6048 results for "canc*"

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• Effector CD4 T Cells Convert Transient Responses to KRAS-Targeted Therapy into Long-Term Durable Remissions in Pancreatic Cancer

  Pancreatic ductal adenocarcinoma (PDAC) is refractory to most therapies, including immunotherapies in which reinvigoration of CD8 T cells is insufficient to induce durable long-term remissions. Direct KRAS inhibitors are clinically promising; however, acquired resistance is common. Using AI-assisted computational design, we developed a de novo IL-21 mimic, 21h10, with enhanced stability and high signaling potency in both humans and mice. Using an orthotopic PDAC mouse model, we evaluated responses and relapse following KRAS inhibitor treatment and demonstrated that, unlike combinations with chemotherapy or checkpoint blockade, the combination of 21h10 and KRAS inhibition is curative. Single-cell transcriptional profiling with TCR-seq revealed oligoclonal expansion of effector Th1-polarized CD4 T cells and depletion of Tregs. To evaluate the efficacy of 21h10 in human samples, we performed single-cell RNA-seq analyses on treatment-naive specimens following short-term ex vivo treatment with 21h10. This dataset consists of Illumina NovaSeq sequencing output (FASTQ files) generated from tumor libraries prepared using the 10x Genomics Single Cell 5′ Immune Profiling platform. FASTQ files are provided for gene expression (GEX), TCR, and, for multiplexed samples, HTO libraries.

  Study phs004509

• NCTN_NCORP: Phase III Trial of LHRH Analog Administration During Chemotherapy to Reduce Ovarian Failure Following Chemotherapy in Early Stage, Hormone-Receptor Negative Breast Cancer (S0230)

  Study ID: S0230NCT Number: NCT00068601 SWOG Cancer Research NetworkSubmitted in collaboration with the NCTN/NCORP Data ArchiveTrial Title: NCTN_NCORP: Phase III Trial of LHRH Analog Administration during Chemotherapy to Reduce Ovarian Failure following Chemotherapy in Early Stage, Hormone-Receptor Negative Breast Cancer (S0230)Trial Description: RATIONALE: Goserelin blocks hormone production in the ovaries. It is not yet known whether ovarian suppression using goserelin will prevent ovarian failure (early menopause) in women receiving chemotherapy for breast cancer.PURPOSE: This randomized phase III trial is studying how well giving goserelin together with chemotherapy works compared with chemotherapy alone in preventing early menopause in women with stage I, stage II, or stage IIIA breast cancer. Clinical data presented in the following publication(s):PMID 25738668Disease type(s): Breast Neoplasm - Breast Cancer - InvasiveClinical Dataset(s) included:NCT00068601-D1 (PMID 25738668): There is one dataset for S0230's primary publication 25738668. This dataset contains baseline characteristics, planned chemotherapy regimen, hormone receptor status, premature ovarian failure, fertility, survival, ovarian failure, and adverse event data.You are encouraged to view the PDF data dictionaries found in the “Documents” tab of the dbGaP study page, which may contain additional information regarding the data or the associated publication(s).

  Study phs004261

• Botensilimab, an Fc-enhanced Anti-CTLA-4 Antibody, is Effective Against Tumors Poorly Responsive to Conventional Immunotherapy

  This study explores the genomic landscape associated with a novel Fc-engineered anti-CTLA-4 antibody (botensilimab) in advanced solid tumors. We seek to understand if enhancing the Fc-region affinity of anti-CTLA-4 antibodies can improve anti-tumor efficacy and expand clinical benefit to tumors poorly responsive to conventional immunotherapy. As part of an ongoing open-label, Phase 1, multicenter study, we conducted an exploratory sub-analysis of genomics data. The primary study evaluates the safety, tolerability, pharmacokinetics, and pharmacodynamics of botensilimab monotherapy and in combination with an anti-PD-1 antibody (balstilimab) in participants with advanced solid tumors. RNA from formalin-fixed paraffin-embedded (FFPE) tumor biopsies and matched normal blood samples were isolated and subjected to RNA-sequencing using the Personalis ImmunoID NeXT Platform. We demonstrated that anti-CTLA-4 engineered for enhanced FcγR affinity leverages FcγR-dependent mechanisms to potentiate T cell responsiveness, reduce intratumoral Tregs, and enhance antigen presenting cell activation. This genomic analysis contributes to our understanding of the molecular mechanisms underlying patient responses to Fc-engineered anti-CTLA-4 therapy and may inform future strategies to expand the clinical benefit of immune checkpoint blockade in cancer immunotherapy.

