Citations

Purpose of review To summarize important papers published in the pediatric heart transplantation in the last year. Recent findings While advances have been made for pediatric patients who need heart transplantation, considerable challenges remain. Donor availability remains a key challenge, and work to both increase the number of donors and the quality of donor organs is ongoing. The field of pediatric heart transplantation benefits from registries such as the Pediatric Heart Transplant Society (PHTS) and learning networks such as the Advanced Cardiac Therapies Improving Outcomes Network (ACTION), allowing for multisite collaboration to optimize survival both before and after transplant, and to share learning about complex cases. Psychosocial evaluations of potential recipients and families can be challenging, and a consensus framework is now available for these evaluations, to provide appropriate oversight and management of a scarce resource. Looking ahead, heart transplant specialists are anticipating advances in xenotransplantation, which has the potential to revolutionize current standards of care. Summary Donor availability and organ scarcity are the dominant challenges we face, with many recent impactful papers addressing this issue either directly or indirectly. It will be critical to maintain the forward progress made in addressing these challenges, while readying the field for big changes to come.

ABSTRACT Background The assessment of gastrointestinal (GI) motility disorders is limited by the invasive, resource‐intensive, and subjective nature of current testing. Artificial Intelligence (AI) is being applied to address these challenges. This review aimed to comprehensively identify, appraise, and synthesize the spectrum of AI applications in GI motility diagnostics. Methods A systematic search of PubMed, Embase, Scopus, Web of Science, and Medline for original studies was conducted in March 2025. Results were narratively synthesized and grouped by anatomic region. Key Results Of 1383 articles, 90 primary studies met the inclusion criteria. In the esophagus ( n = 31), the primary focus was automation of High‐Resolution Esophageal Manometry (HREM), pH impedance, and Functional Luminal Imaging Probe (FLIP) panometry analysis. In the gastroduodenum ( n = 21), studies looked to improve diagnostic accuracy and interpretability of legacy electrogastrography (EGG). In the small and large intestine ( n = 19), AI was used to determine transit time and predict post‐operative ileus. In the anorectum ( n = 9), tools focused on standardizing manometry interpretation. Review of pan‐GI applications ( n = 10) highlighted AI's application to wireless capsule endoscopy and bowel sounds analysis. While promising, all areas need more rigorous research and external validation before widespread deployment. Conclusions and Inferences AI will play an essential role in improving and automating the interpretation of GI motility diagnostics. However, even the most promising models require large‐scale prospective validation before clinical implementation. Trial Registration PROSPERO (ID: 1128662)

PURPOSE Homologous recombination deficiency (HRD) is a key determinant of sensitivity to DNA-damaging agents; however, its genomic characterization in colorectal cancer (CRC) remains limited. This study investigated whether low RNA expression of homologous recombination (HR) genes identifies patients with metastatic CRC who derive survival benefit from oxaliplatin- or irinotecan-based therapy. METHODS A total of 22,957 metastatic CRC samples were subjected to DNA and RNA sequencing (Caris Life Sciences, Dallas, TX). Patients with microsatellite instability–high or pathogenic HR gene mutations were excluded to define a HR-proficient cohort. Overall survival (OS) was compared between patients with low (bottom 25%) versus high (top 25%) RNA expression of HR genes after oxaliplatin or irinotecan exposure. Validation was performed in the PARADIGM phase III trial cohort (n = 262) of first-line modified fluorouracil, leucovorin, and oxaliplatin-treated patients with available RNAseq data. RESULTS In the discovery cohort, low expression of core HR genes correlated with significantly longer OS after oxaliplatin or irinotecan exposure, specifically RAD51 (43.0 v 36.3 months; P < .005) and BLM (42.9 v 34.2 months; P < .005). Similar associations were observed for RAD51 (28.1 v 22.9 months; P = .02) and BLM (29.1 v 23.2 months; P < .005) in irinotecan-treated patients. In the PARADIGM validation cohort, low BLM expression was associated with improved OS (41.5 v 22.4 months; HR = 0.52; P = .002), whereas RAD51 showed a favorable but nonsignificant trend. These findings remained significant after adjustment for treatment arm, tumor sidedness, and metastatic burden. CONCLUSION Low BLM RNA expression is associated with improved survival after treatment with DNA-damaging agents, whereas low RAD51 expression shows a favorable but nonsignificant trend. These findings are exploratory and suggest that RNA-based HR gene expression may warrant further investigation as a potential prognostic biomarker in metastatic CRC.

