Citations

Abstract Background: Mantle cell lymphoma (MCL) is an aggressive and rare B-cell non-Hodgkin lymphoma with poor prognosis, even with treatment. Despite its clinical importance, the etiology of MCL remains largely unknown. Some studies have reported a positive association with family history, suggesting that genetic factors could contribute to risk. Methods: To identify germline genetic variants associated with risk, we conducted the first genome-wide association studies (GWAS) and GWAS meta-analysis for MCL, comprising 1,163 cases and 61,271 controls. The most significant loci were taken forward for replication in three independent studies, including 576 cases and 771,773 controls. To identify potential target genes and pathways of discovered loci, we conducted F-MAGMA, colocalization, and transcriptome-wide association study (TWAS) analyses. To gain insight into underlying regulatory mechanisms, we performed integrative epigenomic analyses using DNase I hotspots and histone mark ChIP-seq data across diverse cell types applying the FORGE2 framework. Results: In the joint analyses, we identified eight genome-wide significant loci (P<5x10-8) associated with MCL risk, several of which were located near genes with known DNA repair (ATM), telomere (TERT), or RNA-binding functions (RBM20). Further analyses using F-MAGMA, which uses DNase-seq data to prioritize genes from GWAS, identified genes that were significantly associated with risk, including SP140, a chromatin reader and immune regulator of pathogen response. This gene also displayed strong colocalization with our lead variant in whole blood (COLOC posterior probability PP4=0.97). TWAS demonstrated significant associations with SP140 and ACTA2, which has been linked to cell proliferation (P<3x10-6). Enrichment for DNase I hotspots was observed in B and T lymphocytes (q-value<0.05), providing evidence for a role in immune cell-specific regulatory regions. Enrichment for enhancer-associated histone mark H3K4me1 was observed in B cells (q-value<0.01), highlighting a role for immune cell-specific enhancers. Transcription factor (TF) motif enrichment analysis pointed to TFs critical for B-cell development and differentiation, notably TCF3 and EP300 (q<0.01 for both), suggesting an association between B-cell lineage regulation and MCL risk. Finally, genome-wide SNP-based heritability was estimated to be 17%, underscoring the importance of common variants in MCL risk. Conclusion: Our study provides novel insight into the inherited susceptibility of MCL by identifying eight significant loci and estimating substantial common variant heritability. These findings highlight a role for several distinct biological pathways -specifically DNA repair, telomerase function, and B-cell differentiation- in the etiology of MCL, offering new targets for mechanistic investigation. Citation Format: Charles E. Breeze, Alyssa Clay-Gilmour, Hanla A. Park, Ólafur B. Davíðsson, Angelica Macauda, Brenda M. Birmann, Elizabeth E. Brown, Murat Güler, Michelle A. T. Hildebrandt, Alexandra Nieters, Krystle Ong, Jojo Biel-Nielsen Dietz, Karin E. Smedby, Karl Smith-Byrne, Rosalie Griffin, Sophia S. Wang, Susan Slager, James R. Cerhan, Jonathan N. Hofmann, Qing Lan, Nathaniel Rothman, Ingrid Glimelius, Henrik Hjalgrim, James Mckay, Sonja I. Berndt. Genome-wide association study of mantle cell lymphoma identifies novel loci suggesting a critical role for B-cell chromatin readers and DNA repair mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3602.

