Citations

Hodgkin lymphoma is one of the most common cancers in adolescents and young adults (AYAs), a population with distinct biological, clinical, and developmental characteristics. Yet care remains fragmented between pediatric and adult systems contributing to variability in treatment exposure and survivorship outcomes. We synthesized current evidence on AYA HL epidemiology, biology, treatment strategies, supportive care needs, long-term toxicity risk, and survivorship. AYAs have access to multiple efficacious treatment options with high cure rates, but long-term survivors face significant medical, psychosocial, and financial effects with notable risks for cardiopulmonary disease, secondary malignancies, fertility impairment, and unmet psychosocial needs. Harmonized pediatric-adult treatment frameworks, AYA-focused support, and developmentally tailored survivorship care are essential to improving outcomes for AYA HL survivors.

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

PURPOSE External beam radiation therapy (EBRT) has gained delayed acceptance as a recommended first-line treatment modality for patients with hepatocellular carcinoma (HCC), given limited evidence that it improves overall survival (OS). We analyzed individual patient data (IPD) from an international cohort to assess OS among patients with HCC treated with EBRT. METHODS We performed a systematic review of publications that assessed EBRT, met prespecified technical standards for HCC, and reported OS (search date December 15, 2022). Corresponding authors were invited to submit IPD for the study. We performed Kaplan-Meier survival analyses to determine OS and restricted mean survival time (RMST) stratified by Barcelona Clinic Liver Cancer (BCLC) stage and treatment status (ie, treatment-naïve and experienced). We performed random effects Cox proportional hazards modeling to assess clinical characteristics associated with OS. RESULTS Data were provided on 4,913 patients treated with EBRT with a median follow-up time of 5.0 years. The median OS was 6.8 years (95% CI, 5.7 to 8.7) for BCLC-0 and 4.6 years (95% CI, 4.1 to 5.1) for BCLC-A. Among treatment-naïve patients, the median OS was not reached (95% CI, 8.6 to not reached) for BCLC-0 and was 5.4 years (95% CI, 4.5 to 6.7) for BCLC-A. In multivariable models, more advanced BCLC stage, higher tumor burden, worse performance status, and Child-Pugh class B or C were associated with a higher risk of mortality. Ablative radiation dose and more recent year of treatment were associated with a reduced risk of death. CONCLUSION To our knowledge, this study represents the largest multinational cohort of patients with HCC treated with EBRT. OS outcomes with EBRT for very early- and early-stage HCC appear to be comparable with resection, thermal ablation, and other ablative locoregional therapies. These data support the inclusion of EBRT in the BCLC HCC clinical decision-making process.

Abstract Background Breast cancer (BC) diagnosed during pregnancy or postpartum often presents with aggressive features, potentially influenced by hormonal, immunological, and tissue remodeling changes. Studies have suggested that postpartum BC may be associated with worse outcomes, though most evidence is retrospective and constrained by methodological limitations. This study evaluated associations between pregnancy history, recency of childbirth, and long-term outcomes in a prospective cohort of young patients with early-stage BC. Patients and Methods Patients aged ≤40 years with stage I–III BC enrolled in the Young Women’s Breast Cancer Study were categorized at diagnosis as nulligravid, nulliparous, pregnant, or parous (≤5 vs 5 to 10 years postpartum). Analyses were stratified by BC subtype (estrogen receptor-positive [ER+]/HER2−, HER2+, and triple-negative [TNBC]), with distant recurrence-free survival (DRFS) as the primary endpoint. Results Among 859 patients, 257 (29.9%) were nulligravid, 50 (5.8%) nulliparous, 37 (4.3%) pregnant, and 515 (60.0%) parous. Pregnant patients had proportionally more TNBC, nodal involvement, T3/T4, and grade 3 tumors. After 11.1 years median follow-up, pregnancy or postpartum status was not independently associated with DRFS in multivariable models adjusted for age, tumor characteristics, and treatment, with consistent findings across ER+/HER2−, HER2+, and TNBC subtypes. Sensitivity analyses, including further categorization of postpartum diagnoses (<2 vs 2 to 5 years), yielded consistent results. Conclusions Pregnancy history and recency of childbirth were not independently associated with long-term DRFS. Despite more aggressive features at diagnosis, patients diagnosed during or after pregnancy had comparable outcomes after adjustment, suggesting no adverse prognostic impact. Clinical trial registration NCT01468246 (https://clinicaltrials.gov/study/NCT01468246? term=NCT01468246&rank=1).

