Yale Cancer Center

In surgical research, statistical sophistication is too often mistaken for scientific rigor. Across a growing body of plastic surgery literature, adjusted odds ratios, hazard ratios, and regression coef- ficients are frequently presented without the crude event rates or absolute measures of effect that give findings clinical meaning. We describe this phenomenon as "runic statistics": results that are statistically valid yet clinically opaque. Through examples drawn from contemporary plastic surgery studies, we highlight three recurrent interpretive flaws: reliance on statistical significance without consideration of clinical relevance, reporting of relative measures without baseline risks or absolute differences, and conflation of association with causation. We further demonstrate how case-mix imbalances can create apparent contradictions in results (Simpson's paradox), and how identical odds ratios can translate into very different clinical implications depending on the base- line risk. To address these challenges, we propose a thirteen-step reporting framework designed to promote transparency, interpretability, and clinical applicability. Key elements include explicit definition of the estimand, presentation of both crude and adjusted data, translation of relative effects into absolute risks and patient-facing numbers, assessment of minimal clinically important differences, careful handling of confounding, and restraint in the use of causal language. By an- choring statistical reporting in clinical realities, surgical research can remain both methodologically rigorous and directly relevant to patient care. Our goal is not to simplify science, but to ensure that its communication is clear, transparent, and ultimately useful at the bedside.

The fibrotic kidney microenvironment is shaped by cellular crosstalk, extracellular matrix (ECM) remodelling, metabolic reprogramming and spatial heterogeneity. While late-stage ECM changes dominate fibrosis, the role of early-activated matrix proteins remains unclear. Here we show that ECM1 is an early regulator of kidney remodelling. Global Ecm1 knockout mice develop spontaneous fibrosis and early death, whereas ECM1 levels markedly increase in biofluids during chronic kidney disease. Targeting Ecm1 through AAV9-mediated knockdown or fibroblast-specific deletion substantially reduces renal fibrosis. Mechanistically, Ecm1 deletion disrupts the integrin α2β1-RhoC axis, suppressing YAP activity. Reduced YAP nuclear translocation and diminished YAP-TEAD4 complex formation relieve TEAD4-mediated repression of Pgc1a, enhancing mitochondrial oxidative phosphorylation (OXPHOS) and promoting repair. Spatial transcriptomics and proteomics confirm this mechano-metabolic pathway, revealing mitochondrial reprogramming in tubules that counteracts fibrotic progression. Notably, YAP inactivation in fibroblasts limits aberrant activation without impairing their OXPHOS. This selective ECM-mitochondrial crosstalk uncovers a mechano-metabolic pathway in which mitochondrial shifts drive defence against kidney fibrosis.

S0221 investigated weekly vs every 2 weeks dosing of doxorubicin (A) and cyclophosphamide (C) followed by paclitaxel in patients with high-risk early breast cancer. After an interim analysis, random assignment to the 2 AC arms was stopped for futility, and the trial was modified to study only the paclitaxel schedules. Between December 2003 and November 2010, a total of 2716 patients were randomly assigned in a 2 × 2 factorial design to 15 weeks of weekly A and daily C vs 6 cycles of every 2 weeks AC; and weekly paclitaxel for 12 weeks vs 6 cycles of every 2 weeks paclitaxel. Between January 2011 and January 2012, an additional 578 patients were assigned to 4 cycles of every 2 weeks AC and randomly assigned to weekly vs every 2 weeks paclitaxel. Updated survival was assessed using log-rank tests and Cox regression models. We compared outcomes by breast cancer subtype as well. At a median follow-up of 12.1 years, there were no statistically significant differences among the 4 treatment arms in disease-free survival (DFS) (P = .91) or overall survival (P = .34) in the original protocol. Among the 578 patients assigned AC for 4 cycles and randomly assigned to paclitaxel weekly vs every 2 weeks paclitaxel, there were no overall differences in DFS (P = .32) or overall survival (P = .42). As there were no statistically significant outcome differences in DFS or overall survival between the studied schedules of AC and paclitaxel with extended follow-up in the original or revised protocol, either paclitaxel schedule may be recommended, with selection based on toxicity, cost, or patient preference.

