Citations

ABSTRACT Background Blinding mitigates bias in randomized trials and may be especially crucial for surrogate endpoints, such as progression‐free survival (PFS). Here, we characterize utilization of and factors associated with blinding in Phase III oncology trials with PFS primary endpoints. Methods Two‐arm, superiority‐design trials investigating systemic therapy were identified in May 2024 from ClinicalTrials.gov with no date limitation. Trials were required to have a PFS primary endpoint. The study outcomes were the presence of double‐blind designs and blinded independent central review (BICR) for the primary endpoint. Ninety‐five percent credible intervals for binary outcomes were estimated from beta distributions, and multivariable logistic regressions explored associations with trial‐level features. Results After screening, 237 trials were included, enrolling 127,518 patients. A double‐blind design was used in 105 trials (44%, 95% CrI 38%–51%). BICR was used in 111 trials (47%, 95% CrI 41%–53%), including 39 double‐blind trials (16%, 95% CrI 12%–22%). Trials with BICR had higher odds of meeting the primary endpoint (OR 1.84; 95% CI 1.06–3.18; p = 0.03). The PFS assessor identity (central vs. local) or blinding status was not reported in 50 trials (26%, 95% CrI 16%–27%). Trials that met prespecified significance criteria for PFS were more likely to report whether PFS assessors were blinded/unblinded and central/local (OR, 3.05; 95% Cl: 1.60–5.81; p = 0.0007). Conclusions Despite the importance of double blinding in combination with BICR for reducing bias, only a few trials blinded physicians, patients, and primary endpoint assessors. This meta‐epidemiological study illuminates the prevalence of potential assessment biases affecting PFS in Phase III oncology and secondarily emphasizes the need for improved methodology reporting.

Abstract Tisagenlecleucel (tisa-cel) is a CD19-directed chimeric antigen receptor T-cell therapy for relapsed/refractory precursor B-cell acute lymphoblastic leukemia (R/R B-ALL). We report infectious complications for 100 days (D100) following tisa-cel therapy in 471 pediatric and young adults (median age 13.8 years) with R/R B-ALL reported from September 2017 to June 2022. By D100, 137 (29%) patients had an infectious event, with an infection density of 0.542 per 100 person-days at risk. D100 cumulative incidences of bacterial, viral, and fungal infections were 14.1%, 11.6%, and 1.3%, corresponding to infection density scores of 0.296, 0.213, and 0.033 per 100 person-days at risk, respectively. In a multivariable analysis, receipt of ≥3 lines of therapy before tisa-cel (hazard ratio [HR], 1.86; 95% confidence interval [CI], 1.13-3.08; P = .015), any-grade cytokine release syndrome (HR, 1.78; 95% CI, 1.17-2.71; P = .007), and lack of neutrophil recovery (HR, 2.63; 95% CI, 1.47-4.69; P = .001) were associated with an increased risk for any infection. Similar associations were observed for bacterial infections, with the addition of younger age as an adverse risk (<6 vs 6-15 years; HR, 2.38; 95% CI, 1.23-4.61; P = .01). Risk factors for viral infections included increasing age (1-year increase; HR, 1.05; 95% CI, 1.01-1.09; P = .016), prior history of any infection (HR, 2.76, 95% CI, 1.40-5.46; P = .004), and prior hematopoietic cell transplant (HR, 2.10; 95% CI, 1.18-3.71; P = .011). D100 infection-related mortality (IRM) rate was low at 0.2% (95% CI, 0.0-0.8). In this multicenter real-world study, we observed a high incidence of infectious complications but a low IRM following tisa-cel for R/R B-ALL.

Pelvicalyceal invasion (PCI) is a relatively novel pT3a staging parameter for renal cell carcinoma (RCC) nephrectomies. While interobserver reproducibility staging studies of sinus/vascular invasion in RCC exist, a similar evaluation for PCI has not been performed. Moreover, in our experience, there is also diagnostic variability in how pathologists interpret PCI. Herein, we explore interobserver reproducibility among genitourinary (GU) pathologists. Twenty hematoxylin and eosin-stained digitized slides from RCCs (all grossly approaching the renal pelvis) were distributed to 31 GU pathologists to classify each as PCI or not PCI based on their respective clinical practices; slides with concomitant sinus/fat/vascular invasion were excluded. Slides were then evaluated for the following 4 morphologic features: tumor abutting renal pelvis, tumor pushing/indenting into the renal pelvis, polypoid configuration of tumor into the renal pelvis, and tumor eroding through renal pelvic urothelium. Interobserver reproducibility was assessed, and the morphologic features were correlated with PCI. Relationships between pathologists’ interpretations, morphologic features, and PCI were evaluated using hierarchical clustering. Although the diagnosis of PCI was relatively uniform with a majority agreement (>67%) reached in 16/20 slides, overall interobserver reproducibility was only moderate (kappa=0.601). While all 4 morphologic features were sensitive for PCI, polypoid configuration of the tumor into the renal pelvis and the tumor eroding through the renal pelvic urothelium were most specific (90%, 100%, respectively). Although we show general consensus among genitourinary pathologists on PCI assessment, clarifying the diagnostic guidelines with specific criteria should be included in pathologic staging systems.