Abstract Background The Global Bipolar Cohort (GBC) was established to identify existing bipolar disorder (BD) cohorts worldwide and foster collaborations focused on descriptive and analytic outcomes relevant to BD. A distributed analytic framework has been implemented to engage multiple sites without the need for central data pooling. This report describes the GBC endeavor and global functional impairment patterns. Cross-cohort comparisons of functional correlates are limited by heterogeneous measures and data-sharing constraints. Large, culturally diverse comparisons are needed to distinguish broadly reproducible correlates from cohort-specific effects. Participating sites completed a 28-item descriptive survey covering diagnostic methods, cognition, genetics, treatment, functioning, and follow-up strategies. We implemented a harmonized local logistic regression model of dichotomized functional outcome and shared summary statistics only. Results We identified 69 cohorts across five continents. Thirty-seven cohorts contributed functional outcome analyses from 17,130 participants. Outcome measures included clinician-rated disability scales and social indicators such as employment and marital status. The proportion classified with poor functioning ranged from 16% to 77% (mean 50%). In 32 of 37 cohorts, the overall regression model significantly explained variance in functioning. Current depressive symptoms were the most robust and reproducible correlate of poor functional outcome: they were assessed in 29 cohorts, significant in 22 (75.8%), ranked among the top three correlates in 22, and were the top-ranked correlates in 19. Associations between depressive burden and poor functioning were observed across clinician-rated disability scales and work or social indicators, and across geographically diverse cohorts. Comorbid substance use disorder and medication-related variables were associated with poorer functioning in subsets of cohorts, whereas sex, ancestry, bipolar subtype, psychosis history, and premorbid IQ showed weak or inconsistent associations. Cognitive measures, available in a minority of regression models, showed modest and non-uniform effects. Conclusions Across heterogeneous international cohorts, current depressive symptom burden emerged as the most consistent correlate of poor functioning in bipolar disorder. These findings replicate earlier multisite work at a larger scale, show that protocol-based distributed analyses can identify reproducible clinical signals without sharing individual-level data, and support prioritizing detection and treatment of depressive symptoms when aiming to improve real-world functioning. Future work should expand longitudinal harmonization and representation of under-studied populations.

Abstract Human genomic studies link reduced CUB domain-containing protein 1 (CDCP1) expression with myocardial recovery in heart failure. While CDCP1 regulates cardiac fibroblast proliferation in vitro, it’s in vivo role in cardiac fibrosis remains unclear. Using a Cdcp1 -knockout (KO) angiotensin II/phenylephrine mouse model, we show that Cdcp1 deletion reduces echocardiographic left ventricular mass, histologic cardiac fibrosis, and pro-fibrotic gene expression, along with decreased fibroblast activation and inflammatory markers. Spatial transcriptomics identified a pressure overload–expanded fibroblast subpopulation enriched for growth factor and TGF-β signaling (FB5), which was markedly attenuated in Cdcp1 -KO hearts, alongside reduction of a pro-inflammatory cardiomyocyte subtype (CM4). Complementary studies in human ventricular fibroblasts demonstrate that CDCP1 knockdown reduced extracellular matrix gene expression and collagen I deposition. These findings establish CDCP1 as a regulator of cardiac fibrotic remodeling in vivo and open avenues for its further investigation as a potential therapeutic target.

Abstract Prostate adenocarcinomas (PRAD) can acquire resistance to androgen receptor signaling inhibitors through lineage transition to a cell state known as neuroendocrine prostate cancer (NEPC). Using a panel of isogenic PRAD and NEPC mouse tumoroids, we show that NEPC cells acquire new transcription factor (TF) dependencies that function in a previously undefined network. Through selective perturbation of each TF, we identify ASCL1 as a key regulator of NE lineage fate whereas MYCL functions downstream to drive NEPC growth/survival by recruitment of the TIP60/KAT5 acetyltransferase. Interestingly, while dependencies on specific TF family paralogs can vary across NEPC models, all show markedly enhanced dependency on TIP60. Moreover, the H2A.Z-acetyltransferase activity of the TIP60 complex (TIP60-C) is required for NEPC as well as the acetyl-reader BRD8, which is newly incorporated as a TIP60-C subunit with the NEPC transition. Targeted degradation studies in isogenic tumoroids reveal increased dependence on MYCL in NEPC relative to its paralog MYC in PRAD. In addition to a paralog switch (MYC to MYCL), the MYC pathway-addicted NE state is accompanied by a chaperone switch (from TIP60-C to SRCAP) for H2A.Z histone exchange and a coactivator switch (to TIP60) for MYC target gene expression. The NE-specific coupling of MYCL with TIP60 reveals a previously unappreciated opportunity to target MYC-driven NE diseases through pharmacological inhibition of TIP60.

