Citations

Immune checkpoint inhibitors (ICIs) are an important class of cancer treatment. Endocrine immune-related adverse events (E-irAEs) account for a significant proportion of irAEs in ICI-treated patients. Diagnosing E-irAEs accurately and timely can be challenging in the absence of clear categorization and standardization across oncology, endocrinology and other specialties. While existing guidelines provide some broad directions to diagnosis and management, they lack clarity on irAE-specific symptom evaluation and work-up, as well as assessment of severity. These limitations can then impact triage, time-sensitive management and care escalation to specialists such as oncoendocrinologists. The objective of this study was to develop consensus-based statements on disease definitions for E-irAEs. A core working group of endocrinologists with expertise in the oncoendocrinology field drafted a survey with statements outlining the general approach to E-irAEs, disease definition and management approach of six specific diagnoses: ir-thyroiditis thyrotoxic phase, ir-thyroiditis hypothyroidism, ir-Graves’ disease, ir-hypophysitis, ir-adrenalitis and ir-type 1 diabetes mellitus. Severity grading tables were drafted for three disease categories—“thyroid”, “pituitary and adrenal”, and “diabetes mellitus”. A two-round modified Delphi process, using the RAND/University of California Los Angeles (RAND/UCLA) Appropriateness Method, was employed. In this process, a 25-member voting panel consisting of endocrinologists, oncologists and other specialists and healthcare providers with experience in management of ICI-treated patients and irAEs was recruited. The panel rated anonymously on usability, accuracy, appropriateness or agreement of 41 items on a 9-point scale in Survey 1, after which a meeting was convened. Statements were modified based on voting results from Survey 1 and Meeting 1, and the process was repeated in Survey 2 and Meeting 2. At the end of this process, consensus was achieved for all statements. Our study findings address the gap in standardized nomenclature, clinical, laboratory and radiological evaluations, and management principles of E-irAEs. With consensus achieved from a panel of experts from a variety of disciplines, we anticipate that the statements can form the basis for standardization of the diagnostic process and improvement of patient care.

Abstract Background The results of a previous phase IIa trial suggested efficacy of the anti-C5a compound vilobelimab in a small number of patients with severe hidradenitis suppurativa (HS) refractory to adalimumab treatment. Objectives To study the efficacy of vilobelimab in a larger-scale randomized phase IIb trial (SHINE) of patients with moderate-to-severe HS. Methods In total, 177 patients with moderate-to-severe HS were treated either with placebo or one of four doses of vilobelimab, a monoclonal antibody that targets the complement split product C5a. Hidradenitis Suppurativa Clinical Response (HiSCR) at 16 weeks was the primary endpoint. Those who achieved HiSCR switched to open-label low-dose vilobelimab; those who did not were switched to medium-dose vilobelimab. The trial was registered with the EU Clinical Trials Register (EudraCT number 2017-004501-40) and ClinicalTrials.gov (NCT03487276). Results The study did not meet the primary endpoint, perhaps due, in part, to an unexpectedly high HiSCR placebo response rate of 47.1%. HS flares decreased and post hoc analysis showed that high-dose vilobelimab significantly decreased the median draining tunnel counts and IHS4 score by 63%. Following the switch to medium-dose vilobelimab at week 16, 45.5% of those who did not respond to treatment achieved HiSCR at week 40. Conclusions Compared with placebo, vilobelimab treatment did not result in significant HiSCR improvements in patients with moderate-to-severe HS. Post hoc analysis revealed significant effects for the highest tested dose on draining tunnel reduction and IHS4 score, which captures reductions in draining tunnels. These findings warrant further investigation.

