Citations

Abstract Rationale Lymphangioleiomyomatosis (LAM) is a rare, progressive, cystic lung disease affecting women. Sirolimus has been shown to stabilize lung function in women with LAM, but real-world data on long-term safety and efficacy are limited. Methods The NIH Multicenter Safety and Durability of Sirolimus for LAM (MIDAS, NCT02432560) observational registry was launched in 2015. All adult (≥18 years) women with LAM (treated or untreated) were eligible to enroll at any of the 20 U.S. sites and followed longitudinally with serial assessments of lung function, health-related quality of life, and treatment related adverse event (TRAEs). Baseline cohort characteristics and TRAEs are summarized using descriptive analyses. Marginal structural models (MSMs) with inverse probability of treatment weighting estimated the causal effect of sirolimus on annualized forced expiratory volume in one-second (FEV1) decline, adjusting for age at LAM diagnosis, prior treatment with sirolimus, menopausal status, race, presence of angiomyolipomas, supplemental oxygen use; time-varying covariates included diffusing capacity for carbon monoxide (DLCO) and serum vascular endothelial growth factor-D (VEGF-D) levels. Results Longitudinal data was available in 350 LAM patients, most of whom (246, 70.3%) had sporadic LAM. The median age at the baseline pulmonary function test (PFT) measurement was 46 years (range: 19 - 74) and the median (IQR) number of serial PFTs obtained per patient was 3 (1 - 5). The average follow-up duration per patient was 2.8 years. Over half of the patients (196, 56%) were treated with sirolimus during the MIDAS observation period for a median (IQR) treatment duration of 4.9 (2.4 - 7.5) years. MSM analysis demonstrated that sirolimus treatment was durably effective and reduced FEV₁ decline by 74.36 mL/year (95% CI: 15.87 - 132.85) compared with no treatment (-85.31 mL/year for the untreated group vs. -10.95 mL/year for the treated group, p = 0.01). Sirolimus was generally well tolerated; treatment interruption ≥3 months was observed in 38 (19.4%) of the 196 sirolimus treated patients. Logistic regression analysis showed that higher levels of FEV1 (odds ratio: OR = 3.12 [1.45 - 7.11], p = 0.005), VEGF-D (OR = 1.0007 [1.0004 - 1.001], p < 0.001), and DLCO (OR = 1.023 [1.0053 - 1.0413, p = 0.01]), were associated with treatment interruption. Conclusions In the MIDAS cohort, sirolimus treatment resulted in durable stabilization of lung function with a favorable safety profile over a 5-year period. These real-world data support sirolimus as a chronic suppressive therapy for LAM, demonstrating durable efficacy in slowing lung disease progression and tolerability with long-term use. This abstract is funded by: National Institutes of Health

ABSTRACT Clinical worsening events are increasingly recognized as a meaningful outcome in pulmonary arterial hypertension (PAH). We applied machine‐learning models to real‐world data to identify clinical features that may predict clinical worsening events in PAH. Data were obtained retrospectively from the electronic health records of adults diagnosed with PAH at Mayo Clinic locations (January 2015–December 2019). Machine‐learning LASSO regularized logistic regression models were developed to analyze the association between 100 clinical features and occurrence of clinical worsening events. In total, 455 patients were included (mean age 62.1 years; 59.3% female). Of these, 232 (51.0%) experienced a clinical worsening event after a median (quartile 1, quartile 3) of 10.9 (4.1, 21.4) months. The best‐performing model had an area under the curve of 0.78, sensitivity of 78%, and specificity of 59%. The model identified 11 clinical features associated with clinical worsening events in PAH with a non‐zero coefficient: baseline age, body mass index (BMI), creatinine level, red cell (erythrocyte) distribution width (RDW), mean pulmonary arterial pressure, pulmonary vascular resistance, sodium concentration, and QT interval, along with dyspnea, number of clinic visits, and other forms of heart disease within a 1‐month window before a clinical worsening event. Baseline RDW and BMI, and number of clinic visits within the 1‐month window were statistically significantly associated with clinical worsening events. Our study used machine‐learning models to identify clinical features associated with risk of clinical worsening events in PAH. Automation of risk prediction could lead to earlier therapeutic intervention to optimize patient outcomes.

