespecified TMB categories: 10–20 mut/Mb (TMB-H) and >20 mut/Mb (TMB-VH). The clinical characteristics, ICI outcomes (in the treated subset), and pathway-level genomic features were compared between groups. Results: TMB-VH was observed in 42/133 (31.6%) patients and spanned more than 20 tumor types. MSI was markedly more prevalent in TMB-VH than in TMB-H tumors (38.1% vs. 2.2%; Fisher’s exact p = 8.9 × 10−8). Pathway-level comparisons did not identify statistically significant differences after false discovery rate correction (all q > 0.05), and the observed patterns were descriptive in nature. In the ICI-treated subset with complete follow-up, objective response did not differ according to the TMB group. Overall survival (OS) was also similar between groups, whether measured from metastatic diagnosis (log-rank p = 0.937) or from ICI initiation (log-rank p = 0.814), although OS was numerically longer in the TMB-VH group in both analyses without reaching statistical significance. Conclusions: In this cohort study, TMB-VH was strongly associated with MSI but not independently associated with improved ICI outcomes. Larger multicenter cohorts are needed to validate pathway-oriented patterns and clarify the clinical utility of extreme TMB thresholds across various histologies. Integrating the functional context (e.g., MSI status, gene-level context, and pathway-level features) with TMB magnitude may enable more robust, tumor-aware biomarker models for immunotherapy selection.

This slide presentation uses real-world examples from diverse modern systems to categorize digital radiographic artifacts by likely cause and outlines investigation and mitigation strategies to improve troubleshooting, artifact prevention, and patient care.

Abstract Objective Advanced adrenocortical carcinoma (ACC) is treated with mitotane alone or combined with cytotoxic chemotherapy, yet outcomes remain poor and prognostic models in this setting are lacking. This study aimed to evaluate the prognostic value of clinical parameters in a large cohort of patients with advanced ACC undergoing systemic therapy. Methods Multicenter, international cohort study investigating 418 patients with advanced ACC (61.5% = women, median age = 52 years) from 11 centers. Patients received mitotane monotherapy (n = 161), etoposide + doxorubicin + cisplatin ± mitotane (n = 178), or second-line regimens (gemcitabine + capecitabine ± mitotane or temozolomide + mitotane, n = 79). Variables included age, cortisol excess, performance status (ECOG-PS), tumor burden, and neutrophil-to-lymphocyte ratio (NLR) at start of therapy. Outcomes were overall survival (OS), time to progression (TTP), and best objective response. Results Tumor burden, cortisol excess, ECOG-PS, and NLR ≥5 independently predicted shorter OS (hazard ratio [HR] 1.55-2.68). We developed an integrated ENSAT Risk Score for Advanced ACC combining these variables: tumor burden (0-2), cortisol excess (0/1), ECOG-PS (0-2), and NLR (0/1). A score >2 (poor-risk) was significantly associated with worse OS and TTP across all treatment groups (HRs for OS: 3.05-3.96; TTP: 2.53-3.08). It also predicted poorer response to mitotane (P < .01) and second-line therapies (P = .04). Conclusions The ENSAT Risk Score for Advanced ACC is a practical, prognostic tool for patients with advanced ACC receiving systemic therapy. Based on accessible clinical and biochemical markers, it can support treatment decisions and facilitate informed discussions in routine care.

Abstract Background: Treatment for patients with triple-negative breast cancer (TNBC) relies on non-specific chemotherapy, underscoring the need for precision-based approaches. Our lab discovered that MALT1, the effector protein of the CARMA3-BCL10-MALT1 (CBM) signaling complex, is activated downstream of several oncogenic G protein-coupled receptors (GPCRs) implicated in breast cancer, including the thrombin (PAR1), angiotensin II (AGTR1), and lysophosphatidic acid (LPAR) receptors. When activated, MALT1 functions as a protease to cleave select protein substrates. Based on our finding that CBM activity in TNBC cells promotes tumor growth in immunocompetent but not in immunodeficient mouse models, we hypothesized that MALT1 protease activity induces a pro-tumor secretome that creates an immune-suppressed tumor immune microenvironment (TIME). Methods/Results: We confirmed by western that MALT1 protease is active in multiple human and mouse TNBC cell lines. Next, to identify MALT1-dependent secreted factors, we performed transcriptomic and proteomic analyses comparing TNBC cells treated with or without MALT1 protease inhibitors. We found that several secreted factors, including GM-CSF, CXCL1, and Pentraxin 3, were reduced by MALT1 protease inhibition. To assess the functional impact of the MALT1 protease-dependent secretome, we performed media transfer experiments comparing the effects of conditioned media (CM) from TNBC cells treated with or without MALT1 protease inhibitors. To account for species differences, experiments were performed evaluating human TNBC cell CM added to human PBMCs and mouse TNBC cell CM added to murine bone marrow cells. We found that the MALT1 protease-dependent secretome reduces the expression of iNOS in both human and murine macrophages. For use in validating our findings in human TNBC clinical specimens, we developed a “MALT1 protease active gene signature” using RNA-seq analysis. Conclusions/Future Directions: Our studies indicate that MALT1 protease activity in TNBC cells promotes expression of numerous immune-suppressive factors. In both human and mouse systems, blockade of MALT1 protease alters the tumor cell secretome and promotes an increase in expression of the anti-tumor M1-like marker iNOS in macrophages. Future studies will evaluate how this change in iNOS expression impacts functional properties of TNBC-associated macrophages. We will also assess the influence of the TNBC MALT1-dependent secretome on the TIME in vivo by comparing the effects of intratumoral injection of CM from MALT1 wild-type or MALT1 protease-deficient TNBC cells. Finally, we will utilize our MALT1 activity gene signature to evaluate TNBC clinical specimens for an association between MALT1 activity and tumor immune contexture, with an emphasis on tumor-associated macrophages. Our studies could nominate MALT1 protease as a potential therapeutic target for improving anti-tumor immunity in TNBC. Since multiple MALT1 protease inhibitors are in clinical trial, our findings could be rapidly translated to improve outcomes for patients with TNBC. Citation Format: John W. Little IV, Jeffrey A. Meridew, Dong Hu, Juliana Hofstätter Azambuja, Linda M. McAllister-Lucas, Peter C. Lucas. The GPCR-MALT1 protease signaling axis drives an immunosuppressive secretome in triple-negative breast cancer [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr B046.

