Faculty Bibliography

BACKGROUND/UNASSIGNED:Asbestosis is a progressive interstitial lung disease caused by inhalation of asbestos fibres. Although asbestos use was banned in the Netherlands in 1993, new cases continue to be diagnosed. Since 2014, a national compensation system has enabled systematic assessment of asbestosis incidence and outcomes. This population-based study examined national trends in asbestosis incidence from 2014-2024 and evaluated survival and prognostic factors. METHODS/UNASSIGNED:We conducted a retrospective national cohort study including all adults (≥18 years) diagnosed with asbestosis between 2014-2024 according to Dutch Health Council criteria used for compensation. Diagnoses were established by consensus of three independent pulmonologists based on radiological evidence of diffuse pulmonary fibrosis, ≥5 fibre-years of exposure, and lung function impairment according to American Medical Association (AMA) criteria. Demographic data, lung function, work history and overall survival were collected. Incidence per 100 000 persons per year was calculated. RESULTS/UNASSIGNED:Of 1004 applicants, 476 (47.4%) met criteria for asbestosis. Median age at diagnosis was 77 years, and 98.9% were male. Annual incidence ranged from 0.115 to 0.347 per 100 000, with no significant temporal trend (Spearman rho 0.41; p=0.214). AMA class 4 was most common (44.5%) and strongly associated with mortality (hazard ratio 2.52, 95% CI 1.81-3.49). Older age also predicted poorer survival. Median survival ranged from 25.5 months (AMA 4) to 83.4 months (AMA 0-2). Time-dependent modelling showed increasing hazard over time for AMA class 4. CONCLUSIONS/UNASSIGNED:More than two decades after the asbestos ban, asbestosis incidence remains stable. AMA class and age are key predictors of survival.

BACKGROUND:Patients with breast cancer and limited English proficiency (LEP) experience barriers to care that may result in greater disease burden. We aim to evaluate breast cancer presentation and pathologic characteristics of patients with LEP compared with patients with English proficiency (EP). PATIENTS AND METHODS/METHODS:We performed an institutional review board (IRB)-approved, retrospective review of prospectively collected patient-reported data among a multilingual population evaluated within a New York City safety-net health system between 2018 and 2025. Comparative analysis and logistic regression were used. RESULTS:) compared with EP (31.2% versus 18.5%; p = 0.012) and was significantly associated with completion axillary lymph node dissection compared with EP (12.8% versus 3.6%; p = 0.0041). Patients with LEP had significantly longer time-to-therapy intervals from biopsy to first therapy compared with EP (52 versus 49 days; p = 0.041). On multivariate analysis, both LEP and delays to first therapy were significantly associated with axillary nodal metastasis. CONCLUSIONS:Patients with breast cancer and LEP were significantly more likely to have axillary nodal metastasis compared with patients with EP. Increased axillary nodal metastasis in this population may, in part, be due to lack of screening and delays to breast cancer treatment.

This narrative review examines how endothelin receptor antagonists (ERAs) can be used at the intersection of difficult-to-control hypertension, chronic kidney disease (CKD), and albuminuria or proteinuria. For clinicians, the central question is not receptor selectivity alone, but whether a specific agent, indication, dose, background therapy, and monitoring plan can deliver meaningful blood-pressure or kidney benefit without unacceptable fluid retention. Pulmonary arterial hypertension established the pharmacology and major safety liabilities of the class; the current implementation questions for hypertension and kidney specialists arise in systemic hypertension and proteinuric kidney disease. Aprocitentan is the first and only ERA approved for hypertension; in PRECISION, the approved 12.5-mg once-daily dose reduced placebo-corrected 24-h ambulatory systolic blood pressure by 4.2 mm Hg, with reductions of 4.2 to 5.9 mm Hg across the studied doses. In IgA nephropathy (IgAN), sparsentan reduces proteinuria and slows estimated glomerular filtration rate (eGFR) decline. Atrasentan has an established antiproteinuric effect and a favorable eGFR slope, although the prespecified week-136 eGFR contrast in the final ALIGN analysis did not reach statistical significance. Zibotentan plus dapagliflozin remains investigational. Across these settings, successful ERA use depends on careful patient selection, indication-specific interpretation of the evidence, optimized diuretic and cardiorenal therapy, and early surveillance for edema, anemia, liver-test abnormalities, and pregnancy risk, with treatment interruption or discontinuation when clinically significant volume expansion or other serious safety signals occur.