  Study phs003704

• Open-Label, Phase I study of NeoVax with Nivolumab in Patients with Ovarian Cancer

  Personalized neoantigen-targeting cancer vaccines (PCV) in the adjuvant setting are of increasing interest across malignancies. Herein, we report the results of a first-in-disease phase I clinical trial testing the feasibility and safety of PCV for high-grade epithelial ovarian cancer (HGOC). ‘NeoVax' consisted of pools of synthetic long peptides targeting patient-specific neoantigens admixed with the immunostimulant poly-ICLC, was combined with delayed administration of anti-PD-1 antibody, and was tested in 10 patients (one newly diagnosed patient (Cohort A) and 9 patients at first recurrence (Cohort B)) with platinum-sensitive OC following standard-of-care (SOC) platinum doublet chemotherapy. Nine of 12 evaluable Cohort B patients were vaccinated (75%, 90% CI 47-93%) and 1 of 9 Cohort A patients (11%, 90% CI 0.6 – 43%). No unexpected safety signals were encountered, and no patients discontinued treatment due to toxicity. Across patients, >70% selected targets remained detectable by non-invasive cell-free DNA analysis despite a median of 6.5 months from the time of diagnostic biopsy to vaccine administration, during which patients received SOC chemotherapy. Biomarker analysis was suggestive of biologic activity of the vaccine in 6 of 10 patients and this was associated with broader tumor and vaccine-specific immune responses in blood and tumor following vaccination. Resistant tumor clones reflected diverse mechanisms affecting antigen presentation, indicative of immune-selective pressure exerted by vaccination. Overall, the interplay between the repertoire of antigens presented by the tumor and the breadth of induced immunity appeared to dictate clinical efficacy following vaccination.We are submitting:WES and WGS data from whole blood samples and tumor FFPE samplesRNA-seq data from tumor FFPE samplesscRNA-seq and scTCR-seq data from tumor biopsiesBulk TCR-seq data from CD3+ PBMC from blood samplesWGS and RNA-seq data from organoids

  Study phs004380

• BPH Tissues for Cell Culture and Analysis - A Patient-Derived Xenograft Model Using Benign Prostatic Tissues

  Our goal was to establish and characterize a patient-derived xenograft model for benign prostatic hyperplasia (BPH) using human benign prostatic tissues. Characterization of the model was done by histology, immunohistochemistry, proteomics, and transcriptome analysis (RNAseq). The RNAseq data will be deposited in dbGaP. Subjects were undergoing prostatectomy for prostate or bladder cancer, with concurrent BPH, and consented to the use of surplus tissue for research studies. The RNAseq studies included 6 patients. Phenotypic data include patient age, sex, prostate size, serum prostate-specific antigen (PSA) level, and international prostate symptom score (IPSS). Sequencing was done on an Illumina NovaSeq 6000, and data were analyzed using Kallisto. Data are submitted as raw sequencing (fastq) files.

  Study phs003692

• A Phase 1-2 Study of the Combination of Olaparib and Tremelimumab in BRCA1 and BRCA2 Mutation Carriers with Recurrent Ovarian Cancer (NCT02571725)

