Importance:The association between medical financial hardship and nonadherence to healthy lifestyle and late-effects surveillance recommendations in long-term survivors of childhood cancer is unknown. Objective:To study the associations between medical financial hardship and nonadherence to healthy lifestyle and late-effects surveillance recommendations. Design, Setting, and Participants:This retrospective cohort study was performed among participants in the multiinstitutional Childhood Cancer Survivor Study. Participants were 5-year cancer survivors diagnosed at age 21 years or younger between January 1, 1970, and December 31, 1999, and who completed both a medical financial hardship survey between 2017 and 2019 and a follow-up survey assessing lifestyle behaviors and adherence to risk-based surveillance between 2020 and 2022. Data were analyzed between September 29, 2023, and September 2, 2025. Exposure:Self-reported medical financial hardship determined by an affirmative response to at least 1 item in the material, behavioral, or psychological domains. Main Outcomes and Measures:Associations of non-guideline-concordant physical activity, problematic drinking, smoking, and abnormal body mass index with domains of medical hardship were examined using separate multivariable logistic regression models. Associations between a composite lifestyle score (unhealthy, moderately healthy, and healthy) and nonadherence to surveillance for cardiomyopathy or breast, colorectal, cervical, and/or skin cancer were examined using polytomous logistic regression models. Results:Among 3322 survivors who completed both surveys (median [range] age, 41 [20-69] years; 1751 female [52.7%]), the presence of material, behavioral, and psychological hardship was reported by 1401 (42.2%), 1003 (30.2%), and 1243 (37.4%), respectively. Material hardship was associated with a greater odds of non-guideline-concordant physical activity (odds ratio [OR], 1.67 [95% CI, 1.29-2.18]) and abnormal body mass index (OR, 1.47 [95% CI, 1.15-1.88]). Behavioral and psychological hardships were associated with a higher odds of smoking (OR, 2.29 [95% CI, 1.13-4.62] and 3.95 [95% CI, 2.42-6.44], respectively). Material and psychological hardship were associated with a composite unhealthy lifestyle score (OR, 1.52 [95% CI, 1.11-2.07] and 1.96 [95% CI, 1.31-2.93], respectively), and a higher risk was noted among survivors reporting hardship in at least 2 domains. Psychological hardship was associated with greater nonadherence to skin cancer surveillance (OR, 1.78 [95% CI, 1.05-3.02]) among survivors at high risk due to treatment exposures. Material hardship was associated with greater nonadherence to breast cancer screening (OR, 2.85 [95% CI, 1.27-6.38]) among survivors at average risk. Associations between multiple medical hardship domains and nonadherence to cervical cancer screening were also observed (material and behavioral hardship: OR, 3.20 [95% CI, 1.44-7.14]; material and psychological hardship: OR, 2.18 [95% CI, 1.10-4.35]; behavioral and psychological hardship: OR, 3.25 [95% CI, 1.50-7.04]). Conclusions and Relevance:This cohort study of adult survivors of childhood cancer found that medical financial hardship was associated with nonadherence to healthy lifestyle behaviors and certain recommended surveillance tests for subsequent malignant neoplasms. These findings underscore the need to identify and address medical financial hardship as a potential risk factor of nonadherence to healthy lifestyle and guideline-concordant survivorship care.

Importance:Survivors of childhood cancer have an increased risk of cardiovascular disease (CVD). However, many survivors at high risk do not receive recommended CVD screening tests as young adults. Objective:To assess whether a survivorship care plan (SCP)-based counseling intervention improves CVD risk factor control in high-risk survivors. Design, Setting, and Participants:The Communicating Health Information and Improving Coordination With Primary Care (CHIIP) Study was a randomized clinical trial that enrolled eligible participants from the Childhood Cancer Survivor Study cohort in 9 US metropolitan areas between August 2017 and April 2020, with follow-up completed July 2022. Participants included adult survivors of childhood cancer exposed to cardiotoxic cancer therapies with undertreated CVD risk factors (hypertension, dyslipidemia, and glucose intolerance defined by standard guidelines); of 1840 survivors approached, 842 consented to participate, and 347 met all eligibility requirements and were randomized after a baseline home assessment. Data analysis was completed March 18, 2025. Intervention:The intervention consisted of a single remote session to review measurements and a SCP with personalized CVD risk information and to develop a CVD risk factor management plan, with a booster session 4 months later. Enhanced care controls received measurements with abnormal findings noted and written encouragement to follow up with their primary care clinician (PCC). PCCs received all materials sent to participants. Main Outcomes and Measures:Blood pressure, lipid profile, and glucose and hemoglobin A1c levels collected by a trained home examiner at baseline and 1-year follow-up, with undertreatment defined by standard guidelines. Results:A total of 347 cancer survivors (mean [SD] age, 40.5 [9.4] years; 182 [52.4%] male) were randomized, 175 to the intervention group and 172 to the enhanced care control group. Of these, 194 participants (53.0%) participants had undertreated hypertension at baseline; 180 (51.9%), undertreated dyslipidemia; and 170 (49.0%) undertreated glucose intolerance. After 1 year, 45 of 173 surviving intervention participants (26.0%) and 52 of 172 enhanced care control participants (30.2%) had less undertreatment, with lower percentages for each condition vs baseline. Although the intervention did not reduce undertreatment compared with the control condition (odds ratio, 1.31; 95% CI, 0.84-2.05), greater engagement was associated with less undertreatment at 1 year among intervention participants (odds ratio, 0.31; 95% CI, 0.18-0.72). The intervention group had improved PCC documentation of CVD risk vs controls after 1 year (14.8% improvement vs 0.9%; P = .002). Conclusions and Relevance:In this randomized clinical trial of long-term survivors of childhood cancer, the addition of survivorship-based self-management counseling did not reduce undertreatment beyond simply providing CVD risk assessments to survivors and PCCs. Additional strategies to mitigate CVD risk in high-risk survivors should be examined in the future. Trial Registration:ClinicalTrials.gov Identifier: NCT03104543.

