Citations

BACKGROUND Predictive biomarkers to guide chemotherapy decisions for metastatic castration–resistant prostate cancer (mCRPC) are lacking. Preclinical studies indicate that circulating tumor cell (CTC) studies of chromosomal instability (CTC-CIN) can predict taxane resistance. METHODS The CARD trial randomized individuals with mCRPC progressing within a year of treatment with an androgen receptor pathway inhibitor (ARPI; enzalutamide or abiraterone acetate plus prednisolone/prednisone) to cabazitaxel or the alternative ARPI. As a preplanned biomarker analysis, CTCs were isolated from blood samples obtained at baseline, cycle 2, and the end of treatment. Associations between baseline CTC and CTC-CIN counts with imaging-based progression-free survival (ibPFS), overall survival (OS), time to prostate-specific antigen (PSA) progression, RECIST 1.1 objective response rate (ORR), and PSA 50 response rate were assessed. RESULTS High baseline CTC-CIN counts significantly associated with worse OS after adjustment for confounding variables (median OS, 15.3 vs. 8.9 months; univariate HR, 2.16; 95% CI, 1.52–3.06; P < 0.001; multivariate HR, 1.56; 95% CI, 1.01–2.43; P = 0.047). Detectable CTC-CIN counts at baseline may predict a lack of ibPFS and OS benefit when comparing cabazitaxel with ARPI. CONCLUSION This preplanned analysis of biomarker data from the CARD trial confirms that CTC-CIN counts are a clinically useful prognostic and predictive biomarker of taxane resistance in mCRPC. Detectable CTC-CIN at baseline defines a patient subpopulation with unmet clinical needs in which alternative therapeutics should be tested. TRIAL REGISTRATION ClinicalTrials.gov number NCT02485691. FUNDING Funded by Sanofi and Epic Sciences.

Background The literature on dyslipidemia and cognitive trajectories among cognitively unimpaired (CU) persons remains inconclusive. Objective To investigate the association between baseline dyslipidemia and change in global and domain specific (i.e., memory, language, attention/executive function, and visuospatial skills) cognition in a population-based setting and whether the association differs by sex, age, or APOE ɛ4 carrier status. Methods We conducted a longitudinal study derived from the Mayo Clinic Study of Aging, involving 4236 CU persons aged ≥ 50 years. We ran linear mixed-effect models to examine baseline dyslipidemia in predicting longitudinal cognitive global and domain-specific z-scores adjusted for age, sex, education, medical comorbidity, repeated cognitive testing, and APOE ɛ4. We examined interactions among dyslipidemia, years since baseline, and separately by sex, age, and APOE ɛ4 carrier status. Results Over a median follow-up period of 6.4 years, CU individuals with dyslipidemia showed faster decline in z-scores of all domains, i.e., memory, language, attention/executive function, visuospatial and global cognition relative to CU individuals without dyslipidemia. Three-way interactions showed that dyslipidemia's effect on decline in z-scores of global cognition, attention and visuospatial skills was less pronounced in males than females. Higher age increased dyslipidemia's effect on decline in z-scores of attention but not global cognition or any other domain. APOE ɛ4 carrier status did not modify the effect of dyslipidemia on cognitive z-scores. Conclusions Dyslipidemia was associated with faster global and domain-specific cognitive decline over time in older community-dwelling individuals who were cognitively unimpaired at baseline. The effect of dyslipidemia on cognitive trajectories may be sex-influenced.

Abstract Background After high‐level spinal cord injury (SCI), motor recovery of wrist extensors has significant functional consequences as it can facilitate grasp through tenodesis. A small seminal study from 1993 established widely used prognostic rules for wrist extensor recovery, though these have not been replicated with larger, real‐world samples since inception. Objective To determine the prognostic value of initial C5 sharp‐dull discrimination, C5 motor strength, and C6 motor strength on predicting 1‐year ipsilateral wrist extensor motor recovery for patients with SCI with neurological level of C4 or C5. Design Retrospective cohort replication study. Setting SCI Model Systems. Participants 35,675 total individuals with acute traumatic SCI with 219 cases of initial wrist extensor weakness (0/5–2/5) meeting inclusion criteria. Intervention Not applicable. Main outcome measure Recovery of wrist extensor strength to ≥3/5 at 1 year. Results The positive predictive and negative predictive values were 57% (95% CI, 47.4%–66.1%) and 66% (56.0%–75.1%) if initial C5 sharp‐dull discrimination was present, 61% (52.7%–69.3%) and 82% (71.4%–89.7%) if initial C5 myotome strength was at least antigravity, and 74% (63.7%–82.5%) and 74% (65.5%–81.4%) if initial C6 myotome strength was at least a 1/5 or 2/5. Synthesizing these three rules, an updated branched nomogram for functional wrist extensor recovery prediction was created. Conclusions In isolation, none of the previously established wrist extensor motor recovery predictive rules had as high of a prognostic value when using a larger dataset. As such, singular reliance on these prediction rules to identify who will gain 1‐year antigravity wrist extension should be approached with decreased certainty. The best positive and negative predictors were trace C6 strength and absent C5 strength, respectively. An updated nomogram provides more nuanced prognostic information to guide clinical care following acute SCI.

