Citations

Abstract Background In randomized clinical trials (RCTs), anticipating control arm outcomes is important for power calculations and enrollment goals. Unexpected overperformance of the control arm can underpower RCTs. The objective of this study was to estimate the prevalence of control arm overperformance in phase 3 oncology RCTs. Methods The authors conducted a meta‐epidemiological study of two‐arm, superiority‐design, phase 3 oncology RCTs. They reviewed articles/publications and protocols for power calculations, justification, and outcomes. Control arm performance was measured as the ratio of observed control arm outcomes relative to pretrial estimates, and overperformance was defined as a 10% improvement. Results In total, 385 RCTs met inclusion criteria. The primary end point was overall survival (OS) in 134 RCTs (35%). Of 311 RCTs (81%) that provided a pretrial estimate for control arm performance, 138 RCTs (44%) cited a justification for the estimate. Greater than expected control arm performance was associated with lower odds of meeting the primary end point (adjusted odds ratio, 0.989; 95% confidence interval, 0.981–0.998; p = 0.015). Of 244 RCTs that were evaluable for control arm performance, 104 (43%) exhibited overperformance. RCTs that used OS as a primary end point were more likely to exhibit control arm overperformance compared with RCTs that used other primary end points (56% vs. 33%; adjusted odds ratio, 2.43; 95% confidence interval, 1.42–4.15; p = .001). Conclusions Control arm overperformance is common in phase 3 oncology RCTs and is associated with trial outcomes, suggesting an effect on study power. Because overperformance appears to be especially prevalent when OS is the primary end point, the effects of postprogression therapies on OS may be underappreciated. Alternative strategies for designing trials should be considered for reliable estimation of treatment effects.

ABSTRACT Background Sentinel lymph node (SLN) biopsy is a critical staging tool in skin and soft tissue cancers. Although technetium lymphoscintigraphy is the most common adjunct, indocyanine green (ICG) demonstrates a promising alternative in pediatric, adolescent, and young adult (AYA) skin and soft tissue cancers. Methods and Objectives Evaluate the safety and efficacy of ICG in SLN biopsy (SLNB) in diverse pediatric and AYA solid cancers in a multi‐institutional environment. This is a prospective, observational study conducted at 13 member institutions in the Pediatric Surgical Oncology Research Collaborative between 2019 and 2023. Eligible patients underwent SLNB for primary or recurrent solid skin and soft tissue tumors. Peritumoral ICG was administered intraoperatively. Outcomes included SLN detection rates, histopathology of excised specimens, and surgeon‐reported assessment of utility. Safety was assessed through adverse event reporting. Results Forty SLNB procedures yielded 84 specimens: 13 melanoma (32.5%), 12 squamous cell carcinoma (30%), 11 non‐rhabdomyosarcoma soft tissue sarcoma (27.5%), two rhabdomyosarcoma (5%), one Ewing sarcoma (2.5%), and one malignant peripheral nerve sheath tumor (2.5%). Histologic evaluation identified 81 lymph nodes, 75 benign (89.3%) and six malignant (7.1%); three specimens were adipose tissue (3.6%). Of 81 lymph nodes, 76% were ICG‐positive. ICG had a sensitivity of 79.5%, a specificity of 33%, and a positive predictive value of 96%. All malignant nodes were ICG‐avid. There were no adverse reactions to ICG at 30 days. Conclusions ICG is a safe and effective adjunct for SLNB in pediatric and AYA soft tissue and skin malignancies.

In this short report, we detail new data on the upper limits of human energy expenditure (9.6 times basal metabolic rate) and water turnover (10.5 L·12 h −1 ) during continuous single-day exercise in the cold. Our results indicated elevated energy use, and impressively, water turnover comparable to exercise in warmer conditions. These findings have implications for training and endurance performance of strenuous exercise in cold weather environments.

Abstract In a real-world analysis of brexucabtagene autoleucel recipients with relapsed/refractory B-cell acute lymphoblastic leukemia (N = 278), lack of response to prior blinatumomab correlates with significantly worse following chimeric antigen receptor T-cell therapy outcomes.

