Citations

Abstract Cancer can recur when a subset of tumor cells, termed persister cells, survive therapy and re-enter the cell cycle. The cellular lineages that give rise to persister cells and the mechanisms that confer the persister state remain poorly understood. Through single-cell multiomic profiling (snRNA-seq and snATAC-seq) on a cohort of (1) non-malignant fallopian tube, (2) treatment-naïve, and (3) neoadjuvant chemotherapy (NACT)-treated high-grade serous ovarian cancer (HGSOC) patient samples, we identified an epigenetic signature that defines the chemotherapy-tolerant persister state. The changes in chromatin accessibility characterizing the signature were identified in residual NACT tumors but are also present in treatment-naive samples from patients who later developed resistance. Furthermore, this epigenetic signature independently predicted chemotherapy response in patient-derived xenograft models of HGSOC and in a separate patient cohort. Cells enriched in the persister state arose from multiple lineages and displayed activation of oncogenic pathways, including altered stress responses, epithelial to mesenchymal transition, and changes to the cell cycle promoting quiescence. Finally, we identified a subset of genes that are epigenetically primed for expression before treatment and are upregulated after treatment. These findings suggest that an intrinsic epigenetic program primes tumor cells towards chemotherapy tolerance and reveal new vulnerabilities that could be exploited to delay or prevent cancer recurrence. Citation Format: Mihai G. Dumbrava, Wazim M. Ismail, Leticia Sandoval, Amelia Mazzone, Syed Mohammed Musheer Aalam, Megan L. Ritting, Xiaonan Hou, Yiwen Xie, Shariska Harrington, Scott H. Kaufmann, Nagarajan Kannan, S. John Weroha, Alexandre Gaspar-Maia. Single cell multiomic analysis of high-grade serous ovarian carcinoma reveals an intrinsic epigenetic program that primes chemotherapy tolerance in persister cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr PR008.

Abstract High-grade serous ovarian cancer (HGSOC), the most prevalent and lethal ovarian cancer subtype, is often diagnosed at an advanced stage due to the lack of effective early detection methods. Current evidence suggests that HGSOC originates from the fallopian tube (FT), specifically from secretory epithelial cells in the fimbriated region, based on the detection of early serous lesions and clonal genetic relationships linking them to HGSOC tumors. However, efforts to improve early diagnosis and interception are hindered by an incomplete understanding of HGSOC’s cellular and molecular origin. To address this, we established a diverse, clinically and genetically annotated living FT organoid biobank at the Mayo Clinic, encompassing specimens from over 200 patient donors. Using robust, multi-step protocols, we enriched FT epithelial stem/progenitor cells from tissue samples and Tao brushings, generating bi-lineage differentiated organoids independent of anatomical site (ampulla, fimbria) or laterality (right, left). To gain deeper insight into FT epithelial lineage dynamics, we applied multi-omic modalities—including single-cell RNA sequencing (scRNA-seq), single-nucleus RNA and ATAC sequencing (snMultiome), and bulk RNA-seq—to fresh cells and pooled organoids, integrating findings with public FT datasets to generate the largest known integrated single-cell atlas of normal and high-risk FTs. This enabled the generation and validation of gene expression-derived signatures for secretory and multiciliated lineages, identification of key lineage-defining transcription factors and their regulatory networks, and validation using immunohistochemistry (IHC) data from the Human Protein Atlas. Subcluster-level analysis of epithelial cells revealed transcriptionally distinct populations with unique biological functions, deepening insight into epithelial heterogeneity and FT lineage differentiation. Further, analysis of FT epithelial subclusters identified a rare population with transcriptomic and proteomic association with the mesenchymal-like HGSOC subtype. These cells retained epithelial identity while expressing mesenchymal and ECM-related genes, forming a hybrid phenotype. Spatial profiling via IHC localized them to a rare, basal, peg-like position within the FT epithelium. Developmental analysis showed shared transcriptional features with fetal mesonephric cells, suggesting both developmental plasticity and potential vulnerability to transformation. Pooled organoid scRNA-seq confirmed that they are preserved in culture, indicating they are stably maintained ex-vivo. Together, these findings suggest that this cell cluster represents a rare, multipotent epithelial population with mesenchymal features, offering a candidate cellular origin for the mesenchyme-like subtype of HGSOC. In conclusion, this living FT organoid biobank serves as a powerful, clinically annotated platform for dissecting epithelial lineage hierarchies, identifying rare cell populations, and uncovering mechanisms that may underlie subtype-specific ovarian carcinogenesis. Citation Format: Megan Ritting, Syed Mohammed Musheer Aalam, Mihai Dumbrava, Wazim Mohammed Ismail, Alexandre Gaspar-Maia, Mark Sherman, Jamie Bakkum-Gamez, Nagarajan Kannan. Tubal organoid biobanking and multi-omics framework uncovers rare basal peg cells as a source of epithelial stemness and a candidate for high-grade serous ovarian cancer origin [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A078.