Background Grade group 5 (GG5) prostate cancer (PCa) carries a less favorable prognosis after standard-of-care (SOC) therapy, necessitating novel therapeutic approaches. High-dose rate brachytherapy (HDRBT) and androgen deprivation therapy (ADT) may modulate immune response in GG5 PCa, particularly in tumors with increased immune content. This study evaluated whether the addition of nivolumab to SOC was associated with improved disease control in patients with high-volume GG5 PCa, including those with oligometastatic disease. Methods In this non-randomized phase II trial, 31 patients with localized or oligometastatic GG5 PCa and >30% positive biopsy cores were evaluated between September 2018 and April 2021. Patients received four doses of nivolumab (240 mg every 2 weeks) beginning 4 weeks prior to HDRBT, alongside ADT, HDRBT, and external beam radiation. The primary endpoint was to evaluate whether the 2-year freedom from biochemical recurrence (FFBR) rate would exceed a prespecified historical control rate of 75%. Results Among the 31 patients, the median follow-up was 38.8 months (IQR 31.0–46.5 months). The addition of nivolumab to SOC RT with ADT was associated with a 2-year FFBR rate of 90.3% (95% CI 74.3% to 98.0%) (median FFBR not reached), exceeding the prespecified historical control rate of 75% (one-sided p value from binomial test=0.024). Definitive and probable nivolumab-related toxicity included 6.3% acute grade 2 and 6.3% acute grade 3 adverse events (AEs), with no grade 4+ AEs observed. A higher Decipher immunosuppression score at diagnosis correlated with early pathologic response (p=0.005) and was independently associated with time to metastatic failure (p=0.044). Conclusions Nivolumab combined with SOC was associated with encouraging FFBR in this high-risk GG5 PCa population and may represent a promising therapeutic intensification strategy. The Decipher immunosuppression score may serve as a predictive biomarker for response. These findings warrant further investigation in randomized trials.

Abstract Aims We hypothesized that targeting interleukin-6—a cytokine central to NOD-like receptor protein 3 (NLRP3) inflammasome activation that is associated with both the onset and progression of heart failure (HF)—may be beneficial in patients with HF and circulating evidence of cardiovascular inflammation but without overtly reduced ejection fraction (EF). We describe the rationale and design of two clinical trials (ATHENA and HERMES) investigating ziltivekimab, a human monoclonal antibody directed against the interleukin-6 ligand, in patients with HF and mildly reduced or preserved EF (HFmrEF/HFpEF) and cardiovascular inflammation. Methods ATHENA (n = 673) and HERMES (n = 4900) are international, multi-centre, double-blind, placebo-controlled trials randomizing adults with HFpEF/HFmrEF and cardiovascular inflammation (high-sensitivity C-reactive protein ≥2 mg/l) to ziltivekimab 15 mg or placebo, administered subcutaneously once monthly on top of standard of care. Eligible participants have a left ventricular EF >40%, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP), and serum high-sensitivity C-reactive protein ≥2 mg/l. The primary endpoint in ATHENA is the change in Kansas City Cardiomyopathy Questionnaire—Clinical Summary Score at 12 months. The primary endpoint in HERMES is time to first composite of cardiovascular death, hospitalization for HF, or urgent HF visit. ATHENA has a fixed duration of 12 months, whereas the HERMES trial is event driven (∼845 adjudicated primary events) with a minimum exposure of 6 months from randomization to the last treatment visit. Conclusion ATHENA and HERMES will investigate the effect of ziltivekimab in HFpEF/HFmrEF and cardiovascular inflammation. ATHENA will determine the effect of ziltivekimab on health status. HERMES will determine the efficacy and safety of ziltivekimab on morbidity and mortality.