Abstract Background: The increasing volume and diversity of clinical genomic reports pose a significant challenge across healthcare institutions for the interpretation and proper implementation of precision oncology research. Reports from multiple different vendors (e.g., Invitae, Ambry Genetics, Foundation Medicine) are typically PDFs and exhibit substantial heterogeneity in panel design, gene coverage, and reporting standards, which hinders efficient retrospective data mining and patient cohort identification within the electronic medical records. We sought to develop a framework to interrogate all of these reports. Methods: We extracted genomic reports from patients with breast cancer treated with neoadjuvant chemotherapy and developed MolHarmonizer, a novel, scalable framework leveraging Python and Gemini LLMs, designed to process and harmonize genomic data from disparate multi-vendor reports. Gemini LLMs are employed explicitly for robust information extraction, normalization, and structuring of key genomic features, transforming unstructured data into a unified, queryable dataset. Results: Our MolHarmonizer framework successfully processed 1,147 genomic reports from 1703 breast cancer patients (2006-2023) from 23 different companies, demonstrating robust capability to extract and standardize critical actionable biomarkers. Data sources included Invitae (n=554), Ambry Genetics (n=189), Natera (n=95), Mayo Clinic (n=88), Tempus (n=63), Guardant Health (n=47), and Foundation Medicine (n=37), with others contributing less than 20 reports. Of the samples, 827/1147 (72.1%) were germline (blood/saliva). A majority of the patients were tested using the panels due to a personal/family history (n=925). Overall, 413/1147 (36.0%) reports identified at least one mutation. For breast cancer, 75 reports showed BRCA1/2 mutations (37 BRCA1, 37 BRCA2, and one patient with both BRCA1 and 2). Other mutations identified included: PIK3CA (n=40), TP53 (n=96), PTEN (n=21), ESR1 (n=13) and AKT1/2 (n=8). Conclusion: MolHarmonizer, a powerful framework leveraging Gemini LLMs, effectively addresses genomic data heterogeneity by automating biomarker extraction and harmonization. This enables rapid cohort identification and deep retrospective analyses for clinical insights, biomarker discovery, understanding disease history, facilitating novel pattern discovery, e.g., predicting BRCA1 mutations from WSI, and accelerating research within our neoadjuvant BC cohort. Future plans include expanding to include over 20,000 breast cancer patients, developing a user-friendly chatbot, and ensuring inter-institutional adaptability for a variety of complex diseases. Citation Format: Krishna Rani Kalari, Xiaojia Tang, Thanmayee Boyapati, Tanya L. Hoskin, Sumathilatha Myla, Sumedha G. Penheiter, Richard M. Weinshilboum, Liewei Wang, Hamid R. Tizhoosh, Karthik Vikram Giridhar, Matthew P. Goetz, Judy C. Boughey. Development of an LLM framework for analysis of heterogeneous breast cancer patients genomic reports [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2756.

Abstract Chimeric antigen receptor (CAR) T-cell therapy achieves high response rates in relapsed/refractory aggressive B-cell non-Hodgkin lymphoma, yet only 40% of patients achieve durable remission. Identifying biological programs linked to long-term response remains critical. As metabolic fitness underlies T-cell persistence and effector function, we profiled metabolic pathways associated with clinical outcomes following commercial CD19 CAR T-cell therapy. Single-cell RNA sequencing of peripheral blood mononuclear cells collected at baseline (BL), peak CAR-T expansion (PK), and one-month post-infusion (M1) was analyzed using CellRanger v7.0.1, immunopipe. Seurat v4.3.0 was applied for unsupervised clustering to delineate cell subsets based on top differentially expressed genes. Patients were categorized as durable complete remission (CR ≥6 months; n = 16), primary refractory (PD1; n = 4), or relapse after initial response (PD2; n = 12). Gene-set enrichment analysis defined metabolic pathway activity across T-cell, monocyte, dendritic cell (DC), and natural killer (NK) subsets. Oxidative phosphorylation (OXPHOS) emerged as the dominant metabolic program distinguishing clinical outcomes. At BL and PK, OXPHOS was consistently enriched in PD1 relative to CR across T-cell, monocyte, and DC subsets, suggesting early oxidative activation in non-responders. By M1, this pattern inverted, with higher OXPHOS activity in CR. PD2 largely paralleled PD1, but several subsets including CD8 T central memory, classical monocytes TGFβ, intermediate monocytes CD38, monocytic myeloid-derived suppressor cell (mMDSC) HIF1A, and mMDSC SIRPA, showed OXPHOS enrichment in CR at BL and/or