Objective: Quality of life (QOL) is an important consideration in vestibular schwannoma (VS) patients when assessing management options. Understanding sex-based differences in QOL may facilitate patient counseling. Study design: Prospective cohort. Setting: Tertiary academic medical center and Acoustic Neuroma Association. Patients: Sporadic VS patients. Interventions: Observation, microsurgery, or radiation. Main outcome measures: Penn Acoustic Neuroma Quality of Life (PANQOL) scores. Results: A total of 481 patients were analyzed. In the observation group, women reported worse anxiety, facial function, and total PANQOL scores at baseline. At follow-up, men declined more in facial function (−5 vs. +3, P =0.01). For microsurgery, women reported worse facial function and balance scores at baseline. At follow-up, men declined more in facial function (−16 vs. −3, P <0.001), balance (−7 vs. +2, P =0.04), energy (−4 vs. +5, P =0.03), and total (−5 vs. +2, P =0.02) PANQOL scores. For radiation, women reported worse anxiety, balance, pain, and total scores at baseline. At follow-up, anxiety improved in women but worsened in men (+5 vs. −6, P =0.008). Sex-based differences exceeding the minimally important difference thresholds established for the PANQOL were observed for the following: anxiety at baseline in the observation group, anxiety and pain at baseline in the radiation group, and change in anxiety from baseline to follow-up in the radiation group. Conclusions: Women had worse anxiety, balance, facial function, pain, and overall QOL at baseline assessed using the PANQOL, whereas men declined more with treatment and observation. The largest difference in PANQOL change between sexes occurred after microsurgery, with men experiencing greater losses in facial function, balance, energy, and total scores.

Suppression of insulin-like growth factor-1 (IGF-1) signaling extends mammalian life span and protects against a range of age-related diseases. Unexpectedly, we found that reduced IGF-1 signaling fails to extend the life span of mitochondrial mutator mice. Most of the longevity pathways that are normally initiated by IGF-1 suppression were either blocked or blunted in the mutator mice. These observations suggest that the prolongevity effects of IGF-1 suppression critically depend on the integrity of the mitochondrial genome, revealing an unexpected hierarchy in the pathways that control mammalian aging. Together, these findings deepen our understanding of the interactions between the hallmarks of aging and underscore the need for interventions that preserve the integrity of the mitochondrial genome.

