Citations

Abstract Background Previous studies in aggressive B-cell lymphoma demonstrate that patients with shorter diagnosis-to-treatment intervals (DTI) represent those with higher risk disease. This suggests that patients enrolled in clinical trials may carry a selection bias as they often have longer DTI than patients in the general population. This has important implications for clinical research design and the generalizability of clinical trials in aggressive lymphomas. However, the prognostic implications of DTI have not been evaluated in peripheral T-cell lymphomas (PTCL). Therefore, we examined DTI and its association with clinical factors and outcomes in a prospective observational cohort of patients with PTCL from the United States within the LEO (Lymphoma Epidemiology and Outcomes) and MER (University of Iowa and Mayo Clinic Specialized Programs of Research Excellence Molecular Epidemiology Resource). Patients and Methods We evaluated patients enrolled to the MER (2002-2015) and LEO (2015-2020) cohorts with the following forms of PTCL: PTCL-not otherwise specified (PTCL-NOS, n=217), nodal T-follicular helper (TFH) cell lymphoma (nTFHL, n=153), anaplastic large cell lymphoma (ALCL), ALK positive (ALCL, ALK+, n=74), ALCL, ALK negative (ALCL, ALK-, n=95), enteropathy associated T-cell lymphoma (n=18), and monomorphic epitheliotropic intestinal T-cell lymphoma (n=2). Associations of DTI with clinical factors and outcomes were examined using Kaplan Meier and Cox models. Event free survival (EFS) was defined as the time from start of treatment to relapse/progression, start of 2nd line therapy, or death from any cause. Overall survival (OS) was defined as the time from start of treatment until death from any cause. DTI was defined as the number of days between the first diagnostic biopsy and the start of therapy. Patients who were initially observed or had DTI > 100 days were excluded. Results In 559 patients (229 MER and 330 LEO), median age was 60, 34% had IPI>2 and 71% were stage III/IV. 472 (84%) patients initially received anthracycline-based chemotherapy. Median DTI was 23 days (interquartile range (IQR): 12-39) and was similar in MER (21 days, IQR: 11-33) and LEO (25 days, IQR: 14-42). 168 (30%) patients had DTI 0-14 days, 178 (32%) 15-28 days, and 213 (38%) 29-100 days. Overall in the cohort, shorter DTI was associated with a worse 5-year OS (DTI 0-14 days: 43%; DTI 15-28 days: 53%; DTI 29-100 days: 58%, p<0.001) and 5-year EFS (DTI 0-14 days: 31%; DTI 15-28 days: 39%; DTI 29-100 days: 45%, p<0.001). In multivariable analyses, the association of DTI with outcomes remained consistent after adjusting for age and International Prognostic Index (IPI). Shorter DTI was strongly associated with adverse clinical factors, including elevated lactate dehydrogenase levels, poor performance status, B-symptoms, and higher IPI in both cohorts (all P < .003). DTI was not associated with age, sex, or distance from the LEO/MER center (all p>0.3). 6% patients with DTI of 0-14 days received 1L treatment on a clinical trial, compared to 11% with DTI 15-28 days and 13% with DTI 29-100 days, underscoring that patients with lower DTI may be underrepresented in clinical trials. When examining within PTCL subtypes, the association between short DTI (0-14 days) and inferior outcomes was most prominent in PTCL, NOS (OS HR=2.13, 95% CI: 1.52-2.94; EFS HR =1.49, 95% CI: 1.19-1.85). Associations between short DTI and outcomes were weaker in other subtypes: nTFHL (OS HR=1.28, 95% CI: 0.83-2.00; EFS HR =1.22, 95% CI: 0.82-1.81), ALCL, ALK-, (OS HR=1.30, 95% CI: 0.59-2.86; EFS HR =1.32, 95% CI: 0.68-2.56), ALCL, ALK+, (OS HR=1.05, 95% CI: 0.26-4.17; EFS HR =2.12, 95% CI: 0.84-5.26). Conclusion Shorter DTI is associated adverse prognostic clinical factors (LDH, stage, high IPI) and inferior EFS and OS in newly diagnosed PTCL. Patients with DTI ≤ 14 days, which represents approximately 1/3 patients with PTCL, may be underrepresented in clinical trials. Understanding of this selection bias should inform clinical trial design and interpretation. Future studies should consider strategies to minimize barriers to enrollment for patients with low DTI.