Abstract Columellar strut graft (CSG) and septal extension graft (SEG) are commonly used in septorhinoplasty for nasal tip support. We aimed to systematically review and compare CSG and SEG in achieving a desired nasolabial angle (NLA) and Goode's ratio (GR). Several databases were systematically searched from inception to August 2024. A two-arm meta-analysis of the pooled means was conducted with a random-effects model. This review was registered in PROSPERO (CRD42024574909). Eligible studies included primary septorhinoplasty patients (≥17 years) receiving CSG or SEG. Eight studies met eligibility criteria including 256 CSG and 371 SEG patients. Intergroup comparison of long-term postoperative NLA favored SEG (p < 0.05) while GR showed no differences. However, SEG patients had significant improvement in GR postoperatively (p < 0.05), unlike CSG patients. SEG may provide superior long-term nasal tip rotation and projection stability.

Abstract Background: Placebo response is crucial in interpreting treatment efficacy in ulcerative colitis (UC) trials. While it has been broadly studied, it remains underexplored in trials involving the growing number of biologics and small molecules for ulcerative colitis. Methods: We systematically searched PubMed, Embase, Scopus, Web of Science, and Cochrane CENTRAL from inception to November 13, 2024. Eligible studies were induction-phase RCTs, including adult patients with moderate-to-severe UC who received a biologic and a small-molecule against a placebo. Primary outcomes were pooled clinical and endoscopic response and remission rates. Safety outcomes included adverse events (AEs), serious adverse events (SAEs), and withdrawal rates. Random-effect models were used for meta-analysis. Meta-regression identified predictors of placebo outcomes. Results: 26 induction RCTs with 3,937 placebo-treated patients were included. IL inhibitor trials had the highest placebo clinical response (36%) and endoscopic remission (21%), while JAK inhibitors had the lowest (21% and 2%). Overall placebo rates were 34% for clinical response, 8% for clinical remission, 19% for endoscopic response, and 11% for endoscopic remission. Adverse events occurred in 54%, SAEs in 8%, and withdrawals in 18%. Younger age and longer follow-up were linked to higher placebo responses; recent trials showed reduced endoscopic effects. Conclusion: These findings highlight the need to account for placebo variability in trial design and interpretation, particularly as biologic and small-molecule therapies continue to expand in UC treatment.