Accurate assessment of distal tibiofibular syndesmotic injuries is essential to prevent chronic instability and poor functional outcomes, and conventional radiography, CT, and MRI play complementary and critical roles in the imaging of these injuries.

Background: Interfacility transfers, especially in rural settings, present challenges including limited ambulance availability, bed capacity, image sharing and disparities in access. Regional transfer minimizes time to definitive stroke center care, relies less on costly helicopter transport, supports local healthcare economies, and preserves comprehensive stroke center (CSC) resources for those most likely to benefit. Although these advantages are well-established and reflected in the guidelines, transfers within our connected care rural network were not previously accepted at hospitals outside of our central comprehensive stroke center (CSC). Methods: We identified a local primary stroke center to serve as the regional stroke transfer center (rSTC) within our larger telestroke network. Over one year, (2023-2024), stakeholder meetings with representatives from the rSTC, surrounding smaller hospitals and the CSC were conducted to pinpoint potential roadblocks and create workflows that facilitated regional transfer. Regionally appropriate transfers were defined as patients without LVO, low likelihood for any neurosurgical decompression, or critical illness requiring dedicated neuro-intensive care. Education surrounding these criteria occurred quarterly and case logs were maintained and reviewed by the rSTC stroke coordinator. Retrospective chart review one year following the intervention period (2024-2025) was performed. Results: Of the 99 total transferred patients, 73 (73.7%) patients were transferred regionally. Their average LOS was 2.1 days, with 0% mortality rate and 0% requiring a secondary transfer to the CSC. 26 (26.3%) patients went to the CSC; LOS was 10.6 days and mortality 23.1%. Transfer times were shorter for rSTC patients (60 min vs 188 min). Six CSC patients met regional criteria (26.3% overtriage rate). Conclusion: Establishing an effective regional transfer model is possible with broad stakeholder engagement and regular network maintenance. Following our intervention, most eligible patients remained local and were treated appropriately. Although there was a significant reduction of the patients transferred to the CSC, the majority of CSC transfers were also appropriately triaged. This rSTC model facilitates the care of all stroke patients by providing the right level of care for the right patient, avoiding futile transfers with costly admissions far from home while opening beds and reducing transfer times to CSCs.

Abstract Background Intracranial mesenchymal tumors, FET::CREB fusion-positive (ICMT), show fusions involving FET RNA-binding protein family genes (EWSR1 or FUS) and CREB family of transcription factors (ATF1, CREB1, or CREM). The methylation signature(s), gene expression characteristics, and clinical behavior of this important tumor type require further characterization. Methods We study the methylation profiles of 81 ICMT cases (61 newly profiled cases and 20 cases from publicly available sources). Clinicopathologic and genomic data were recorded for each case when available. Results ICMT showed a relatively distinct methylation signature compared to related tumors. Among the 65 cases where fusion types were documented, the identified fusions included EWSR1::ATF1 (25 cases), EWSR1::CREB1 (12 cases), EWSR1::CREM (21 cases), FUS::CREM (3 cases), and SMARCA2::CREM (4 cases). We confirmed the prior description of 2 distinct subgroups of ICMT (subclasses A and B). The majority of the cases belonged to subclass A (n = 69; 85%), which showed a higher median age compared to subclass B patients (26 years vs. 15 years). Subclass B cases (n = 12; 15%) showed shorter progression-free survival (P < 0.01). Gene expression analysis of ICMT showed key overexpressed markers in ICMT, with significant CREM overexpression regardless of fusion type, when compared to either meningioma alone or a larger group of CNS tumors. Conclusions This work provides further characterization of ICMT as an important CNS mesenchymal neoplasm that is prone to tumor recurrence, showing 2 prognostically relevant methylation subclasses and warranting diagnostic distinction from other epigenetically and histologically related tumors. ICMTs show substantial overexpression of the CREM gene, independent of fusion type.