Abstract INTRODUCTION The ECHELON-2 trial for newly diagnosed CD30+ peripheral T-cell lymphomas (PTCL) demonstrated superior overall survival with brentuximab vedotin plus chemotherapy (BV-CHP) compared to CHOP. However, total enrollment was restricted to only 30% of patients with non-anaplastic large cell lymphoma (ALCL) histologies and was not powered to analyze survival benefits in this cohort. Thus, the benefit of BV-CHP in non-ALCL patients remains less clear. Adding to this uncertainty, CHOP plus etoposide (CHOEP) remains a standard regimen for many non-ALCL PTCL histologies for patients <60 years of age. Which of these three regimens offers superior outcomes for patients with CD30+ non-ALCL PTCL remains to be determined, is a critical knowledge gap in this area, and could meaningfully inform the management of these patients. METHODS We conducted a retrospective analysis of chemotherapy-naïve CD30+ (≥1%) PTCL from 7 centers in the United States. Histologies were limited to PTCL-NOS and PTCL with a T follicular helper phenotype (PTCL-TFH). Frontline regimens were defined as BV-based (BV-CHP), etoposide-based (CHOEP/EPOCH), novel-CHOP (CHOP/CHOEP + novel drug on a clinical trial), or CHOP. CD30 was considered positive if any expression was reported, and when available, stratified as ≥10% or <10% of the total lymphocyte population. RESULTS The CD30+ PTCL cohort consisted of 194 patients with a median age of 68 years at diagnosis and a male (65%) predominance. Nodal PTCL-TFH (65%) was the most common histology. Most had stage III-IV disease (89%) with a high-intermediate to high-risk IPI score of 3-5 (54%). 18% had an ECOG of ≥2, 45% had ≥2 extranodal sites, and 43% had bone marrow involvement, although biopsies were not performed in all patients. CD30 expression in ≥10% of malignant T cells was observed in 55% of all quantitatively reported cases. Frontline therapy consisted of BV-based (36%), etoposide-based (30%), CHOP (27%), and novel-CHOP (7%). Baseline characteristics and CD30 expression were similar between treatment groups. The ORR was 72% (64% CR, 8% PR), with no differences observed by treatment or histology. On multivariate analysis (MVA), a high LDH was associated with lower CR (OR 2.84, p=0.003). For the patients who demonstrated a CR to frontline therapy, 61% underwent ASCT. With a median follow-up of 26.1 months (IQR 12.3-51.6), the median PFS and OS were 11.4 (9.8-14.2) and 47 (32-60.3) months, respectively. The 2-year PFS and OS were 34.9% (28.1-41.7) and 62% (54.5-68.6), respectively. PFS and OS were similar for PTCL-NOS compared to PTCL-TFH, and AITL fared similarly to non-AITL PTCL-TFH. By treatment, novel-CHOP demonstrated the most favorable PFS (median 41.9 months) and OS (median 68.1 months). Survival curves overlapped continuously with all other treatment regimens and was not statistically significant. For patients <60, PFS and OS were equivocal with BV-based (n=17) compared to etoposide-based (n=26) regimens. On MVA, stage III/IV disease conferred an inferior PFS (HR 2.00, p=0.018) as did an IPI score of 3-5 for OS (HR 2.15, p=0.001). Neither histology nor frontline treatment impacted PFS or OS. The chosen frontline treatment also had no survival impact in key subgroup analyses including patients <60 (n=56) or with CD30-expression ≥10% (n=43). For patients with CR to frontline therapy, ASCT demonstrated a significant PFS benefit (HR 0.59, p=0.028) but no statistically significant difference in OS benefit (HR 0.58, p=0.073). CONCLUSION These data provide valuable insight into the lesser-represented patient population from the pivotal ECHELON-2 trial. In this cohort of CD30+ (≥1%) non-ALCL PTCL, there was no clearly superior standard frontline regimen. The number of patients with quantitively reported CD30 expression was too small for definitive conclusions in the ≥10% CD30+ cohort and retrospective pathology review is ongoing. ASCT for patients in CR offered superior outcomes, supporting this strategy regardless of the frontline regimen, recognizing the limitations of non-randomized, retrospective analyses. Novel-CHOP regimens demonstrated encouraging survival, and clinical trials should maintain priority over standard regimens for patients with CD30+ (1-10%) PTCL-NOS and PTCL-TFH.

