Developing a cost-effective and efficient safety case management solution for data coordinating center projects.

A centralized safety function can support multiple clinical trials and provide efficient, standardized processes for the management of serious adverse events. From 2017 to 2022, the centralized safety desk used pharmacovigilance software compliant with FDA regulations, including 21 CFR Part 11. This software assisted with processing safety cases for regulated clinical trials, including allowing capture of event data, and provided process flow management, documentation storage, and transmission of safety reports to FDA.

Sequencing of genes of drug response in tumor DNA and implications for precision medicine in cancer patients.

Tumor DNA sequencing is becoming standard-of-care for patient treatment decisions. We evaluated genotype concordance between tumor DNA and genomic DNA from blood and catalogued functional effects of somatic mutations in 21 drug response genes in 752 solid tumor patients. Using a threshold of 10% difference between tumor and blood DNA variant allele fraction (VAF), concordance for heterogenous genotype calls was 78% and increased to 97.

Development and implementation of the National Heart, Lung, and Blood Institute COVID-19 common data elements.

Background: Coronavirus Disease 2019 (COVID-19) instigated a flurry of clinical research activity. The unprecedented pace with which trials were launched left an early void in data standardization, limiting the potential for subsequent data pooling. To facilitate data standardization across emerging studies, the National Heart, Lung, and Blood Institute (NHLBI) charged two groups with harmonizing data collection, and these groups collaborated to create a concise set of COVID-19 Common Data Elements (CDEs) for clinical research.

Differentiation Trajectory of Limbal Stem and Progenitor Cells under Normal Homeostasis and upon Corneal Wounding.

Limbal stem cells (LSCs) reside discretely at limbus surrounded by niche cells and progenitor cells. The aim of this study is to identify the heterogeneous cell populations at limbus under normal homeostasis and upon wounding using single-cell RNA sequencing in a mouse model. Two putative LSC types were identified which showed a differentiation trajectory into limbal progenitor cell (LPC) types under normal homeostasis and during wound healing.

Genomic Analysis of Germline Variation Associated with Survival of Patients with Colorectal Cancer Treated with Chemotherapy Plus Biologics in CALGB/SWOG 80405 (Alliance).

Purpose: Irinotecan/5-fluorouracil (5-FU; FOLFIRI) or oxaliplatin/5-FU (FOLFOX), combined with bevacizumab or cetuximab, are approved, first-line treatments for metastatic colorectal cancer (mCRC). We aimed at identifying germline variants associated with survival in patients with mCRC treated with these regimens in Cancer and Leukemia Group B/SWOG 80405.

Experimental Design: Patients with mCRC receiving either FOLFOX or FOLFIRI were randomized to either cetuximab or bevacizumab.

Genetic variation determines VEGF-A plasma levels in cancer patients.

Angiogenesis is essential in tumor biology and is regulated by vascular endothelial growth factor (VEGF) ligands and receptors. Here we aimed to discover genetic variants associated with levels of circulating angiogenic proteins in cancer patients. Plasma was collected at baseline in 216 pancreatic and 114 colorectal cancer patients.

VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma.

Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bind VHL when hydroxylated.

Intrinsic molecular subtypes of breast cancers categorized as HER2-positive using an alternative chromosome 17 probe assay.

The 2013 update of the American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) human epidermal growth factor receptor 2 (HER2) testing guidelines recommend using an alternative chromosome 17 probe assay to resolve HER2 results determined to be equivocal by immunohistochemistry (IHC) or fluorescence in-situ hybridization (FISH). However, it is unclear if cases considered HER2-positive (HER2) by the alternative probe method are similar to those classified as HER2 by traditional IHC and FISH criteria and benefit the same from HER2-targeted therapies. We studied the clinical and pathologic features of all 31 breast cancers classified as HER2 by the alternative probe method at our institution since 2013 and determined their PAM50 intrinsic molecular subtypes.

Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles.

Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas, of a set of predominantly intrahepatic CCA cases, and propose a molecular classification scheme. We identified an -mutant enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number.

Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles.

Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number.

Exceptional Chemotherapy Response in Metastatic Colorectal Cancer Associated With Hyper-Indel-Hypermutated Cancer Genome and Comutation of and .