Introduction: Young-onset esophageal adenocarcinoma (EAC) often presents at advanced stages and is associated with poor outcomes. We aimed to examine the epidemiology of young-onset Barrett’s esophagus (BE) using the TriNetX database. Methods: Young-onset BE patients (age 18 to younger than 50 y) with esophagogastroduodenoscopy (EGD) within 1 year before index BE diagnosis between 2014 and 2023 were included. Negative binomial regression was used to evaluate incident-time trends, and logistic regression to assess for independent predictors of young-onset BE. Results: BE diagnosis was present in 76,691 (3.3%) of 2,337,786 patients that underwent EGD, of which 14,120 (18%) had prevalent young-onset BE. BE dysplasia/EAC was present in 6% of young-onset patients at initial diagnosis. Conventional BE risk factors also predicted young-onset BE: GERD (OR=2.4), White race (OR=2.4), male sex (OR=2.2), smoking (OR=1.2), and obesity (OR=1.1). Each additional risk factor increased the probability of BE prevalence by 74% in young patients versus 54% in older patients. The prevalence of young-onset BE was 4.5% with GERD and ≥3 additional risk factors, and 2.3% when ≥3 risk factors were present. Discussion: Young-onset BE accounts for 18% of all BE cases, demonstrates a striking 6% rate of dysplasia/neoplasia at initial diagnosis, and has a prevalence of 4.5% in those with GERD and ≥3 risk factors. These findings suggest that young-onset BE is an important patient population that merits further study. Additional studies are necessary to study the cost-effectiveness of BE screening in younger patients with multiple risk factors.

Introduction Endovascular abdominal aortic aneurysm repair (EVAR) is the primary treatment for abdominal aortic aneurysm (AAA). Despite favorable early outcomes, lifelong surveillance is essential as endoleaks remain a major cause of reintervention. Among these, type II endoleaks (T2E) remain controversial regarding optimal management. This study aimed to identify factors associated with intervention for T2E using time-to-event analysis and predefined anatomic thresholds. Secondary objectives included comparing outcomes between T2E patients with (intT2E) and without (nointT2E) intervention. Methods A retrospective review of EVAR procedures from 2011-2024 was performed. Patients with newly diagnosed or persistent T2E were identified on completion and follow-up CT angiography. Patients were categorized as intT2E or nointT2E. Multivariable Cox regression evaluated time to first intervention, and logistic regression served as sensitivity analysis. Kaplan-Meier curves assessed freedom from intervention by inferior mesenteric artery (IMA) size. Results Among 207 EVAR patients, 78 (37.6%) developed T2E over a mean 3.4 ± 2.4 years. Nineteen (24.3%) required intervention. IntT2E patients were younger (74.9 ± 6.8 vs 78.3 ± 7.9 years, P = 0.02), had more frequent anticoagulation use (47.4% vs 20.3%, P = 0.02), larger IMAs (4.2 ± 0.6 vs 3.3 ± 0.7 mm, P < 0.01), and more lumbar arteries (6.0 ± 1.2 vs 5.0 ± 1.3, P = 0.02). IMAs >4 mm occurred in 68.4% of intT2E vs 8.5% of nointT2E ( P < 0.01). Mean sac growth was greater in intT2E (9.7 ± 5.3 mm vs −1.9 ± 6.5 mm, P < 0.01). Thirty-day complications following the index EVAR procedure, mid-term reinterventions, and overall mortality were similar between groups. Post-embolization, T2E resolved in 36.9%, with sac regression in 63.1%. Among embolized patients, 26.3% required a second embolization and one patient required 3 attempts without achieving resolution. IMA >4 mm independently predicted intervention (HR 7.18, 95% CI 1.97-26.16, P < 0.01). Logistic regression confirmed IMA >4 mm (OR 23.4, 95% CI 6.17-88.6, P < 0.01), >6 lumbar arteries (OR 4.2, 95% CI 1.10-15.98, P = 0.02), and anticoagulation (OR 3.4, 95% CI 1.17-10.6, P = 0.02) as predictors. Conclusions Approximately one-quarter of T2E patients required embolization. IMA >4 mm was the strongest predictor of intervention, while anticoagulation and increased lumbar artery number also increased risk. Management should prioritize risk-stratified surveillance and selective intervention.