Abstract BackgroundWarm autoimmune hemolytic anemia (wAIHA) is clinically characterized by autoantibody-mediated (typically IgG) erythrocyte destruction at body temperature. While oral corticosteroids remain first-line therapy, rituximab is frequently used as a second-line agent, mostly supported with concomitant background medications, yet real-world evidence is limited and utilization is driven by published retrospective data and expert opinion. Real-world evidence characterizing its utilization patterns and outcomes is needed to inform clinical practice. AimsThis study aimed to: 1) describe treatment patterns among patients with newly diagnosed wAIHA, 2) evaluate rescue therapy use and healthcare resource utilization (HCRU) with current standard of care (SOC), 3) characterize patterns of rituximab use during the first year. MethodsNewly diagnosed wAIHA patients were identified from multiple US databases (MarketScan® Databases, IQVIA PharMetrics, Optum Clinformatics®, and Optum PanTher EHR). Patients with ≥1 wAIHA diagnosis code in any position (ICD-10-CM D59.11) from October 2020 to December 2023 and 12-month post-index follow-up were pooled together. Secondary wAIHA was defined with evidence of hematologic malignancy, solid tumors, immunodeficiencies, or autoimmune diseases in the 6 months prior to diagnosis. Patients on treatment were defined by use of oral corticosteroids (OCS), immunosuppressants (IST) (including azathioprine, mycophenolate mofetil, cyclosporine, cyclophosphamide, or tacrolimus) or rituximab. Initial therapy was defined as the first treatment occurring ≥ 30 days prior to diagnosis. Therapies were identified as combination when initialized within 21 days of each other. The regimen is considered active until all therapies are discontinued or a new agent is initiated. Rituximab regimens were classified as standard (4 weekly doses), alternative (2 doses given 2 weeks apart), single infusion, or extended (>4 infusions). Results Among 2,028 wAIHA patients (median age 62.0 years, 59% female), 55% had secondary wAIHA. Among patients on treatment (n=1,439), 64% received OCS monotherapy; rituximab and IST, alone or in combination with OCS were received by an additional 28% and 5% of patients, respectively. Overall, 80% of treated patients received OCS in some combination during initial therapy. Within 12 months following diagnosis, 1 in 4 patients required ≥ 1 blood transfusion, 1 in 8 required either erythropoiesis-stimulating agents (ESA) or intravenous immunoglobulin (IVIG). Within 12 months of diagnosis, 35% of patients required ≥ 1 hospitalization, average length of stay 3.8 days; AIHA was the principal diagnosis for 65% cases. Greater than 1/3 of patients (38%) had ≥ 1 emergency department visit. Almost all wAIHA patients (98%) had an all-cause outpatient visit with a median of 31 visits per patient. Among patients receiving rituximab in any line (n=613), median time from diagnosis to first administration was 59.0 days (interquartile range: 42.0-171.0). For the first course of rituximab, 62.2% of patients received a complete course (standard, alternative, or extended courses). Among patients with a completed course, 39.8% had >4 infusions without a 90-day gap between administrations with a median of 8 administrations within 12 months. Of the nearly 38% of patients that did not receive a complete course of rituximab, 33% received a single infusion. The use of rescue medications in the period prior to rituximab treatment was compared to the period after treatment (defined as 60 days to 12-months post final rituximab infusion). Use of blood transfusions was observed to increase from 9.0% to 32.8%, while the use of ESA and IVIG were stable at approximately 2% and 4%, respectively.Conclusion With current wAIHA SOC, US HCRU remains high, posing a financial burden in terms of the rate of outpatient and emergency department visits, and inpatient stays. Rituximab is an early line therapy post-diagnosis, typically in combination with OCS. No changes in rescue treatments, and an increase in blood transfusions after rituximab infusion suggest treatment gaps remain. Analysis reveals heterogeneity in rituximab dosing patterns including high deviation from standard dosing practices; this variance from published expert opinion along with common use of rescue therapies suggests continued need for standardized guidelines and development of targeted therapies in wAIHA.