10010 Background: Childhood cancer survivors face elevated risks for chronic health conditions and premature mortality. Engaging in healthy behaviors may mitigate these risks, yet neighborhood-level vulnerability may constrain survivors’ ability to adopt or sustain them. Methods: Among survivors (n=3,303) and community controls (n=652) in SJLIFE, neighborhood-level vulnerability was measured using census tract level overall and domain-specific (i.e. socioeconomic status, household composition, minority status, housing type and transportation) Social Vulnerability Index (SVI) scores, with higher values indicating higher vulnerability, and the U.S. Department of Agriculture’s persistent poverty measure. Health behaviors, including sedentary time/physical activity, smoking, alcohol, and illicit drug/marijuana use, were categorized as healthy, moderately unhealthy (1-2 unhealthy behaviors), and unhealthy (≥3 unhealthy behaviors). Multinomial logistic regression evaluated associations between neighborhood-level vulnerability at enrollment and health behavior patterns at most recent evaluation among survivors, adjusted for sociodemographic and cancer treatment factors as determined by backward selection. Interaction models compared associations between survivors and controls. Results: Survivors were 53.1% male, 82.5% non-Hispanic White, with a median age of 31.0 years (interquartile range: 23.5 – 38.5) at health behavior assessment. The most common childhood cancer diagnosis was acute lymphoblastic leukemia (28.8%). Survivors in the highest vs. lowest SVI tertile had higher odds of reporting moderately unhealthy (Odds Ratio [OR]: 1.46, 95% Confidence Interval [95% CI]: 1.08 – 1.98) or unhealthy (OR: 1.70, 95% CI: 1.13 – 2.56) behavior patterns, compared to a healthy behavior pattern. Socioeconomic and housing type SVI domains drove these associations, with survivors in the highest tertiles more likely than those in the lowest to have an unhealthy rather than healthy behavior pattern (Socioeconomic OR: 1.55, 95% CI: 1.02 – 2.35; Housing type OR: 1.53, 95% CI: 1.03 – 2.27). Persistent poverty was associated with greater odds of a moderately unhealthy behavior pattern (OR: 1.70, 95% CI: 1.09 – 2.66) in survivors. Housing type vulnerability was associated with disproportionately higher odds of an unhealthy behavior pattern among survivors compared to controls (ratio of ORs: 2.80, 95% CI: 1.19 – 6.60). Conclusions: Neighborhood-level vulnerability was associated with higher likelihood of unhealthy behavior patterns in childhood cancer survivors with housing type vulnerability having a greater impact on health behaviors in survivors compared to controls. Effective interventions to improve survivors’ health behaviors should incorporate neighborhood-level factors.

5544 Background: Persistent infection with high-risk human papillomavirus (HPV), particularly HPV16 and HPV18, drives the development of high-grade squamous intraepithelial lesions (HSIL), an obligate precancerous condition. The standard care of cervical HSIL requires either surgical excision (LEEP or cold-knife conization), or in some circumstance, watchful waiting. AFN0328 is a novel mRNA-based immunotherapy encoding HPV16/18-related antigens, designed to elicit antigen-specific immune responses and interrupt viral antigen-driven disease progression. Methods: Safety, tolerability and preliminary efficacy of AFN0328 were assessed in patients with HPV16- and/or HPV18-associated HSIL (CIN2/3) in an ongoing, multicenter, open-label Phase 1 trial. The study comprised two sequential parts: Part 1 employed a classic 3+3 dose-escalation design to assess safety and determine the maximum tolerated dose (MTD); Part 2 is a dose-expansion cohort at selected doses (150 μg and 300 μg) to further characterize safety, tolerability, and preliminary efficacy. AFN0328 was administered intramuscularly at 0, 4, and 12 weeks. The primary endpoints included safety and tolerability (dose-limiting toxicities within 28 days post-first dose, adverse events graded per CTCAE v5.0). For Part 2, the efficacy endpoints included viral clearance rate at Week 24 and Week 36, and histopathological regression at Week 36. Secondary endpoints included pharmacokinetic parameters, HPV16/18-specific IgG antibody titers, and pharmacodynamic markers (cellular immune responses and serum cytokines). Results: As of December 29, 2025, 23 patients had received at least one dose of AFN0328. No DLTs, serious adverse events, or grade ≥3 treatment-related adverse events (TRAE) were observed. PK analyses of first and last doses showed that circulating mRNA encoding HPV-related antigens peaked within 48 hours and declined gradually, with detectable levels persisting for up to at least 4 weeks across dose levels. All evaluable patients developed specific IgG responses and viral clearance was observed in evaluable patients during follow-up. Conclusions: AFN0328 demonstrated favorable safety and tolerability with robust immune responses in HPV16/18-associated HSIL, supporting further clinical development as an immunotherapy for HPV-driven precancerous disease. Clinical trial information: CTR20244013. Summary of safety and immunogenicity outcomes. Outcome Result Patients treated 23 Dose-limiting toxicities 0 Grade ≥3 treatment-related AEs 0 Most common TRAEs Injection-site reactions, fever Specific IgG response rate 100%* Observed viral clearance Yes* *Observed in evaluable patients during interim follow-up.