Abstract Background Primary aldosteronism (PA) is a common treatable cause of hypertension. When caused by unilateral adrenal disease, it is potentially curable by adrenalectomy. However, specialized tests and other factors may delay definitive treatment. We assessed the time to adrenalectomy (TTA) for patients worldwide. Methods We conducted an international, multicentre retrospective study involving 39 centres from 15 countries to determine the total time taken from the first presentation to adrenalectomy and the intervals between each stage (screening, confirmatory, subtyping, and adrenalectomy). We included patients with PA who underwent adrenalectomy from January 1, 2018, to October 30, 2022. Post-adrenalectomy outcomes were evaluated using the Primary Aldosteronism Surgery Outcome criteria. We performed multivariable quantile and linear regression to identify characteristics associated with longer TTA. Results We included 861 patients, mean age 49.3 ± 11.1 years, and 44.5% were women. Overall median TTA was 13.5 months, IQR: 6.6-24.5. Median intervals were 0.1 months (screening), 1.0 months (confirmatory), 4.1 months (subtyping), and 4.3 months (adrenalectomy). On multivariable analysis, median TTA was increased by 5.4 months for each additional adrenal vein sampling (AVS) procedure. Other factors associated with longer TTA included adrenalectomy post-COVID-19, younger age, and additional screening tests. Compared with countries with routine AVS, those without AVS had a shorter TTA (6.1 vs 15.1 months, P &lt; .001), but greater likelihood of absent/partial biochemical success post-adrenalectomy (27.4% vs 12.4%, P &lt; .001). Conclusion Primary aldosteronism management is time-consuming worldwide, especially for subtyping tests and adrenalectomy. While omitting AVS reduces overall time, patients are less likely to achieve biochemical cure post-adrenalectomy.

e13162 Background: BRCA1/2 mutations impair homologous recombination repair, forcing cancer cells to rely on alternative DNA repair pathways, such as those mediated by poly(ADP-ribose) polymerase (PARP). PARP inhibitors (PARPis), like iniparib, olaparib, talazoparib, niraparib, and veliparib, exploit this dependency, inducing lethality in cells of BRCA-mutated, HER2-negative breast cancers (BRCAm, HER2-BC). Only 2 PARPis, talazoparib and olaparib, are FDA-approved for BRCAm, HER2-BC. However, the treatment with the highest efficacy remains unclear. We conducted a network meta-analysis (NMA) of randomised controlled trials (RCTs) to compare the efficacy of PARPis in treating BRCAm, HER2-BC. Methods: We systematically searched PubMed, Cochrane CENTRAL, SCOPUS, and ClinicalTrials.gov (up to December 2024) for randomized controlled trials (RCTs) following PRISMA-NMA guidelines. Primary outcome was overall survival(OS), with hazard ratios (HRs) and 95% confidence intervals (CIs). Secondary outcome was progression-free survival (PFS). Survival times were converted to HRs under the assumption of exponential distribution. Standard of care (SOC) was defined as taxane/anthracycline-based regimens with additional platinum-based chemotherapy. Physician's choice chemotherapy (PCT) included capecitabine, eribulin, gemcitabine, or vinorelbine. A frequentist approach with random-effects modeling was used to pool estimates, and P-scores ranked treatment efficacy. Heterogeneity and inconsistency were assessed using τ², I², and Q-statistics. Analyses were conducted in R version 4.4.1. Results: 8 studies including 4432 participants incorporating 8 pairwise comparisons and 7 treatments were analyzed for OS. Compared to SOC (reference), HRs of OS were significantly reduced with talazoparib+SOC (HR = 0.49, 95% CI: 0.32–0.74; P = 0.64), olaparib+SOC (HR = 0.46, 95% CI: 0.36–0.59; P = 0.69), niraparib+SOC (HR = 0.44, 95% CI: 0.26–0.76; P = 0.76), and veliparib+SOC (HR = 0.38, 95% CI: 0.29–0.48; P = 0.91). No heterogeneity or inconsistency was detected (τ² = 0; I² = 0; Q = 1.27, p = 0.53). For PFS, iniparib/gemcitabine, talazoparib, olaparib, and niraparib showed significant reduction in HR with increasing order of P-scores, in combination with SOC. Conclusions: Veliparib combined with SOC showed the highest OS improvement, while niraparib ranked highest for PFS, followed by talazoparib and olaparib. Further trials are needed to confirm these findings and refine treatment strategies for BRCAm, HER2-BC.