Abstract The purpose of this study was to identify glioblastoma (GBM) proteins that contribute to the hijacking of the tumor microenvironment through extracellular vesicles (EVs). GBM is the most aggressive primary brain tumor in adults. It presents significant challenges due to its universal recurrence and limited survival rates, exacerbated when its located proximal to the lateral ventricles (LV). The cellular subpopulation of brain tumor-initiating cells (BTICs) plays a pivotal role in tumor initiation and invasiveness, interacting with the microenvironment, particularly the cellular components in the subventricular zone (SVZ) in the LV. We employed an integrated multi-omic strategy combining cell-specific proteomics of EV cargo and whole-cell transcriptomics of EV-treated neural progenitor cells (NPCs) to define mechanisms by which BTICs remodel the tumor microenvironment. Using the TurboID cell-specific protein labeling system, we identified a previously unrecognized repertoire of BTIC-derived proteins selectively packaged into EVs. Among these, DPYSL2 (CRMP2) emerged as a prominent EV cargo as it is implicated in cancer cell migration and invasion. Functionally, exposure of human NPCs to BTIC-derived EVs significantly increased NPC proliferation and migratory capacity in vitro, findings that were recapitulated in vivo following intracranial and intranasal delivery of GBM-derived EVs. To define the molecular basis of these phenotypic changes, we performed RNA sequencing of NPCs following EV treatment. Bioinformatic integration, including ontogenic and pathway enrichment analyses, revealed robust activation of oncogenic signaling pathways, notably JAK/STAT, mTOR, and WNT, accompanied by upregulation of downstream effector genes. Importantly, integrative proteomic-transcriptomic analyses identified DPYSL2 as a mechanistic link between EV cargo and NPC transcriptional reprogramming. Prior studies demonstrate that DPYSL2 can interact with JAK kinases, promoting STAT3 activation and transcription of genes such as Vimentin (VIM) and CALCA, consistent with the transcriptomic changes observed in EV-treated NPCs. Overall, we have identified DPYSL2 as a novel regulator of tumor microenvironment hijacking mediated by extracellular vesicles. This multi-omic approach is the first use of cell-specific proteomics to study extracellular vesicles and the first time pairing this method to identify upstream regulators of transcriptomic changes in neural progenitor cells. Collectively, these findings establish a direct molecular connection between BTIC-derived EV proteins and functional reprogramming of neural progenitor cells, providing mechanistic insight into how glioblastoma exploits developmental programs to promote tumor progression. Citation Format: Marissa Russo, Emily Norton, Weiwei Wang, Shreyartha Mukherjee, Daniel Wickland, TuKiet Lam, Hugo Guerrero-Cazares. DPYSL2 mediates extracellular vesicle-driven reprogramming of the glioblastoma tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB228.

Diagnosing rare genetic diseases remains a major challenge despite widespread clinical testing. Long-read RNA sequencing (RNA-seq) offers a powerful approach to capturing the effects of genetic variants on the transcriptome, yet challenges with sequencing coverage, cost, tissue selection, and scalability have limited its clinical adoption. To address this, we developed STRIPE (Sequencing Targeted RNAs Identifies Pathogenic Events), a targeted long-read RNA-seq–based strategy for rare disease diagnosis and variant interpretation. STRIPE enables deep sequencing of full-length transcripts for any customized disease-specific gene panel such that a wide range of clinically informative readouts, including transcript aberrations and sequence variants, can be detected at haplotype-level resolution. Applying STRIPE to 88 individuals spanning two major rare disease groups, we accurately reidentified known pathogenic variants and revealed their transcript consequences, including many unexpected ones. For 8 of 15 splice site region variants, we observed more complex RNA processing defects beyond single exon skipping or cryptic splice site activation. Notably, we find that donor splice site variants frequently activate cryptic intronic polyadenylation sites, leading to premature transcript termination. Leveraging unique strengths of long-read RNA-seq, STRIPE also resolved variants of uncertain significance and uncovered disease-causing variants in five previously undiagnosed individuals. Overall, STRIPE is a powerful, adaptable, and scalable strategy with broad potential to improve clinical variant interpretation and advance genetic diagnosis of rare diseases.

Abstract Background Approximately 12 000 adolescents and young adults (ages 15-39, AYAs) are diagnosed with a primary central nervous system (CNS) tumor each year. DNA methylation profiling has transformed CNS tumor classification by refining diagnostic accuracy and identifying biologically distinct subtypes, but its application has not been systematically evaluated in the AYA population. In this study, we examined the spectrum of CNS tumor types across age groups, with a focus on the AYA population. Methods We assembled a large dataset of CNS tumor samples with age annotations and methylation profiles matching with high confidence to a CNS tumor type using the NCI/Bethesda classifier. Prevalence of tumor type, methylation class and DNA copy number aberrations were compared across age strata (pediatric, AYA, and adult). Results The cohort of 21 712 CNS tumors included 5351 tumors from AYAs (25%), which showed a mixed pattern, with tumors typical of childhood (eg, medulloblastoma) as well as those common in older adults (eg, glioblastoma). Several tumor types were specifically enriched in the AYA, including IDH-mutant astrocytoma, pleomorphic xanthoastrocytoma, posterior fossa group B ependymoma, and diffuse hemispheric glioma, H3 G34-mutant, among others. Distinct methylation subclasses of multiple tumor types were observed in the AYA, and patterns of genomic aberrations showed age-specific distributions. Conclusion Large-scale methylation profiling revealed unique classification patterns of CNS tumors in AYAs, with specific tumor types, subclasses, and genomic alterations enriched in this population. These data may serve as a valuable reference resource for better understanding the spectrum of CNS tumors affecting AYA patients.