BACKGROUND:To investigate the outcomes of combined lenvatinib plus immune checkpoint inhibitors (ICIs) in patients with unresectable, recurrent, or metastatic hepatocellular carcinoma (HCC) in a real-world setting. MATERIAL AND METHODS:This retrospective study included patients with unresectable, recurrent, or metastatic HCC who received lenvatinib combined with ICIs at the Fifth Medical Center of the Chinese PLA General Hospital between May 2018 and November 2022. The study outcomes were overall survival (OS), progression-free survival (PFS), and treatment response. RESULTS:This study included 117 patients. The objective response rate (comprising both complete and partial responses) was 53.2%. Among those with first-line lenvatinib plus ICI (n = 109), the disease control rate (complete response, partial response, and stable disease) was 89.9%. In all patients, the median OS and PFS were 26.0 (95% CI, 22.0-30.4) and 15.3 (95% CI, 13.2-17.5) months, respectively. In first-line patients, the median OS and PFS were 27.6 (95% CI, 23.4-34.6) and 15.4 (95% CI, 13.4-18.2) months, respectively. Among the 117 patients, treatment was discontinued in 58 (50%) because of AE (n = 9, 16%), PD (n = 43, 74%), or an unknown reason (n = 6, 10%). Among the 117 patients, treatment was interrupted in 26 (22%), and the dose was adjusted in 24 (21%). CONCLUSION:This real-world study supports the possibility of using lenvatinib combined with ICI for the management of patients with unresectable, recurrent, or metastatic HCC, including first-line treatment. Confirmation through a formal clinical trial would provide firmer conclusions.

12114 Background: Survivors of childhood cancer are at high risk for chronic health conditions that may result in disability. However, the prevalence and financial burden of disability, defined using the World Health Organization International Classification of Functioning, Disability and Health (WHO ICF), have not been described in this population. Methods: Disability-related items ascertained using clinical and patient-report data from SJLIFE were classified using standardized WHO ICF childhood cancer components, including impairments in body function or structure (strength, neurocognition, vision, hearing, speech, balance, neuropathy, ataxia, hemiparesis, tone, bowel and bladder, flexibility, gait, posture, pain, fatigue), activity limitations (motor function, communication, personal care), and participation restrictions (physical activity, education, independent living, employment, quality of life). Aggregate disability severity scores (ADSS) were calculated by summing item-level indicators (0 = none/mild; 1 = moderate, severe, or life-threatening disability) across 55 items spanning 3 components (38 body impairments, 5 activity limitations, and 12 participation restrictions). Disability was classified using either age- and sex-specific z-scores derived from 815 community controls (0 = ≥ −1.5; 1 = < −1.5) or NCI Common Terminology Criteria for Adverse Events (CTCAE) grades (0 = < 2; 1 = ≥ 2). Logistic regression evaluated associations between disability and financial burden (cancer-related financial impact), adjusting for sex, race, age at evaluation, and cancer treatment exposures (chemotherapy, cranial radiation, amputation). Results: Among 3,549 survivors (mean age at evaluation 33.6 years; range 18.0–68.9; 52.1% male; 80.7% White non-Hispanic), the most common diagnoses were acute lymphoblastic leukemia (31.9%), central nervous system tumors (14.5%), and Hodgkin lymphoma (10.5%). The point (most recent visit) prevalence (95% CI) of ≥1 item rated as moderate or greater disability was 87.4% (86.3–88.5). Component-specific prevalence was 74.6% (73.2–76.0) for body impairments, 32.9% (31.3–34.4) for activity limitations, and 63.3% (61.7–64.9) for participation restrictions; all were higher than controls (p < 0.001). Higher overall ADSS was associated with greater financial hardship (OR = 2.97; 95% CI 2.05–4.30) with similar associations across all components, including body impairments (OR = 2.67; 95% CI 2.09–3.41), activity limitations (OR = 2.28; 95% CI 1.91–2.72), and participation restrictions (OR = 2.61; 95% CI 2.13–3.21). Conclusions: WHO-defined disability is highly prevalent among adult survivors of childhood cancer and is strongly associated with financial burden. These findings highlight the need for integrated survivorship care that addresses both medical and socioeconomic risk factors.

Childhood cancer survivors have a heightened risk of developing subsequent neoplasms (SN) related to therapy. We analyzed whole-genome, exome, and RNA sequencing of 200 breast, meningioma, and thyroid SNs, which developed a median of 26.4 years after childhood cancer, among 160 survivors. Meningioma and thyroid SNs were enriched for driver gene rearrangements compared with de novo tumors, including NF2-disrupting alterations and kinase fusions potentially induced by radiation. Radiation correlated with increased insertion-deletion signature ID5. Nitrogen mustard treatment correlated with elevated "flat" signature SBS5 in breast and meningioma SNs; in vitro, these agents caused an unresolved flat signature associated with multiple flat signatures from the Catalogue of Somatic Mutations in Cancer. In meningioma, platinum therapy correlated with NF2 splice-site variants. Analysis of 19 multisample survivors revealed intrapatient heterogeneity in meningioma, including clonally independent tumors. These results demonstrate the long-term impact of childhood cancer treatment on the genomes of SNs developing in adulthood, which may guide SN treatment and prevention. SIGNIFICANCE:This represents the most comprehensive genomic characterization of SNs from childhood cancer survivors to date, revealing the mutagenic impact of multiple therapies on the SN genome, including the potential impact of nitrogen mustards such as cyclophosphamide. These results may guide the optimization of future cancer treatment regimens to prevent SN development. See related commentary by Bertrums and van Boxtel, p. 1483.