Abstract Background: The coexistence of systemic mastocytosis (SM) and lymphoid neoplasms is rare and remains poorly defined. These cases are classified under SM with associated hematologic neoplasm (SM-AHN) in the WHO framework, though the ICC distinguishes SM with associated myeloid neoplasm (SM-AMN) as a separate entity. Emerging evidence points to SM with associated lymphoid neoplasms (SM-ALN) as a biologically distinct and clinically indolent subgroup (Aperna F et al, 2025). We performed a multisite retrospective study to characterize the clinico-molecular features and outcomes of SM-ALN. Methods: We conducted a retrospective analysis across Mayo Clinic sites, reviewing records from January 1980 to December 2024 to identify patients with SM-ALN. IRB approval was obtained. Of 22 cases identified, 4 were excluded due to co-occurring myeloid neoplasms. The final cohort included 18 patients. Variables analysed included age, sex, SM subtype, KIT mutation, symptoms, treatment, and survival outcomes. Results: Eighteen patients were included (median age: 61.5 years; range: 38–80; 11 female). Most had indolent SM (ISM, n=16); two had aggressive SM (ASM). SM preceded the lymphoid neoplasm in 4 cases (22%), followed it in 6 (33%), and was concurrent in 8 (44%). Low-grade lymphomas (n=12, 67%) included follicular lymphoma (n=2), CLL (, n=2), marginal zone (n=1), lymphoplasmacytic (n=1), and mantle cell (n=1). High-grade lymphomas (n=6, 33%) included diffuse large B-cell lymphoma (DLBCL, n=3), Hodgkin lymphoma (n=2), and T-cell acute lymphoblastic leukemia (n=1). SM-related symptoms were present in 16 of 18 patients (89%). The most common manifestations included dermatologic symptoms (rash/pruritus, 56%), systemic complaints (fatigue/weight loss, 39%), GI symptoms (17%), and anaphylaxis (6%). KIT D816V testing mutation was positive in 10 of 16 patients tested (63%). Tryptase was elevated (>20 ng/mL) in 15 of 18 (83%). NGS data was available for 9 patients: among the two ASM cases, both harbored SRSF2 mutation; one also had JAK2, DNMT3A, RUNX1, TET2, and TP53, while the other carried DNMT3A and IDH1. Mutations observed in ISM cases included CCND3, CXCR4, NOTCH2, SF3B1, MYD88 L265P, ASXL1, and TET2. SM management was divided into two categories: (1) Conservative approach, including observation alone in 4 patients (22%) and symptomatic therapies such as antihistamines or leukotriene inhibitors in 7 (39%); and (2) Cytoreductive treatments, comprising avapritinib in 5 patients (28%), cladribine in 1 (6%), and imatinib in 1 (6%). Management of lymphoid neoplasms included intensive regimens such as R-CHOP and hyper-CVAD for high-grade subtypes (e.g., DLBCL and T-ALL), while indolent forms (e.g., CLL and follicular lymphoma) were treated with bendamustine-rituximab or observation depending on disease burden. Overall, 13 patients (72%) received systemic therapy. At a median follow-up of 81 months (6.7 years), 17 of 18 patients (94%) were alive and progression-free. Median OS and PFS were not reached. The sole death occurred in a patient with ASM, while all ISM cases remained alive. ASM was associated with a higher (though nonsignificant) risk of death (OR 33.0; 95% CI, 0.89–1220.9; p = 0.111). Among patients with high-grade lymphomas (n=5), 80% were alive at follow-up, compared to 100% with indolent lymphomas (n=13). Discussion: Our findings support SM-ALN as a clinically indolent and biologically distinct subset within SM-AHN. Most patients had ISM and low-grade lymphoid neoplasms, with favorable outcomes regardless of lymphoma subtype or diagnostic sequence. High-risk mutations were confined to ASM cases, reinforcing underlying biologic differences. These findings align with prior