Citations

Abstract Purpose: Homozygous deletion of the 9p21 locus, containing CDKN2A/B and MTAP [CDKN2A/MTAP deletion (CMdel)], underlies emerging therapeutic strategies, including PRMT5/MAT2A inhibition. The clinicogenomic context and treatment outcome associations of CMdel in non–small cell lung cancer (NSCLC) remain incompletely defined. Experimental Design: We analyzed Tempus Lens records with paired DNA (xT) and RNA (xR) sequencing. After quality filtering (purity ≥40%), 16,947 patients were included in the primary dataset, and 10,996 were included in the validation dataset and stratified by deletion status [CMdel vs. CM wild-type (CMwt)]. IFN status was defined by IFN-kappa (IFNK) expression [log2(TPM + 1)] using the 25th percentile of CMwt as the threshold. Immune composition was inferred by quanTIseq. First-line regimens were grouped as immune checkpoint inhibitor (ICI) monotherapy, ICI chemotherapy, chemotherapy, or tyrosine kinase inhibitors (TKI). Best response and time to next treatment (TTNT) with risk-set adjustment and 18-month truncation were assessed. Results: CMdel occurred in 11.7% (n = 1,991) and 15% (n = 1,676), respectively, and was enriched in mucinous histology, stage IV disease, and never smokers. CMdel was associated with EGFR, TERT, and SMARCA4 alterations, whereas CMwt was associated with RB1, SETD2, and ARID2. More than 50% of CMdel tumors harbored targetable coalterations, enriched in EGFR/ALK/RET and relatively depleted in KRAS. CMdel tumors exhibited lower PD-L1, mutation burden, and immune infiltration. TTNT did not differ by CM status for ICI monotherapy or TKI but was shorter in CMdel for ICI chemotherapy and chemotherapy. Discordant and broad deletions were less common and had weaker TTNT association. IFNK-low expression marked immune-excluded subgroups with worse treatment outcomes. Conclusions: CDKN2A/MTAP loss defines a prevalent, genomically distinct NSCLC subset enriched in actionable drivers. CMdel associates with worse outcomes to ICI/chemotherapy-containing regimens. These findings highlight convergent biology at 9p21 and support biomarker-guided development of PRMT5/MAT2A inhibitors in MTAP-deleted NSCLC.

Context.— One objective of the College of American Pathologists/American College of Medical Genetics Cytogenetics Committee is to ensure the accurate detection and clinical interpretation of abnormalities observed by fluorescence in situ hybridization (FISH) analysis when evaluating hematologic neoplasms. Objective.— To report a 20-year performance summary (2005–2024) of FISH challenges focusing on hematologic neoplasms. Design.— A retrospective review was performed from 2005 through 2024 to identify FISH challenges specifically addressing hematologic neoplasms. The overall performance of participants was evaluated to identify potential recurring errors of clinical relevance. Results.— A total of 124 hematologic neoplasm FISH challenges from 2005 to 2024 were provided to participating laboratories, including 45 paper challenges (results and/or images were provided for interpretation purposes), 43 liquid challenges (bone marrow aspirate or peripheral blood), and 36 formalin-fixed paraffin-embedded (FFPE) tissue challenges. Of the 124 challenges, 120 (97%) exceeded the required 80% consensus for grading purposes. Of the 4 failed challenges (3%), 2 (1 liquid, 1 paper) involved the interpretation of atypical FISH signal patterns; 1 (paper) involved the interpretation of FISH signal patterns correlating involvement by myeloid versus lymphoid interphase nuclei; and 1 (liquid) likely involved a specimen processing or handling error that resulted in discordant participant responses. All 36 FFPE tissue challenges exceeded the 80% consensus for grading purposes. Conclusions.— This 20-year retrospective review demonstrates that clinical cytogenomic laboratories have been and continue to be highly proficient in the detection and interpretation of FISH abnormalities associated with hematologic neoplasms.