BackgroundChronic hepatitis B (CHB) patients with milder baseline fibrosis have traditionally been considered more likely to achieve histological improvement after antiviral therapy. However, our previous finding suggests that patients with Ishak stage 6 may have greater potential for fibrosis regression than those with stage 5. This study aimed to evaluate whether CHB patients with Ishak stage 6 are more likely to achieve fibrosis regression than those with stage 5 after entecavir (ETV) monotherapy or ETV in combination with Biejia-Ruangan (ETV + BR) therapy.MethodsBaseline Ishak fibrosis stage served as the main analytic variable, while the use of concomitant traditional Chinese medicine was included as a stratification factor. Demographic characteristics, viral markers, and baseline laboratory parameters were incorporated as covariates. A logistic regression model was applied to evaluate the association between baseline Ishak stage and fibrosis regression. Based on this model, a sensitivity analysis was further performed in the subgroup of patients with baseline Ishak stage 5 or 6 to assess the robustness of the findings. A generalized additive model (GAM) was additionally applied to explore potential non-linear stage-related patterns.ResultsA total of 705 patients had paired biopsy data. The fibrosis regression rate was 50.21% in stage 6 versus 45.58% in stage 5. In the multivariable logistic regression analysis, baseline Ishak stage 6 was associated with a higher likelihood of fibrosis regression compared with stage 5 (OR:1.612, 95%CI:1.027 ~ 2.529, p = 0.038). GAM analysis revealed a stage-related, non-linear trajectory with a nadir at stage 5 and an upward trend at stage 6. Sensitivity analyses yielded consistent results (OR: 1.835, 95%CI: 1.148 ~ 2.931, p = 0.011).ConclusionAmong CHB patients treated with ETV, those with baseline Ishak stage 6 were more likely to achieve histological fibrosis regression than those with stage 5.Clinical trial registrationIdentifier NCT01965418.

10050 Background: Survivors of childhood cancer face a higher risk of late mortality than the general population. Yet no prior study has integrated patient-reported symptoms and social determinants of health with treatment exposures to predict late mortality risks. Methods: A total of 9,569 survivors from the CCSS cohort who completed two surveys (baseline [T1], follow-up [T2]) reported 37 symptoms spanning 10 domains (cardiac, pulmonary, sensory, musculoskeletal, nausea, pain, fatigue, memory, anxiety, depression) at T1 and T2. Additional predictors included sociodemographic and lifestyle factors, address-linked Area Deprivation Index, and treatment exposures. Standardized mortality ratios (SMRs) were calculated, stratified by individual symptoms and domains at T2 and T1-T2 change, to compare mortality rates between survivors and the general population five years after T2. Multivariable Cox proportional hazards models with LASSO regularization were used to predict 5-year health-related and cause-specific late mortality (cardiac, pulmonary, subsequent neoplasm) after T1 and T2. The dataset was randomly split into training and test datasets in a 7:3 ratio, and prediction performance was assessed using the area under the receiver operating characteristic curve (AUC). Results: Among 9,569 survivors (52.4% female), the median age at T1 and T2 was 27.1 and 36.9 years; median years from diagnosis to T1 and T2 were 16.6 and 26.3, respectively. Acute lymphoblastic leukemia (31.3%) and Hodgkin lymphoma (15.3%) were the most frequently observed primary diagnoses. Compared with the sex/age/race/calendar year-matched general population, survivors had significantly higher health-related mortality 5 years after T2, with SMR of 4.21 (95%CI 3.76-4.70). Presence of cardiac and pulmonary symptom domains at T2, and their persistence and worsening from T1 to T2, were associated with >10-fold higher SMRs. Presence, persistence, and worsening of individual symptoms, including angina pectoris, chronic cough, and trouble breathing, were also associated with SMRs >10. For 5-year health-related mortality after T2, the symptom-based model yielded an AUC of 0.79 (95%CI 0.75-0.84), surpassing the symptom-agnostic model (AUC 0.76, 95%CI 0.71-0.81) and the T1 model (AUC 0.73, 95%CI 0.67-0.79). Cause-specific models also showed strong prediction performance, with symptom-based AUCs of 0.87 for cardiac, 0.89 for pulmonary, and 0.78 for subsequent neoplasms mortality. Conclusions: Adult survivors of childhood cancer experience elevated SMRs, with the greatest excess late mortality observed in those reporting cardiopulmonary symptoms. Longitudinal symptom-based models yielded the highest predictive performance, outperforming single-time-point and symptom-agnostic models. Incorporating symptom data can strengthen mortality prediction and inform targeted survivorship care.

BACKGROUND Chronic hepatitis B (CHB)-related liver fibrosis is a major driver of severe hepatic complications, with substantial interindividual heterogeneity in histological outcomes after antiviral therapy. Histopathological images contain rich biological information, but deep learning (DL) models for predicting on-treatment histological outcomes in CHB-related liver fibrosis are scarce. AIM To develop and independently validate a DL-based multimodal model to predict fibrosis reversal following antiviral therapy using histopathological images and clinical features. METHODS This multicenter study included 238 patients from 14 institutions who received antiviral therapy and had both hematoxylin and eosin (HE) and Masson-stained liver biopsy slides available. The training, validation, and test cohorts comprised 114, 50, and 74 patients, respectively. Convolutional neural network models were independently developed using HE- and Masson-stained images, and subsequently combined with clinical features to construct a multimodal predictive model for evaluating fibrosis regression after antiviral treatment. RESULTS The HE model achieved areas under the receiver operating characteristic curves (AUCs) of 0.657 and 0.615 in the validation and test sets, respectively. The Masson model yielded AUCs of 0.727 and 0.676 for the corresponding sets. The clinical model exhibited AUCs of 0.658 in the validation set and 0.588 in the test set. The multimodal fusion model demonstrated enhanced discriminatory performance, reaching AUCs of 0.741 and 0.694 in the validation and test sets, respectively. Subgroup analysis showed robust predictive capacity in patients with progressive fibrosis (AUC = 0.779) and in those with hepatitis B e antigen-positive status (AUC = 0.755). Gradient-weighted class activation mapping revealed that the model focused primarily on key histological features associated with non-reversal, including hepatocyte degeneration, disorganized hepatic cords, and thick-bridging fibrous septa. CONCLUSION Digital pathology and clinical-based DL accurately predict fibrosis regression after antiviral therapy in CHB-related liver fibrosis, particularly in patients with progressive fibrosis and hepatitis B e antigen-positive status, supporting personalized treatment strategies.