Mayo Clinic data showing longer survival in SM-ALN compared to SM-AMN (median OS 8.1 vs 2.0 years; p<0.01). Treatment was primarily directed by the lymphoid malignancy, with limited need for cytoreduction in ISM. Larger, prospective studies are needed to confirm these observations and optimize management strategies. Limitations include the study's retrospective, single-center design and limited racial diversity. Multi-institutional studies are warranted to validate these findings and guide optimal management. Conclusion: SM-ALN is a rare but distinct SM subtype characterized by indolent behavior, favorable treatment responses, and prolonged survival. Recognition of this subset is critical to avoid over-treatment and to guide risk-adapted management strategies.

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains among the most aggressive cancers, due to its limited therapeutic options and poor prognosis. Even with the adoption of total neoadjuvant therapy (TNT) and potentially curative surgical resection, PDAC relapse rates remain unacceptably high. Current systems for evaluating tumor response are valuable but limited, as they fail to capture the ecological complexity and broader architecture of the tumor microenvironment (TME). This results in uncertainty regarding the prognosis and recurrence risk of patients. To address this and to capture the complexity of the PDAC TME, we developed the Tumor Landscape Analysis (TLA). Using digitized H&E slides from 203 PDAC patients who received TNT and surgical resection at our institution, we applied a machine-learning pipeline to segment tumor and stromal compartments. We then quantified the TME architecture using ecological frameworks to assess the disease in multiple scales: individual patches, whole-slide landscapes, and aggregated patient-level summaries. Our analysis revealed that higher-order spatial features are independently prognostic of disease-free survival (DFS). Two statistical models showed different but complementary spatial characteristics that predict disease risk. In the first model, patients with more irregular cancer patch shapes and lower variability in stromal shape had significantly better DFS, with high-risk patients relapsing in a median of 7.2 months compared to 11.6 months in the low-risk group (HR=1.82, p=0.0003). In the second model, smaller stromal patch areas combined with greater tumor-stroma edge density identified patients at elevated risk, with high-risk individuals showing a median DFS of 8.0 months versus 15.7 months in low-risk patients (HR=1.73, p=0.0007). Importantly, these associations persisted even after adjustment for the T and N stage, showing that spatial features provide unique information beyond traditional pathology measures. These models help visualize PDAC as a comprehensive ecosystem that carries clinical significance. By quantifying tumor conformation and configuration, our models reveal prognostic information not available through CAP grading, percent tumor burden, or routine cell counts. This study suggests that tumor-stroma interactions and their spatial organizations are potentially biologically important for recurrence. We present a new, ecologically inspired approach to digital pathology for PDAC that not only improves our ability to predict recurrence and survival in PDAC but also sheds light on cancer as a complex, evolving ecosystem. Citation Format: Merih D. Toruner, Luis H. Cisneros, Miranda Lin, Andrea Maraone, Carlo Maley, Paul Dizona, Qian Shi, Martin E. Fernandez-Zapico, Ryan M. Carr. Ecological landscape analysis of the tumor microenvironment predicts recurrence risk in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85(23_Suppl):Abstract nr B027.