PK that persisted through M1. In contrast, DC and NK subsets exhibited the opposite pattern: OXPHOS was enriched in CR at PK (conventional DC 2 (cDC2), plasmacytoid DC (pDC), NK, proliferating NK), but shifted toward enrichment in PD2 at M1 (cDC2, NK, NK CD56bright). Glycolysis (GLY) followed a similar trajectory in monocytes and NK cells, with enrichment in PD1/PD2 at BL and PK, followed by enrichment in CR at M1. In T-cells, PD1 maintained GLY enrichment from BL through PK, with no significant differences observed at M1. The inositol-phosphate metabolism pathway showed a more static pattern and was consistently enriched in multiple PD2 effector and memory T-cell subsets without reversal at M1. Taken together, these data reveal distinct, lineage-specific metabolic signatures that differentiate durable remission from early and late progression. Dynamic OXPHOS and GLY programming, characterized by lower activity early and enhanced activity at M1 in CR, may reflect adaptive metabolic programming that supports sustained antitumor immunity. Immune-metabolic profiling may therefore serve as a biomarker of response and highlight actionable metabolic pathways to enhance CAR T-cell durability. Citation Format: Melinda S.Y. Tan, Panwen Wang, Patrizia Mondello, Jacqueline Turner, Andre de Menezes Silva Corraes, Chen Wu, Zuoyi Shao, Kevin Regan, Ma Audrey, Arushi Khurana, Nora N. Benanni, Yucai Wang, Paul Hampel, Jonas Paludo, Saad J. Kenderian, Urshila Durani, Patrick B. Johnston, Jose Caetano Villasboas, Stephen M. Ansell, Ying Li, Haidong Dong, Hu Zeng, Yi Lin. Metabolic pathway signatures defining response to CD19 CAR T-Cell therapy in aggressive B-cell non-hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3278.

Abstract Phosphatase and Tensin Homolog (PTEN) is a critical tumor suppressor frequently mutated in cancers, notably endometrial cancer (EC), where it drives early carcinogenesis. PTEN mutations disrupt lipid phosphatase activity, causing PI3K/AKT/mTOR pathway hyperactivation. However, clinical trials targeting this pathway in advanced EC yield suboptimal outcomes, with PTEN loss showing poorly predictive value for therapeutic response, indicating other mechanisms are involved. TCGA Pan-Cancer Atlas data show a 39.1% co-mutation rate of PTEN and PIK3CA in EC, much higher than the 3.6% pan-cancer rate, challenging the idea of mutual exclusivity in driver mutations within the same pathway. PTEN missense mutations are most common in EC (41.44%), with R130 as a hotspot, especially among PIK3CA-mutant patients (45.28%), while other cancers with frequent PTEN mutations show much lower R130 rates. These findings suggest PTEN R130 missense mutants undergo positive selection and may have unique oncogenic effects in EC.To characterize these mutants, a Tet-on inducible system in PTEN-null SPAC-1-S EC cells compared wild-type PTEN (PTENWT), loss of function mutant PTENR173C, and ultrahigh frequency mutant PTENR130G. PTENWT suppressed proliferation, PTENR173C showed reduced tumor suppressive activity, while PTENR130G increased proliferation, indicating a PTENWT-independent tumor-promoting function. In MFE 296 cells with PTEN R130Q/N332fs mutations, knockdown of PTENR130Q suppressed proliferation, providing functional evidence that PTENR130G has PTENWT-independent oncogenic activity in EC. To elucidate the underlying mechanisms, we performed quantitative proteomic and BioSITe analyses in SPAC-1-S cells inducibly expressing PTENWT or PTENR130G, enabling comprehensive mapping of the unique signaling alterations specific to this ultrahigh-frequency PTENR130G mutant. Our initial analysis revealed that PTENWT induction caused broad transcriptional suppression of oncogenic and structural pathways, including MAPK/ERBB, focal adhesion, ECM-receptor interaction, and lysosomal function, consistent with restored tumor-suppressive activity. In contrast, PTENR130G induction led to a distinct transcriptional response; while partially repressing lysosomal and adhesion pathways, stress-adaptive and metabolic programs like TGF-β signaling and glutathione metabolism remained active or were reactivated. These results suggest PTENR130G not only loses PTEN’s inhibitory functions but may gain new transcriptional and metabolic activities that promote cell survival and tumor progression. Overall, our analysis indicates wildtype PTEN restores signaling restraint, while PTENR130G reprograms the transcriptome toward a pro-cancer, stress-resilient state, suggesting a gain-of-function oncogenic role. Citation Format: Xiangyi Kong, Li Wang, Md Kamrul Hasan Khan, Jidong Wang, Huaijun Zhou, Xinyan Wu. Unique oncogenic mechanisms of ultrahigh-frequency mutant PTENR130Gin endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7654.

