Citations

144 Background: Androgen receptor pathway inhibitors (abiraterone acetate [AAP], apalutamide [APA], enzalutamide [E], darolutamide [DARO] have become the cornerstone for pts with PCa due to survival benefits. Comparative data on fracture risk among ARPi are limited. This study quantified the risk of bone fractures with ARPi plus androgen deprivation therapy (ADT) and compared fracture risk across different ARPi agents. Methods: MEDLINE and EMBASE were searched from inception through September 1 st 2025 to identify positive phase III trials assessing ARPi in addition to ADT in pts with PCa (m0CRPC, mCSPC, mCRPC). Trials were included if they reported bone fractures in either arm. Pairwise, random-effects meta-analysis was conducted using Paul-Mendel approach. Sensitivity analyses using Hartung-Knapp (HK) adjustment was performed to assess robustness of results. To assess the comparative risk of bone fractures among different ARPi agents, mixed treatment comparisons were made using frequentist network meta-analysis. P-scores were computed to assess relative treatment rankings. Treatment effect was expressed as odds ratio (OR) with 95% confidence intervals (CI). Results: This systematic review included 13 phase III trials with 15468 pts (8890 received ARPi+ADT, 6578 received ADT alone). A total of 596 (6.7%) bone fractures were observed with ARPi+ADT compared to 180 (2.74%) with ADT alone. Patients receiving ARPi+ADT were associated with an increased risk of bone fractures compared to those receiving ADT (OR: 2.40; 95% CI: 1.93-2.98). Sensitivity analyses with HK adjustment showed consistent results (2.40; 1.88-3.06). There was no statistically significant effect modification by PCa clinical setting (p: 0.27). Mixed treatment comparisons showed a statistically significant increased risk of bone fractures with AAP+ADT (2.35; 1.29-4.27), APA+ADT (2.04; 1.47-2.86), and E+ADT (3.13; 2.44-4.00) but not with DARO+ADT (1.30; 0.80-2.08) when compared to ADT alone. Among different ARPi agents, E+ADT was associated with an increased risk compared to APA+ADT (1.54; 1.01-2.33) and DARO+ADT (2.44; 1.41-4.17). Ranking analysis showed that E+ADT was ranked as potentially the least safe treatment (P score: 0.05) in terms of relative fracture risk followed by AAP+ADT (P score: 0.30), APA+ADT (P score: 0.43), DARO+ADT (P score: 0.76). Sensitivity analyses limiting to mCSPC trials only showed consistent results. Conclusions: The risk of bone fractures varies among different ARPi agents, with enzalutamide posing the highest relative risk and darolutamide the lowest. These differences may guide treatment selection, particularly in pts with mCSPC and bone metastases. Prospective studies adjusting for covariates are needed to evaluate bone-protective strategies to mitigate fracture risk particularly in mCSPC patients who are considering treatment with ARPi.

Abstract Response Assessment in Pediatric Neuro-Oncology (RAPNO) is an international working group dedicated to developing standardized recommendations for response assessment in children with central nervous system tumors enrolled on clinical trials. This standardization facilitates easier and more reliable comparison of responses across trials. Since the first RAPNO publication in 2013, response guidelines have been issued for medulloblastoma (MB), low-grade glioma (LGG), high-grade glioma (HGG), diffuse intrinsic pontine glioma, ependymoma, and craniopharyngioma. Many of these guidelines have already been incorporated into clinical trials to evaluate their effectiveness and accuracy. RAPNO has always been predicated on the idea that these consensus recommendations will require updates over time as they are applied in practice given technological advancements, evolving treatment approaches, and growing knowledge of disease pathology. A half-day RAPNO symposium sponsored by the Society of Neuro-Oncology was held in San Diego, California, United States, on May 15, 2025. This event coincided with the 8th Biennial Pediatric Society of Neuro-Oncology meeting. The main objectives were to identify ongoing RAPNO challenges, discuss potential updates, and plan future initiatives across 3 specific groups: (1) LGG/Craniopharyngioma, (2) HGG/diffuse midline glioma (DMG)/Ependymoma, and (3) MB and other seeding tumors. This manuscript reviews the symposium proceedings and highlights key topics and challenges discussed, as well as outlining future RAPNO initiatives.