  INST1419: A phase 1-2 study of the combination of olaparib and tremelimumab in BRCA1 and BRCA2 mutation carriers with recurrent ovarian cancer (NCT02571725) was designed to evaluate the safety and efficacy of combined treatment with the PARP inhibitor olaparib and the CTLA4 immune checkpoint inhibitor tremelimumab in women with recurrent ovarian cancer and a germline BRCA1 or BRCA2 mutation. This was a multi-site single-arm open-label study that enrolled 50 subjects with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer between 2016 and 2020. Treatment efficacy was assessed using best overall response by modified WHO (mWHO) criteria, and secondary endpoints included disease control rate, duration of response, and progression-free and overall survival. The median age was 56 (range 39-78). All patients had measurable disease and pathogenic germline mutations in BRCA1 (72%) or BRCA2 (28%). Subjects received 300mg of olaparib by mouth, twice daily, and tremelimumab at 10mg/kg IV every four weeks for 6 doses, and then every 12 weeks for up to 24 months. Following an interim data safety monitoring review in 2018, the protocol was modified to reduce the frequency of tremelimumab infusions to 10mg/kg IV every four weeks for 4 doses, followed by infusions every 12 weeks. Exploratory biomarker assessments were performed using archived formalin-fixed paraffin-embedded (FFPE) tumor samples collected at the time of initial cytoreductive surgery from 33 subjects. Clinical characteristics and outcomes for the biomarker cohort were similar to the overall and response cohorts. Candidate biomarkers were identified based on differential gene expression in samples from patients with clinical benefit from treatment, defined as disease control for at least 12 weeks, versus those with progressive disease. For RNAseq, sample integrity was assessed using Agilent Tapestation, to ensure the DV200 was greater than or equal to 30. Sequencing was done on the Illumina NovaSeq instrument by Personalis. Gene expression used in this analysis was the normalized measure defined as transcripts per million (TPM) total RNA molecules. Welch's t-test was used to assess whether there was a difference in gene expression based on clinical benefit. The area under the receiver operating characteristic curve (AUC) was also computed for TPM gene expression based on clinical benefit. The AUC, as determined by the trapezoidal rule, was estimated by the concordance index (SAS 9.4 LOGISTIC procedure). DNA quality was confirmed if the DNA integrity number was greater than or equal to 3. Exome enrichment was performed using the Accuracy and Content Enhanced (ACE) version 4 (ACE ImmunoID NeXT) enrichment platform of Personalis. Briefly, DNA from tumor and cryopreserved PBMC samples were used to construct whole-exome capture libraries, and additional custom probes and optimized chemistry improved uniformity of coverage in sequence regions of high G-C content across the exome using ACE technology. Sequencing was performed at 20 Gigabase (G) sequencing depth for normal samples and 35G sequencing depth for tumor samples. All DNA and RNA reads were aligned to the hs37d5 reference genome built in accordance with the Personalis ACE Cancer Exome Analysis Pipeline, duplicate reads were removed, and the Genome Analysis toolkit was used to correct base quality scores and improve sequence alignment. Mutational burdens were generated using tumor-specific genomic events (SNVs, indels and fusions) of at least 5% allelic fraction that were verified using transcriptomic data. All potential neoepitopes were created for each mutation and tested for presentation, and considered putative neoepitopes if they were predicted to bind to any patient-specific alleles. The Xenium platform was used for spatial transcriptomic analyses using Xenium slides and sample prep reagents (10x Genomics). The immune panel was augmented with custom-ordered genes. Initial preprocessing included quality control, normalization, batch correction, and clustering. Cells with fewer than 20 detected features were excluded as low-quality. High-quality cell-by-gene count matrices were processed using Seurat 5.3.0, with normalization performed using SCTransform. Batch correction was carried out using Harmony integration, following standard preprocessing: individual dataset normalization, merging, PCA (RunPCA), and integration via RunHarmony. Clustering was performed on the Harmony-corrected embeddings using FindNeighbors and FindClusters (resolution = 0.03), and visualized with UMAP (RunUMAP). Cell types were initially assigned using SingleR with the HPCA reference dataset. To resolve cellular heterogeneity, subclustering was performed on select clusters using the FindSubCluster function in Seurat. Canonical marker genes used for cell type identification included CD3E for T cells, MS4A1 for B cells and EPCAM for epithelial and DCN for fibroblasts. Results from this trial demonstrated grade 3 or 4 non-hematologic toxicity in 57% of subjects. The overall response rate was 32.7% (95% CI 19.5-45.8%), with a disease control rate of 47.7% (95% CI 33.0-62.5%). In exploratory biomarker analyses, low VSTM5 or IFIT1B expression predicted treatment benefit and progression-free survival (pData available through dbGaP include RNAseq, whole exome sequencing, and Xenium spatial transcriptomic data.