Abstract Background: Hypogammaglobulinemia at the time of CLL diagnosis predicts shorter time to first therapy (TTFT). However, the depth of immunoparesis and its impact on TTFT in newly diagnosed MBL/CLL remains unexplored. Methods: We identified previously untreated MBL/CLL patients from Mayo Clinic CLL Database (2000-2024) who had serum immunoglobulin (Ig; IgG, IgM and IgA) and monoclonal protein assessed within 1 year of diagnosis. Immunoparesis was evaluated: a) qualitatively by classifying patients into preserved, partial and full Ig suppression, based on the number of suppressed Igs; and b) quantitatively by calculating the average relative difference (ARD), defined as the mean percentage below normal for all Igs. For both methods, only uninvolved Igs were considered for those with monoclonal protein. TTFT was estimated by Kaplan-Meier with competing risk of death. Cox models estimated hazard ratios (HR) and 95% confidence intervals (CI). Results: Among 1420 patients, median age at diagnosis was 65 (range 28-96); 954 (67%) were male; 493 (44.8%) had unmutated IGHV, and 86 (6.8%) had TP53 disruption. The median [range, mg/dL] serum IgG, IgA, and IgM were 889 [111-5290], 132 [1-4880], and 49 [4-9480]. Low IgG was present in 472 (33.2%), low IgA in 223 (16.4%), and low IgM in 530 (37.3%) patients. An M-spike was detected in 122 (8.6%) patients; distribution was: IgG (73), IgM (30), IgA (6), or multiple (13). By qualitative assessment, preserved Ig were seen in 664 (46.8%), partial Ig suppression in 604 (42.5%), and full suppression in 152 (10.7%) patients. By quantitative assessment, median ARD was 0.6 (-0.8 to 11.3); 280 (19.7%) patients had negative ARD, and 1140 (80.3%) had positive ARD. In those with negative ARD, 128 (9%) had partial Ig suppression and 152 (10.7%) had full Ig suppression; in those with positive ARD, 664 (46.8%) had preserved Ig and 476 (33.5%) had partial Ig suppression. Median follow-up was 14.7 years; 510 patients progressed requiring therapy. Median TTFT was 9.6 years. Median TTFT for patients with preserved Ig was 12.6 years, 8.0 years for partial Ig suppression (HR 1.4, 95%CI 1.1-1.7), and 1.8 years for full Ig suppression (HR 3.1, 95%CI 2.4-4.0). The median TTFT was 2.3 and 12.1 years for patients with negative vs positive ARD; negative ARD was associated with shorter TTFT (HR 2.4, 95%CI 2.0-2.9). After adjusting for sex and CLL-International Prognostic Index (CLL-IPI) score, full Ig suppression (HR 2.9, 95%CI 2.2-3.9) and partial Ig suppression (HR 1.6, 95% CI 1.3-2.0) were associated with shorter TTFT (model 1, c-stat 0.77); and negative ARD (HR 2.4, 95%CI 2.0-2.9) was associated with shorter TTFT (model 2, c-stat 0.76). Negative ARD identified an additional 9% of patients at higher risk for shorter TTFT beyond full Ig suppression. Conclusions: The depth of immunoparesis at diagnosis predicts TTFT and enhances risk stratification in newly diagnosed MBL/CLL. Citation Format: Yuan Yao, Kari G. Rabe, Eli Muchtar, Paul Hampel, Yucai Wang, Lindsey Roeker, Saad Kenderian, Amber Koehler, Catherine Wagner, Amy Behnken, Jose F. Leis, Mazie Tsang, Talal Hilal, Ricardo Daniel Parrondo, Susan M. Schwager, Min Shi, Curtis A. Hanson, Celine M. Vachon, Shaji Kunnathu Kumar, Esteban Braggio, Neil E. Kay, Susan Slager, Sameer A. Parikh. Depth of immunoparesis predicts time to first therapy in newly diagnosed monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1191.