Abstract BACKGROUND Volumetric analysis of brain metastatic lesions is of great relevance in neuro-oncology. Since manual annotation of a lesion is a laborious and time-consuming task, utilizing artificial intelligence (AI) tools for automated segmentation of brain metastases has shown promising potential, but published algorithms are not incorporated into clinical practice because of poor generalizability across institutions. Large publicly available and well-annotated datasets from across the world are critical for further clinical translation. MATERIAL AND METHODS The Brain Tumor Segmentation - Metastases (BraTS-METS) 2025 Lighthouse Challenge provides a competitive environment where scientists from various disciplines can benchmark their AI-based algorithms for automatic segmentation of pre- and post-treatment brain metastases on a well-curated publicly available brain metastasis dataset comprising 1,778 multiparametric brain MRI cases. Each case consists of T1-weighed, T1 post-contrast and FLAIR sequences. The cases were retrospectively obtained from 8 institutions in the USA and overseas, and underwent 3D nnU-Net pre-segmentation, followed by manual refinements performed by medical students and neuroradiologists, and a final approval by two independent board-certified neuroradiologists. A testing dataset was prepared through four rounds of annotation: two completed ‘from scratch’ and two following 3D nnU-Net pre-segmentation, all conducted by two independent neuroradiologists, with the segmentation process screen recorded for future analysis. This allowed us to establish inter- and intra-rater variability in brain metastases segmentation and create a reference standard dataset that will be publicly available after the conclusion of the challenge. The model performance of the participating teams in the challenge will be assessed via the following metrics: Dice Similarity Coefficient (DSC), Normalized Surface Distance (NSD), sensitivity, and precision of the model. RESULTS A multi-annotator testing dataset of 75 MRI cases of brain metastases and 300 segmentations (150 created ‘from scratch’ and 150 from 3D nnU-Net pre-segmentations of the cases) was developed as a new reference standard. The mean intra- and inter-rater DSC for the segmentations ‘from scratch’ were 0.68 and 0.59, respectively. The mean intra- and inter-rater DSC for the segmentations built upon 3D nnU-Net pre-segmentations were 0.88 and 0.77, respectively. CONCLUSION The BraTS-METS 2025 Lighthouse Challenge is a key initiative designed to advance the use of AI to improve characterization of brain metastases by providing algorithms for automatic segmentation of all lesions and peritumoral edema that are measured against a novel reference standard based on rigorous multi-annotator brain MRI segmentations.

Abstract Background People with HIV (PWH) are at increased risk of stroke likely due to many factors including antiretroviral therapy (ART). We sought to evaluate the association between ARTand risk of stroke in PWH. Methods We conducted a prospective case-control study at the University Teaching Hospital in Lusaka, Zambia between March 2022 and October 2024 in PWH comparing those with stroke (cases) and without (controls) matched (1:2) for age, sex and race. Standardized data collection instruments were used to collect demographic, clinical, laboratory and imaging information. Comparisons were made between the cases and controls, and subgroup analysis by ART duration was done for the cases. Results We analyzed results for 205 cases and 410 controls. Compared to controls, cases were more likely to have hypertension (71% vs. 18%, p=0.001), lower CD4 counts [293(163-592) cells/µl vs. 533 (376-688) cells/µl, p=0.0001] and to be on second line ART (23% vs. 4%, p=0.001). Hypertension (aOR 19.7, 95% CI 3.1-126.4, p=0.002) and Tenofovir Disoproxil Fumarate (TDF) use (aOR 85.3, 95% CI 5.3-1380.7, p=0.002) were associated with increased odds of stroke, whereas Dolutegravir (aOR 0.03, 95% CI 0.001-0.58, p=0.02) and alcohol use (aOR 0.24, 95% CI 0.06-0.95) were associated with reduced odds of stroke. The majority of stroke patients on long-term ART were using Dolutegravir (80% vs. 35%, p=0.001) and TDF (72% vs. 42%, p=0.01). Conclusion In PWH, TDF associates with higher odds of stroke. Although Dolutegravir associates with reduced odds of stroke, stroke patients on long-term ART are more likely to be on it.

Abstract Infection is increasingly recognized as a significant cause of morbidity and mortality in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) receiving CD19 chimeric antigen receptor (CAR) T-cell therapy. The current study analyzed the natural history, risk factors, and outcomes of infection in 3350 patients with R/R LBCL receiving commercial CD19 CAR T-cell therapy (n = 2804 axicabtagene ciloleucel [axi-cel], n = 546 tisagenlecleucel) from December 2017 to June 2022. Infection developed in 834 patients (24.9%) within 100 days after infusion, resulting in an infection density of 0.43 per 100 patient days and a 100-day cumulative incidence of 22%. Bacterial, viral, and fungal infections were recorded in 527 (15.7%), 374 (11.2%), and 108 patients (3.2%), respectively, with corresponding infection densities of 0.23, 0.15, and 0.04 per 100 patient days. After a 24-month median follow-up, 1482 patients (44%) had died, with infection as the primary cause in 173 cases (12%). The 100-day infection-related mortality (IRM) was 1.6% (95% confidence interval, 1.2-2.0). Patients with a Karnofsky performance score of ≤80, infection history before CAR T-cell therapy, axi-cel therapy, severe cytokine release syndrome (grade ≥3), and severe immune effector cell–associated neurotoxicity syndrome (grade ≥3) had increased infection risk. Infections within 100 days were an independent risk factor for inferior overall survival beyond day 100 after CD19 CAR T-cell therapy. In conclusion, study results show a significant incidence of infection and IRM in patients with R/R LBCL treated with CD19 CAR T-cell therapy. Furthermore, results identify patients at a heightened risk of infection, offering insights to guide potential interventions aimed at mitigating infection and improving patient outcomes after CAR T-cell therapy.