  Study phs004512

• Epigenomics of Prostate Cancer from Cell Free Plasma

  We sought to perform epigenomic characterization of prostate cancers by profiling circulating nucleosomes isolated from patient plasma using cell free chromatin immunoprecipitation followed by sequencing (cfChIP-seq). Our major findings include identification of prostate-cancer specific regulatory elements using a novel statistical method accounting for variable tumor DNA fraction in plasma, inferring transcription factor activity based on binding motif enrichment within regulatory elements, and epigenetically phenotyping patients based on clinical and genomic features. Data available in dbGaP will include cfChIP-seq and targeted sequencing from approximately 50 patients with a known diagnosis of cancer and healthy patient controls.

  Study phs003482

• HINTS Geo-Coded Data 2017 (HINTS 5 Cycle 1)

  The Health Information National Trends Survey (HINTS) is a nationally representative survey which has been administered every few years by the National Cancer Institute since 2003. HINTS 5 includes four data collection cycles over the course of four years. The first round of data collection for HINTS 5 (Cycle 1) was conducted from January 25 through May 5, 2017 with a goal of obtaining 3,500 completed questionnaires, with a final sample including 3,285 respondents.

  Study phs004210

• WGS of Five Pancreatic Cancer Patients-Tumor and Normal

  We performed whole genome sequence on tumor-derived and normal cell lines from patients who had terminal pancreatic cancer and consented for rapid autopsy upon their death. The 5 samples are from Dr. Christine Iacobuzio-Donahue's rapid autopsy program as reported in Boland et al. (PLOSOne, 2024, In Press, PMID 38352348).

  Study phs003775

• Luminal Androgen Receptor-Enriched Triple Negative Breast Cancer

  This is a study to determine the efficacy of androgen receptor (AR) inhibitors in LAR (luminal androgen receptor)-enriched triple-negative breast cancer (TNBC) in the neoadjuvant setting. Twenty-four patients were treated with neoadjuvant AR inhibitor enzalutamide and paclitaxel for 12 weeks. Whole exome sequencing and RNA-sequencing was performed prior to treatment. The data for only two patients are consented for release through dbGaP. The remaining data are available under a Materials Transfer Agreement with the University of Texas MD Anderson Cancer Center.

  Study phs003586

• Field Effect-Informed Urine Liquid Biopsy Analysis for Assessment of Adjuvant BCG Response in Non-Muscle Invasive Bladder Cancer

  The goal of this study was to develop a urine tumor DNA-based minimal residual disease liquid biopsy assay for bladder cancer that improves specificity by considering field effect mutations. We performed targeted cell free DNA sequencing on tumor, adjacent normal, and urine cell free DNA (cfDNA) from non-muscle invasive bladder cancer patients and urine cfDNA from healthy controls. We developed a method called RePhyNERX and used it to identify three molecular response classes: complete responders to surgery, responders to adjuvant Bacillus Calmette-Guérin immunotherapy, and non-responders. These molecular classifications correlated with patient outcome. We also performed RNA sequencing on tumor tissues to identify expression differences between the response classes.

  Study phs004110

• The Discovery and Validation of AML Prognostic Biomarkers

  This study includes RNA-Seq and targeted DNA sequencing from a large collection of unsorted mononuclear cells (MNCs) and enriched viable leukemic blasts (VLBs) from bone marrow (BM) and peripheral blood (PBL) specimens collected at diagnosis from adult patients with acute myeloid leukemia (AML). Viable leukemic blasts were isolated using forward by side scatter, DAPI staining and fluorescently-labeled antibodies to CD45, CD34, CD38, and CD117. DNA and RNA were extracted using Qiagen AllPrep DNA/RNA Extraction kits. Transcriptome libraries were generated using KAPA Stranded RNA-Seq Library Preparation Kit after ribosomal RNA depletion with Roche RiboErase. Paired-end 75 bp reads were sequenced on either Illumina HiSeq 2500 (HiSeq) or NovaSeq 6000 (NovaSeq) instruments. RNA-Seq data were analyzed by the Fred Hutch Cancer Center Bioinformatics Shared Resource. STAR 2.7.1, with 2-pass mapping, was used to align reads to human reference genome GRCh37/hg19. Internal tandem duplication in FLT3 (FLT3-ITD) were identified via fragment analyses. DNA was sequenced using Illumina TruSight™ Myeloid Sequencing Panel and supplemented with in-house targeted MiSeq assays for CEBPA and NRAS exon 3 loci inadequately covered by TruSight™ platform on Illumina MiSeq instrument. Paired-end reads were first aligned to the human genome reference assembly (GRCh37/hg19) using Burrows-Wheeler Aligner (BWA, v0.7.12) and then, the resulting alignment data were processed according to the best practice of Genome Analysis Toolkit (GATK, v3.5).

