Citations

Abstract Objectives: In the RadComp randomized trial, we compared radiation dose to cardiac substructures in patients treated with proton versus photon radiation therapy (RT) ; evaluated changes in cardiac-specific health-related quality of life (HRQOL) outcomes from baseline to 6 months following RT; and determined associations between radiation dose volume histogram (DVH) parameters and changes in cardiac-specific HRQOL. Methods: The study cohort included patients with locally advanced breast cancer enrolled on RadComp who completed treatment per protocol, had available radiation DVH metrics for all cardiac substructures, and completed both the baseline and at least one follow-up cardiac-specific HRQOL over the 6 months post-RT. Cardiac-specific HRQOL measures included PROMIS fatigue, PRO-CTCAE shortness of breath (SOB) (severity and interference with daily activities), and PRO-CTCAE chest pain, chest tightness, and angina (frequency, severity, and interference). Detailed dose volume histograms (DVH) for cardiac substructures included the whole heart, left ventricle (LV), right ventricle (RV), left atrium (LA), right atrium (RA), and left anterior descending artery (LAD) were derived. The Wilcoxon rank-sum test was used to compare dose distributions between photon and proton RT. Associations between DVH metrics and HRQOL outcomes were evaluated using repeated-measures linear regression via generalized estimating equations with an independent working correlation structure. All models were adjusted for RT type, age, cardiovascular risk factors, surgery type, laterality, ethnicity, education, timepoint, and race. Additional stratified analyses was performed according to laterality (right versus left + bilateral). Results: Across 1160 RadComp participants, RT exposure to cardiac substructures differed significantly between proton and photon RT and by laterality. Median mean heart dose was lower with protons, 0.9 Gy (Q1, Q3 0.49, 1.46), compared to photons 2.83 Gy (Q1, Q3 1.49, 4.52) (p< 0.001), and lower for right-sided disease, 0.91 Gy (Q1, Q3 0.44, 1.55), compared to left and bilateral 1.99 Gy (Q1, Q3 1.11, 3.63) (p<0.001). Similarly, for the LAD, LA, LV, and RA, mean proton dose was significantly lower (p<0.001). However, for the whole heart, RA, and RV, maximum doses to small-volume parameters and dose to 0.03cc were higher with proton RT. PRO-CTCAE measures of HRQOL were generally favorable at all timepoints across all participants, and grade ≥3 toxicity was rare (≤5.5%) for all measures. The PROMIS Fatigue T-Score increased from baseline (median 49 [Q1, Q3 46, 57]) to end of RT (55 [Q1, Q3 49, 63]), and returned to baseline levels at 6 months (p<0.001). While there were no significant differences in PRO-CTCAE SOB severity (p=0.24) and interference (p=0.11) over time, PRO-CTCAE chest pain worsened compared to pre-RT with respect to frequency (p<0.001), severity (p<0.001), and interference (p=0.008). However, the absolute changes were small. No DVH metrics were significantly associated with any cardiac-specific HRQOL outcomes. Stratification by laterality yielded similar results. Conclusions: Proton RT generally conferred significantly lower doses to the heart and cardiac substructures compared to photon RT. HRQOL outcomes were favorable across all participants, with fatigue returning to baseline, no change in SOB parameters, and a slight worsening of chest pain outcomes over 6 months following RT. Cardiac-specific HRQOLs appear not to be significantly affected by RT dose to cardiac substructures within the first 6 months post-RT. Other organs at risk that could also impact cardiac HRQOL endpoints, longer follow-up, and major cardiac events will be evaluated in future analyses. Citation Format: J. L. Wright, K. Ko, W. Kenworthy, W. Bosch, L. Braunstein, G. Freedman, E. Gillespie, R. Jimenez, S. Pugh, H. Lu, M. Pankuch, N. Remmes, W. Straube, W. Zou, E. Berlin, L. Fang, S. MacDonald, N. Taunk, J. Kim, A. Thukral, A. Taghian, M. Mishra, R. Mutter, V. Croog, D. Boggs, J. Urbanic, N. Ohri, A. Chawla, T. Meier, L. Rosen, M. Fegundes, O. Cahlon, K. Hoffman, A. Ferriozzi, J. Bekelman, A. Lin, B. Ky. Associations Between Cardiac Radiation Dose Volume Metrics and Cardiac Specific Health Related Quality of Life for Patients with Breast Cancer Randomized to Proton versus Photon Radiation on the RadComp Trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr RF6-04.