e15520 Background: Fruquintinib is a highly selective tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, which play a critical role in angiogenesis and tumor growth. As a novel anti-angiogenic agent, Fruquintinib has demonstrated promising efficacy in the treatment of various advanced malignancies, including metastatic colorectal cancer. However, concerns about its cardiovascular safety have emerged, given that VEGFR inhibition is often associated with cardiovascular adverse events. Methods: We conducted a systematic search through PubMed, Scopus, Embase, and Web of Science to identify randomized controlled trials and cohort studies that assessed the safety of Fruquintinib compared with placebo in patients with metastatic colorectal and other cancers. The evaluated outcomes included hypertension, coronary artery disease, cerebrovascular accidents, peripheral artery disease, heart failure, thromboembolism, arrhythmias, aortic dissection, and superior vena cava syndrome. Two independent reviewers screened the titles/abstracts based on predefined inclusion and exclusion criteria, followed by a full-text review of potentially relevant studies. Any disagreements between the reviewers were resolved through consultation with a third reviewer to ensure the accuracy and consistency of the study selection. Results: Fifteen reports were included in our study. Out of 3832 patients taking Fruquintinib monotherapy, a total of 997 developed hypertension with a pooled estimate incidence of 0.329 (95% CI: 0.248, 0.410; P < 0.001). In comparison to placebo, Fruquintinib was associated with significantly higher odds of developing hypertension (OR: 6.856; 95% CI: 5.071, 9.268; P < 0.001). Compared to Regorafenib, Fruquintinib demonstrated an OR of 1.549 (95% CI: 0.804, 2.983; P = 0.191) for the development of hypertension. Additionally, patients taking Fruquintinib had a pooled estimate incidence of 0.041 (95% CI: 0.021, 0.060, P < 0.001) for thromboembolism development with an OR of 2.092 (95% CI: 0.813, 5.385; P = 0.126) compared to placebo. Other reported cardiovascular side effects included sinus tachycardia, superior vena cava syndrome, peripheral edema, heart failure, myocardial enzymes elevation, and vascular access complications. Conclusions: Our study found that Fruquintinib is associated with significant cardiovascular risks, with hypertension being the most common adverse event, while thromboembolism did not reach statistical significance. Therefore, close monitoring for treatment-related cardiovascular events should be considered in these patients.

Importance Nontraumatic subarachnoid hemorrhage (SAH) represents the third most common stroke type with unique etiologies, risk factors, diagnostics, and treatments. Nevertheless, epidemiological studies often cluster SAH with other stroke types leaving its distinct burden estimates obscure. Objective To estimate the worldwide burden of SAH. Design, Setting, and Participants Based on the repeated cross-sectional Global Burden of Disease (GBD) 2021 study, the global burden of SAH in 1990 to 2021 was estimated. Moreover, the SAH burden was compared with other diseases, and its associations with 14 individual risk factors were investigated with available data in the GBD 2021 study. The GBD study included the burden estimates of nontraumatic SAH among all ages in 204 countries and territories between 1990 and 2021. Exposures SAH and 14 modifiable risk factors. Main Outcomes and Measures Absolute numbers and age-standardized rates with 95% uncertainty intervals (UIs) of SAH incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) as well as risk factor–specific population attributable fractions (PAFs). Results In 2021, the global age-standardized SAH incidence was 8.3 (95% UI, 7.3-9.5), prevalence was 92.2 (95% UI, 84.1-100.6), mortality was 4.2 (95% UI, 3.7-4.8), and DALY rate was 125.2 (95% UI, 110.5-142.6) per 100 000 people. The highest burden estimates were found in Latin America, the Caribbean, Oceania, and high-income Asia Pacific. Although the absolute number of SAH cases increased, especially in regions with a low sociodemographic index, all age-standardized burden rates decreased between 1990 and 2021: the incidence by 28.8% (95% UI, 25.7%-31.6%), prevalence by 16.1% (95% UI, 14.8%-17.7%), mortality by 56.1% (95% UI, 40.7%-64.3%), and DALY rate by 54.6% (95% UI, 42.8%-61.9%). Of 300 diseases, SAH ranked as the 36th most common cause of death and 59th most common cause of DALY in the world. Of all worldwide SAH-related DALYs, 71.6% (95% UI, 63.8%-78.6%) were associated with the 14 modeled risk factors of which high systolic blood pressure (population attributable fraction [PAF] = 51.6%; 95% UI, 38.0%-62.6%) and smoking (PAF = 14.4%; 95% UI, 12.4%-16.5%) had the highest attribution. Conclusions and Relevance Although the global age-standardized burden rates of SAH more than halved over the last 3 decades, SAH remained one of the most common cardiovascular and neurological causes of death and disabilities in the world, with increasing absolute case numbers. These findings suggest evidence for the potential health benefits of proactive public health planning and resource allocation toward the prevention of SAH.