Abstract Individuals who have serum elevations of anti-cyclic citrullinated protein (anti-CCP) antibodies are at risk for developing rheumatoid arthritis (RA), yet immunologic factors that lead to a transition from pre- to clinical RA remain unclear. Here, we used materials from anti-CCP antibody-positive individuals enrolled in a clinical trial that evaluated the efficacy of hydroxychloroquine to prevent clinical RA, and performed multi-modal single-cell profiling (transcriptome, surface proteins, T/B-cell receptor sequencing, and chromatin accessibility) on samples obtained at baseline and at RA onset in those who developed clinical RA (Converters) or follow-up point in matched Nonconverters. At both baseline and follow-up, Converters had expansions of peripheral helper T (Tph) cells and CD8 + T cells expressing GZMK and GZMB , along with elevated potentially autoreactive T-cell receptors in CD4 + T cells compared to Nonconverters. Induction of age-associated B cell signatures was observed in B cells of Converters prior to RA onset. Epigenetic profiling further identified chromatin accessibility changes in Converters over time, particularly within myeloid and NK cells. Lastly, predictive modeling using baseline immune features, including Tph cells, GZMK + XCL1 + CD8 + , and GZMB + CD57 + CD8 + T cells, together with clinical features such as anti-CCP3 levels, RF-positivity, and HLA shared epitope status, stratified RA risk and predicted time to onset. These findings define immune endotypes in pre-RA that could serve as targets for future preventive interventions and be used to stratify the risk of developing clinical RA in anti-CCP antibody-positive individuals.

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.