Abstract Background: Postpartum breast cancer (PPBC) is associated with increased morbidity and mortality among women within 5 to 10 years following childbirth. The postpartum breast undergoes involution, involving tissue remodeling and immune cell infiltration, potentially creating a pro-tumorigenic microenvironment. The molecular mechanisms underlying this elevated risk remain poorly understood. In this study, we compared normal breast tissue samples and human mammary epithelial cells (HMECs) from postpartum women to those from age- and BMI-matched nulliparous women to elucidate potential molecular contributors to PPBC risk. Methods: Transcriptomic profiling was performed on RNA extracted from FFPE normal breast tissues using the NanoString IO 360 and BC 360 platforms to examine gene expression in nulliparous and postpartum women under 45 years of age. HMECs were isolated from organoids derived from breast tissue samples and used for next-generation sequencing and knockdown experiments targeting STAT1 and GBP1. Gene set enrichment analysis (GSEA) was applied to NanoString and RNA-seq datasets to identify differentially enriched genes between postpartum and nulliparous women. Results: Transcriptomic analysis revealed significant upregulation of interferon-stimulated genes, including STAT1 and GBP1, in postpartum breast tissues, consistent with increased immune responses during involution. NanoString data showed that markers of cell proliferation, such as Ki67, STAT1, and GBP1, were significantly higher in samples from parous compared to nulliparous women (p < 0.05). GSEA revealed that cell cycle-promoting genes (GBP1, cyclins, CDKs) were upregulated, while cyclin-dependent kinase inhibitors (CDKNs) were downregulated in postpartum breast tissues. Immunohistochemistry confirmed significantly higher expression of Ki67, STAT1, and GBP1 in postpartum versus nulliparous breast tissues (p < 0.0001). Silencing STAT1 and GBP1 in HMECs resulted in decreased cell proliferation, G1 cell cycle arrest, and increased expression of CDKN1A and CDKN1C. Conclusion: These findings suggest that STAT1 and GBP1 promote proliferation in postpartum breast epithelial cells by downregulating cyclin-dependent kinase inhibitors, potentially contributing to the increased risk of PPBC. Targeting these pathways may offer novel strategies for mitigating postpartum breast cancer risk. Citation Format: Joshua Ogony, Melody Stallings-Mann, Sarah McLaughlin, Mark Sherman, Derek C. Radisky. STAT1 and GBP1 promote proliferation in postpartum breast epithelium by downregulating cyclin-dependent kinase inhibitors: implications for increased postpartum breast cancer risk [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 187.