AbstractEnterocutaneous fistulas (ECFs) profoundly impact patients’ quality of life, contributing to high morbidity rates and increased mortality due to ineffective treatment options. To address this challenge, ECFGel, a multifunctional, tissue adhesive injectable hydrogel, designed to occlude, sterilize, and promote healing of ECF tracts, is developed. ECFGel is formulated using gelatin and oxidized dextran (O‐Dex) as base components, which form chemical crosslinks within the hydrogel and with surrounding biological tissues, ensuring tissue adhesiveness. A choline and geranate‐based ionic liquid (IL) is incorporated to provide dual functionality, potent antimicrobial activity, and mechanical enhancement. By optimizing IL concentration, ECFGel achieves rapid gelation, enhanced mechanical strength, and improved elastic recoverability. Additionally, iohexol (IOH) is added for radiopacity, enabling real‐time imaging and further strengthening the hydrogel's mechanical properties. ECFGel demonstrates antiswelling properties, biodegradability, and effective tract occlusion in porcine soft tissues. It shows strong antimicrobial activity against highly resistant, patient‐derived pathogens isolated from clinical ECF cases. In a porcine perianal fistula model, ECFGel enables rapid occlusion and complete healing, promoting tissue maturation, reducing bacterial load, and increasing markers of cell proliferation and vascularization compared to untreated controls. These promising results highlight ECFGel's potential as a new therapeutic option for treating infected ECFs.

Abstract Cancer can recur when a subset of tumor cells, denoted here as persister cells, are able to survive therapy and re-enter the cell cycle. The precise mechanisms that confer the persister state and whether it is characteristic of a subgroup of cells or arises from multiple cellular lineages remain poorly understood. We hypothesize that an epigenetic signature underlies the drug-tolerant persister state, characterized by transcriptional and chromatin accessibility changes that promote survival of residual cancer following chemotherapy. To identify clinically relevant features of persister cells in untreated tumors and residual disease, we performed single-cell multiomic profiling (snRNA+snATAC) on a cohort of non-malignant fallopian tube, treatment-naïve, and neoadjuvant chemotherapy (NACT)-treated high-grade serous ovarian cancer (HGSOC) samples. We identified differences in gene expression and open chromatin between naïve and residual patient tumors following chemotherapy. Although only a small proportion of the differentially expressed genes enriched in residual HGSOC overlapped with established gene sets for chemo-response and patient prognosis, the epigenomic analysis revealed activity of several DNA-binding factors that are both enriched upon chemotherapy and also high in resistant tumors prior to treatment. From this analysis, we identified an epigenetic signature that precedes expression and defines the persister state. This epigenetic signature also correlated with chemotherapy sensitivity and resistance using patient-derived xenograft models of HGSOC. Gene regulatory networks driven by the persister signature are involved in the activation of oncogenic pathways, including changes to the cell cycle promoting quiescence and stress response. Further study of the persister cells identified by this epigenetic signature may increase understanding of the mechanisms underlying persister cell survival and reveal new vulnerabilities that could be exploited to delay or prevent cancer recurrence.