Early-life respiratory syncytial virus infection (eRSV) causes severe respiratory illness in vulnerable populations and has a significant global health burden. eRSV-associated pathologies are exacerbated by low levels of cadmium (Cd) in the diet, leading to increased cytokine and chemokine levels, inhibited autophagy by mechanistic target of rapamycin complex 1 (mTORC1) signaling and enhanced fibrosis. In this study, we used single-cell RNA sequencing of lung samples from mice subjected to eRSV at 2 weeks of age, followed by low-dose Cd (3.3 mg CdCl2/L in drinking water from 5 weeks old to 21 weeks old; eRSV+Cd) to determine responsive cell populations and identify new mechanistic targets. Alveolar macrophages exhibited the strongest response to eRSV+Cd treatment, with evidence of activated mTORC1 signaling and changes to macrophage phenotypes. Extensive differential expression also occurred in other cell types involved in alveolar repair, and analysis of cell-cell signaling revealed a significant strengthening of galectin-9 signaling between endothelial and innate immune cells only with eRSV+Cd. These results support mTORC1 signaling in macrophages, macrophage polarization, and galectin-9 signaling as promising areas of study to mitigate lung damage in individuals affected by eRSV with subsequent dietary Cd exposures.

Importance:Posterior fossa syndrome is a debilitating surgical complication affecting communication, motor skills, mood, language, and working memory in children treated for posterior fossa tumors. Although many recover from acute symptoms, the lifetime impact of posterior fossa syndrome remains unknown. Objective:To evaluate the long-term neurological, neurocognitive, social, and quality of life outcomes associated with posterior fossa syndrome among survivors of medulloblastoma. Design, Setting, and Participants:This retrospective cohort study included survivors of childhood medulloblastoma diagnosed between 1985 and 2012, with more than 5 years from diagnosis. All participants were treated at a tertiary academic center. Data were analyzed from January 1, 2024, to December 1, 2025. Exposure:History of posterior fossa syndrome. Main Outcomes and Measures:Outcomes of interest included neurocognitive functioning (attention, cognitive flexibility, and visuomotor speed), neurological outcomes (cerebellar dysfunction, cranial nerve disorders, dysarthria, headaches, movement disorders, paralytic disorders, peripheral motor or sensory neuropathy, and seizures), physical performance, and social functioning. Statistical analysis included Mann-Whitney U, χ2, or Fisher exact tests, with multivariable linear regression used to assess the associations of posterior fossa syndrome with outcomes while adjusting for confounders. Results:A total of 158 participants (median [range] age at assessment, 25 [11-44] years; 96 [60.8%] male) were assessed, including 37 (23%) who developed posterior fossa syndrome and 121 controls who did not, with no differences in age at diagnosis, radiation dose, or age at assessment a median (range) follow-up of 14.2 (7.8-33.1) years. In adjusted models, participants with posterior fossa syndrome performed worse than those without in focused attention (β = -1.04 [95% CI, -1.62 to -0.45]; P < .001), motor-processing speed (β = -0.62 [95% CI, -1.16 to -0.09]; P = .02), cognitive flexibility (β = -0.85 [95% CI, -1.44 to -0.27]; P = .005), visuomotor processing speed (β = -0.65 [95% CI, -0.97 to -0.33]; P < .001), and physical performance test scores (β = -3.65 [95% CI, -5.36 to -1.93]; P < .001). Participants with posterior fossa syndrome were also more likely to require assistance with routine daily needs (odds ratio, 8.00 [95% CI, 2.56 to 25.04]; P < .001). Conclusions and Relevance:In this long-term cohort study of survivors of medulloblastoma, individuals with history of posterior fossa syndrome exhibited persistent neurocognitive and physical deficits compared with those without history of posterior fossa syndrome. Despite resolution of acute postoperative symptoms, posterior fossa syndrome was associated with lasting impairment, underscoring the need for improved surgical approaches, continued surveillance, and tailored interventions to optimize functional outcomes.

PURPOSE Predictors of optimal or improved health-related quality-of-life (HRQOL) in adult survivors of childhood cancer are understudied. METHODS This cohort study used data from 4,755 survivors in the Childhood Cancer Survivor Study who completed baseline (T0) and two follow-up surveys (T1, T2) between 1992 and 2016. HRQOL was assessed using SF-36 Physical and Mental Component Summaries (PCS; MCS), classified as optimal (≥40) or suboptimal (<40), with improvement being suboptimal at T1 to optimal at T2. RESULTS At T1, 88.4% and 82.5% had optimal physical and mental HRQOL; among those suboptimal, 51.3% and 63.9% improved by T2. Higher education, physical activity, income, mental health, and absence of chronic conditions predicted optimal or improved HRQOL using multivariable logistic regression with backward selection. Model performance was acceptable for optimal PCS (0.81), MCS (0.72), and improved models (0.69 each). CONCLUSION Findings may inform targeted interventions addressing education, lifestyle, mental health, and chronic conditions to enhance well-being in childhood cancer survivors.