Abstract Breast and ovarian cancers are major causes of cancer mortality in women with frequent relapse after curative intent treatment, underscoring the need for novel therapeutics. To this end, we identified CTPS1 as an essential gene in multiple breast and ovarian cancer models, including those resistant to chemotherapy and PARP inhibitors. CTPS1 and CTPS2 are responsible for de novo synthesis of cytidine triphosphate (CTP) which is required for DNA/RNA polymerization, phospholipid synthesis and protein glycosylation. We found CTPS1 to be the predominant isoform expressed in cancer cells, with significantly higher levels in advanced and resistant disease models compared to normal tissue, benign lesions and treatment naïve cancers. Using CTPS1 siRNAs and CTPS1-dTAG (degradation tag) cell lines, we discovered that depletion of CTPS1 induces S-phase cell cycle arrest followed by apoptosis. Leveraging a first-in-class, highly selective, and orally bioavailable CTPS1 inhibitor (STP938) developed by Step Pharma, we identified nanomolar IC50 values across a panel of cell lines, both in 2D and 3D culture systems, and potent anti-neoplastic activity ex vivo and in vivo using patient-derived xenograft (PDX) models. STP938 also synergized with standard-of-care chemotherapy agents and PARP inhibitors, including in therapy-resistant models. Given the essentiality of CTP for biosynthetic processes, we performed bulk and single cell RNA-seq, total and phospho-proteomics, metabolomics, and lipidomic strategies to examine changes induced by acute and chronic STP938 exposure. This revealed that cancer cells are able to overcome pharmacologic CTPS1 inhibition by rewiring of pyrimidine and purine synthesis pathways, upregulation of the pentose phosphate pathway, and extensive remodeling of lipid synthesis pathways including shifts in PC/PE content, increased lysophospholipid production, and altered mitochondrial lipid composition (decreased cardiolipin and increased PG). To identify genetic drivers of STP938 resistance and synthetic lethal vulnerabilities, we performed a genome-wide CRISPR knockout screen together with a PRISM drug sensitivity screen. Genes regulating dNTP biosynthesis, S-phase progression, and RNA processing were identified as primary escape mechanisms, while DHODH inhibitors, purine and nucleoside analogs, and mitosis modifiers were implicated as synthetic lethal opportunities. Notably, we discovered that 25% of ovarian tumors lack CTPS2 protein expression, suggesting near complete reliance on CTPS1 for survival. Thus, a Phase 1a/b clinical trial of STP938 (NCT06297525) has been initiated, including an expansion cohort for patients with CTPS2-null ovarian tumors. These laboratory discoveries and ongoing clinical efforts aim to enable broader uptake of this novel therapeutic approach to improve long-term outcomes in patients with CTPS1-dependent disease. Citation Format: Xiyin Wang, Michael Emch, Lauren Voll, Rebecca Epp, Esther Rodman, Noa Odell, Hannah Smith, Nicole Pearson, Xiaonan Hou, Matthew Goetz, Scott Kaufmann, S. John Weroha, Phillip Beer, John Hawse. CTPS1 as a metabolic vulnerability and novel therapeutic target in breast and ovarian 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 4560.

Abstract Background: Cholangiocarcinoma (CCA) is an aggressive hepatobiliary malignancy with limited treatment options. CCA exhibits a distinct desmoplastic and tolerogenic tumor immune microenvironment (TIME) characterized by elevated bile acid concentrations resulting from obstructive cholestasis and dysregulated bile acid metabolism. TGR5 is an essential component of bile acid signaling. We hypothesize that bile acids promote CCA progression by establishing an immunosuppressive TIME through TGR5 signaling, which can be therapeutically targeted using SBI-364, a novel potent small molecule TGR5 inhibitor. Methods: Single-cell RNA sequencing (scRNA-seq) of immune cells from human intrahepatic (iCCA) and perihilar (pCCA) CCA tumors were conducted. Therapeutic studies were performed using syngeneic murine models of iCCA (PMID: 38458319), a novel syngeneic model of pCCA, and patient-derived xenograft (PDX) models. In collaboration with Sanford Burnham Prebys, SBI-364, a first in-class competitive TGR5 antagonist, was assessed in vivo. Additionally, we performed co-culture experiments with bile acid +/- SBI-364-treated murine bone marrow-derived monocytic myeloid-derived suppressor cells (M-MDSCs) and CD8+ T cells to assess functional immunosuppressive effects. Results: Human scRNA-seq revealed significantly increased TGR5 (GPBAR1) expression predominantly in myeloid cell populations within the CCA TIME. SBI-364 treatment significantly reduced tumor burden in both syngeneic orthotopic iCCA models and a novel pCCA model that recapitulates the anatomic characteristics of perihilar CCA. In contrast, NOD/SCID mice bearing PDX535 (predicted sensitive) and PDX136 (predicted resistant), SBI-364 treatment did not achieve tumor reduction, suggesting that TGR5 inhibition predominantly attenuates tumor progression through modulation of bile acid-immune cell interactions. SBI-364 treated murine tumors had a significant reduction in immunosuppressive macrophages expressing interleukin-10 and M-MDSCs compared to vehicle treated tumors. Furthermore, bile acid-treated M-MDSCs exhibited enhanced suppression of CD8+ T cell proliferation and function, an effect that was abrogated by SBI-364 co-treatment. Conclusion: We demonstrate that TGR5 inhibition represents a promising therapeutic strategy across multiple immunocompetent preclinical CCA models. We demonstrate that the bile-acid TGR5 axis promotes CCA progression via immunosuppressive myeloid cells. Specifically, TGR5 signaling potentiates the immunosuppressive capacity of M-MDSCs, contributing to an immunosuppressive niche that facilitates tumor progression. These results establish TGR5 as a rational therapeutic target for overcoming immune evasion in cholangiocarcinoma. Citation Format: Enis Hikmet Ozmert, Binbin Li, Jingchun Yang, Hannah Elizabeth Stumpf, Jessica R. Willhite, Danielle Carlson, Jennifer L. Tomlinson, Jon Covel, Raghuveer Ramachandra, Steven Olson, Rory L. Smoot, Sumera Ilyas. Therapeutic targeting of TGR5 abrogates bile acid driven myeloid cell immunosuppression in cholangiocarcinoma [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 2896.