Abstract Introduction: Therapeutic outcomes in B-cell non-Hodgkin’s lymphoma (B-NHL) have substantially improved with the introduction of chimeric antigen receptor T-cell (CAR-T) therapy. Yet, persistent immune dysfunction and underlying metabolic dysregulation remain major obstacles to achieving durable clinical responses in B-NHL. We hypothesize that mitochondrial pathways play a critical role in mediating anti-tumor immunity during CAR-T therapy. Methods: Peripheral blood mononuclear cells were collected from healthy controls (CNTRL, n=5) and patients with advanced stage lymphoma (LYM) who received FDA approved CAR-T (n=32). Samples were collected before lymphodepletion (BL), at peak CAR-T expansion (PK) and one-month post-infusion (M1). Single-cell RNA sequencing was used to interrogate differential mitochondrial gene expression. Samples were obtained from LYM patients with complete remission for >6 months (CR), primary refractory (PD1), or relapsed (PD2) disease. Results: Compared to CNTRLs, LYM patients exhibited reduced expression of cytochrome c oxidase. At BL, CR patients demonstrated broader mitochondrial differential gene expression across all T-cell subsets relative to PD1 and PD2 and showed higher expression of MT-ATP-6, MT-ATP-8, and MT-CO3. Following CAR-T infusion, global mitochondrial gene expression increased across patients corresponding with expansion of CD8 effector T cells (Tem tumor circulating) and activated peripheral memory T cells (Tpm). Certain mitochondrial genes, such as MT-CO1, were durably expressed across LYM patients at BL, PK, and M1 in peripheral and central memory T cells (Tpm, Tcm). At PK, cytochrome c oxidase and ATP synthase genes were upregulated in CR Tpm and Tcm. At M1, MT-ATP-6, MT-ATP-8, MT-CO3 were significantly upregulated in CD8 memory precursor effector T-cells (MPECs) of CR patients compared to both PD1 and PD2. While CR and PD2 patients appeared clinically responsive at M1, CR samples maintained significantly higher MT-ATP-8 expression across T cell subsets (CD8 MPECS, Tpm, Tcm) compared to PD2 (p values 0.008; <0.0001; <0.0001). Conclusions: We report a temporal shift in immunometabolism with CAR-T therapy in LYM. Clinical responders exhibited sustained mitochondrial activity characterized by persistent expression of ATP synthase in CD8 MPECs and cytochrome c oxidase in Tpm and Tcm. In sum, mitochondrial programming may distinguish effective versus dysfunctional T cells and identify targets for therapeutic development. Citation Format: Jacqueline Turner, Panwen Wang, Patrizia Mondello, Melinda Tan, Christoph Schaefers, Chen Wu, Andre de Menezes Silva Corraes, Kevin Regan, Zuoyi Shao, Ma Audrey, Arushi Khurana, Nora N. Benanni, Yucai Wang, Paul Hampel, Saad J. Kenderian, Jonas Paludo, Urshila Durani, Patrick B. Johnston, Jose Caetano Villasboas, Stephen M. Ansell, Haidong Dong, Ying Li, Zeng Hu, Yi Lin. Mitochondrial transcriptome profiles associated with clinical responses to CAR-T therapy in aggressive lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1213.

