Citations

PURPOSE The continuous development of new imaging approaches, molecular phenotyping, genetic subtypes, prognosis assessments, and effective therapies across a range of disease states has created a need to redefine terminology and best practices for clinical trial conduct in patients with advanced prostate cancer. Methods We convened an international expert committee of diverse working groups, the Prostate Cancer Working Group 4 (PCWG4), between 2016 and 2025. Our objective was to formulate updated criteria based on emerging evidence and clinical trial data in a biomarker context to provide guidance for clinical trial design, eligibility, and end point assessments for patients with advanced prostate cancer. RESULTS PCWG4 redefines terminology around the disease state and previous therapies in a patient-centric context and terminology focused on androgen pathway modulation. We consider imaging, with a particular focus on positron emission tomography (PET)–defined disease. New recommendations are provided for disease state terminology, defining eligibility criteria, response and delay/prevent end points, intervals for reassessments including imaging, and patient-reported outcome determination. We provide recommendations in a biomarker-based context of use for the intended indication, reflective of patient benefit for specific interventions. We emphasize the need for development of validated PET imaging and molecular and phenotypic criteria as well as trial designs to appropriately risk stratify patients, predict and assess benefit, and measure post-treatment outcomes reliably in a trial framework. CONCLUSION PCWG4 updates recommendations on patient and tumor characterization, therapy development, and imaging criteria and extends guidance into earlier androgen pathway modulator–naïve/sensitive disease states to reflect an evolving, heterogeneous, and diverse patient population to optimize treatment benefits for all patients.

Background/Objectives: Streptococcus intermedius, a member of the Streptococcus anginosus group, is characterized by a marked propensity for abscess formation but only rarely causes native-joint septic arthritis. Involvement of the acromioclavicular (AC) joint is particularly uncommon. We describe a case of native AC joint septic arthritis due to S. intermedius in a patient with multiple predisposing factors and highlight diagnostic and management considerations. Methods: We report the clinical course of a 72-year-old man with poorly controlled type 2 diabetes mellitus who presented with progressive right shoulder pain, erythema, and swelling following recurrent minor skin abrasions from a newly adopted dog. Initial management for presumed inflammatory shoulder pathology included brief systemic corticosteroids and an ultrasound-guided intra-articular ketorolac injection. Magnetic resonance imaging (MRI) was performed after symptom progression. The patient underwent operative irrigation and debridement with collection of synovial fluid and deep tissue cultures. Blood cultures and transthoracic echocardiography were obtained to evaluate for systemic involvement. Results: MRI demonstrated multiloculated periarticular abscesses and osteolysis centered on the AC joint. Operative cultures yielded high colony counts of S. intermedius from synovial fluid and deep tissues. Blood cultures and echocardiography were negative. The patient required multiple operative debridements with irrigation, adjunctive local antibiotic therapy, and prolonged targeted β-lactam treatment. Clinical and radiographic improvement was achieved following surgical source control and antimicrobial therapy. Conclusions: Native AC joint septic arthritis due to S. intermedius is rare. Older age, uncontrolled diabetes, recent intra-articular intervention, and possible zoonotic inoculation from canine wound licking may represent contributory risk factors. Early imaging, prompt surgical source control, and guideline-concordant antimicrobial therapy are essential when bone and soft tissue involvement is present.

Objective We sought to characterize factors associated with postoperative complications in patients undergoing primary cleft lip repair (CLR). Design The National Surgical Quality Improvement Program-Pediatric database was queried to identify patients under 12 months old undergoing CLR using CPT codes. Multivariable analysis was conducted to characterize complications and associated comorbidities. Setting A multicenter sample. Patients/Participants A total of 11 957 cases (81.9% unilateral CLR and 18.1% bilateral CLR) were identified. Interventions None. Main Outcomes/Measures The postoperative outcomes of significance were surgical site infection (SSI), wound dehiscence, and unplanned reintubation within 30 days of CLR. Results The cohort had a mean age of 4.7 ± 2.0 months and a median American Society of Anesthesiologists classification of 2. SSIs occurred in 0.6% of cases and were independently associated with bilateral cleft anatomy (OR 2.16, P = .003) and longer anesthesia time (OR per minute: 1.004, P = .009). Wound dehiscence occurred in 0.4% of patients and was independently associated with bilateral cleft anatomy (OR 4.03, P < .001) but was associated with shorter anesthesia duration (OR per minute: 0.991, P < .001). Unplanned reintubation occurred in 0.2% of cases, with these patients having significantly higher rates of multiple comorbidities. Conclusion Wound dehiscence, SSI, and unplanned reintubation were rare complications following CLR. Patients with a bilateral cleft lip had increased odds of both SSI and wound dehiscence.

