Improving Accuracy of Somatic Mutation Profiling in Large Epidemiologic Studies: Addressing Cases without Matched Normal Samples.

Ideally, detection of somatic mutations in a tumor is accomplished using a patient-matched sample of normal cells as the benchmark. In this way somatic mutations can be distinguished from rare germline mutations. In large retrospective studies, archival tissue collection can pose challenges in obtaining samples of normal DNA.

Molecular Heterogeneity and Immune Infiltration Drive Clinical Outcomes in Upper Tract Urothelial Carcinoma.

Background And Objective: Molecular classification of upper tract urothelial carcinoma (UTUC) can provide insight into divergent clinical outcomes and provide a biological rationale for clinical decision-making. As such, we performed multi-omic analysis of UTUC tumors to identify molecular features associated with disease recurrence and response to immune checkpoint blockade (ICB).

Methods: Targeted DNA and whole transcriptome RNA sequencing was performed on 100 UTUC tumors collected from patients undergoing nephroureterectomy.

Zanubrutinib, Obinutuzumab, and Venetoclax for First-Line Treatment of Mantle Cell Lymphoma with a TP53 Mutation.

TP53-mutant mantle cell lymphoma (MCL) is associated with poor survival outcomes with standard chemoimmunotherapy. Dual BTK and BCL2-inhibition with or without anti-CD20 monoclonal antibody therapy has shown promising activity in TP53-mutant MCL. We conducted a multi-center phase 2 study of zanubrutinib, obinutuzumab, and venetoclax (BOVen) in untreated MCL patients with TP53 mutation.

Spatial Immunophenotyping from Whole-Slide Multiplexed Tissue Imaging Using Convolutional Neural Networks.

The multiplexed immunofluorescence (mIF) platform enables biomarker discovery through the simultaneous detection of multiple markers on a single tissue slide, offering detailed insights into intratumor heterogeneity and the tumor-immune microenvironment at spatially resolved single cell resolution. However, current mIF image analyses are labor-intensive, requiring specialized pathology expertise which limits their scalability and clinical application. To address this challenge, we developed CellGate, a deep-learning (DL) computational pipeline that provides streamlined, end-to-end whole-slide mIF image analysis including nuclei detection, cell segmentation, cell classification, and combined immuno-phenotyping across stacked images.

Susceptibility of healthcare personnel with severe acute respiratory coronavirus virus 2 (SARS-CoV-2) hybrid immunity to XBB lineage reinfection.

Among 8,678 vaccinated healthcare personnel (HCP) with previous coronavirus disease 2019 (COVID-19), by August 28, 2023, 909 (10%) had an infection of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) omicron XBB variant. Reinfection risk was comparable irrespective of previous infection type except for the omicron BQ.1 variant.

Tafasitamab and lenalidomide in large B-cell lymphoma: real-world outcomes in a multicenter retrospective study.

In this real-world evaluation of tafasitamab-lenalidomide (TL) in relapsed or refractory LBCL, patients receiving TL had higher rates of comorbidities and high-risk disease characteristics, and substantially lower progression-free survival and overall survival, compared with the L-MIND registration clinical trial for TL.

InterMEL: An international biorepository and clinical database to uncover predictors of survival in early-stage melanoma.

Introduction: We are conducting a multicenter study to identify classifiers predictive of disease-specific survival in patients with primary melanomas. Here we delineate the unique aspects, challenges, and best practices for optimizing a study of generally small-sized pigmented tumor samples including primary melanomas of at least 1.05mm from AJTCC TNM stage IIA-IIID patients.

Novel Genetic Subtypes of Urothelial Carcinoma With Differential Outcomes on Immune Checkpoint Blockade.

Purpose: Immune checkpoint blockade (ICB) therapy has significantly improved clinical outcomes in bladder cancer. Identification of correlates of benefit is critical to select appropriate therapy for individual patients.

Methods: To reveal genetic variables associated with benefit from ICB, we performed whole-exome sequencing on tumor specimens from 88 patients with advanced bladder cancer treated with ICB.

Pathway Alterations in Stage II/III Primary Melanoma.

Purpose: Genomic classification of melanoma has thus far focused on the mutational status of , , and . The clinical utility of this classification remains limited, and the landscape of alterations in other oncogenic signaling pathways is underexplored.

Methods: Using primary samples from the InterMEL study, a retrospective cohort of cases with specimens collected from an international consortium with participating institutions throughout the United States and Australia, with oversampling of cases who ultimately died of melanoma, we examined mutual exclusivity and co-occurrence of genomic alterations in 495 stage II/III primary melanomas across 11 cancer pathways.