Abstract Background Studies show that only 20–30% of untreated ductal carcinoma in situ (DCIS) cases will evolve into invasive breast cancer. Thus, many patients are subject to overtreatment and its associated morbidities. The ecological context of the tumor microenvironment may impact how DCIS evolves. We applied landscape ecology statistics to hematoxylin and eosin (H&E) images from DCIS to test whether they predict recurrence of DCIS or progression to invasive disease. The ability to make such predictions is key for optimizing treatment decisions, reducing associated risks, and improving the efficiency of healthcare resource allocation. Methods We conducted a retrospective cohort study comprising 158 patients with a DCIS diagnosis, which included 57 cases of DCIS recurrence (2–228 months) and 45 cases of progression to invasive disease (12–180 months). Of these, 21 patients received lumpectomy, 92 had lumpectomy followed by radiation therapy, and 45 had total mastectomy. We generated a digital pathology library of whole-slide images (WSIs) from H&E tumor sections and performed machine learning guided nuclear segmentation and classification. A comprehensive set of spatial statistics was calculated for each WSI to characterize the spatial architecture and cellular interactions within the microenvironment. Cross-validation using a linear spline-based hazard regression model (HARE) was applied to a training subset of the data. The resulting survival model was validated on the test subset to predict disease-free survival (DFS) of recurrence and progression. Results We found that the type of DCIS treatment significantly stratified patients based on DFS (log-rank test p<0.0001). Further analysis of patients who received lumpectomy + radiation or mastectomy revealed that decreased mean nearest neighbor distance between tumor cells and lymphocytes, and between fibroblasts and lymphocytes, was significantly associated with improved recurrence-free survival (concordance=0.68). Stratification of samples based on the median risk score derived from our model was discriminatory with a p-value <0.015. Additionally, a decreased nearest neighbor distance between lymphocytes and fibroblasts showed a marginal association with an increased time to invasive disease (p<0.06). Conclusions Integrating spatial ecological statistics derived from digital pathology provides enhanced risk stratification for DCIS, beyond the established effects of initial treatment. Our findings underscore the importance of the tumor microenvironment's ecological dynamics in DCIS recurrence and progression. The predictive risk associated with specific spatial interactions, particularly involving lymphocytes and fibroblasts, suggests that previously unappreciated ecological mechanisms may play a role in the development of early micro-metastases, influencing outcomes even after standard therapies such as mastectomy or lumpectomy with radiation. These insights highlight novel targets for improved prognostic tools and more personalized therapeutic strategies. Citation Format: Luis H. Cisneros. Microenvironmental drivers of DCIS recurrence and progression to breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85(23_Suppl):Abstract nr A016.

Abstract Background: The spatial organization of the tumor microenvironment (TME) encodes the selective pressures that drive cancer evolution, but many tools focus on local cell contacts or single-modality readouts. We developed Tumor Landscape Analysis (TLA), a modular framework that borrows from landscape ecology and spatial statistics to quantify heterogeneity, fragmentation, and diversity across scales, from single cells to whole-slide ecosystems. Methods: TLA ingests whole-cell or nuclear centroids and region-level segmentations to compute (i) point statistics such as nearest-neighbor distance, Ripley’s H, and Morisita-Horn colocalization; (ii) kernel-smoothed local spatial profiles including Getis-Ord Gi* hot and cold spots; and (iii) fragmentation, shape, and diversity metrics such as patch density, contagion, shape index, and Shannon entropy. We also introduce Local Microenvironments (LMEs), unsupervised ecological niches defined by joint cell-type abundance and spatial mixing. Pilot analyses were performed in ductal carcinoma in situ (DCIS; n=353 samples, 175 patients) with cell-level maps of epithelial, lymphocyte, and fibroblast populations, and in pancreatic ductal adenocarcinoma (PDAC; n=203 resected cases after neoadjuvant therapy) using cancer and stroma segmentations. Results: In