Abstract Background Glioblastoma (GB) exhibits marked tumor microenvironmental heterogeneity, contributing to both therapy resistance and poor survival outcomes. Intercellular adhesion molecule 1 (ICAM1) is an inflammation-associated adhesion molecule implicated in immune-stromal interactions, but its clinical and biological significance in GB remains incompletely defined. Methods We performed ICAM1 immunohistochemistry, bulk RNA sequencing, DNA methylation analysis, single-nucleus RNA sequencing, and preoperative MRI-derived morphologic feature analysis across multi-institutional cohorts of treatment-naïve IDH-wildtype GB. Results High ICAM1 expression at both transcript and protein levels is associated with shorter overall survival, particularly within the mesenchymal transcriptional subtype. ICAM1 expression is inversely associated with promoter methylation. Single-nucleus RNA-sequencing analysis shows that ICAM1-high tumors are enriched for mesenchymal, hypoxia, stress-associated, and immunosuppressive myeloid programs, suggesting that ICAM1 reflects a multicompartment inflammatory tumor ecosystem. ICAM1 expression, tumor surface irregularity, and patient age are independently prognostic and minimally correlated, capturing complementary clinical, imaging, and molecular features of GB biology. When combined, our Clinical-Imaging-Molecular (CIM) framework refines outcome prediction across independent GB cohorts using routinely available clinical data, conventional imaging, and standard immunohistochemistry. Conclusions ICAM1 characterizes an immune-remodeled, stress-adapted GB ecosystem associated with poor clinical outcomes. Integrating patient age, surface irregularity, and ICAM1 expression yields a scalable and clinically accessible prognostic framework for GB, supporting tailored outcome prediction, particularly in low- and middle-resource settings without routine access to advanced molecular profiling.

SignificanceCurrent clinical care following ischemic stroke provides intermittent assessments, potentially missing early detection of neurological deterioration. Optical imaging offers the potential for a continuous, portable alternative to the current combination of physical exams and radiological imaging. However, optical imaging technology has lacked the crucial combination of portability, resolution, and coverage required to assess spatially distributed brain function.AimHere, we present a proof-of-principle study that applies recent advancements in portable high-density diffuse optical tomography (HD-DOT) instrumentation and a functional connectivity analysis strategy to assess spatially distributed brain connectivity. Point-of-care brain health assessments with these tools may inform clinical care and our understanding of brain injury throughout acute stages of stroke recovery.ApproachWe measured spatially distributed cortical oxygenation with HD-DOT within the intensive care unit in N=13 patients with ischemic stroke within the first 72-h since last known normal. To assess brain function integrity, we developed a Similarity metric of functional connectivity (FC) through comparisons to FC in a healthy young adult population. To assess the sensitivity of this FC Similarity metric to disruptions caused by stroke, we compared these data with FC Similarity assessed in an older healthy cohort. We administered the NIH Stroke Scale to stroke patients to evaluate the potential of the FC Similarity metric to inform the severity of functional disruptions.ResultsThe FC Similarity metric applied to HD-DOT data in both acute stroke patients and healthy older controls exhibited a significant sensitivity to the presence of a stroke (Cohen’s d=1.5, p=1.2×10−3) and a significant relationship with the degree of neurological disruption as measured by the NIH Stroke Scale (R2=0.69, p=4.7×10−4).ConclusionsWe present a proof-of-principle for HD-DOT and the FC Similarity metric for assessing brain function during the acute stage of ischemic stroke recovery at the point-of-care.

Abstract Accurate taxonomic profiling of human microbiomes is essential for advancing research and understanding the complex role microbial communities play in human health. When using shotgun metagenomics, the sequencing data is analyzed through metagenomic pipelines, which incorporate various open-source tools and classify microbes based on matched paired-end DNA reads. However, differences in sequencing and computational approaches can produce substantially different microbiome profiles from the same sample, making validation critical. One approach for validation is benchmarking with realistic mock communities, but this remains relatively rare. Additionally, existing benchmarks often overlook microbiome variability across life stages and body sites, limiting their clinical and research utility. Here, we developed age- and body site-stratified synthetic metagenomes, enabling context-aware benchmarking of microbiome pipelines. Using novelty-based sampling to prioritize microbial diversity and minimize redundancy among selected samples, we selected 300 representative, real biological samples spanning six categories: adult, child, toddler, and infant (>6 months and <6 months) gut samples, as well as adult vaginal samples. We validated three pipelines, Tiny Health’s proprietary Metagenomic Classifier v2 (THMCv2), MetaPhlAn4, and Kraken2+Bracken, using precision, recall, F1 score, and area under the precision-recall curve (AUPR) across age groups and sample types. THMCv2 demonstrated higher recall and F1 scores, detecting more taxa across sample types and ages, while MetaPhlAn4 achieved the highest precision. THMCv2 also achieved the highest area under the precision-recall curve, reflecting peak performance across both abundant and rare species. When analyses were weighted by abundance, THMCv2 and MetaPhlAn4 each characterized the mock community nearly perfectly. Errors for THMCv2 were largely restricted to very low-abundance taxa (<0.001%), whereas MetaPhlAn4 occasionally produced false positives for higher-abundance taxa. Species-level analyses of clinically relevant microbes confirmed these patterns, with THMCv2 demonstrating higher sensitivity, MetaPhlAn4 higher specificity, and Kraken2 lower overall performance. These results demonstrate clear precision-recall trade-offs in metagenomic profiling. This benchmarking framework provides a reproducible approach for evaluating pipeline performance across diverse microbiome contexts and life stages.