  Study phs002805

• Southern Community Cohort Study - the Gut Microbiome Project

  The Southern Community Cohort Study (SCCS) is an ongoing prospective cohort study, with the aim to investigate risk factors of cancer and other chronic diseases across 12 southeastern U.S. states: Alabama, Arkansas, Florida, Georgia, Kentucky, Louisiana, Mississippi, North Carolina, South Carolina, Tennessee, Virginia, and West Virginia. Approximately 86,000 adults, two-thirds Black people, between 40 and 79 years of age were enrolled from 2002 to 2009. Approximately 86% of the participants were recruited from community health centers (CHCs) and institutions providing basic health care and preventative services in underserved areas, so the cohort encompassed a substantial number of individuals characterized by low income, low education, and lack of insurance. The remaining 14% of cohort participants were recruited through mail-based general population sampling. Sociodemographic characteristics, lifestyle factors including tobacco exposure and alcohol consumption, and personal medical history were collected at cohort enrollment. Data collection methods varied by recruitment source: CHC participants completed standardized computer-assisted personal interviews, while individuals from the general population responded to self-administered mailed questionnaires. The SCCS Biospecimen Repository includes blood samples from ~40,000, mouth cells from 39,000, urines from 24,000, stool specimens from 8,000 participants, and tumor blocks from incident cancer cases. This microbiome study nested within SCCS included 594 Black participants whose stool samples were analyzed using shotgun metagenomic sequencing. We investigated associations between the gut microbiome and several physical activity measures.

  Study phs004716

• Childhood Cancer Data Initiative (CCDI): NCI-COG Pediatric MATCH Precision Medicine Clinical Trial

  The National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial provides a framework for biomarker-driven early phase trials of targeted therapies in pediatric and young adult cancer patients across the United States. Pediatric MATCH enrolled more than 1,300 patients with treatment-refractory cancers, offering access to molecular screening and investigational targeted therapies. To further advance this, matched diagnostic, refractory tumor, and normal samples from Pediatric MATCH cases were molecularly characterized, creating one of the largest comprehensive data sets available for childhood cancers. This analysis has the potential to provide novel insights into the genetics of refractory pediatric, adolescent, and young adult cancers, as well as inform potential therapeutic strategies. The following molecular characterization assays were performed: Tumor whole exome sequencing (WES) Tumor whole genome sequencing (WGS) Tumor RNA sequencing (RNA-seq) Blood whole exome sequencing (WES) Blood whole genome sequencing (WGS)

  Study phs002883

• Childhood Cancer Data Initiative (CCDI): CCDI Pediatric In Vivo Testing Program - Leukemia

  The goal of this study is to molecularly characterize a large panel of pediatric acute lymphoblastic leukemia (ALL) patient-derived xenografts (PDXs) previously established in immune-deficient mice. These PDXs are utilized as part of the NCI-funded Pediatric Preclinical In vivo Testing (PIVOT) program to identify novel agents and combinations. Biospecimen data include next-generation sequencing (RNAseq, whole exome sequencing, DNA copy number variation), whole-genome analysis of cytogenetic abnormalities, and DNA fingerprint for quality control.

  Study phs003164

• APOLLO-OV: Applied Proteogenomics of High Grade Serous Ovarian Carcinoma

  APOLLO is a proteogenomic study seeking to describe the major genome, transcriptome, proteome and phosphoproteome alterations, subtypes, and molecular predictors of patient outcomes. This study includes 70 high grade serous ovarian carcinoma tissues from the Gynecologic Cancer Center of Excellence (https://medschool.usuhs.edu/gso/research/gyn-cancer-center-of-excellence). Bulk and laser microdissection enriched tumor tissues were profiled by whole genome sequencing, transcriptome sequencing, MS-based proteomics and reverse phase protein arrays. Clinical and sample data include survival times, patient features, and tumor characteristics.