DCIS, spatial relationships rather than raw abundance associated with recurrence risk. Shorter lymphocyte-to-fibroblast minimum nearest-neighbor distance and lower Ripley’s H, indicating greater intermixing, correlated with earlier recurrence independent of cell counts. This highlights immune–stromal proximity as a candidate eco-evolutionary driver of persistence. In PDAC, tissue-level fragmentation captured prognostic architecture after therapy. Two shape-based signatures emerged: (1) stromal uniformity, where lower standard deviation of stromal patch shape index associated with improved disease-free survival, consistent with a more constrained, less reactive stroma; and (2) tumor geometric complexity, where higher mean cancer patch shape index, reflecting more irregular or dendritic nests, associated with lower recurrence risk, whereas compact nests predicted worse outcomes. Across datasets, LME maps localized niche phenotypes, such as mixed-immune or segmented tumor habitats, that align with hypothesized selection landscapes and provide inputs for fragmentation analysis. Conclusions: TLA operationalizes an eco-evolutionary view of cancer by unifying interpretable, multiscale spatial metrics in a single workflow that works with any rasterized data input. By quantifying how habitats, edges, and mixing patterns are organized, TLA reveals niche structures and architectural motifs linked to clinical outcomes and complements foundation models and modality-specific pipelines with theory-grounded, clinically translatable descriptors. Ongoing work integrates TLA features with molecular data and outcomes to derive robust biomarkers and to inform adaptive, niche-targeted strategies in precision oncology. Citation Format: Ryan M. Carr, Luis Cisneros, Merih Deniz. Toruner, Martin E. Fernandez-Zapico, Carlo Maley. Tumor landscape analysis: An ecologically informed framework to understand tumor microenvironments [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85(23_Suppl):Abstract nr A015.

Key Points Understanding how heme proteins/heme induce AKI and whether NAD + -boosting ameliorates heme protein–mediated AKI is clinically relevant. Heme proteins/heme directly decrease kidney NAD + content and NAD + -boosting is markedly protective in heme protein–mediated AKI. These findings provide new insights in heme protein–mediated AKI and support interest in NAD + -boosting as a therapeutic strategy in AKI. Background Understanding how heme proteins and heme induce AKI is clinically relevant from numerous perspectives, and, in this regard, a widely used model of heme protein–mediated AKI (HP-AKI) involves the glycerol model in mice. Using this model, we have previously demonstrated that NAD + content is decreased in HP-AKI. Because there is significant current interest in NAD + -boosting as a strategy in clinical AKI, we examined the effect of NAD + -boosting in this model. Methods NAD + -boosting was achieved by the administration of nicotinamide mononucleotide (NMN) in the glycerol model of HP-AKI. The effect of NMN, compared with vehicle, was examined in mice with HP-AKI and with sham AKI at day 1 after HP-AKI was induced. Results The administration of NMN preserved kidney NAD + content in HP-AKI, and compared with the administration of vehicle in HP-AKI, NMN improved glomerular filtration markers; reduced histologic injury as assessed by tubular necrosis, dilation, and cast formation and by assessment of dystrophic calcification; reduced expression of kidney injury marker 1, a sensitive marker of AKI; preserved mitochondrial ultrastructure and increased expression of proteins that promote mitochondrial integrity; reduced apoptosis as assessed by terminal deoxynucleotidyl transferase–mediated digoxigenin-deoxyuridine nick-end labeling staining and genes and protein expression that contribute to apoptosis, while increasing expression of an anti-apoptotic gene; reduced expression of several renal injury-related genes; and mitigated the severity of the senescence phenotype, as assessed by multiple markers. Finally, the administration of myoglobin or heme in vivo diminished kidney NAD + content in mice with intact kidneys. Conclusions These findings demonstrate the remarkable protective effects of NAD + -boosting by NMN in HP-AKI as revealed by a multitude of markers relevant to AKI. The reduction in NAD + content in the kidney in HP-AKI may reflect the direct effects of heme proteins and/or heme. We suggest that these findings support current interest in NAD + -boosting as a therapeutic strategy in clinical AKI.