Prior work demonstrated racial disparities in lung cancer care for Medicare beneficiaries in the 1990s and early 2000s, with a 13% to 15% difference in receipt of curative therapy between Black and White patients. With the evolving landscape of treatment modalities and the addition of stereotactic body radiotherapy (SBRT) as the standard of care, it is unknown whether disparities have persisted. To assess temporal trends in racial disparities in the receipt of curative treatment, as well as specific curative modalities, for early-stage NSCLC among Medicare beneficiaries. This retrospective cohort study used the Surveillance, Epidemiology, and End Results (SEER)-Medicare linkage to identify 28 287 non-Hispanic Black and non-Hispanic White patients aged 66 to 85 years who received a diagnosis of stage I or II NSCLC in 2005 to 2007, 2011 to 2013, and 2017 to 2019. Statistical analysis was performed from November 2024 to April 2025. Race (non-Hispanic Black compared with non-Hispanic White), as defined in the SEER-Medicare data. Outcomes included receipt of any curative treatment (surgery or radiotherapy) for all patients, receipt of surgery or radiotherapy, and receipt of preferred treatment (lobectomy or SBRT) among patients receiving surgery or radiotherapy, respectively. Disparities in the data were compared with findings from the 1990s and early 2000s. Among 28 287 patients (mean [SD] age, 75.1 [5.3] years; 52.4% men; 7.5% Black and 92.5% White), 82.3% (95% CI, 81.8%-82.7%) received curative treatment. Adjusted probabilities of receiving curative treatment were significantly lower for Black compared with White patients in each period: 73.9% (95% CI, 70.6%-77.1%) of Black patients and 83.3% (95% CI, 82.5%-84.1%) of White patients from 2005 to 2007 (difference, -9.4% [95% CI, -12.8% to -6.1%]; P < .001); 76.3% (95% CI, 73.2%-79.4%) of Black patients and 85.2% (95% CI, 84.4%-86.0%) of White patients from 2011 to 2013 (difference, -8.9% [95% CI, -12.1% to -5.8%]; P < .001); and 78.4% (95% CI, 75.3%-81.4%) of Black patients and 86.8% (95% CI, 86.0%-87.5%) of White patients from 2017 to 2019 (difference, -8.4% [95% CI, -11.6% to -5.3%]; P < .001). Disparities were associated primarily with differences in surgical treatment, with 52.3% of Black patients compared with 65.9% of White patients undergoing surgery from 2005 to 2007, 48.3% of Black patients compared with 61.0% of White patients undergoing surgery from 2011 to 2013, and 43.7% of Black patients compared with 53.1% of White patients undergoing surgery from 2015 to 2017 (P < .001 for all). SBRT use increased sharply, and disparities in its use emerged only during the time interval of its initial implementation, from 2011 to 2013 (Black, 39.6%; White, 51.6%; P = .004). This study suggests that racial disparities in the receipt of curative treatment for early-stage NSCLC among Medicare beneficiaries have persisted since the 1990s, with the most marked differences in the receipt of surgical treatment and significant racial differences in the receipt of SBRT as the therapy emerged. Further work must explore factors that can address and mitigate these disparities.

B-cell maturation antigen (BCMA)-targeting therapies provide a new approach to treating multiple myeloma (MM). Alnuctamab (ALNUC) is a 2 + 1 immunoglobulin G1-based bispecific antibody binding BCMA and CD3ε receptors on myeloma and T cells, respectively. CC-93269-MM-001 is a first-in-human, phase 1 dose escalation/expansion study investigating ALNUC in relapsed/refractory MM. Patients had ≥3 prior regimens, disease progression ≤60 days of last regimen, and were BCMA-directed therapy-naïve. ALNUC was administered intravenously (IV) and subcutaneously (SC); however, SC was selected for further evaluation due to the more favorable safety profile. Ninety-five patients received ALNUC SC; at data cutoff, 44.2% remained on treatment and median follow-up was 8.0 months. The recommended phase 2 dose was 30 mg. The most common treatment emergent adverse events (any grade/grade 3/4) were CRS (57.9%/0%), and neutropenia (53.7%/43.2%). Infections were also frequent (64.2%/14.7%). ORR was 58.9% for all ALNUC SC-treated patients and 71.4% for the 30-mg cohort; 47/95 (49.5%) were measurable residual disease (MRD) negative. Overall, the safety and efficacy of ALNUC SC were comparable to other BCMA-targeted therapies. These results support improved safety of SC versus IV, and corroborate a step-up dosing strategy to mitigate CRS. Importantly, a schedule that de-intensifies over time provides favorable toxicity that may be applicable to other bispecific engagers.