Abstract Introduction: Hormone receptor positive (HR+), HER2- breast cancer (BC) is the most common subtype of BC. Despite advances in chemotherapy and endocrine therapy optimization, local and systemic recurrences frequently occur, especially for patients with node-positive disease. Recent data suggest a subset of patients with this tumor phenotype may benefit from the addition of anti-Programmed Death-1(aPD1) to neoadjuvant chemotherapy. However, T-cell infiltration (TCI), a biomarker of response to aPD1 and chemotherapy, is typically low in this BC subtype. Preclinical models show that combining preoperative radiation therapy (preop RT) with immune checkpoint inhibitors can enhance TCI and anti-tumor immunity. We conducted the first randomized trial to test whether no-, low- or high-dose RT combined with aPD1 increases TCI and improves responses in non-irradiated, metastatic lymph nodes in HR+/HER2- BC (NCT04443348). Materials & Methods: Eligible patients had ER and/or PR≥10%, HER2 negative invasive BC with clipped and biopsy-proven positive axillary node(s), cT1c-T4c, cN1-3, and at least one of the following criteria: grade 3 or grade 1-2 with cN2-N3, Ki67 >20%, or high genomic assay score. Between 2022-2024, 51 patients from 10 centers were randomized to no (0Gy; control arm), low (9Gy) or high (24Gy) doses of preop RT to the primary tumor with concurrent pembrolizumab followed by a 2-week tumor biopsy. Stratification factors were T1c vs. T2-4 and N1 vs. N2-3. Patients subsequently received pembrolizumab with 12 weeks of paclitaxel, followed by 4 cycles of adriamycin-cyclophosphamide (q2wk or q3wk) with pembrolizumab (200 mg q3 wks or 400 mg q6 wks). Surgery and adjuvant therapy followed standard-of-care. Dual co-primary endpoints were 2wk tumor TCI and nodal pathologic complete response (ypN0) at time of definitive surgery. TCI was assessed by multiplex immunofluorescence (pan-cytokeratin, CD3, CD8), using a rank-based Immunoscore (range 0-1), compared to baseline reference biopsies via two-tailed Mann-Whitney test. ypN0 was evaluated non-comparatively. Secondary endpoints included pCR and Residual Cancer Burden (RCB) 0/1. Results: Among 51 patients enrolled, 49 were evaluable for TCI and 48 for the ypN0 endpoint. Median age was 49.5 years (range 23-78). The cohort had a high-risk clinical profile: 92% had cT2-4, 50% N2-3, and 62% grade 3 tumors. Median ER and PR positivity were 90% (20-100) and 68% (1-98), respectively. Multifocal or multicentric tumors were present in 32%. TCI was assessed at 2 weeks post-treatment. The proportion of tumors with TCI in the upper quartile increased with RT dose escalation: 31% (0Gy), 40% (9Gy), and 53% (24Gy). Median TCI scores at 2 weeks were 0.60 (0Gy), 0.56 (9Gy), and 0.82 (24Gy), compared to a median baseline value of 0.50 from untreated reference samples. A statistically significant increase in TCI was observed only in the 24Gy cohort relative to the untreated group (p=0.027). 70.8% underwent mastectomy, with 39.6% receiving immediate reconstruction. 8% experienced G2/3 wound complications, balanced across arms. Median number of lymph nodes removed was 6.5 (1-42). The overall ypN0 rate was 29%, and 24%(0Gy), 29%(9Gy) and 33%(24Gy) per arm. pCR/RCB 0-1 rates were 18%/27% in the entire cohort and 6%/18%(0Gy), 29%/29%(9Gy), and 19%/33%(24Gy), respectively. Conclusion: The addition of 24Gy preop RT to aPD1 significantly increased tumor TCI in HR+/HER2- early-stage BC. Non-irradiated nodal response rates were promising despite over one-third of the study population with grade 1/2 tumors and high disease burden, laying the foundation for a future randomized trial comparing the efficacy of this novel approach against standard of care for node-positive HR+/HER2- BC. Citation Format: G. Gupta, A. Y. Ho, F. Gharibpoor, Y. Abdou, J. D. Anampa, R. C. Blitzblau, B. C. Calhoun, D. L. Casey, S. F. Dent, L. A. Carey, J. R. Bellon, L. E. Warren, J. Lu, T. J. Hieken, A. G. Taghian, A. Bardia, T. Traina, G. Plitas, K. Gallagher, K. Daugherty, A. Thompson, I. Krop, A. Wolff, E. Mittendorf, J. Fox, H. Garber, E. Hwang, A. J. Khan, J. P. Loene, R. Mutter, S. Patil, C. Santa-Maria, B. V. Vincent, J. L. Wright, L. Spring.Primary Results from the HR+/HER2- Cohort of TBCRC-053 (P-RAD): A Randomized Trial of No, Low, or High Dose Preoperative RADiation with Pembrolizumab and Chemotherapy in Node-Positive, HER2-Negative Breast Cancer [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 GS2-05.