ABSTRACT Introduction Cardiac resynchronization therapy (CRT) improves clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF). However, data on its efficacy in patients with sarcoidosis and HFrEF are limited. Methods Using the TriNetX network, we identified patients with sarcoidosis, heart failure with a left ventricular ejection fraction (LVEF) below 35%, and either left bundle branch block (LBBB) or prolonged QRS duration ( > 150 ms) between 2014 and 2019. Patients were categorized into two cohorts: (1) those who received CRT and (2) those who received an ICD‐only implant. Five‐year outcomes included all‐cause mortality, all‐cause hospitalization, heart failure exacerbation, and the proportion of patients with improvement in LVEF to greater than 40% and greater than 50%. Results Out of 245 eligible patients, we identified a cohort of 87 patients (mean age 62.6 ± 9.5 years) who received CRT and 87 patients (mean age 62.1 ± 11.1 years) who received ICD‐only implant, with similar propensity scores, and included them in a comparative analysis. At 5‐year follow‐up, the CRT group demonstrated outcomes comparable to the ICD‐only implant group for all‐cause mortality (14.9% vs. 20.7%; HR 0.63; 95% CI 0.31–1.28; p = 0.19), all‐cause hospitalization (83.9% vs. 77.0%; HR 1.24; 95% CI 0.89–1.73; p = 0.19), and heart failure exacerbation (28.7% vs. 28.7%; HR 0.90; 95% CI 0.52–1.57; p = 0.72). The proportion of patients with improvement in LVEF to greater than 40% and greater than 50% was also similar in both groups (LVEF > 40%, 43.7% vs. 33.3%; HR 1.30; 95% CI 0.80–2.10; p = 0.29; LVEF > 50%, 31.0% vs. 17.2%; HR 1.72; 95% CI 0.92–3.24; p = 0.09). Conclusion CRT implantation had similar long‐term outcomes compared to ICD‐only implantation in patients with sarcoidosis and HFrEF, particularly all‐cause mortality, all‐cause hospitalization, heart failure exacerbation, and the proportion of patients with improvement in LVEF to greater than 40% and greater than 50%.

Importance The ideal duration of androgen deprivation therapy (ADT) for treating localized prostate cancer is unknown due to variable adherence and treatment durations tested in clinical trials. Objective To determine the ideal duration of ADT for patients with prostate cancer treated with radiotherapy. Data Sources This individual patient data meta-analysis of 13 randomized phase 3 clinical trials evaluated the use of radiotherapy alone or with ADT. It included patients with a median follow-up of 11.3 (IQR, 9.5-14.5) years and ADT duration of 0 to 36 months. Most patients (7392 [72%]) included had National Comprehensive Cancer Network high-risk or very high-risk disease. Study Selection For this meta-analysis, a systematic literature search from 1980 to 2020 was performed in trial registries (Cochrane Central Register of Controlled Trials and ClinicalTrials.gov), MEDLINE (1966-2020), Embase (1982-2020), Web of Science, and Scopus to identify trials. Data Extraction and Synthesis Intention-to-treat and as-treated analyses were performed. The number needed to treat to prevent 1 distant metastasis at 10 years was calculated based on prognostic risk group. The analyses were conducted from January 5 to August 15, 2023. Main Outcomes and Measures The primary end point for this study was overall survival, defined as time to death or last follow-up from randomization. Secondary end points included biochemical recurrence, distant metastasis (DM), prostate cancer–specific mortality, and other-cause mortality. Results The median (IQR) age among the 10 266 male patients was 70 (65-74) years. Longer durations of ADT were associated with nonlinear improvement in relative benefits of DM, prostate cancer–specific mortality, and overall survival, with reduced estimated benefits beyond 9 to 12 months of ADT based on the end point. There was a near-linear increase in other-cause mortality associated with long-term ADT use (hazard ratio, 1.28; 95% CI, 1.09-1.50; P = .002 for 28 vs 0 months of ADT). The optimal ADT duration based on 10-year DM was 0, 6, 12 months, and undefined for patients with 1 intermediate-risk factor, 2 or more intermediate-risk factors, and National Comprehensive Cancer Network high-risk and very high-risk disease, respectively. Conclusions and Relevance The results of this meta-analysis suggest that, for men with localized prostate cancer treated with definitive radiotherapy and ADT, there are relative and absolute benefits from increasing durations of ADT that help provide individualized risk estimates.