ABSTRACT Background Preparation of the right ventricular outflow tract (RVOT) using covered stent placement is a common preparatory step for transcatheter pulmonary valve replacement (TPVR) to reduce the risk of disruption associated with dilating calcified RVOT conduits. Aim We present a novel method employing a self‐expanding covered aortic endoprosthesis and discuss its advantages as an alternative strategy. Methods Patients with congenital heart disease undergoing RVOT conduit preparation with the GORE TAG Thoracic Branch Endoprosthesis Extender (W.L. Gore & Associates, Newark, DE) followed by TPVR, were prospectively enrolled in a dedicated database. To date, 14 patients have been included. Data on demographics, diagnoses, procedural details, hemodynamic parameters, and outcomes were analyzed. Results Fourteen patients (median age: 35 years [range: 18–79]; 57% female) successfully underwent endograft placement immediately before TPVR. Treated conduits included pulmonary homografts ( n = 8), surgical bioprostheses ( n = 2), Hancock conduit ( n = 1), Contegra conduit ( n = 1), native RVOT ( n = 1), and Melody valve within a surgical bioprosthesis ( n = 1). Most patients presented with mixed stenosis and regurgitation ( n = 9), with the remaining having stenosis ( n = 4) or regurgitation ( n = 1). Valves implanted post‐preparation included the Sapien S3 valve (Edwards Lifesciences, Irvine, CA) ( n = 10) and the Melody valve (Medtronic, Minneapolis, MN) ( n = 5). Significant reductions in RVOT systolic gradient were observed (median 34 mmHg pre‐procedure to 3 mmHg post‐procedure), along with marked conduit expansion (median diameter 13 mm pre‐procedure to 25.5 mm post‐procedure). No complications were reported. Conclusions This study highlights the feasibility of a self‐expanding aortic endoprosthesis for RVOT preparation before TPVR. Further comparative study is warranted. Procedural success was achieved in all cases.

Objective: To determine the impact of modifiable surgical factors on ossiculoplasty outcomes after controlling for ear environment risk. Study Design: Multi-institutional retrospective review. Setting: Six tertiary care centers from 2011 to 2019. Patients Adults and children. Interventions: Ossiculoplasty, including synthetic ossicular replacement prosthesis, autograft interposition, bone cement repair, and mobilization. Main Outcome Measure: Correlation between modifiable surgical factors and pure-tone average air-bone gap (ABG) at most recent audiogram after controlling for preoperative risk using the statistically validated Ear Environment Risk (EER) score. Results: A total of 1,679 cases were included with a median follow-up time of 20 months (IQR, 5–51). After controlling for EER score, malleus engagement of prosthesis yielded favorable ABG versus direct contact to tympanic membrane without malleus engagement (beta = −2.4 dB [−3.8, −1.1], p < 0.001). For total ossicular replacement prostheses (TORP), use of a footplate prosthesis yielded favorable ABG as compared with no footplate prosthesis (−3.6 dB [−6.1, −1.1], p = 0.005). For synthetic prostheses, polyethylene prostheses had a less favorable ABG compared with full titanium or titanium with hydroxyapatite prostheses ( p < 0.05). In cases where the malleus was not engaged in reconstruction, amputation of the malleus head yielded worse ABG (+3.9 dB [1.2, 6.7], p = 0.005). There was no significant difference ( p > 0.05) in ABG for single-stage versus multistaged approach, use of a cartilage cap over the prosthesis versus no cartilage, use of bone cement to secure a PORP to the stapes versus no cement, mastoid cavity obliteration versus no obliteration, and incudostapedial joint reconstruction with joint prosthesis/bone cement versus synthetic PORP. Conclusions: With statistical correction for ear environment risk, several modifiable surgical factors are noted to impact ossiculoplasty hearing outcomes. Level of Evidence: 4.

Abstract With global aging, assessing functional status is vital for precision medicine. Electronic Health Records (EHRs), particularly unstructured data, hold abundant information on patient mobility. This study explores using Large Language Models (LLMs) to extract and standardize mobility status from unstructured EHR data (i.e., clinical notes). We annotated 600 clinical notes from three health care institutions located in southeastern Minnesota and west-central Wisconsin, focusing on expressions of mobility and associated impairment. Leveraging the open-source Llama 3 model, we tested various prompting strategies—including zero-shot, few-shot, and task decomposition—and evaluated their performance. Error analysis showed that while the model sometimes inferred impairments without explicit evidence, most errors were clinically reasonable, often reflecting borderline or ambiguous cases. While considering reasonable inference as correct, at the patient-level, Mobility Extraction achieves a micro-average accuracy of 0.952 with an F1-score of 0.962, and Impairment Classification produces a micro-average accuracy of 0.912 and an F1-score of 0.948. A local, deterministic setup improved trustworthiness by ensuring consistent outputs, safeguarding privacy, and demonstrating cross-institution generalizability. These findings highlight the feasibility of LLM-based solutions for extracting mobility functional status from unstructured EHR data, supporting both clinical applications and research.