Abstract Metabolic reprogramming is a fundamental determinant of immune cell fate and effector function during inflammation, yet how distinct metabolic pathways regulate pathogenic lung macrophage activity and contribute to fibrotic remodeling remains incompletely understood. Here, we integrated single-cell RNA sequencing, lineage-specific genetic mouse models, and fate-mapping approaches to define the metabolic pathways that regulate the pro-fibrotic activity of lung macrophages. We found that such cells undergo pronounced aerobic glycolysis in the bleomycin-induced mouse model of pulmonary fibrosis. Myeloid cell-specific depletion of lactate dehydrogenase A (Ldha), but not of mitochondrial pyruvate carrier (Mpc), markedly attenuated lung fibrosis and improved survival. Mechanistically, enhanced glycolytic flux increased lactate production, which promoted histone lysine lactylation and facilitated Arginase 1 (Arg1) expression in lung macrophages, thereby driving fibrotic progression. Using monocyte fate-mapping, we further demonstrated that Arg1 expression is largely restricted to recruited monocyte-derived macrophages rather than lung-resident macrophages. Notably, selective deletion of Ldha in granulocyte-monocyte progenitors and their progeny was sufficient to suppress Arg1 expression and reduce fibrosis severity. In human lung samples, we observed significantly elevated expression of ARG1 and key glycolytic enzymes in patients with idiopathic pulmonary fibrosis, despite species-specific differences in the immune cell types expressing ARG1. Together, these findings identify an aerobic glycolysis–lactate–histone lactylation axis that regulates pro-fibrotic myeloid cell function and represents a potential therapeutic target in pulmonary fibrosis.

Background: A summary of pharmacist-based practices and preferences regarding the prevention and management of high-dose methotrexate (HDMTX) toxicity in patients with lymphoma does not exist. The objective of the study was to describe current practices surrounding management of HDMTX therapy. This was done through a self-administered, web-based, cross-sectional survey of hematology/oncology pharmacists to ascertain practices and individual attitudes about HDMTX therapy management. Responses were summarized with descriptive statistics. Response comparisons were made using Chi-square or Fisher’s exact test for categorical data, and Kruskal-Wallis test for variables on the Likert scale. A total of 175 pharmacists provided 116 eligible surveys [68 (59%) complete responses and 48 (41%) partial responses] for analysis. The Cockcroft-Gault estimated creatinine clearance formula was the most preferred method (61%) to estimate kidney function and determine HDMTX dosing. Respondents would proceed with HDMTX therapy until the predicted risk of AKI, or AKI stage 2 or 3, exceeded 50% and 20%, respectively. Preferred treatment modifications for a high predicted AKI risk after HDMTX exposure included additional prehydration, HDMTX dose reduction, and increased kidney function monitoring, although levels and degrees of agreement varied. Respondents indicated that serum cystatin C-based GFR estimates lacked evidence, accuracy, and practicality in HDMTX therapy management. There was limited familiarity with cell cycle arrest biomarker use during HDMTX therapy. Glucarpidase was considered time-sensitive and highly effective; however, acquisition cost represented a barrier to use, and the optimal dose was felt to be unknown. In conclusion, there is significant heterogeneity in supportive practices and beliefs about the optimal management for patients with lymphoma receiving HDMTX therapy.

Introduction Cerebellar transcranial direct current stimulation (tDCS) combined with language therapy can aid in chronic aphasia recovery, but the neural mechanisms and biomarkers of treatment efficacy remain uncertain. Methods In this secondary analysis of data from a previously conducted clinical trial, we used a randomized, double-blind, sham-controlled, within-subject crossover design with a study sample of 19 participants with post-stroke aphasia. We assessed the degree to which baseline properties of cerebro-cerebellar white matter tracts can predict or moderate longitudinal treatment effects at three time points: post-treatment, 2 weeks post-treatment, and 2 months post-treatment. Tract properties were measured by fractional anisotropy (FA) and mean diffusivity (MD) from diffusion tensor imaging (DTI). We also tested whether there are differential effects between trained and untrained language tasks and between cerebellar tDCS polarity (anodal and cathodal). Results Baseline measures of tracts connecting the left lesioned cortex to the right posterolateral cerebellum (stimulation target) influenced treatment gains for untrained tasks, relative to sham control. In contrast, for the trained task, treatment gains were influenced by baseline measures of tracts connecting the non-stimulated left cerebellum with the contralateral right cerebral cortex. Although there were no consistent effects from cerebellar tDCS polarity, a highly consistent pattern emerged across all tasks and tracts. Specifically, language improvements were predicted by a baseline tract profile (i.e., higher FA and lower MD) typically associated with higher white matter integrity, especially within the context of stroke-induced white matter decline. Discussion These findings corroborate the potential for baseline tract properties as a biomarker of treatment efficacy and support the notion that adjuvant (cerebellar tDCS + language) therapy preferentially benefits individuals with relatively preserved structural connections within functionally relevant networks. Clinical trial registration ClinicalTrials.gov , identifier (NCT02901574).