Abstract 5-Fluorouracil (5FU)-based chemotherapy remains a front-line treatment for most patients with colorectal cancer. However, approximately 30% of patients who receive 5FU experience severe, life-threatening toxicity. Dihydropyrimidine dehydrogenase (DPD, DPYD gene) mediates the rate determining step in 5FU catabolism. Deleterious genetic variations in DPYD have been associated with elevated concentrations of circulating 5FU and significantly increased risk for 5FU toxicity. Five deleterious variants in DPYD have been identified as clinical biomarkers of toxicity and have led to prospective genotyping and differential dosing recommendations for carriers of these variants, as noted on recent updates to the FDA label for the 5-FU prodrug capecitabine. Our previous studies also established the importance of epigenetic control of DPD expression. In this study, we used existing epigenetic repositories to identify candidate enhancer elements for DPYD. We selected 20 novel high-priority putative enhancers for further study using a combination of reporter assays and CRISPRi applied across multiple cell models. Further studies will investigate means to target these regulatory mechanisms as a means to increase localized efficacy of 5-FU-based therapies in colorectal cancer. Citation Format: Hannah Marie Krause, Julia Magee, Kelly Bouchonville, Lauryn Allyn Hahn, Ryan Jonathan Swartz, Brianna Bembenek, Lulu Jiang, Steven M. Offer. Characterizing the critical role of enhancer-gene regulation in 5-fluorouracil toxicity and resistance [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 3140.