Objective To assess the impact of renal replacement therapy in people with lupus nephritis (LN)–associated end‐stage kidney disease (ESKD) and support the development of the 2024 American College of Rheumatology LN treatment guidelines. Methods We conducted a systematic literature review and meta‐analysis to address three Population, Intervention, Comparison, and Outcome (PICO) questions related to renal replacement therapy for ESKD due to LN, including comparisons of kidney transplant versus dialysis, hemodialysis versus peritoneal dialysis, and preemptive kidney transplant versus no preemptive kidney transplant. Outcomes of interest included mortality, cardiovascular (CV) events, infections, lupus flares, disease‐related damage, graft failure, and quality of life. We conducted a meta‐analysis and analyzed hazard ratios for time‐to‐event analyses and risk ratios for dichotomous outcomes, as well as absolute risk estimates. Results Sixteen comparative observational studies addressed at least one of the three PICO questions. Kidney transplant was found to reduce the risks of all‐cause mortality, CV mortality, infection‐related mortality, and CV events compared with dialysis (high certainty). Dialysis modality (peritoneal vs hemodialysis) was not associated with mortality (high certainty) or with other outcomes of infection, CV complications, and systemic lupus erythematosus flares (low certainty). Preemptive kidney transplant was associated with lower risks of graft failure and mortality (low certainty). Conclusion This systematic review identified improved outcomes with kidney transplant versus dialysis for people with LN‐associated ESKD and potential benefits of preemptive kidney transplant. This evidence supports the use of kidney transplant as a preferred renal replacement therapy for people with LN‐ESKD.

Abstract Description Evidence consistent with immunoediting in human cancer has been identified through associative studies. To provide direct evidence that differences in the neoantigen profile are immune-mediated, we compared the neoantigen profiles of cutaneous squamous cell carcinoma (cSCC) from immunocompetent and immunosuppressed patients. Despite consistency in the overall mutational burden and signature, immunocompetent patients have a lower clonal mutational burden compared to immunosuppressed patients. Furthermore, clonal mutations in cSCC from immunocompetent patients have a lower proportion of neoantigens predicted to bind MHC class I, supporting the role of the immune system in shaping the neoantigen profile. In single-cell RNA sequencing of intratumoral CD8+ T cells from a separate cohort of cSCC from immunocompetent and immunosuppressed patients, we observe an increase in exhausted CD8+ T cells in tumors from immunocompetent patients, suggesting an explanation for the persistence of binding neoantigens subclonally. Finally, we compare clonal and subclonal neoantigens as an unbiased screen for characteristics associated with neoantigen immunogenicity. Neoantigens with a large increase in predicted MHC class I binding relative to the normal peptide are enriched in subclonal neoantigens in immunocompetent patients. Overall, this work supports the immune system’s role in sculpting the neoantigen profile of cSCC. Funding Sources Supported by American Cancer Society - Simone Charitable Foundation - Discovery Boost Grant, AZ-DBG-23-1151311-01-IBCD; NIH F30CA281056; R35GM149235 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Objective To provide evidence‐based and expert guidance for the treatment and management of non‐renal systemic lupus erythematosus (SLE); treatment and management of lupus nephritis are addressed in a separate guideline. Methods Clinical questions for treatment and management of SLE were developed in the PICO format (population, intervention, comparator, and outcome). Systematic literature reviews were developed for each PICO question, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess evidence quality and formulate recommendations. The Voting Panel achieved a consensus of ≥70% agreement on the direction (for or against) and strength (strong or conditional) of each recommendation. Results We present recommendations and ungraded, consensus‐based good practice statements for the treatment and management of SLE that are applicable to pediatric and adult patients. Recommendations emphasize uniform treatment with hydroxychloroquine, limiting duration of glucocorticoid use, and early introduction of conventional and/or biologic immunosuppressive therapies to achieve and maintain control of SLE inflammation (remission or a low level of disease activity), reduce SLE‐related morbidity and mortality, and minimize medication‐related toxicities. Conclusion This guideline presents direction regarding treatment and management of SLE and provides a foundation for well‐informed, shared clinician–patient decision‐making. These recommendations should not be used to limit or deny access to therapies, as treatment decisions may vary due to the unique clinical situation and personal preferences of each person with SLE.