ABSTRACT The objective of this study is to describe outcomes of rapid exome (rES) and rapid genome sequencing (rGS) in an inpatient setting. This is a retrospective cohort of inpatients with rES or rGS during their hospitalization between April 2016 and November 2023. Medical records were reviewed to measure primary outcomes: diagnostic yield, medical management changes, and anticipatory guidance updates. Descriptive analysis and formal comparisons (Welch's t ‐test with post hoc power analysis, Fischer's exact test) were performed, with rES and rGS comparisons limited to 2023 due to test distribution. Of 95 patients, most (74.7% [71/95]) were < 12 months old and admitted in neonatal (44.2% [42/95]) or pediatric (29.5% [28/95]) intensive care units. Common indications for rapid sequencing included multiple congenital anomalies (24.2% [23/95]), neurological concerns (23.3% [22/95]), and acute illness (16.8% [16/95]). Mean turnaround time of testing significantly shortened for rES from 2021 (13.2 [SD = 5.9] days) to 2023 (8.1 [SD = 4.1] days) ( p ‐value = 0.018; power = 0.74). Diagnostic yield was 29.5% (28/95) and did not significantly differ between rES (13.6% [3/22]) and rGS (35.0% [7/20]) ( p ‐value = 0.15). Sequencing led to medical management changes (86.0% [74/86]) and anticipatory guidance updates (41.4% [39/95]) with similar rates observed in diagnostic and non‐diagnostic tests. Our findings suggest rES or rGS implementation may influence diagnosis and care strategies in critically ill patients.

Abstract Background: Two years of adjuvant abemaciclib plus endocrine therapy is approved and guideline-recommended in patients (pts) with HR+, HER2-, node-positive, early breast cancer (EBC) at high risk of recurrence. In initial real-world studies, the high rate (&gt;85%) of treatment (tx) persistence beyond 3 months suggests that adjuvant abemaciclib is well-tolerated in routine clinical practice.1,2 Dose reductions were associated with higher persistence in prior studies and clinical trial data have shown that efficacy of abemaciclib was maintained with dose reductions. This study describes 6-month tx persistence and dosing patterns in pts with HR+, HER2-, node-positive EBC initiating abemaciclib 150 mg twice daily (BID). Methods: Retrospective data were accessed from the US de-identified Flatiron Health Research Database. Adults with HR+, HER2-, node-positive, EBC, who initiated abemaciclib 150 mg BID from Jan 2022-Jun 2024 were eligible and further characterized by ≥1 vs no dose reduction. Data cut-off was Dec 2024. Persistence rate was the proportion of pts on abemaciclib &gt;6 months, allowing for ≤60-day medication gap within this period. Time to dose modifications and reasons for discontinuation (DC) were summarized. Subgroup analyses were conducted in pts confirmed as meeting the monarchE high-risk criteria (N2, N3, or N1 plus Grade 3 and/or tumor &gt;5 cm). All analyses were descriptive. Results: Of 1063 eligible pts, median age was 56 years (IQR 47, 65). Most had N1 (48%) or N2 (34%) disease. Median follow-up was 17.5 months (IQR 11, 25). Tx persistence at 6 months was 75%. DC was mostly due to adverse events (AEs; 19%) and &lt;1% due to recurrence. Approximately 50% of pts had ≥1 dose reduction. Persistence was 85% in pts with ≥1 dose reduction and 64% in pts with no dose reductions. 70% of pts who DC’d by 6 months did not have a dose reduction. Median time from start of abemaciclib to first dose change and/or hold was 49 days (IQR 23, 111). During the first 30 days of tx and Days 31-90, DCs due to AEs were lower in pts with dose reductions vs pts with no dose reductions (Table). Persistence and use of dose reductions were similar in pts confirmed as meeting the monarchE high-risk criteria. Conclusion: In US clinical practice, a majority (75%) who initiated adjuvant abemaciclib continued abemaciclib beyond 6 months. Tx persistence was higher among pts with dose reductions relative to those with no dose reductions, and rates of early DCs due to AEs were low in pts with dose reductions. Given that dose reductions in monarchE were not associated with reduced efficacy, these additional real-world data support the use of early dose modifications to improve tolerability and tx persistence for adjuvant abemaciclib in pts with high risk of recurrence. Citation Format: H. Soliman, S. Dent, A. Liepa, V. Stefaniak, M. Huang, T. Sugihara, K. Moreira, K. Hudson, M. Goetz. Treatment Persistence and Dose Modifications in US Patients with HR+, HER2-, Node-Positive, Early Breast Cancer Treated with Adjuvant Abemaciclib [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 PS5-05-09.