  Study phs003488

• NCTN: A Randomized Phase III Comparison of Standard-Dose (60 Gy) versus High-Dose (74 Gy) Conformal Radiotherapy with Concurrent and Consolidation Carboplatin/Paclitaxel +/- Cetuximab in Patients with Stage IIIA/IIIB Non-Small Cell Lung Cancer (RTOG-0617)

  Study ID: RTOG-0617 NCT Number: NCT00533949 NRG Oncology Submitted in collaboration with the NCTN/NCORP Data Archive Trial Title: NCTN: A Randomized Phase III Comparison of Standard-Dose (60 Gy) versus High-Dose (74 Gy) Conformal Radiotherapy with Concurrent and Consolidation Carboplatin/Paclitaxel +/- Cetuximab in Patients with Stage IIIA/IIIB Non-Small Cell Lung Cancer (RTOG-0617) Trial Description: RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as paclitaxel, carboplatin work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether high-dose radiation therapy is more effective than standard-dose radiation therapy when given together with combination chemotherapy with or without cetuximab in treating patients with non-small cell lung cancer. PURPOSE: This randomized phase III trial is studying high-dose or standard-dose radiation therapy given together with chemotherapy with or without cetuximab to see how well they work in treating patients with newly diagnosed stage III non-small cell lung cancer that cannot be removed by surgery. Clinical data presented in the following publication(s): • PMID 25601342 Disease type(s): Lung, Mediastinal and Pleural Neoplasm - Non-Small Cell Lung Cancer Clinical Dataset(s) included: • NCT00533949-D1 (PMID 25601342): There are three datasets for RTOG-0617's primary publication 25601342 (-D1 through -D3). This dataset, NCT00533949-D1, contains treatment arm, baseline characteristics, radiotherapy technique used, EGFR H-score, radiation treatment details, select toxicity data, and survival data. • NCT00533949-D2 (PMID 25601342): There are three datasets for RTOG-0617's primary publication 25601342 (-D1 through -D3). This dataset, NCT00533949-D2, contains adverse events reported in Appendix 10. • NCT00533949-D3 (PMID 25601342): There are three datasets for RTOG-0617's primary publication 25601342 (-D1 through -D3). This dataset, NCT00533949-D3, contains the most frequently reported adverse events reported in Tables 3 and 4. You are encouraged to view the PDF data dictionaries found in the "Documents" tab of the dbGaP study page, which may contain additional information regarding the data or the associated publication(s).

  Study phs004191

• Reduction of Lethal Prostate Cancer Disparities in Underserved Hispanic/Latino Populations

  This pilot study investigated the genomic underpinnings of prostate cancer in Puerto Rican Hispanic/Latino men, a group disproportionately affected by this disease, in terms of incidence, mortality and aggressiveness. By examining tumors from 35 patients for specific genetic mutations and gene expression patterns using cutting-edge genomic sequencing, we aimed to identify distinct genetic profiles that could influence the course of the disease and its treatment. Our initial findings suggest the presence of unique genomic characteristics in this population, offering a promising avenue for developing personalized treatments that could reduce the health disparities observed in these men. This study underscores the importance of including diverse ethnic groups in genomic studies to ensure that the published data required for personalized cancer care are available.