Objective To provide evidence‐based and expert guidance for the treatment and management of non‐renal systemic lupus erythematosus (SLE); treatment and management of lupus nephritis are addressed in a separate guideline. Methods Clinical questions for treatment and management of SLE were developed in the PICO format (population, intervention, comparator, and outcome). Systematic literature reviews were developed for each PICO question, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess evidence quality and formulate recommendations. The Voting Panel achieved a consensus of ≥70% agreement on the direction (for or against) and strength (strong or conditional) of each recommendation. Results We present recommendations and ungraded, consensus‐based good practice statements for the treatment and management of SLE that are applicable to pediatric and adult patients. Recommendations emphasize uniform treatment with hydroxychloroquine, limiting duration of glucocorticoid use, and early introduction of conventional and/or biologic immunosuppressive therapies to achieve and maintain control of SLE inflammation (remission or a low level of disease activity), reduce SLE‐related morbidity and mortality, and minimize medication‐related toxicities. Conclusion This guideline presents direction regarding treatment and management of SLE and provides a foundation for well‐informed, shared clinician–patient decision‐making. These recommendations should not be used to limit or deny access to therapies, as treatment decisions may vary due to the unique clinical situation and personal preferences of each person with SLE.

Objective A patient‐centered approach for chronic disease management, including systemic lupus erythematosus (SLE), aligns treatment with patients’ values and preferences, leading to improved outcomes. This paper summarizes how patient experiences, perspectives, and priorities informed the American College of Rheumatology (ACR) 2024 Lupus Nephritis (LN) and 2025 SLE screening, treatment guidelines. Methods We completed a cross‐sectional qualitative study using content analysis of two Patient Panel meetings for the ACR LN and SLE guidelines. Key themes were presented by Patient Panel representatives during Voting Panel Meetings along with evidence for each recommendation, to ensure comprehensive discussions and align treatment recommendations with patients’ priorities and values. Results Nineteen people (90% women) with diagnoses of SLE and/or LN participated in the Patient Panels and 17 consented to use their feedback for analysis. Thematic analysis of their discussions revealed nine patient‐reported key themes in three domains: (1) treatment and monitoring of LN and SLE: medication side effects, daily function, treatment goals, and monitoring and screening; (2) clinical communication: strategies to optimize communication and provider and structural impediments to effective communication; and (3) improving transparency and information sharing: clinical trial participation, and medical costs and insurance coverage. These themes were actively incorporated into discussions during the Voting Panels for the ACR LN and SLE guidelines. Conclusion This work supported the integration of patient experiences in the clinical practice guideline development process and aligned recommendations with real‐world patient experiences and priorities, thereby enhancing the clinical applicability of the ACR LN and SLE guidelines. image

Abstract Understanding tumor cell dynamics can improve prognosis and treatment but remains limited for lung adenocarcinoma in people who have never smoked (NS-LUAD). With RNA sequencing data from 684 NS-LUAD cases and validation in an independent dataset, we identified three subtypes with distinct phenotypic traits and cell compositions. Additional genomic and histologic data further characterized the subtypes. “Steady,” marked by low proliferation, high alveolar cell fraction, moderate-to-well differentiation, and fewer driver gene alterations, is linked to prolonged survival and low immune evasion. “Proliferative” shows high proliferation markers, TP53 mutations, and gene fusions. “Chaotic,” with high epithelial-to-mesenchymal transition markers, has the worst prognosis, even within stage I tumors. Lacking known molecular or histologic characteristics, this aggressive subtype is solely identified by transcriptomic data. A 60-gene signature recapitulates the classification and predicts survival even within subgroups based on tumor stage or known genomic features, emphasizing its potential for improving early-stage NS-LUAD prognostication in clinical settings. Significance: The transcriptome of 684 NS-LUAD identifies three subtypes with different cellular dynamics and genomic and morphologic features. A 60-gene signature accurately stratifies subjects for mortality risk, even in stage I, offering a potential clinically applicable tool for treatment decision-making in patients with NS-LUAD. See related commentary by Azizi et al., p. 423