Abstract Breast cancer accounts for nearly a quarter of all cancers in women with an estimated 2.3 million new diagnoses and over 670,000 deaths annually. Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by lack of estrogen receptor alpha (ERα) and progesterone receptor (PR) expression in the absence of HER2 amplification. TNBC accounts for ∼15% of all incident breast cancers and is associated with poor patient outcomes. Problematically, TN tumors exhibit vast inter-patient molecular heterogeneity making the identification of novel therapeutic vulnerabilities difficult and the development of alternative treatment strategies problematic. We and others have demonstrated that estrogen receptor beta (ERβ) is expressed in about 20% of TN tumors and potently suppresses proliferation, invasion, and migration in TNBC cells in vitro and in vivo. We thus hypothesized that endocrine therapies that selectively activate ERβ would be an effective treatment approach for this subset of patients. We also anticipated that some tumors would display de novo or acquired resistance to ERβ targeted therapies despite ERβ protein expression. We therefore sought to define mechanisms of resistance to ERβ targeted therapy and to identify synthetic lethal vulnerabilities. We generated the first models of ERβ resistant TNBC through chronic exposure to estradiol or an ERβ specific agonist (LY500307) and through a CRISPR genome wide knockout screen. We identified the LncRNA XIST as one of the most upregulated transcripts in multiple models of ERβ resistant disease, and knockdown of XIST expression was shown to resensitize resistant cell to estradiol and LY500307 treatment. XIST was not found to be directly regulated by ERβ in TNBC further suggesting that its overexpression is a bona fide mechanism of resistance to ERβ mediated suppression of proliferation. The phenomena of chronic ligand exposure leading to activation of XIST expression in ERβ+ cells is not shared with ERα suggesting that the mechanism by which XIST expression is elevated during the development of resistance is distinct between the two sister receptors. We further characterized XIST expression in patient samples of TNBC and found that XIST expression varies, but largely exhibits a bimodal distribution with most tumors displaying either low or high transcript levels. In conclusion, we have identified the X-inactivating transcript as a driver of resistance to ERβ targeted therapies in TNBC. Future studies aimed at uncovering the consequences of XIST over-expression on global gene expression, functionality of ERβ, and aggressiveness of TNBC are ongoing. Citation Format: Michael Emch, Kirsten Aspros, Matthew P. Goetz, John Hawse. The LncRNA XIST mediates resistance to estrogen receptor beta targeted therapies in triple negative breast 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 2293.

Abstract Background: Kidney transplant recipients (KTRs) have a markedly elevated risk of aggressive malignancies, yet the use of immune checkpoint inhibitors (ICIs) in this population remains limited by concerns for allograft rejection and the absence of prospective evidence. We evaluated real-world antitumor activity, graft safety, and immunosuppression-related outcomes of ICI therapy in KTRs with advanced cancers. Methods: We retrospectively analyzed 57 KTRs with locally advanced unresectable or metastatic malignancies treated between 2018-2025 at a single tertiary center. Thirty-three received ICIs and 24 received non-ICI systemic therapy. Outcomes included objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival from diagnosis (OSd), overall survival from treatment initiation (OSt), acute allograft rejection, and immune-related adverse events (irAEs). Tumor response was assessed by RECIST v1.1. Results: ICI-treated patients achieved higher ORR (40.0% vs 26.1%) and CBR (60.0% vs 33.3%) compared with non-ICI therapy. Median OSd was 35.8 vs 23.3 months, and median PFS was 4.3 vs 3.5 months (both not statistically significant). Median OSt was significantly longer with ICIs (15.1 vs 7.9 months; p=0.012). Acute rejection occurred in 12.1% of ICI-treated patients (3% irreversible) versus 4.2% with systemic therapy; rejection events were heterogeneous in timing (3 weeks-14 months) and largely responsive to pulse-dose corticosteroids. IrAEs occurred in 27.3% of ICI patients, with grade ≥2 events in 12.1%, and no treatment-related deaths. In the cutaneous squamous cell carcinoma (cSCC) subgroup (n=33), ICI therapy produced an ORR of 47.4% and CBR of 63.2%, with trends toward improved survival relative to controls. Conclusions: ICIs produced clinically meaningful antitumor activity in KTRs, particularly in cSCC, with a manageable rate of allograft rejection under carefully tailored immunosuppression. Despite higher historical concerns, irreversible graft loss was uncommon. These findings support the feasibility of ICI therapy in selected transplant recipients and highlight the importance of immunosuppression strategy in balancing antitumor efficacy and graft safety. Prospective, biomarker-integrated studies are needed to define optimal immunosuppression during PD-1 blockade in this high-risk population. Citation Format: Ali Rezazadeh Roudkoli, Elena Barbir, Shahin Kavousi, Mohamed A. Aboelatta, Claudia-Denise Haivas, Byron H. Smith, Aleksandra Kukla, Arkadiusz Z. Dudek. Immune checkpoint inhibitor therapy in kidney transplant recipients: Real-world outcomes of antitumor activity and graft rejection risk [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 6544.