Patients with plasma cell leukemia (PCL) are generally excluded from pivotal T-cell redirecting bispecific antibody (BsAb) trials. We evaluated real-world outcomes in a multicenter retrospective study of 122 patients with primary or secondary PCL across 15 academic centers, categorized as 'active' (≥5% circulating plasma cells within 30 days of BsAb initiation) or 'historical'. In a heavily pretreated population, patients received teclistamab (37%), elranatamab (11%), talquetamab as a line of therapy (Tal LOT, 42%), or talquetamab as bridging therapy to CAR-T (Tal Bridge, 11%). Cytokine release syndrome (CRS) was grade 1-2 in 56% and grade 3-4 in 4%, whereas neurotoxicity was grade 1-2 in 16% and grade 3-4 in 5%. Among 110 evaluable patients, the overall response rate (ORR) was 55%, including 61% with Tal LOT, 58% with Tal Bridge, 46% with elranatamab, and 33% with teclistamab. With a median follow-up of 8.3 months, talquetamab demonstrated superior survival. Tal LOT showed a median progression-free survival (mPFS) of 5.5 months and a median overall survival (mOS) of 11.5 months, and both were unreached in the Tal Bridge cohort. In contrast, teclistamab and elranatamab showed a mPFS of 1.2 and 1.6 months and mOS of 8.1 and 3.6 months, respectively (P=0.007, P=0.023). In active PCL, Tal LOT achieved mPFS/mOS of 6.9/12.2 months versus 0.7/1.4 months with teclistamab and 1.0/3.1 months with elranatamab, respectively (P&lt;0.001, P=0.002). Multivariable analysis associated active PCL with worse survival and Tal LOT with improved outcomes. BsAbs were safe in PCL, with talquetamab showing superior outcomes compared with BCMA-directed BsAbs.

BACKGROUND: Acoramidis achieves near-complete (≥90%) transthyretin stabilization and is approved to reduce cardiovascular-related mortality and hospitalization in transthyretin amyloid cardiomyopathy. Its effects on kidney function are not well characterized. METHODS: Data from randomized phase 2 (N=49) and phase 3 (N=632) studies in transthyretin amyloid cardiomyopathy were included. The estimated glomerular filtration rate (eGFR) slope was generated using a linear spline mixed-effects model. The urinary albumin-to-creatinine ratio was measured longitudinally. Relationships between changes in kidney function and clinical outcomes were explored using Cox proportional hazards models. RESULTS: Acoramidis initiation resulted in a modest acute dip in eGFR that was dose-dependent, reversible, and not associated with adverse kidney-related events. At Day 28, the mean (±SE) dip in eGFR from baseline with acoramidis was 8.5±0.48 mL/min per 1.73 m 2 ; the placebo-corrected reduction in the urinary albumin-to-creatinine ratio was 15.5% (95% CI, 0.4%–28.4%; P =0.044). The rate of decline in kidney function (chronic eGFR slope) was significantly improved with acoramidis versus placebo (−1.01 versus −3.48 mL/min per 1.73 m 2 per year; P <0.001), and the reduction in the urinary albumin-to-creatinine ratio was sustained (13.7% [95% CI, 1.7%–24.2%]; P =0.026) over time. Concomitant tafamidis use did not influence the chronic eGFR slope in either arm. Comparing acoramidis versus placebo subgroups with acute eGFR dips ≥ the median (4.89 mL/min per 1.73 m 2 ) favored acoramidis for all-cause mortality or cardiovascular-related hospitalization (hazard ratio, 0.42 [95% CI, 0.22–0.78]; P =0.006; P interaction=0.043) and cardiovascular-related hospitalization (hazard ratio, 0.34 [95% CI, 0.17–0.66]; P =0.002, P interaction=0.025). Within the placebo arm, eGFR dips portended worse outcomes. CONCLUSIONS: Acoramidis initiation resulted in an acute dip in eGFR and reductions in both the chronic eGFR slope and urinary albumin-to-creatinine ratio versus placebo without adverse kidney-related events. Acoramidis effects on kidney function may be mediated through direct kidney-protective hemodynamic effects. Importantly, the acute dip in eGFR was associated with a reduced risk of adverse clinical outcomes within the first year. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT03458130, NCT03536767, NCT03860935, NCT04988386.