e16162 Background: Advanced intrahepatic cholangiocarcinoma (ICC) carries a dismal prognosis, with limited second-line options after failure of gemcitabine-based chemotherapy. Adebrelimab (anti-PD-L1 antibody) plus lenvatinib has shown potential in hepatobiliary cancers. This study evaluated the efficacy and safety of this combination in advanced ICC patients with heavy tumor burden and impaired liver function. Methods: This single-arm, open-label, phase II study enrolled patients with histologically confirmed unresectable or metastatic ICC who progressed on or were intolerant to first-line chemotherapy. Patients received adebrelimab (20 mg/kg IV Q3W) and oral lenvatinib (8 mg/day for weight < 60 kg; 12 mg/day for ≥60 kg). The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety (CTCAE v5.0). Results: As of January 12, 2026, 28 patients were enrolled (median age, 60.0 years). The cohort represented an exceptionally high-risk population: 18 patients (64.3%) had extrahepatic metastases, 13 (46.4%) had vascular invasion, and 20 (71.4%) were Child-Pugh class B. Furthermore, 24 patients (85.7%) met the "up-to-seven" criteria. After a median follow-up of 8.5 months (95% CI, 4.5 to 12.2), the median OS reached 12.2 months (95% CI, 6.3 to not reached), with a 12-month OS rate of 59.5% (95% CI, 40.9% to 86.5%). The median PFS was 6.3 months (95% CI, 4.0 to 12.4). In the ITT population, the ORR was 7.1% (2 of 28) and the DCR was 53.6% (15 of 28); however, response assessment was confounded by early treatment discontinuation or pending evaluations in 12 patients (42.9%). Treatment-related adverse events (TRAEs) of any grade occurred in 27 patients (96.4%). Grade 3-4 TRAEs were reported in 6 patients (21.4%), most commonly hepatic encephalopathy (3 patients, 10.7%), limb/shoulder pain (2 patients, 7.1%), and hyperbilirubinemia (2 patients, 7.1%). No treatment-related deaths were observed. Conclusions: Adebrelimab combined with lenvatinib demonstrated an unprecedented median OS of 12.2 months in second-line advanced ICC. Importantly, this survival benefit was maintained even in a population predominantly comprised of Child-Pugh class B patients with significant tumor burden. This combination represents a potential breakthrough for this difficult-to-treat population and warrants further validation in a randomized controlled trial. Clinical trial information: ChiCTR2300078869.

BACKGROUND:Chronic hepatitis B (CHB) virus infection is the leading cause of hepatocellular carcinoma (HCC). Nucleos(t)ide analogs (NAs) effectively suppress HBV replication, but residual HCC risk remains in treated patients, highlighting the need for reliable risk stratification tools. Existing prediction models rely heavily on age and liver function parameters and often overlook hepatitis B surface antigen (HBsAg) quantification, a key marker closely tied to HBV-related HCC, resulting in inadequate clinical predictive accuracy. METHODS:To address this gap, we developed the novel HBsAg-HCC Score using a two-cohort design: retrospective training (1190 NA-treated CHB patients) with Cox regression to identify independent HCC risk factors, followed by validation in an independent prospective cohort (506 patients). Its performance was compared with three established tools (PAGE-B, mPAGE-B, aMAP). RESULTS:Five independent HCC risk factors were identified: higher HBsAg levels, older age, male sex, hypoproteinaemia, and elevated APRI. The HBsAg-HCC Score derived from these factors showed strong predictive power: 3-/5-/7-year AUCs of 0.867/0.872/0.871 in the training cohort (significantly outperforming PAGE-B, mPAGE-B, aMAP) and 0.784/0.780/0.777 in the validation cohort. Internal and external cross-validation confirmed its stability and reliability. CONCLUSIONS:By incorporating HBsAg quantification, a virus-specific marker often missing from conventional models, the HBsAg-HCC Score offers a more comprehensive and accurate approach to HCC risk stratification in NAs-experienced CHB patients, addressing a critical limitation of existing models directly.