Summary In adults with classic Hodgkin lymphoma (cHL), metabolic tumour volume (MTV) is valuable for risk stratification. This systematic review explored the role of volumetric parameters in children, adolescents and young adults (CAYA) with cHL. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) method. Five databases were searched on 16 October 2024. Eligible studies were peer‐reviewed manuscripts, written in English, published since database inception that included patients ≤21 years of age with a diagnosis of cHL treated with chemotherapy ± radiotherapy with a baseline 18 F‐Fluorodeoxyglucose (F‐FDG) PET/CT scan for MTV quantification. The search strategy identified 3669 studies, of which 35 were eligible for inclusion. Fifteen studies (43%) evaluated a cohort exclusively ≤21 years of age. All eight studies that explored the association of baseline PET parameters with known risk factors identified a significant correlation. Nine of 12 papers (75%) demonstrated a statistically significant correlation with disease response to therapy on PET/CT. Fifteen of 20 papers (75%) demonstrated an independent statistically significant correlation with clinical outcomes. In the CAYAHL population, volumetric PET parameters are valuable for risk stratification despite heterogeneity in results. Future harmonization of the segmentation approach will facilitate incorporation of MTV into clinical practice.

TPS256 Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residual disease (MRD) post-surgery in CC patients (pts), and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA-) are at a much lower risk of recurrence and may be spared the toxicities associated with AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose CC has been resected, ctDNA status may be used to risk-stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage IIB, IIC, and III CC will be enrolled. Based on the post-operative ctDNA status using personalized and tumor-informed assay (Signatera, bespoke assay), those who are ctDNA- (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP)+oxaliplatin (Ox) for 3-6 mos per established guidelines v serial ctDNA monitoring. Patients who are ctDNA+ post-operatively, or with serial monitoring (Cohort B), will be randomized to FP+Ox v more intensive AC with addition of irinotecan (I) for 6 mos. One cycle of chemotherapy is allowed while awaiting ctDNA testing results for cohort assignment. The primary endpoints for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) (phase III) in the immediate v delayed AC arms. The primary endpoint for Cohort B is DFS in the FP+Ox v FP+Ox+I arms for both phase II and phase III portions of the trial. Secondary endpoints include prevalence of detectable ctDNA post-operatively, time-to-event outcomes (overall survival and time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, as well as post-operative plus serial matched/normal blood samples, will be collected for exploratory correlative research. Active enrollment across the NCTN started in June 2022 with CCTG sites joining in August 2023. Current accrual (as of 9-4-2025): 967/1,912. Drs. Lieu and Dasari contributed equally to the development of this trial. Clinical trial information: NCT05174169 .

Abstract Background Previous studies demonstrated an association between tau pathology and the development of neuropsychiatric symptoms (NPS) in individuals with Alzheimer's disease (AD). However, the extent to which tau influences each specific NPS domain remains unclear. Here, we aim to investigate the association of tau and each NPS domain in the AD continuum. We hypothesized that tau plays a comparatively greater effect on the emergence of hyperactive and psychotic symptoms compared to other NPS domains. Method We assessed 385 individuals (216 cognitively unimpaired (CU), 128 MCI, and 41 AD dementia) from the HEAD study who underwent clinical assessments with the Neuropsychiatry Inventory Questionnaire (NPI‐Q) and had positron emission tomography (PET) for amyloid‐β (Aβ) ([ 18 F]AZD4694 or [ 11 C]PiB), and tau tangles ([ 18 F]MK6240) at the same visit. Tau SUVR values were tailored with a mask from Braak stages I‐VI, using the inferior cerebellar gray matter as a reference region. All individuals with dementia had a positive Aß‐PET. Voxel‐wise and Tobit censored regression tested the association between NPS domains and biomarkers accounting for age, sex, cognitive status, and study site. We used censored regression models to account for skewed data alongside a leave‐one‐out (loo) approach to identify which NPS domains most contributed to results. Result CI individuals had significantly higher NPI‐Q scores and Tau PET SUVR than CU (Figure 1A, 1B). NPI‐Q score was significantly associated with tau‐PET predominantly in fronto‐parietal regions. Removing irritability from the models strengthened this association (Figures 2A‐C). Regression loo models revealed that motor disturbances contributed most to the association between NPS and tau‐PET across all Braak stages. Notably, irritability had a negative effect on the association in all Braak stages, suggesting that tau does not play a role in the development of irritability and is highly associated with motor disturbances (Figure 3). Conclusion Our study suggests that tau contributes to the development of motor disturbances but has no effect on the development of irritability across the AD continuum. These findings provide additional rationale for the development of new therapeutics aiming to mitigate motor disturbances and irritability in AD patients.