Citations

ABSTRACT Pediatric radiation therapy presents unique challenges compared to adult treatments, including those of immobilization, potential need for sedation, and the critical importance of accurate, reproducible positioning. Additionally, heightened attention to imaging doses is necessary to minimize long‐term toxicity in survivors. Many of these challenges must be addressed during the process of simulation. This report provides guidelines for pediatric radiotherapy simulation from the Children's Oncology Group. These guidelines cover all anatomic sites and include recommendations for photon and proton therapies, as well as specialized procedures such as stereotactic body radiation therapy, brachytherapy, and total body irradiation. These guidelines are presented as recommendations rather than prescriptive standards as the practice will vary depending on patient age, diagnosis, clinical judgment, and institutional resources.

Polycystic kidney disease (PKD) arises from mutations in cilia-associated genes, such as PKD1 and PKD2 , expressed in renal epithelial cells, leading to progressive kidney dysfunction and end-stage kidney disease (ESKD). PKD patients exhibit significant heterogeneity in disease progression, largely due to genetic and environmental modifiers. Like patients, mouse models of PKD also exhibit significant heterogeneity with regards to the gene mutated, age of disease onset, and rate of disease progression. To elucidate the cellular and molecular consequences of these variables, we constructed an integrated single-cell RNA sequencing atlas across mouse models of PKD, mapping changes in cell type composition, gene expression, and intercellular signaling networks across the whole atlas and within individual models. Across models, single cell RNA sequencing (scRNAseq) data revealed increased Spp1 (osteopontin) expression and signaling from PKD-enriched clusters. Global deletion of Spp1 in Pkd1 RC/RC mice resulted in a modest reduction in cyst severity and improved kidney function. From these studies, we created a freely available, searchable website (https://bmblx.bmi.osumc.edu/scPKD/) that can be used to identify cross- and intra-model changes in gene expression, guiding researchers to new therapeutic targets for treating PKD.

Abstract In response to a Cochrane review (published in April 2026) on the clinical trials of monoclonal antibodies targeting beta amyloid, this perspective outlines a number of critiques. The scientists, methodologists, subject‐matter experts, and clinicians on this perspective strongly recommend that the Cochrane editorial board consider a call for editorial response, correction of press materials, or commissioned reply to this review for four overarching reasons: (1) decision to pool antibodies that do and do not clear beta amyloid, (2) decision to include studies from a time when biomarkers of Alzheimer's disease were not available, (3) analytical and methodological limitations of the approach used, (4) conflating the distinct roles and methodological processes of systematic review and guideline methodologies, (5) contextualizing the present critique within the existing evidence‐synthesis literature, and (6) mechanistic inference beyond the scope of the presented analyses. Conclusions that may not accurately reflect treatment‐specific effects could cause significant downstream clinical and psychosocial harm to those currently undergoing treatment and their family members as well as individuals considering participation in Alzheimer's clinical trials.

Abstract Frailty influences treatment outcomes in older patients with multiple myeloma (MM), yet existing frailty tools capture limited geriatric domains and are incompletely studied in the context of contemporary therapies. We prospectively evaluated patient-reported comprehensive geriatric assessment (CGA) domains and their associations with treatment toxicity and patient-reported outcomes (PRO) in older adults with MM. Patients aged ≥60 years with newly diagnosed or relapsed/refractory MM initiating a new therapy completed electronic CGA and PRO questionnaires at baseline and 4 months. Outcomes included clinician- and patient-reported treatment toxicity, treatment adaptations, health care use, and health-related quality of life (HRQOL). A cumulative deficit frailty index (FI) was derived from CGA and HRQOL domains. Among 90 patients (mean age, 72 years), geriatric impairments were common, particularly physical function domains. High-grade nonhematologic toxicities were significantly associated with older age, comorbidities, patient-reported functional limitations, and anxiety. Toxicity rates on the PRO version of the Common Terminology Criteria for Adverse Events (CTCAE) were higher than on CTCAE, highlighting a discordance between physician- and patient-reported treatment toxicity. Frailty was present in 22% and associated with worse baseline HRQOL and increased high-grade nonhematologic toxicity but not treatment adaptations or health care use. Average CGA and HRQOL scores remained stable over 4 months, although individual trajectories varied. Patient-reported geriatric impairments are prevalent in older adults with MM and strongly associated with nonhematologic toxicities even in the contemporary treatment era. Physician-reported CTCAE may not fully reflect patients' symptom burden. Heterogeneity in individual geriatric trajectories during treatment emphasize the need for longitudinal assessment. This study was registered at www.clinicaltrials.gov as NCT05918185.

Abstract Background There is limited data on immune checkpoint inhibitor (ICI) use in patients with non-small cell lung cancer (NSCLC) and known pericardial effusions. Methods This international multi-center observational retrospective study included patients with advanced NSCLC with or without pericardial effusions receiving ICIs. Immune-related adverse events (irAEs) were graded per CTCAE v5.0. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. Cox proportional hazards multivariable models assessed the association between survival outcomes and clinicopathologic variables, and an inverse probability of treatment weighting (IPTW) model compared outcomes between the two groups. Results A total of 1248 patients with advanced NSCLC treated with ICIs across 13 institutions were included. Of these, 85 patients (6.8%) had pre-existing pericardial effusions. Compared to controls, patients with pericardial effusions were younger (median age 63 vs 67 years, P = .007), diagnosed more frequently with PD-L1 positive tumors (96% vs 76%, P < .001), and had a higher median number of baseline metastatic sites (3 vs 1, P < .001). IrAEs were similar between both groups (42% vs 38%), and no cardiac irAEs occurred in patients with pericardial effusions. PFS (median 5.6 vs 4.6 months, P = .3) and OS (median 10.2 vs 14.7 months, P = .50) were not statistically different between patients with pericardial effusions and the controls, respectively. In both multivariable and IPTW models, pericardial effusions were not associated with PFS or OS. Conclusions Among patients with NSCLC and pre-existing pericardial effusions, ICIs demonstrate meaningful clinical benefit similar to those without effusions, with no new cardiac or severe toxicities.