QuestionAmong adult survivors of childhood cancer with undertreated hypertension, dyslipidemia, or glucose intolerance, can remotely delivered, clinician-led, self-management counseling sessions reduce undertreatment more than provision of screening results alone?FindingsIn a randomized clinical trial of 347 participants, there was no significant difference after 1 year between the study groups: 26% of intervention participants and 30% of enhanced usual care control participants had less undertreatment of cardiovascular disease risk factors.MeaningIn this study, self-management counseling did not reduce cardiovascular risk factor undertreatment beyond simply providing hypertension, lipid level, and diabetes screening results to high-risk cancer survivors and their primary care clinicians. This randomized clinical trial assesses whether a survivorship care plan with remotely delivered counseling increases control of risk factors for cardiovascular disease among adult survivors of childhood cancer. ImportanceSurvivors of childhood cancer have an increased risk of cardiovascular disease (CVD). However, many survivors at high risk do not receive recommended CVD screening tests as young adults.ObjectiveTo assess whether a survivorship care plan (SCP)-based counseling intervention improves CVD risk factor control in high-risk survivors.Design, Setting, and ParticipantsThe Communicating Health Information and Improving Coordination With Primary Care (CHIIP) Study was a randomized clinical trial that enrolled eligible participants from the Childhood Cancer Survivor Study cohort in 9 US metropolitan areas between August 2017 and April 2020, with follow-up completed July 2022. Participants included adult survivors of childhood cancer exposed to cardiotoxic cancer therapies with undertreated CVD risk factors (hypertension, dyslipidemia, and glucose intolerance defined by standard guidelines); of 1840 survivors approached, 842 consented to participate, and 347 met all eligibility requirements and were randomized after a baseline home assessment. Data analysis was completed March 18, 2025.InterventionThe intervention consisted of a single remote session to review measurements and a SCP with personalized CVD risk information and to develop a CVD risk factor management plan, with a booster session 4 months later. Enhanced care controls received measurements with abnormal findings noted and written encouragement to follow up with their primary care clinician (PCC). PCCs received all materials sent to participants.Main Outcomes and MeasuresBlood pressure, lipid profile, and glucose and hemoglobin A1c levels collected by a trained home examiner at baseline and 1-year follow-up, with undertreatment defined by standard guidelines.ResultsA total of 347 cancer survivors (mean [SD] age, 40.5 [9.4] years; 182 [52.4%] male) were randomized, 175 to the intervention group and 172 to the enhanced care control group. Of these, 194 participants (53.0%) participants had undertreated hypertension at baseline; 180 (51.9%), undertreated dyslipidemia; and 170 (49.0%) undertreated glucose intolerance. After 1 year, 45 of 173 surviving intervention participants (26.0%) and 52 of 172 enhanced care control participants (30.2%) had less undertreatment, with lower percentages for each condition vs baseline. Although the intervention did not reduce undertreatment compared with the control condition (odds ratio, 1.31; 95% CI, 0.84-2.05), greater engagement was associated with less undertreatment at 1 year among intervention participants (odds ratio, 0.31; 95% CI, 0.18-0.72). The intervention group had improved PCC documentation of CVD risk vs controls after 1 year (14.8% improvement vs 0.9%; P = .002).Conclusions and RelevanceIn this randomized clinical trial of long-term survivors of childhood cancer, the addition of survivorship-based self-management counseling did not reduce undertreatment beyond simply providing CVD risk assessments to survivors and PCCs. Additional strategies to mitigate CVD risk in high-risk survivors should be examined in the future.Trial RegistrationClinicalTrials.gov Identifier: NCT03104543

Objective Evaluate late effects in survivors of childhood pelvic sarcoma by disease origin (bony vs. soft-tissue) and local control modality (bone surgery, pelvic organ resection, radiotherapy). Methods Among 5-year pediatric pelvic sarcoma survivors, we assessed long-term outcomes including late (>5 years) mortality, graded chronic health conditions (CHCs), subsequent malignant neoplasms (SMNs), physical function/activity, cancer-related pain, and pregnancy/siring a pregnancy. Associations with disease origin and local control modality were analyzed using cumulative incidence and Cox or multivariable logistic regression. Results Among 745 eligible survivors, the 35-year cumulative incidence of late all-cause and health-related mortality was 25.7% (95%CI=22.1%-29.3%) and 12.2% (95%CI=9.4%-15.1%), vs. 2.5% (95%CI=1.3%-3.7%) and 1.4% (95%CI=0.5%-2.4%) in matched US population. Cumulative incidence of severe/life-threatening CHCs was 47.6% (95%CI=43.0%-52.1%) for survivors vs. 12.2% (95%CI=11.3%-13.2%) for siblings. Cumulative incidence of SMNs was 7.6% (95%CI=5.0%-10.2%). Bone sarcomas were associated with increased all-cause mortality (HR=1.92, 95%CI=1.16-3.17), health-related mortality (HR=2.12, 95%CI=1.03-4.38), and CHCs (HR=2.55, 95%CI=1.65-3.95) vs. soft-tissue sarcomas. Analyzing all survivors, radiotherapy was associated with increased CHCs (HR=2.42, 95%CI=1.53-3.81), multiple CHCs (HR=2.27, 95%CI=1.03-4.97), functional impairment (OR=2.21, 95%CI=1.30-3.74), and pain (OR=2.29, 95%CI=1.33-3.93). Bone surgery was associated with functional impairment (OR=2.64, 95%CI=1.30-5.37), performance limitations (OR=2.12, 95%CI=1.19-3.79), and pain (OR=2.59, 95%CI=1.37-4.89). Pelvic organ resection was associated with decreased pregnancy (OR=0.25, 95%CI=0.10-0.63). Conclusions Late effects differed by pelvic sarcoma origin (bone vs. soft-tissue) and local control modality. The associations between local control choices and late effects in this study can guide counseling of patients and families at the time of diagnosis, treatment, local control, or after completion of therapy.Clinical Trial Registration: ClinicalTrials.gov ID: NCT01120353

Supplementary Table S1 shows SN sample clinical variables and metadata. Supplementary Table S2 shows a comparison of variables between good-quality vs. excluded samples. Supplementary Table S3 shows a summary of prior treatments across SN patients. Supplementary Table S4 shows a summary of original childhood cancer diagnoses for SN patients. Supplementary Table S5 shows metadata for 33 pediatric cancers with matched FFPE and fresh-frozen exome data. Supplementary Table S6 shows a list of coding-region somatic SNVs used for mutation burden analysis. Supplementary Table S7 shows multivariable analysis comparing SNV burdens between cohorts. Supplementary Table S8 shows multivariable analysis comparing age between cohorts. Supplementary Table S9 shows multivariable analysis comparing SNV burdens between thyroid cancer cohorts among samples with coverage below 100x. Supplementary Table S10 shows cancer-predisposing germline alterations among SN patients. Supplementary Table S11 shows a list of coding-region somatic indels used for mutation burden analysis. Supplementary Table S12 shows multivariable analysis comparing indel burdens between cohorts. Supplementary Table S13 shows SNV signature levels among SNs. Supplementary Table S14 shows multivariable analysis comparing SBS5 burdens in breast SNs stratified by prior treatment. Supplementary Table S15 shows multivariable analysis comparing SBS5 burdens in meningioma SNs stratified by prior treatment. Supplementary Table S16 shows multivariable analysis testing SBS5-cyclophosphamide dose-response relationship in meningioma SNs. Supplementary Table S17 shows variation in cyclophosphamide-containing regimens among meningioma SNs. Supplementary Table S18 shows indel signature levels among SNs. Supplementary Table S19 shows multivariable analysis testing ID5-radiation dose-response relationship in each SN type. Supplementary Table S20 shows multivariable analysis testing ID5-radiation dose-response relationship with all 3 SN types combined. Supplementary Table S21 shows NF2-disrupting structural variants detected in meningioma SNs. Supplementary Table S22 shows multivariable analysis comparing driver alteration frequency between meningioma cohorts. Supplementary Table S23 shows driver fusions in thyroid SNs. Supplementary Table S24 shows multivariable analysis comparing mutation group frequency between thyroid cancer cohorts. Supplementary Table S25 shows multivariable analysis comparing driver alteration frequency between thyroid cancer cohorts. Supplementary Table S26 shows multivariable analysis comparing driver alteration frequency between breast cancer cohorts