OBJECTIVES: To compare whether femoral version more closely mirrors the contralateral femur or a population norm estimate of 15 degrees of anteversion. METHODS: Design: Radiologic observational study. Setting: Level I Trauma Center. Patient Selection Criteria: Patients with no history of anatomy-altering femoral injury who underwent bilateral lower extremity computed tomography scans. Outcome Measures and Comparisons: Computed tomographies were analyzed to measure femoral version on each side. The asymmetry in femoral version between left and right in each patient (interfemoral rotational variance [IRV]) was recorded. The difference of each femur's version from a proposed population mean of 15 degrees of anteversion was also recorded. RESULTS: A total of 219 patients with a mean femoral version of 14.9 degrees ± 10.5 degrees of anteversion were included. Mean IRV was 5.3 degrees, compared with 8.2 degrees of mean variation from the population norm of 15 degrees of anteversion (P < 0.001). Five percent of patients had IRV >15 degrees compared with 15% that had femoral rotation >15 degrees from the population mean of 15 degrees (P < 0.001). CONCLUSIONS: In the setting of a comminuted diaphyseal femur fracture, knowledge of the appropriate target for restoration of rotational alignment is critical. This radiologic cohort study found that on average, femoral version more closely mirrors an individual patient's contralateral femur as opposed to a population norm of 15 degrees of anteversion.

Abstract Brexucabtagene autoleucel (brexu-cel) is a chimeric antigen receptor T-cell therapy approved for relapsed/refractory mantle cell lymphoma (R/R MCL). Here, we report real-world effectiveness and safety outcomes of brexu-cel in a prospective study of patients with R/R MCL, including subgroups based on prior treatment with Bruton's tyrosine kinase inhibitor, bendamustine, or autologous hematopoietic cell transplant (auto-HCT) and number of prior therapy lines, using Center for International Blood and Marrow Transplant Research registry data. A total of 476 patients with R/R MCL who received brexu-cel between July 2020 and December 2022 were included in the analysis. With a median follow-up of 13.5 months, the overall response rate was 91% and complete response rate was 82%. One-year overall survival and progression-free survival rates were 76% and 63%, respectively. One-year cumulative incidence of nonrelapse mortality was 8%. Prior auto-HCT was associated with better duration of response within 6 months after infusion (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.28-0.85) but greater risk of immune effector cell–associated neurotoxicity syndrome (odds ratio [OR], 1.66; 95% CI, 1.06-2.60). Prior bendamustine was associated with increased risk of prolonged thrombocytopenia (OR, 1.90; 95% CI, 1.13-3.21). In patients with 1 to 2 prior therapy lines, relapse or progression was less frequent compared with those with ≥3 prior lines (HR, 0.64; 95% CI, 0.42-1.00). Collectively, our results suggest that real-world outcomes with brexu-cel were consistent with those of the ZUMA-2 trial, regardless of prior therapy type or number of prior therapy lines.

Abstract Front-line pharmaceutical interventions for treating acute graft-versus-host disease (GVHD) are not uniformly effective and have toxic side effects. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with potent in vitro and in vivo immunosuppressive functions. Clinical translation of in vitro–generated MDSCs has been limited because of requirements for multiple, high infusion doses, the relatively low yield from peripheral blood–sourced MDSCs (PB-MDSCs), and inconsistent product quality. To circumvent these obstacles, we developed a methodology to generate MDSCs using human induced pluripotent stem cell (iPSC)–derived CD34+ cells. Compared with PB-MDSCs, iPSC-derived MDSCs (iMDSCs) shared similar morphology, phenotype, and suppressive function. We found that the CD14+ iMDSC subset possessed the highest suppressor function. In previous studies, we reported that MDSCs transferred into mice with GVHD lost suppressor function because of inflammasome activation and immature myeloid cell maturation. In striking contrast to human PB-MDSCs, we show herein that iMDSCs retained 95% of suppressor function in vitro despite exposure to lipopolysaccharide (LPS) plus adenosine triphosphate (ATP), which are stimuli that activate the inflammasome via danger-associated molecular patterns released during early posttransplant conditioning and GVHD-induced injury. In an in vivo xenogenic GVHD model with PB mononuclear cells, iMDSCs significantly increased recipient survival without loss of antileukemia effects. iMDSC RNA sequencing and gene knockdown studies revealed that the maintenance of the purine metabolizing enzyme, phosphoglycerate dehydrogenase, during LPS plus ATP treatment, was linked to iMDSC inflammasome resistance. Taken together, these findings provide a platform for translating in vitro–generated, off-the-shelf iMDSCs into the clinic for suppressing a spectrum of adverse immune responses, including GVHD.