Abstract Introduction: Pseudoangiomatous stromal hyperplasia (PASH) is a benign breast lesion characterized by stromal myofibroblast accumulation. While most women with PASH do not develop breast cancer, a subset eventually does, often in the same breast where PASH was originally diagnosed, even after surgical removal of the lesion. This pattern suggests the presence of a field effect, where alterations in the PASH microenvironment extend beyond the lesion itself, potentially influencing neighboring breast tissue. This study aims to identify specific fibroblasts within PASH-containing tissues that may create a microenvironment conducive to cancer initiation. Methods: We conducted a retrospective analysis of formalin-fixed, paraffin-embedded breast tissue samples from women diagnosed with PASH, comparing those who later developed breast cancer (cases) to those who remained cancer-free (controls). Using transcriptional profiling with NanoString IO360/BC360 panels, multiplex immunofluorescence (MxIF), and spatial transcriptomics via NanoString CosMX SMI, we investigated molecular and histopathological differences. We focused on the expression of fibroblast activation markers (ITGB1, PDGFRβ) and their spatial relationships with proliferating epithelial cells, as well as changes in extracellular matrix (ECM) composition and stiffness. Results: Transcriptional profiling revealed significant upregulation of proliferation-associated genes in epithelial cells from cases. MxIF showed higher Ki-67 levels in epithelial cells from cases, with proliferating cells forming clustered regions. Activated fibroblasts expressing ITGB1 and PDGFRβ were markedly increased in cases and were located closer to proliferating epithelial cells. Spatial transcriptomics uncovered gene expression changes in fibroblasts indicative of an activated phenotype, and in epithelial cells, consistent with responses to increased tissue stiffness and mechanotransduction signaling. Polarized light imaging with picrosirius red staining revealed enhanced collagen cross-linking and thick fibril formation in cases, indicating greater ECM stiffness. Conclusions: Our findings suggest that a subset of activated fibroblasts in benign breast tissue creates a pro-tumorigenic microenvironment through ECM remodeling and increased tissue stiffness, promoting epithelial proliferation and potentially driving cancer development. The spatial proximity of these fibroblasts to proliferating epithelial cells underscores their possible role in early carcinogenesis. This study introduces the novel concept of cancer-predisposing fibroblasts in benign breast tissue, providing new insights into microenvironmental changes that precede cancer and offering potential targets for early detection and intervention. Citation Format: Nicole Cruz-Reyes, Pria Westerman, Matilde Rossi, Camila Pacheco Erak, Melody Stallings Mann, Bryan McCauley, Robert Vierkant, Stacey Winham, Mark Sherman, Amy Degnim, Derek Radisky. Activated fibroblasts in benign breast tissue are associated with subsequent breast cancer development [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 2083.

Abstract Background: Breast cancer (BC) remains a leading health concern worldwide and is often undetected until it metastasizes, limiting treatment options and worsening prognosis. Early detection of molecular and immune markers in benign breast disease (BBD) could identify women at elevated risk of developing invasive, node-positive BC, enabling targeted surveillance and prevention efforts. Building on this premise, we investigated the immune and molecular landscape of BBD biopsies preceding BC development to enhance risk stratification and inform preventive strategies. Methods: Utilizing the Mayo Clinic BBD cohort, we conducted a case-control study comparing women who developed node-positive BC following their BBD biopsy (cases; n=8) to those who remained cancer-free (controls; n=11), matched on patient age and biopsy date. Differential gene expression was assessed using the NanoString nCounter system to identify differentially expressed genes between cases and controls. We developed a multiplex immunofluorescence (MxIF) approach using the Opal system by Akoya Biosciences for comprehensive marker detection in formalin-fixed, paraffin-embedded (FFPE) tissue samples. Digitized images were segmented for cell phenotyping, and spatial relationships of immune cells were analyzed and compared between cases and controls. Results: Our findings revealed significantly increased expression levels of immunosuppressive genes in the case group, including CD48, CD84, IL-32, and LAIR1. Immunohistochemical analyses showed that controls exhibited higher frequencies of CD68+ (macrophages), CD11c+ (M1 macrophages), and CD206+ (M2 macrophages) cells compared to cases. Notably, controls had a significant increase in CD68+CD11c+ cells, indicative of a pro-inflammatory, antitumorigenic M1 macrophage polarization. Furthermore, our MxIF analyses provided novel insights into spatial biomarker localization, enhancing prognostic accuracy. Conclusions: The decreased numbers of immune cells and increased expression of immunosuppressive genes in BBD biopsies may be associated with an elevated risk of developing axillary node-positive BC. These findings emphasize the importance of dissecting molecular and immune interactions in BBD for risk assessment. Our results have the potential to improve individualized risk stratification, leading to more targeted surveillance and informed screening. This research not only contributes to our understanding of BC pathogenesis but also opens avenues for developing novel preventive strategies, potentially reducing BC incidence and mortality through early intervention. Citation Format: Matilde Rossi, Nicole Cruz-Reyes, Trista Navarro, Melody L. Stallings-Mann, Bryan M. McCauley, Robert A. Vierkant, Stacey J. Winham, Mark E. Sherman, Amy C. Degnim, Derek C. Radisky. Immune and molecular markers in benign breast disease predict risk of node-positive breast cancer [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 1912.

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.