PURPOSE It is not known whether temporal changes in childhood cancer therapy have reduced risk of subsequent malignant neoplasms (SMNs) of the central nervous system (CNS), a frequently fatal late effect of cancer therapy. METHODS Five-year survivors of primary childhood cancers diagnosed between 1970-1999 in the Childhood Cancer Survivor Study with a subsequent CNS SMN were identified. Cumulative incidence rates and standardized incidence ratios (SIR) were compared among survivors diagnosed between 1970-1979 (N = 6223), 1980-1989 (N = 9680), and 1990–1999 (N = 8999). Multivariable models assessed risk factors for CNS SMN. RESULTS 157 CNS SMNs (1970s, 52; 1980s, 63; 1990s, 42) were identified, excluding meningiomas, which were most often malignant gliomas. The proportion of survivors receiving any cranial radiotherapy (CRT) exposure was reduced over time (1970s 77.0%, 1980s 54.3%, 1990s 33.9%), while the proportion receiving >35Gy CRT showed a smaller reduction (11.4%, 10.8%, and 8.5%, respectively). Twenty-year cumulative incidence (95% CI) and SIR (95% CI) for CNS SMN by treatment decade were 0.32% (0.18-0.46%) and 6.6 (5.0–8.7); 0.55% (0.41-0.70%) and 8.3 (6.6-10.4); and 0.43% (0.31-0.55%) and 9.2 (7.0–12.0), respectively, with no statistically significant decreases between eras. Multivariable analyses showed increased risk for CRT dose levels >10Gy and for primary diagnoses of medulloblastoma/PNET (HR 18.7, 9.2-37.9) and astrocytoma (HR 10.1, 5.3-19.5). Three-year cumulative incidence of death after CNS SMN, by treatment decade, were 76%, 74%, and 73%, respectively. CONCLUSION CNS SMN incidence has not decreased despite fewer survivors exposed to CNS-directed radiotherapy. CNS SMNs remain a substantial source of mortality for affected patients.

10057 Background: Childhood cancer survivors experience a large burden of chronic health conditions (CHCs) with the progression of these conditions facilitating potential economic burden. This study examined the association between CHC progression and financial hardship in adult survivors of childhood cancer. Methods: The study included CCSS participants diagnosed with pediatric cancer (1970–1999) who survived > 5 years post-diagnosis and were ≥26 years old at the assessment of financial burden. Participants completed surveys (2017-2019) assessing three financial hardship domains: behavioral, material, and psychological. CHCs were self-reported at baseline and on up to 4 follow-ups. CHC severity was graded using CTCAE v4.03. To estimate the impact of multiple CHCs, a severity score was calculated based on published methods (PMID: 17595271) accounting for the frequency and grade of conditions. Notable CHC burden was defined as any CHC above low severity grade. Multivariable logistic regression evaluated associations of CHC burden with financial hardship adjusting for age at diagnosis, attained age, sex, insurance, personal income, education, marital status, smoking status, and body mass index. Additional analyses examined whether neighborhood deprivation using the Area Deprivation Index (ADI) (range 0-100) modified the relationship between CHC burden and financial hardship. Results: Among 3,638 evaluable participants, the prevalence of notable CHC burden was 66%, material hardship 16%, psychological hardship 26%, and behavioral hardship 21%. Survivors with very high CHC burden had 2.6-fold (95%CI 1.6-4.1) higher odds of material and 1.6-fold (95%CI 1.0-2.4) higher odds of psychological hardship vs. those with low CHC burden. Survivors who progressed to moderate, high, or very high CHC burden had 1.7-fold (95%CI 1.2-2.5) higher odds of material hardship and 1.6-fold (95%CI 1.1-2.2) higher odds of psychological hardship vs. those with persistent low CHC burden. For survivors living in more deprived neighborhoods (ADI≥50), having notable CHC burden was associated with 2.5-fold (95%CI 1.5-4.3) higher odds of material hardship vs. those without notable CHC burden. For survivors living in less deprived neighborhoods (ADI < 50), having notable CHC burden was associated with 1.5-fold (95%CI 1.1-2.2) higher odds of psychological hardship and 1.6-fold (95%CI 1.1-2.1) higher odds of behavioral hardship vs. those without notable CHC burden. Conclusions: Longitudinal CHC burden shows strong temporal associations with material and psychological financial hardship. Neighborhood deprivation is associated with financial hardship, beyond individual sociodemographic factors. Multi-level interventions will be crucial to address financial hardship in survivors who develop CHCs earlier than peers.