Abstract Background: The association of TILs with pathologic complete response (pCR) and survival in HER2+ breast cancer is not well established with several prior studies showing inconsistent results. In this secondary analysis of EA1181, we evaluated the association between stromal TILs (sTILs) and pCR rates. Methods: EA1181 (NCT04266249) enrolled patients (pts) with anatomic clinical stage II/III HER2+ breast cancer who preoperatively received 4 cycles of trastuzumab and pertuzumab with 12 weeks of paclitaxel or docetaxel q3w x 4 (THP), followed by surgery. sTILs density was assessed on full-face hematoxylin and eosin (H&E)-stained tumor biopsy sections. sTILs scores were analyzed per protocol as a continuous variable (every 10% increment) and as a categorical variable (<10% vs 10-60% vs >60% as per Denkert et al, 2018), and also with an exploratory 30% cutoff commonly used in TNBC. Cox proportional hazards models were used to examine the association between sTILs and pCR, adjusting for available baseline factors. The associations between sTILs (by category) and clinicopathologic characteristics were examined using Fishers’ exact test. Results: Among 2141 pts with HER2+ BC treated on EA1181, H&E slides were available for 1328 (62%). The study population evaluated for sTILs was comparable to the overall population. pCR rates were 44.5% overall, 64% for HER2+/ER- and 33% for HER2+/ER+ disease. sTILs distribution was: 623 (47%) <10%, 698 (52%) 10-60%, and 7 (0.5%) >60%, which led us to merge the latter two groups (705 [53%] had ≥10% sTILs). In univariable and multivariable analyses, increasing sTILs (as a continuous variable) were associated with increasing pCR rates in both HER2+/ER+ and HER2+/ER- disease (p<0.001; Table). sTILs analyzed as a categorical variable (<10% vs ≥10%) were significantly associated with pCR for all patients (combined) and for those with HER2+/ER+ disease. In exploratory analysis using a cutoff of <30% vs ≥30% sTILs, an association with pCR was also seen in univariable analysis for both HER2+/ER+ disease (p<0.001) and HER2+/ER- disease (p=0.045), though in multivariable analysis with clinical factors, sTILs >30% remained a significant predictor for pCR only in HER2+/ER+ disease. Additional exploratory analysis with other molecular biomarkers, intrinsic subtypes, and immune signatures will be presented. Conclusion: sTILs were associated with pCR after THP, further supporting the important role of immune mechanisms in HER2+ breast cancer, and highlighting a potentially robust predictive tool to assess pathologic response. Baseline sTILs could potentially inform the preoperative design of future trials of therapy optimalization. Association of baseline sTILs with recurrence free survival in EA1181 will be reported in the future. Citation Format: S. S. Badve, F. Zhao, N. Tung, Y. Gokmen-Polar, C. C. O'Sullivan, A. Prat, E. P. Winer, J. L. Wright, A. Recht, A. C. Weiss, J. A. Tjoe, S. M. Feldman, G. B. Rocque, M. Smith, N. Unni, S. Sardesai, S. Tang, S. Modi, W. J. Irvin, P. Villagrassa, C. Battelli, A. K. Krie, N. Bagegni, M. A. George, M. L. Telli, V. F. Borges, N. D’Abreo, P. Shah, K. D. Miller, A. H. Partridge, L. A. Carey, A. M. DeMichele, A. C. Wolff, ECOG-ACRIN.Tumor infiltrating lymphocytes (TILs) and pathologic complete response (pCR) in stage II/III HER2+ breast cancer treated with taxane, trastuzumab, and pertuzumab (THP): secondary results from the ECOG-ACRIN EA1181/CompassHER2 pCR 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 GS1-04.

Background/Objectives: Precocious puberty (PP), defined as the onset of secondary sexual characteristics before 8 years in girls and 9 years in boys, is associated with psychosocial distress, compromised adult height, and long-term metabolic risk. Early identification remains challenging, as current diagnostic approaches are largely reactive and rely on invasive or resource-intensive testing. This narrative review examines how artificial intelligence (AI) can support earlier risk prediction and detection of PP through integration of clinical, hormonal, imaging, lifestyle, and environmental data. Methods: A narrative literature review was conducted using PubMed, Scopus, Embase, Web of Science, and Google Scholar to identify relevant studies published between 2005 and 2025. Eligible studies included original research and high-quality reviews that examined AI-based approaches, such as machine learning and deep learning, in pediatric endocrinology, particularly for the prediction or diagnosis of central or peripheral precocious puberty. Studies incorporating clinical, hormonal, radiological, lifestyle, environmental, or multi-omics data relevant to AI modeling were included. Results: AI models, including XGBoost, random forest, convolutional neural networks, and regression-based approaches, have demonstrated potential utility in predicting central precocious puberty using hormonal, imaging, and growth data. Reported applications include automated bone age assessment, lifestyle and dietary risk stratification, and exploratory use of wearable-derived behavioral data. However, progress is limited by small pediatric datasets, population bias, limited interpretability, and unresolved ethical challenges related to privacy, consent, and equity. Conclusions: Artificial intelligence represents a promising decision-support approach for earlier, non-invasive, and individualized risk assessment in precocious puberty. Future progress will depend on the integration of longitudinal, multimodal data, the development of ethical models, and interdisciplinary collaboration among pediatric endocrinologists, data scientists, and public health stakeholders.