Abstract Ovarian endometrioid carcinoma (OEC) is the second most common histotype associated with the most favorable prognosis among ovarian carcinomas. Similar to endometrial carcinoma, OEC exhibit significant molecular diversity. We aimed to develop a practical immunohistochemical (IHC) prognosticator by integrating IHC biomarkers with clinical substage, and surgical outcomes. This multi-institutional study included participants with primary invasive OEC from the Alberta Cancer Registry (AOVT), Mayo Clinic, and Disease of the Ovary and their Evaluation Study (DOVE). Pathology review excluded misclassified high-grade serous and mesonephric carcinomas leaving 422 OEC cases (AOVT N=158; DOVE N=143; Mayo N=121) with available tumor biospecimens who did not receive neoadjuvant treatment. Clinical characteristics included age, stage, grade, residual disease and 5-year survival. Clinical risk group was defined by combining stage and residual disease: Low (FIGO stage IA/IB & no macroscopic disease), Intermediate (stage IC-II& no macroscopic disease), High (stage III/IV or macroscopic disease). Tissue microarrays were stained for TP53, PMS2, MSH6, PGR, and CTNNB1 using IHC and were scored by a single pathologist. Tumors were hierarchically categorized as TP53-abnormal (TP53abn)/PGR-loss, mismatch-repair deficient (MMRd, via PMS2 and MSH6), nuclear-CTNNB1 (nCTNNB1), or no-specific-immunohistochemical-profile (NSIP). Overall survival (OS) at 5 years was compared across clinical risk and biomarker groups using Cox regression, adjusted for age and site to generate hazard ratios (HR), and 5-year survival rates (5-YSR). High clinical risk group was associated with worse 5-year OS compared to low & intermediate risk (p<0.0001). Hierarchical IHC biomarker groups were also associated with 5-year OS, adjusted for age and study site (p<0.0001), with consistently worse survival for combined TP53abn/PGR-loss (n=17, HR=6.07, 95% CI 2.78-13.26), PGR-loss only (n=55, HR=4.17, 95% CI 2.19-7.94), TP53abn only (n=29, HR=2.04, 95% CI 0.85-4.90), and better survival for nuclear-CTNNB1 (n=146, HR=0.22, 95% CI 0.07-0.65) compared to NSIP (n=132). Within the low-risk group, MMRd, nCTNNB1, or NSIP had greater than 97% 5-YSR, while OEC with TP53abn/PGR-loss or PR-loss only had less than 75% 5-YSR. Within the intermediate group, only nCTNNB1 exceeded a 5-YSR of greater than 97%. Within the high-risk group, 5YSR for nCTNNB1 OEC was 90.9%, compared to only 16.7% for TP53abn/PGR-loss. This IHC-based algorithm refines prognosis beyond clinical substage. It identifies low-risk patients with unfavorable prognosis (TP53abn/PGRloss, PGR loss only) who may benefit from adjuvant therapy, and also patients with favorable prognosis within the intermediate group for whom adjuvant therapy could be de-escalated. Further patient selection for chemo vs. hormone therapy in the high-risk group may be improved by biomarkers. Citation Format: Gamaliel Taengwa, Hunter J. Atkinson, Bryan M. McCauley, Sebastian M. Armasu, Chen Wang, Jennifer A. Doherty, Holly R. Harris, Ellen L. Goode, Martin Koebel, Stacey J. Winham. IHC-based prognostic sub-stratification of ovarian endometrioid carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1184.

The underlying immunopathogenesis of inflammatory arthritis (IA) immune-related adverse event (irAE) remains obscure. Unlike rheumatoid arthritis (RA), where autoantibodies and B cell dysfunction are central features, the contribution of humoral immunity to IA-irAE is unclear. Here, we performed immunophenotyping of peripheral blood from patients with IA-irAE and compared them with patients with seronegative RA, immune checkpoint inhibition–treated patients without irAE, and healthy controls. IA-irAE was marked with increased cytotoxic gene expression and metabolic activation in T cells and reduced CXCR3 and CCR6 expression in CD4 + T cells. Contrary to seronegative RA, patients with IA-irAE displayed no substantial elevation in autoantibody levels or atypical CD11c + CD21 − B cells. IA-irAE was further characterized by elevated levels of interleukin-6 (IL-6), IL-12, and type I interferon, which correlated with the T cell activation phenotypes. Together, our findings define IA-irAE as a disease with certain immunological features distinctive from RA, representing a potentially T cell–driven, autoantibody-independent autoimmunity. These results offer insights into immune tolerance breakdown and therapeutic targeting in irAEs.