Importance The NRG Oncology research organization and NSABP B-35 randomized clinical trial prospectively collected margin width data on postmenopausal women with hormone receptor (HR)–positive ductal carcinoma in situ (DCIS) who underwent lumpectomy, whole-breast irradiation (WBI), and randomly assigned adjuvant anastrozole or tamoxifen therapy. This permitted analysis of outcomes per margin width. Objective To analyze the effect of margin width on ipsilateral breast tumor recurrence (IBTR). Design, Setting, and Participants NSABP B-35 was a phase 3, double-blind, randomized clinical trial in which patients were randomized to either 5 years of tamoxifen or anastrozole. Postmenopausal women with HR-positive DCIS and tumor-free margins were eligible. Enrollment was from January 6, 2003, to June 15, 2006, in academic and community hospital members of the NSABP. Study data were analyzed from July 2024 to April 2025. Interventions There were no specific interventions based on lumpectomy margin width. Main Outcomes and Measures Lumpectomy margin width data were prospectively collected within 3 months of randomization. A pathology form classified margins as positive (ink on tumor), close (&amp;lt;1 mm), or negative (≥1 mm). For the negative margin subgroup, closest margin width was stated separately. Thus, an ancillary analysis using 1-mm and 2-mm margin width partitions was performed. Results A total of 3104 postmenopausal women (mean [SD] age, 61 [7.8] years) were enrolled in NSABP B-35. In an ancillary analysis, 2707 patients were included in the 1-mm margin width partition group, and 2546 patients were included in the 2-mm margin width partition group. IBTR was the most common first event, occurring in 90 of 2707 patients (3.3%): 24 of 502 patients (4.8%) with a margin width less than 1 mm and 66 of 2205 patients (3.0%) with a margin width greater than or equal to 1 mm. Ten-year unadjusted cumulative incidence of IBTR events was 5.6% vs 4.0% for margins less than 1 mm vs margins greater than or equal to 1 mm ( P = .04). Using 2 mm as the discriminant threshold for margin width, 39 of 879 patients (4.4%) with margins less than 2 mm and 49 of 1667 patients (2.9%) with margins greater than or equal to 2 mm experienced an IBTR first. Ten-year unadjusted cumulative incidence of IBTR events with margins less than or equal to 2 mm was 5.3% vs 3.8% for those with margins greater than 2 mm ( P = .05). In models adjusting for other patient and tumor factors, margin width was not a significant predictor of IBTR risk (2-mm threshold hazard ratio, 1.33; 95% CI, 0.86-2.06). Conclusions and Relevance Results of this ancillary analysis of the NSABP B-35 trial show that absolute differences in IBTR rates using margin width groupings of less than 1 mm or greater than or equal to 1 mm and margin width groupings of less than 2 mm or greater than or equal to 2 mm in postmenopausal women with HR-positive DCIS receiving lumpectomy, WBI, and adjuvant endocrine therapy were small. Omission of reexcision lumpectomies based on margin widths of less than 1 mm or less than 2 mm can be reconsidered in appropriate patients. Trial Registration ClinicalTrials.gov Identifier: NCT00053898