An accurate differential diagnosis for diffuse lung disease can be confidently established by using a systematic approach to identify the predominant radiographic pattern, determine the distribution of disease, and assess for architectural or volume change.

Importance Limited granular data exist on breast cancer in transgender, nonbinary, and/or gender-diverse (TGD) individuals. Objective To describe patient demographic and tumor clinicopathological variables, clinically relevant risk factors, method of breast cancer detection, treatment characteristics, and locoregional outcomes and to estimate a 5-year breast cancer–specific survival (BCSS). Design, Setting, and Participants This cohort study obtained data on patients treated from 1990 to 2023 from 22 US academic medical centers using institutional databases, electronic medical records, and tumor registries. Included participants were TGD individuals 18 years or older with stage 0 to IV breast cancer. A comparative breast cancer cohort was selected from the 2016 to 2021 Surveillance, Epidemiology, and End Results Program (SEER) breast cancer dataset. Data were analyzed from January to October 2025. Exposure Breast cancer. Main Outcomes and Measures Estimated 5-year BCSS and locoregional recurrence rates. Wilcoxon rank sum and χ 2 tests were used to compare continuous and categorical variables. Kaplan-Meier analysis was used to estimate 5-year BCSS. Results A total of 112 TGD persons (median [IQR] age at diagnosis, 42.5 [36.5-51.0] years; 104 individuals [92.9%] were assigned female at birth) with breast cancer and 1 with bilateral disease were included in the analysis. Forty-three patients (38.4%) used gender-affirming hormone therapy before diagnosis. Among the entire cohort, 58 patients (51.8%) detected their own breast cancer, 68 (60.7%) had a familial breast cancer history, and 16 (14.3%) had a pathogenic germline variant. Tumors were predominantly hormone receptor positive (96 [85.7%]) and early stage (29 [25.7%] ductal carcinoma in situ [DCIS]; 51 [45.1%] stage I). The TGD cohort, compared with patients with breast cancer in the SEER dataset (N = 480 915), was younger (median [IQR] age, 42.5 [36.5-51.0] years vs 62.0 [52.0-72.0] years), had a higher proportion of persons assigned male at birth (8 [7.1%] vs 3522 [0.7%]), more often had progesterone receptor–positive disease (89 [79.5%] vs 335 491 [69.8%]), and presented with earlier-stage disease (eg, DCIS: 29 [25.9%] vs 79 604 [16.6%]). With a median (IQR) follow-up time for the TGD cohort of 38 (24-74) months, 5-year BCSS was favorable at 96.2% (95% CI, 85.3%-99.0%). Conclusions and Relevance This cohort study of TGD patients with breast cancer found that this population was young and often detected their own tumors via self-examination, suggesting opportunities to improve early detection through screening for individuals at elevated risk. Although short-term BCSS appeared favorable, prospective research is essential to define evidence-based guidelines and elucidate long-term outcomes.

Abstract Early-phase clinical trials of Bruton’s tyrosine kinase (BTK) degraders have demonstrated efficacy in patients with BTK inhibitor-resistant chronic lymphocytic leukemia (CLL). How clinical resistance to BTK degraders arises is unknown. Here we sequenced serial CLL samples from patients enrolled in the phase I trials of zelebrudomide and bexobrutideg and observed recurrent expansion of preexisting BTK A428D mutations at relapse. Unlike previously studied BTK inhibitor resistance mutations, BTK A428D conferred pan-resistance to BTK inhibitors and degraders. In the absence of BTK-directed therapies, however, cells bearing BTK A428D exhibited a competitive disadvantage. A crystal structure of BTK A428D revealed that the mutant aspartate clashes with the adenine ring of ATP and the adenine-mimetic moiety of BTK inhibitors and degraders. Combining BTK degraders with venetoclax mitigated the expansion of BTK A428D. These results provide the molecular basis for clinical resistance to BTK degraders and will inform the development of next-generation BTK degrader therapies.

Background: Although skin cancer survivors have an increased risk of future malignancies, many are unaware of this and may not undergo preventative screening. Objective: To evaluate skin cancer survivors’ prevalence of breast, colorectal, cervical, and lung cancer screening. Methods: This is a retrospective cross-sectional analysis of The Behavioral Risk Factor Surveillance System database from 2017 to 2021 comparing skin cancer, other cancer, and non-cancer controls. Multivariate analysis compared screening rates, controlled for socioeconomic, chronic disease, and behavioral factors. Results: Compared to non-cancer controls, skin cancer survivors had higher odds of undergoing screening for breast (odds ratios [OR]: 1.35, 95% confidence interval [CI] 1.20–1.51), colorectal (OR 1.53, 95% CI 1.40–1.66), and cervical cancer (OR 1.32, 95% CI 1.12–1.56). Lung cancer screening rates were low and similar between skin cancer survivors and non-cancer individuals (OR 1.21, 95% CI 0.84–1.74). In a subset analysis of skin cancer survivors, those who had melanoma were less likely to be screened for breast and colorectal cancer. Limitations: This study is based on anonymous, national survey data, relying on patient recall of their health information. Conclusion: Skin cancer survivors undergo cancer screenings for breast, colorectal, and cervical cancer at higher rates compared to non-cancer controls. Melanoma survivors have lower rates of breast and colorectal screening compared to non-melanoma skin cancer survivors. Skin cancer survivors should be reminded of preventive cancer screening, particularly for lung cancer.