TP53 mutations and RNA-binding protein MUSASHI-2 drive resistance to PRMT5-targeted therapy in B-cell lymphoma.

To identify drivers of sensitivity and resistance to Protein Arginine Methyltransferase 5 (PRMT5) inhibition, we perform a genome-wide CRISPR/Cas9 screen. We identify TP53 and RNA-binding protein MUSASHI2 (MSI2) as the top-ranked sensitizer and driver of resistance to specific PRMT5i, GSK-591, respectively. TP53 deletion and TP53 mutation are biomarkers of resistance to GSK-591.

Effectiveness of MRNA booster vaccine among healthcare workers in New York City during the Omicron surge, December 2021 to January 2022.

Objective: To describe effectiveness of mRNA vaccines by comparing 2-dose (2D) and 3-dose (3D) healthcare worker (HCW) recipients in the setting of Omicron variant dominance. Performance of 2D and 3D vaccine series against SARS-CoV-2 variants and the clinical outcomes of HCWs may inform return-to-work guidance.

Methods: In a retrospective study from December 15, 2020 to January 15, 2022, SARS-CoV-2 infections among HCWs at a large tertiary cancer centre in New York City were examined to estimate infection rates (aggregated positive tests / person-days) and 95% CIs over the Omicron period in 3D and 2D mRNA vaccinated HCWs and were compared using rate ratios.

Landscape of mutations in early stage primary cutaneous melanoma: An InterMEL study.

It is unclear why some melanomas aggressively metastasize while others remain indolent. Available studies employing multi-omic profiling of melanomas are based on large primary or metastatic tumors. We examine the genomic landscape of early-stage melanomas diagnosed prior to the modern era of immunological treatments.

FACETS: Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing.

Clinical sequencing studies routinely involve molecular profiling of patients for mutations and copy number alterations. However, detection of "actionable" aberrations to guide treatment decisions require accurate, tumor purity-, ploidy-, and clonal heterogeneity-adjusted integer copy number calls. In this chapter, we describe the FACETS algorithm, an Allele-Specific Copy Number (ASCN) analysis tool with a broad application to whole-genome, whole-exome, as well as targeted panel sequencing platforms to annotate the genome for the detection of copy number alterations including homozygous/heterozygous deletions, copy-neutral loss-of-heterozygosity (LOH) events, allele-specific gains/amplifications, and cellular fraction profiles.

Clinical outcomes with use of radiation therapy and risk of transformation in early-stage follicular lymphoma.

Between 1998 and 2009, a total of 295 patients (median age 58, 53% females) with newly diagnosed early-stage follicular lymphoma (FL) were managed at Memorial Sloan Kettering Cancer Center. Approximately half of patients (137, 46%) underwent initial observation and half (158, 54%) immediate treatment: radiation alone (n = 108), systemic treatment alone (n = 29), or combined modality treatment (n = 21). Median follow-up was 8.

Enhancing Radioiodine Incorporation in -Mutant, Radioiodine-Refractory Thyroid Cancers with Vemurafenib and the Anti-ErbB3 Monoclonal Antibody CDX-3379: Results of a Pilot Clinical Trial.

Oncogenic activation of mitogen-activated protein kinase (MAPK) signaling is associated with radioiodine refractory (RAIR) thyroid cancer. Preclinical models suggest that activation of the receptor tyrosine kinase erbB-3 (HER3) mitigates the MAPK pathway inhibition achieved by BRAF inhibitors in mutant thyroid cancers. We hypothesized that combined inhibition of BRAF and HER3 using vemurafenib and the human monoclonal antibody CDX-3379, respectively, would potently inhibit MAPK activation and restore radioactive iodine (RAI) avidity in patients with mutant RAIR thyroid cancer.

Accounting for Delayed Entry in Analyses of Overall Survival in Clinico-Genomic Databases.

Background: Clinico-genomic databases favor inclusion of long-term survivors, leading to potentially biased overall survival (OS) analyses. Risk set adjustments relying on the independent delayed entry assumption may mitigate this bias. We aimed to determine whether this assumption is satisfied in a dataset of patients with advanced non-small cell lung cancer (aNSCLC), and to give guidance for clinico-genomic OS analyses when the assumption is not satisfied.

Multiple Primary Cancers in Patients Undergoing Tumor-Normal Sequencing Define Novel Associations.

Background: Cancer survivors are developing more subsequent tumors. We sought to characterize patients with multiple (≥2) primary cancers (MPC) to assess associations and genetic mechanisms.

Methods: Patients were prospectively consented (01/2013-02/2019) to tumor-normal sequencing via a custom targeted panel (MSK-IMPACT).