BACKGROUND:Post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic cell transplantation has been associated with clinically significant graft and organ toxicity at the standard dose (50 mg/kg/day on days +3, +4). We conducted a two-center retrospective cohort analysis to assess outcomes after a uniform dose reduction to 40 mg/kg/day on days +3, +4 (PTCy 40-40). OBJECTIVES/OBJECTIVE:The primary objectives were to evaluate cumulative incidence of acute (aGVHD) and chronic GVHD (cGVHD) and relapse. Secondary objectives included assessment of organ toxicity, engraftment, non-relapse mortality (NRM), progression-free survival (PFS), and overall survival (OS). STUDY DESIGN/METHODS:Patients receiving PTCy 40-40 from 11/2020 to 3/2025 at two academic centers were included. Exclusion criteria were history of aplasia after chimeric antigen receptor T-cell therapy as indication for HCT or history of prior HCT complicated by GF. Only the initial HCT was included for patients who had > 1 allogeneic HCT with PTCy. Patients received cyclophosphamide at a dose of 40 mg/kg/day on days +3, +4 after peripheral blood allogeneic HCT. RESULTS:115 patients received PTCy 40-40. Most patients received reduced-intensity conditioning (80%) from matched unrelated donors (63%). Median follow-up was 9.0 months (range, 4.9-28.8). Median time to neutrophil and platelet engraftment was 14 (range, 11-27) and 19 days (range, 15-55), respectively, with one case of primary graft failure and few cardiac, renal, or hepatic events of interest. Cumulative incidence of grades 2-4 aGVHD by day +180 was 13% (95% CI 8-20), with only one grade 3-4 case. Cumulative incidence of moderate-severe cGVHD by 12 months was 13% (95% CI 7-22). At 12 months, relapse was 18% (95% CI 10-27), NRM 5% (95% CI 2-10), PFS 77% (95% CI 66-85), and OS 84% (95% CI 74-91). CONCLUSION/CONCLUSIONS:PTCy 40-40 resulted in low rates of GVHD, toxicity events of interest, and NRM, with excellent 12-month PFS and OS. Our findings from this two-center retrospective cohort analysis suggest that PTCy 40-40 is safe and effective for GVHD prophylaxis after MAC or RIC HCT from any donor type.

BACKGROUND:Glioblastoma (GBM) is the most aggressive primary malignant brain tumor in adults and demonstrates substantial transcriptomic heterogeneity associated with patient survival. High-dimensional genomic datasets present statistical challenges because the number of measured molecular features often exceeds the number of available patient samples. Penalized regression methods such as Least Absolute Shrinkage and Selection Operator (LASSO) regression enable simultaneous feature selection and survival modeling in these settings. METHODS:Transcriptomic expression and survival data from The Cancer Genome Atlas (TCGA) GBM cohort were analyzed using LASSO-regularized Cox proportional hazards regression implemented through the glmnet package in R. After preprocessing and sample matching, 518 tumor samples and 12,042 transcriptomic features were retained for analysis. Patients were randomly divided into training (n=414) and test (n=104) cohorts. Ten-fold cross-validation using Harrell's concordance index (C-index) was performed to identify optimal regularization parameters. Kaplan-Meier survival analysis was used to evaluate risk stratification performance, and receiver operating characteristic (ROC) analysis was performed for selected candidate genes. RESULTS:Cross-validation identified a maximum C-index of 0.583 at the optimal lambda.min regularization parameter. The final LASSO-Cox model retained 74 genes with nonzero coefficients. Two identified genes, CLEC5A and RANBP17, overlapped with previously reported GBM prognostic genes from an independent study. Kaplan-Meier analysis demonstrated significant survival separation between predicted high-risk and low-risk groups in both the training cohort (log-rank p < 0.0001) and the held-out test cohort (log-rank p < 0.05). ROC analysis of selected candidate genes demonstrated moderate discriminatory performance, with area under the curve values ranging from 0.604 to 0.701. CONCLUSIONS:LASSO-regularized Cox regression identified sparse transcriptomic features associated with survival in TCGA GBM patients. Survival stratification performance persisted in a held-out test dataset, supporting the reproducibility of the derived transcriptomic risk model. These findings demonstrate the applicability of penalized survival modeling approaches to high-dimensional cancer transcriptomic datasets and support further investigation of transcriptomic biomarkers in GBM prognosis.

PURPOSE/OBJECTIVE:Clinical guidelines for interpreting genetic variants in the context of Mendelian disease require converting the outputs of pathogenicity prediction tools into well-calibrated probabilities. However, the existing calibration method is only valid when pre-committing to one tool, preventing clinical laboratories from using multiple tools with complementary strengths. To lift this restriction, we introduce Pathogenicity K-Nearest Neighbors (P-KNN), a flexible method that jointly calibrates any set of tools. METHODS:P-KNN represents each variant in a multidimensional space defined by tool scores and estimates the probability of pathogenicity based on the proportion of pathogenic neighbors. We compared P-KNN against standard single-tool calibration of multiple predictors and meta-predictors at four historical time points. RESULTS:P-KNN outperforms standard calibration of single tools and meta-predictors in two aspects: i) overall evidence strength and ii) alignment of the calibrated probabilities with true pathogenicity frequencies. Additionally, the evidence from P-KNN keeps improving with the addition of newer tools. It also correctly integrates correlated computational and experimental evidence that is overestimated by existing protocols. CONCLUSION/CONCLUSIONS:P-KNN provides robust joint calibration for any set of pathogenicity prediction tools, thereby alleviating the constraint of pre-committing to a single predictor while enhancing statistical rigor and diagnostic yield. P-KNN is available via command line (https://github.com/Brandes-Lab/P-KNN) and precomputed scores (https://huggingface.co/datasets/brandeslab/P-KNN).