BACKGROUND AND OBJECTIVES: Myelomeningocele is defined by the presence of a fluid-filled sac that contains the neural placode and cerebrospinal fluid (CSF) at the level of the spinal defect. Alternatively, the term myeloschisis is used when the neural placode is not contained within a CSF-filled sac. While both are eligible for prenatal closure, few studies have characterized the impact of the type of lesion on postnatal outcomes. This study compares the outcomes of these 2 types of open spinal dysraphism using data from the Fetal Myelomeningocele Consortium registry sponsored by the North American Fetal Therapy Network. METHODS: The prospective observational Fetal Myelomeningocele Consortium registry was used to extract deidentified data corresponding to patients who underwent fetal closure of myelomeningocele vs myeloschisis. Demographics, operative characteristics, perioperative complications, and postnatal outcomes were collected. RESULTS: A total of 1327 patients were identified, including 991 (74.7%) with myelomeningocele and 336 (25.3%) with myeloschisis. Compared with myelomeningocele, myeloschisis was associated with lower rates of prenatal talipes (11% vs 24%, P < .001) and higher rates of favorable prenatal movement (94% vs 86%, P < .001). Postnatally, myeloschisis conferred higher rates of leg movement (97% vs 90%, P = .002) and an increased likelihood of ambulation in the household (10.4% vs 4.1%, P = .009) and outside (7.2% vs 1.9%, P = .004) at 1 year. However, myeloschisis was also linked to greater use of skin patches during closure (49% vs 27%, P < .001), higher CSF leak rates among those with wound dehiscence (26% vs 8%, P = .014), and more frequent CSF diversion and tethered cord surgeries at follow-up. CONCLUSION: Myeloschisis and myelomeningocele demonstrate distinct clinical profiles. Although patients with myeloschisis may have favorable motor outcomes, they are also characterized by higher rates of CSF leakage, CSF diversion, and tethered cord surgery. These findings highlight the need for lesion-specific prognostication and may inform surgical planning and parental counseling in the context of prenatal spina bifida closure.

Abstract Background Alcohol consumption and its relationship with cardiovascular disease (CVD) remains controversial. Observational studies have reported J-shaped associations suggesting cardioprotective effects of moderate drinking, while other observational and Mendelian Randomization studies have found dose-response harm. Biases such as abstainer misclassification, sick quitter effects, and residual confounding may obscure true associations. This study aimed to reassess alcohol’s impact on CVD using novel methods to minimize bias. Purpose We evaluated the relationship between alcohol and subclinical (coronary artery calcium [CAC]) and clinical (myocardial infarction [MI], stroke, cardiovascular death, major adverse cardiovascular events [MACE], and heart failure) outcomes in the Multi-Ethnic Study of Atherosclerosis (MESA). We compared conventional models with those using (1) occasional drinkers as the reference group instead of lifetime abstainers and (2) intention-to-treat (ITT) reallocation of former drinkers based on past drinking patterns. Methods MESA is a prospective cohort study of 6,814 participants aged 45-84 years without baseline CVD. Alcohol use was classified as lifetime abstainer, former drinker, or current drinker (occasional [≤1 drink/week], light [2-7 drinks/week], moderate [8-14 drinks/week], heavy [&gt;14 drinks/week]). We used multinomial logistic regression for CAC and Cox proportional hazards models for clinical outcomes across four models: (1) non-drinker reference, (2) lifetime abstainer reference, (3) occasional drinker reference, and (4) occasional drinker reference with ITT reallocation of former drinkers to their previous drinking levels. Results Increasing alcohol consumption correlated with a dose-response increase in CAC. Heavy drinking was consistently associated with severe CAC (&gt;300). In fully adjusted models, light (OR: 1.23, 95% CI: 1.02-1.48), moderate (OR: 1.27, 95% CI: 1.04-1.55), and heavy drinking (OR: 1.42, 95% CI: 1.12-1.78) were associated with higher CAC scores compared to occasional drinkers. Traditional models replicated protective effects of moderate drinking for MI and cardiovascular mortality. However, these associations attenuated in adjusted models. Moderate drinking showed an attenuated, non-significant benefit for MI (HR: 0.64, 95% CI: 0.38-1.06) and cardiovascular mortality (HR: 0.81, 95% CI: 0.53-1.25) in fully adjusted models. Light drinking shifted from null to increased risk for MI (HR: 1.46, 95% CI: 1.11-1.92), stroke (HR: 1.54, 95% CI: 1.17-2.03), MACE (HR: 1.33, 95% CI: 1.12-1.57), and heart failure (HR: 1.42, 95% CI: 1.10-1.84). Conclusion Adjusting for abstainer and sick quitter biases altered the observed relationship between alcohol and CVD, showing increased harm with light drinking, attenuated protective effects of moderate drinking, and a dose-response relationship for CAC in bias-adjusted models. These findings illustrate the importance of methodology in alcohol-CVD relationships.