Context.— Pathology is essential to global health care, yet disparities remain in access to education and training. The College of American Pathologists (CAP) Foundation addresses these gaps through grants and awards that support trainees, early-career pathologists, and initiatives promoting equity worldwide. Since 2015, total funding has increased from $18,400 to $84,098, an astounding 357%. Objective.— To evaluate the CAP Foundation Grants and Awards Program during a 10-year period, assessing financial investment, award distribution, recipient characteristics, and impact. Design.— A mixed-methods retrospective study integrated (1) quantitative analysis of program data, (2) qualitative feedback from awardees, and (3) a quantitative award impact survey of past CAP Foundation awardees. Variables included demographics, award type, funding amounts, geographic distribution, and career stage. Surveys assessed professional development, mentorship, and long-term engagement with CAP. Results.— From 2015 to 2024, a total of 744 applicants submitted 760 applications, resulting in 355 awards across 14 categories. Applications increased more than 8-fold, peaking in 2023, with surges during the COVID-19 pandemic. Medical student applications grew from 1 in 2020 to 17 in 2024 (76% annual growth); 9 of 12 Medical Student Travel Award recipients (75%) entered pathology residency. Geographic disparities were noted, with smaller residency programs showing higher per capita application rates. Among 174 survey respondents, 129 (74%) reported networking benefits, 127 (73%) learning benefits, and 99 (57%) mentorship benefits, though only 49 (28%) sustained long-term mentoring relationships. Conclusions.— The CAP Foundation’s awards program has expanded access, supported career development, and fostered future pathologists. Strengthening long-term mentorship and bridging education-to-practice gaps may further enhance its impact.

Background: A critical component of conducting systematic reviews or meta-analyses is assessing the methodological quality and bias of included studies. Several methodological quality assessment tools have been developed; however, these tools may not be relevant to observational sports medicine research, which carries numerous unique nuances and biases. Purpose: To develop the Sport Publication Observational Research Tool (SPORT), which evaluates and scores the methodological quality of observational sports medicine research. Study Design: Consensus statement. Methods: SPORT was developed through a modified Delphi approach involving members from the Herodicus Society and The FORUM. All active members were invited to participate in the process aimed at building consensus on SPORT content and scoring. After finalizing SPORT, a power analysis led to the independent selection of 55 observational clinical sports medicine studies, which were scored twice by 4 reviewers of varying training levels. Interrater and intrarater reliability for SPORT was assessed using intraclass correlation coefficients (ICCs). The distribution and percentiles for total SPORT score across the 55 studies were calculated. SPORT was also compared with the methodological index for non-randomized studies (MINORS), a commonly utilized quality assessment tool. Results: A total of 51 members participated and achieved 100%, 100%, 98.0%, and 98.0% completion rates for rounds 1 through 4, respectively. The final SPORT included 19 subscores related to methodological quality and bias and achieved 94% consensus approval. Mean SPORT completion time was 6 minutes and 19 seconds per study, which varied significantly by reviewer training level. The subscore "peer review" demonstrated unacceptable reliability and was removed. The remaining 18 subscores exhibited ICC ranges of 0.599 to 0.955 for interrater reliability and 0.530 to 0.936 for intrarater reliability. Total SPORT score demonstrated excellent agreement, for interrater (ICC, 0.967) and intrarater reliability (ICC, 0.966). Median SPORT score across the 55 studies was 20.0 and skewed toward lower scores. There was a moderate significant correlation between SPORT and MINORS ( r [53] = 0.575; P < .001). Conclusion: An objective tool to assess the methodologic quality of observational sports medicine research (SPORT) was successfully developed through a modified Delphi approach with numerous content experts in the field. This tool may be useful in assessing the methodological quality of primary observational sports medicine studies included in systematic reviews and meta-analyses.