Abstract Objective: The National Institutes of Health (NIH) Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (EXAMINER) is a validated laptop-based battery of executive functioning tests. A modified tablet version of the EXAMINER was developed on the UCSF Tablet-based Cognitive Assessment Tool (TabCAT-EXAMINER). Here we describe the battery and investigate the reliability and validity of a composite score. Methods: A diagnostically heterogeneous sample of 2135 individuals (mean age = 65.58, SD = 16.07), including controls and participants with a variety of neurodegenerative syndromes, completed the TabCAT-EXAMINER. A composite score was developed using confirmatory factor analysis and item response theory. Validity was evaluated via linear regressions that tested associations with neuropsychological tests, demographics, clinical diagnosis, and disease severity. Replicability of cross-sectional results was tested in a separate sample of participants ( n = 342) recruited from a frontotemporal dementia study. As this separate sample also collected longitudinal TabCAT-EXAMINER measures, we additionally assessed test-retest reliability and associations between baseline disease severity and changes in TabCAT-EXAMINER scores. Results: The TabCAT-EXAMINER score was normally distributed, demonstrated high test-retest reliability, and was associated in the expected directions with independent tests of executive functioning, demographics, disease severity, and diagnosis. Greater baseline disease severity was associated with more rapid longitudinal TabCAT-EXAMINER decline. Conclusions: The TabCAT-EXAMINER is a tablet-based executive functioning battery developed for observational research and clinical trials. Performance can be summarized as a single composite score, and results of this study support its reliability and validity in cognitive aging and neurodegenerative disease cohorts.

ImportanceReceipt of anthracycline-based chemotherapy and statin therapy have been found to be associated with deterioration of cognitive function in patients with cancer.ObjectiveTo assess the association of statins with attention, verbal fluency, and executive function in patients receiving doxorubicin treatment for cancer.Design, Setting, and ParticipantsThis secondary analysis of the Preventing Anthracycline Cardiovascular Toxicity With Statins randomized clinical trial, conducted across 31 US community and academic sites from February 5, 2014, through September 24, 2020, involved participants with stage I to IV lymphoma or stage I to III breast cancer undergoing doxorubicin treatment. The data analysis was conducted between August 1, 2024, and April 4, 2025.InterventionsParticipants were randomized (1:1) to receive a daily 40-mg dose of atorvastatin or placebo before initiating doxorubicin treatment and then continued for 24 months.Main Outcomes and MeasuresAttention, executive function, and verbal fluency were assessed using the Trail Making Test part A (TMT-A) and part B (TMT-B) and the Controlled Oral Word Association test, respectively. Time to complete the assessments were modeled using a linear mixed model, while errors (counts) were modeled using a generalized linear mixed model assuming a Poisson distribution.ResultsA total of 238 participants (mean [SD] age, 49 [12] years; 217 female [91.2%]) were randomized to the statin (n = 118) or placebo (n = 120) groups. Values for TMT-A at 6 and 24 months were similar between the statin group (mean, 32.5 seconds [95% CI, 29.4-35.7 seconds] and 29.8 seconds [95% CI, 26.4-33.2 seconds], respectively) and the placebo group (mean, 28.4 seconds [95% CI, 25.2-31.5 seconds] and 27.8 seconds [95% CI, 24.5-31.0 seconds], respectively). From before treatment to 24 months after treatment, statin recipients had a significant mean improvement of 10.2 seconds for TMT-B (95% CI, 1.9-18.5 seconds), whereas placebo recipients had a nonsignificant improvement of only 0.2 seconds for TMT-B (95% CI, −8.5 to 8.1 seconds). Analysis of the time-by-treatment interaction showed no significant difference between groups. For Controlled Oral Word Association scores in the same period, both the placebo and statin groups showed a mean improvement of 3.62 points (95% CI, 1.71-5.54 points) and 4.74 points (95% CI, 2.69-6.79 points), respectively, with no difference between groups.Conclusions and RelevanceThis secondary analysis of a randomized clinical trial suggests that the receipt of statins during doxorubicin therapy for lymphoma or breast cancer was not associated with worsening cognitive functions over 24 months. Within-group analyses suggested that statins may have contributed to better executive function on the TMT-B.Trial RegistrationClinicalTrials.gov Identifier: NCT01988571