469 Background: Febrile neutropenia (FN) is a potentially life-threatening complication of myelosuppressive chemotherapy. Multiple professional organizations, including the American Society of Clinical Oncology (ASCO), Infectious Diseases Society of America (IDSA), National Institute for Health and Care Excellence (NICE), European Society for Medical Oncology (ESMO), and National Comprehensive Cancer Network (NCCN), have developed clinical guidelines addressing FN management. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework offers a structured method for assessing the evidence underlying these recommendations. Methods: A comparative analysis was conducted across guidelines. Key domains, including definitions, risk stratification, empiric antimicrobial therapy, duration of antimicrobial therapy, use of granulocyte colony-stimulating factor (G-CSF), and antimicrobial prophylaxis were assessed. Recommendations were analyzed for concordance and the certainty of supporting evidence was appraised using the GRADE framework. The certainty of the evidence was graded as high, moderate, low, or very low. Results: All five guidelines uniformly defined FN as fever ≥38.3°C or sustained ≥38.0°C accompanied by neutropenia (absolute neutrophil count <500 cells/µL), despite very low-certainty evidence supporting these specific thresholds. Risk stratification using validated tools, such as the Multinational Association for Supportive Care in Cancer (MASCC) score and the Clinical Index of Stable Febrile Neutropenia (CISNE), is recommended based on moderate-certainty evidence. Empiric monotherapy with anti-pseudomonal beta-lactam agents is recommended across guidelines and supported by high-certainty evidence. Antifungal therapy is recommended for persistent fever beyond 4–7 days in high-risk patients based on low-certainty data. Variability was noted in the suggested duration of antibacterial therapy and the role of therapeutic G-CSF based on low-certainty evidence. Recommendations for antimicrobial prophylaxis are consistent across high-risk populations. Conclusions: Despite broad agreement in foundational management principles for febrile neutropenia, differences exist in the application of therapeutic G-CSF and the duration of empiric antibiotics. These findings underscore the need for high-quality clinical trials to inform harmonized, evidence-based recommendations. This synthesis identifies priority areas for stewardship initiatives and quality-of-care improvement.

606 Background: NCCN guidelines are among the most comprehensive and widely adopted clinical practice standards in oncology, frequently used by both clinicians and payors across the United States. Theys encompass three main categories: treatment, detection/prevention/risk reduction, and supportive care. While the evidence base for treatment recommendations has been examined in prior studies—and early detection guidelines largely align with those from other major medical societies—the strength of evidence supporting recommendations in supportive care guidelines remains poorly characterized. Methods: We conducted a systematic analysis of the categories of evidence and consensus (EC) supporting recommendations in 5 widely utilized NCCN supportive care guidelines (versions 2025): antiemesis, cancer-related fatigue, distress management, hematopoietic growth factors, and smoking cessation. Recommendations were classified into the following EC levels: category 1 (high-level evidence with uniform consensus [>85%]), category 2A (lower-level evidence with uniform consensus), category 2B (lower-level evidence with moderate consensus [50–84%]), and category 3 (any level of evidence with major disagreement). Results: Of the 120 recommendations found in the 5 guidelines of supportive care, the proportions of category I, IIA, IIB, and III EC were 18%, 82%, and 0%, and 0%, respectively. Recommendations with category I EC were found in antiemesis supportive care (30%), cancer-related fatigue (21%), distress management (12%), hematopoietic growth factors (20%), and smoking cessation (13%) guidelines. Conclusions: A substantial proportion of recommendations in the NCCN supportive care guidelines are derived from lower levels of evidence. While these guidelines are invaluable in standardizing care and guiding clinical decision-making, their reliance on expert opinion underscores a critical gap in the oncology evidence base. This situation presents both a challenge and a compelling opportunity to design and conduct rigorous clinical research that can validate current practices, inform future recommendations, and further improve patient outcomes. Level of recommendation by guideline. Guideline Recommendations I IIA IIB III Antiemesis 23 30% 70% 0% 0% Cancer-related fatigue 19 21% 79% 0% 0% Distress management 43 12% 88% 0% 0% Growth factors 19 20% 80% 0% 0% Smoking cessation 16 13% 87% 0% 0%

Introduction Male circumcision (MC) has been shown to decrease transmission of HIV and is a critical strategy to decrease its incidence in countries with high rates of heterosexually transmitted HIV. Early infant MC (EIMC), with single-use MC devices, could increase rates of MC in Sub-Saharan Africa. Our objective was to determine the safety, efficacy and satisfaction of ShangRing EIMC in resource-constrained environments. Methods Healthy male infants aged 1–60 days underwent ShangRing EIMC performed by non-physician clinicians in 14 sites in Kenya, Tanzania and Uganda. The primary outcomes were the safety and efficacy of ShangRing EIMC. Secondary outcomes were pain related to the procedure, wound healing and parental satisfaction. Male infants were assessed at discharge and on postoperative days 7 and 28 for wound healing and complications. This trial is registered with Clinical.Trials.gov, NCT03338699 , and is complete. Results From the 1697 participants enrolled from February to November 2020, 1691 (99.6%) underwent ShangRing EIMC. Median duration of the procedure was 10 min (IQR 6–13). The mean Neonatal Infant Pain Scale 20 min postprocedure was 0.3 (SD 0.8), indicating no pain. At the time of discharge, 1679 (99.0%) participants had a normal-appearing wound and 1574 (93.1%) demonstrated complete wound healing at 28 days. A total of 17 (1.0%) AEs were reported, most related to bleeding. A total of 1635 (99.1%) of parents were satisfied with the appearance of the circumcised penis at 28 days. Conclusion ShangRing EIMC is a simple and successful MC method that non-physician clinicians can perform safely, with low AE rate, satisfactory wound healing and high satisfaction rate among parents. This indicates that the ShangRing EIMC can be considered a long-term strategic approach to accelerate the scale-up of MC in Sub-Saharan Africa. Trial registration number NCT03338699 .