Purpose: A73-year-old woman with metastatic colon cancer experienced a complete response to chemotherapy with dose-intensified irinotecan that has been durable for 5 years. We sequenced her tumor and germ line DNA and looked for similar patterns in publicly available genomic data from patients with colorectal cancer.

Patients And Methods: Tumor DNA was obtained from a biopsy before therapy, and germ line DNA was obtained from blood.

Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma.

Background: Papillary renal-cell carcinoma, which accounts for 15 to 20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist.

Methods: We performed comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas, using whole-exome sequencing, copy-number analysis, messenger RNA and microRNA sequencing, DNA-methylation analysis, and proteomic analysis.

Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas.

Background: Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis.

A genome-wide association analysis of temozolomide response using lymphoblastoid cell lines shows a clinically relevant association with MGMT.

Objective: Recently, lymphoblastoid cell lines (LCLs) have emerged as an innovative model system for mapping gene variants that predict the dose response to chemotherapy drugs.

Methods: In the current study, this strategy was expanded to the in-vitro genome-wide association approach, using 516 LCLs derived from a White cohort to assess the cytotoxic response to temozolomide.

Results: Genome-wide association analysis using ∼2.

Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas.

Mutations in the genes encoding isocitrate dehydrogenase, IDH1 and IDH2, have been reported in gliomas, myeloid leukemias, chondrosarcomas and thyroid cancer. We discovered IDH1 and IDH2 mutations in 34 of 326 (10%) intrahepatic cholangiocarcinomas. Tumor with mutations in IDH1 or IDH2 had lower 5-hydroxymethylcytosine and higher 5-methylcytosine levels, as well as increased dimethylation of histone H3 lysine 79 (H3K79).

Genomic-derived markers for early detection of calcineurin inhibitor immunosuppressant-mediated nephrotoxicity.

Calcineurin inhibitor (CI) therapy has been associated with chronic nephrotoxicity, which limits its long-term utility for suppression of allograft rejection. In order to understand the mechanisms of the toxicity, we analyzed gene expression changes that underlie the development of CI immunosuppressant-mediated nephrotoxicity in male Sprague-Dawley rats dosed daily with cyclosporine (CsA; 2.5 or 25 mg/kg/day), FK506 (0.

Gene therapy: Have the risks associated with viral vectors been solved?

Gene therapy has the potential to cure monogenic diseases through the replacement of the deleterious gene with a functional copy. While the field of gene therapy has been plagued by serious adverse events associated with therapy, it is hoped that new, safer viral vectors have reduced these risks greatly. However, recently published reports indicate that these new viral vectors are a potential risk to patients receiving gene therapy.

Amplification of thymidylate synthetase in metastatic colorectal cancer patients pretreated with 5-fluorouracil-based chemotherapy.

Resistance to 5-fluorouracil (5-FU) represents a major contributor to cancer-related mortality in advanced colorectal cancer patients. Genetic variations and expression alterations in genes involved in 5-FU metabolism and effect have been shown to modulate 5-FU sensitivity in vitro, however these alterations do not fully explain clinical resistance to 5-FU-based chemotherapy. To determine if alterations of DNA copy number in genes involved in 5-FU metabolism-impacted clinical resistance to 5-FU-based chemotherapy, we assessed thymidylate synthetase (TYMS) and thymidine phosphorylase (TYMP) copy number in colorectal liver metastases.

Colorectal cancer cell lines lack the molecular heterogeneity of clinical colorectal tumors.

Background: Histologically similar colorectal cancers (CRCs) exhibit a wide range of outcomes, suggesting that knowledge of the molecular differences might provide insight into this heterogeneity. Cancer cell lines have been used in preclinical studies to identify gene expression alterations that influence response to chemotherapeutic agents. However, it is not clear to what extent available CRC cell lines reflect the molecular heterogeneity observed in clinical colorectal tumors.

Applications of genomic tools to colorectal cancer therapeutics.

Clinically and histopathologically similar colorectal cancers exhibit considerable variability in their responses to chemotherapeutics. The advent of genomic technologies has enabled the unbiased determination of changes in DNA and RNA, alterations that may be responsible for, or predictive of the variability in response to chemotherapy. This review highlights several advances made in applying genomic tools toward colorectal cancer therapeutics.