Abstract Background: Epidemiologic and other studies have identified environmental, occupational, and genetic risk factors for lymphoid and myeloid malignancies, but most studies have been conducted in Western populations. Investigations in populations with differing exposure patterns, distributions of disease subtypes, and genetic architecture are needed to fully understand hematopoietic tumor etiology. Methods: We conducted a large, multicenter, hospital-based case-control study of lymphoid and myeloid neoplasms in East Asia (AsiaLymph), including 5,671 lymphoid cases, 1,879 myeloid cases, and 3,858 controls. Participants completed a computer-assisted personal interview and provided biospecimens. Cases underwent central pathology review and were coded into the WHO Classification. Herein, we describe the study methods in detail and report association results for education, body mass index, and family history. Results: Greater BMI at age 20 but not at age 40 was associated with odds of total lymphoid neoplasm (per 5 kg/m2 increase: OR [95% CI]: 1.18 [1.09-1.27]), total myeloid neoplasm (OR [95% CI]: 1.17 [1.05-1.29]), and several subtypes. Greater educational attainment was associated with increased odds of total lymphoid neoplasm (for college vs. less than primary education: OR [95% CI]: 1.41 [1.21-1.65]) but not myeloid neoplasm (OR [95% CI]: 1.17 [0.95-1.45]; p-heterogeneity=0.02). There were also positive associations between family history of hematologic cancer in first degree relatives and odds of lymphoid neoplasm (OR [95% CI]: 1.53 [1.15-2.03]) and myeloid neoplasm (OR [95% CI]: 1.65 [1.11-2.44]) and specific subtypes. None of the evaluated risk factors were associated with NK/T-cell lymphoma, which supports a distinct etiology for this subtype. Conclusion: The AsiaLymph Study is one of the largest molecular epidemiology studies of both lymphoid and myeloid neoplasms with standardized World Health Organization classification of histopathologic subtypes and will serve as a valuable resource for etiologic investigations into risk factors for these malignancies. Citation Format: Qing Lan, Lauren M. Hurwitz, John K. Chan, Tai Hing Lam, Kexin Chen, Yok Lam Kwong, Xu Caigang, Brian CH Chiu, Raymond Liang, Ip Dennis, Wei Hu, Bryan Bassig, Mark Purdue, Jun Xu, Sarah Locke, Sophia S. Wang, James R. Cerhan, Sonja Berndt, Jonathan N. Hofmann, Jianxin Shi, Kai Yu, Shahinaz Gadalla, Lisa J. McReynolds, Rena Jones, Hongji Dai, Zhangyan Lyu, Lugui Qiu, Wei Liu, Huilai Zhang, Xianhuo Wang, Lindsay M. Morton, Stephen Chanock, Martha Linet, Melissa C. Friesen, Roel Vermeulen, Nathaniel Rothman. A multi-center hospital-based case-control study of lymphoid and myeloid neoplasms (AsiaLymph): Study design and initial findings for education, body mass index, and family history [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 5051.

Introduction: Upper limb spasticity can result from a variety of insults to the central nervous system. Disruption of the closely regulated spinal reflex arc, owing to loss of brain inhibition, results in an imbalance between antagonist and agonist muscle groups, leading to a loss of fluid coordination of motion across joints. Management strategies: A detailed, individualized assessment of each patient is mandatory in a multidisciplinary setting. Although there are objective parameters which guide treatment, variation and customization of strategies are needed for each patient, including defining a functional vs. a non-functional hand, and whether mobility or stability is the primary goal for surgery. Challenging areas in spasticity management: Surgical options include bony, tendon and nerve procedures. These aim to reduce tone, release contractures or reanimate paralysed muscles. This article examines four challenging areas in decision making for choosing these options: lengthening vs. hyperselective neurectomy for tone management, stability vs. mobility in wrist spasticity, grasp and release recovery through finger flexion and extension, and dystonia. Evidence-based treatments are discussed where available, along with key unresolved issues and future research directions. Conclusion: Restoring balance in the spastic upper limb, especially when voluntary control is lost, remains one of the most complex challenges in hand surgery. A thorough understanding of biomechanical principles and neurological pathways is necessary for the hand surgeon. Furthermore, working within a multidisciplinary team is essential to utilize a comprehensive array of assessment tools, ensuring accurate diagnosis and individualized patient care.