Background: Distal femoral osteotomy (DFO) may be performed via either a lateral opening-wedge (LOW) or medial closing-wedge (MCW) osteotomy with meaningful clinical improvements; however, the effects of each DFO technique on leg length have not been well characterized. Purpose: To (1) validate a radiographic measurement technique to predict leg length changes after DFO and (2) compare the change in leg length after DFO for the LOW and MCW techniques. Study Design: Cohort study; Level of evidence, 3. Methods: Preoperative and postoperative full-length standing radiographs obtained from patients who underwent DFO at 1 of 2 academic medical centers were evaluated. The region on the medial (for LOW) or lateral (for MCW) distal femur cortex that would be the “hinge point” during DFO was identified on the radiographs. The distance from the center of the femoral head to the hinge point ( A ), the distance from the hinge point to the center of the talus ( B ), and the resultant angle (α) were measured. The equation presented within the text was used to plot the predicted leg length changes corresponding to the change in alpha angle produced by DFO. Comparisons were made between (1) the predicted and measured leg length changes after DFO and (2) the measured leg length change after LOW versus MCW osteotomies. Results: For both LOW (n = 10) and MCW (n = 10) osteotomies, the predicted leg length change was equivalent to the true change measured on postoperative radiographs (LOW: P = .16; MCW: P = .85). There was a mean lengthening of 0.85 mm (range, 0.5-1.3 mm) for every 1° of mechanical axis correction with LOW DFO, compared to a mean shortening of 0.45 mm (range, 0.1-1.4 mm) per 1° of MCW correction. Conclusion: Preoperative radiographic imaging can be used to predict leg length change after DFO with high reliability. Surgeons can expect approximately 0.85 mm of lengthening per 1° of DFO correction when performing LOW osteotomies, compared to 0.45 mm of shortening per 1° of correction for MCW osteotomies. However, the most accurate prediction results from patient-specific calculations.

PURPOSE Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. The higher incidence and earlier onset of HCC in sub-Saharan Africa suggest a potential role for a genetic predisposition. This study evaluated the association of TERT -rs2242652-(A), a variant linked to lower HCC risk, with HCC in populations from Ghana, Nigeria, and Cameroon, compared with a population from the United States. METHODS The study included 537 patients with HCC: United States (n = 348), Ghana (n = 79), Nigeria (n = 43), and Cameroon (n = 67). The control group had 2,872 cancer-free individuals: United States (n = 2,399), Ghana (n = 323), Nigeria (n = 85), and Cameroon (n = 65). Whole-exome sequencing was conducted using germline DNA, and data for TERT -rs2242652 were analyzed. Odds ratios (ORs) and 95% CIs were calculated using unconditional logistic regression. Chi-square tests assessed protective allele frequencies. RESULTS In the US cohort, TERT -rs2242652 was significantly associated with lower HCC risk (OR, 0.75 [95% CI, 0.58 to 0.96]; P = .02), with an allele frequency of 18.8% (15.4% in HCC cases v 19.3% in controls). In the combined sub-Saharan African population, no significant association was observed, but there was a trend toward decreased HCC risk (OR, 0.80 [95% CI, 0.53 to 1.22]; P = .29), with an allele frequency of 12.2% (10.6% in HCC cases v 12.9% in controls). Separate analyses of Ghanaian, Nigerian, and Cameroonian populations showed similar nonsignificant trends. The protective allele frequency in the combined African populations was significantly lower than in the US cohort ( P < .0001). CONCLUSION In sub-Saharan African populations, there was a lower frequency of the HCC protective allele TERT -rs2242652 compared with European Americans. These findings underscore the importance of multiethnic genetic studies in understanding population differences in HCC risk and developing prevention strategies.