  Study phs004487

• Blood and Marrow Clinical Trials Network - Allogeneic Hematopoietic Cell Transplant for Hematological Cancers and Myelodysplastic Syndromes in HIV-Infected Individuals (BMT CTN-0903-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions.Objectives: To evaluate the safety and effectiveness of allogeneic hematopoietic cell transplantation for patients with hematologic malignancies or myelodysplastic syndromes and coincident-HIV infection.Background: Allogeneic hematopoietic cell transplantation (alloHCT) has been a safe and curative option for many patients with hematologic malignancies but was not well studied in the HIV+ population despite the interest in the HIV research community of the curative potential of alloHCT. Hematologic malignancies in people with HIV infection (HIV+) have been associated with poor outcomes due to opportunistic infections, but the development of antiretroviral therapy (ART) has increased the possibility of these patients achieving clinical outcomes comparable to those of the general population following stem cell transplant. The BMT CTN 0903 trial was designed to evaluate the safety and effectiveness of alloHCT for patients with HIV infection and hematologic malignancies.Participants: Patients had documented HIV infection, were a minimum of 15 years of age and had acute myeloid leukemia (AML) or acute lymphocytic leukemia (ALL) in first or second complete remission (CR); Int-2 or high-risk myelodysplastic syndromes (MDS) with CCR5delta32. AlloHCT using cord blood units or T-cell depletion was not allowed. Patients with history of prior alloHCT were excluded. Patients had to meet adequate organ function. Karnofsky/Lansky performance status ≥ 70% and could not have active central nervous system disease, HIV infection resistant to all antiretroviral therapy, or opportunistic infection unresponsive to treatment.There were seventeen HIV-infected patients with acute leukemia, myelodysplasia (MDS), NHL or classical HL who were enrolled in the trial.Design: Patients with HIV infection and hematological malignancies or myelodysplastic syndromes (MDS) were treated with either reduced-intensity conditioning (RIC) or myeloablative conditioning (MAC) followed by alloHCT. RIC or MAC was at the discretion of investigator. Where feasible, an attempt was made to identify hematopoietic cell donors who were homozygotes for the CCR5delta32 polymorphism. Graft-versus-host disease (GVHD) was treated per institutional standards.Four regimens were permitted for conditioning. RIC regimens were: fludarabine and busulfan (Flu/Bu), and fludarabine and melphalan (Flu/Mel). MAC regimens were busulfan and fludarabine (Bu/Flu), or cyclophosphamide and total body irradiation (Cy/TBI). GVHD prophylaxis regimens included tacrolimus/methotrexate, tacrolimus/sirolimus, and post-transplant cyclophosphamide with tacrolimus/mycophenolate. Patients receiving busulfan-containing preparative regimens were not eligible to receive tacrolimus/sirolimus. A committee reviewed individual patient's HIV treatment history and ART options before initiation of the transplant conditioning regimen and advised changes to minimize potential drug interactions. It was recommended that ART be continued except ritonavir-containing regimens during MAC.The goal of the study was to assess the 100-day non-relapse mortality. Secondary endpoints included 100-day disease status, percentage donor chimerism, hematologic function, infections, six-month overall survival (OS), incidence of acute and chronic GVHD, immunologic reconstitution, and impact of alloHCT upon measures of HIV persistence in blood including peripheral blood mononuclear (PBMC)-associated HIV DNA and infectious virus from resting CD4+T-cells using a quantitative virus outgrowth assay.Follow-up visits occurred weekly through 8 weeks post-transplant, at 100 days, 6 months, 1 year, and 2 years.Conclusions: There was no non-relapse mortality (NRM) at 100 days, or at 6 months, and therefore no evidence to suggest that NRM is prohibitive or more than that seen in non-HIV-infected patients. The cumulative incidence of grades II-IV acute GVHD was 41%. After year one, overall survival was 59%. In patients who achieved complete chimerism, cell-associated HIV DNA and inducible infectious virus in the blood were not detectable.

  Study phs004697

• Niraparib in Pancreatic Cancer

  Pancreatic cancer patients with pathogenic variants in DNA repair genes may benefit from PARP inhibitor therapy, but efficacy beyond germline BRCA1/2 mutations remains uncertain. This multicenter phase II trial (NCT03601923) enrolled 32 patients with advanced pancreatic cancer harboring germline or somatic pathogenic variants in BRCA1, BRCA2, PALB2, ATM, or CHEK2 who had not progressed on prior platinum-based chemotherapy. Patients received niraparib 200-300 mg daily. Here we deposit the whole exome samples of six patients from the study (N=13 total samples). Patients P02, P03, P06, and P21 have matched tumor-normal blood pairs; patient P22 has a single tumor sample; and patient P30 has four tumor samples collected at different timepoints for longitudinal analysis.

  Study phs004405

• The Cancer Dependency Map (DepMap)

  The Cancer Dependency Map (DepMap) aims to accelerate precision cancer medicine by creating a comprehensive map of tumor vulnerabilities. The DepMap project genomically profiles a wide range of cancer models and characterizes them for their sensitivity to genetic and compound perturbations. The data is computationally analyzed to create a systematic overview of the genetic dependencies and compound sensitivities of cancer types and the predictive biomarkers that point to patient populations most likely to benefit from targeting of these vulnerabilities. The DepMap public portal has become a comprehensive resource to identify cancer vulnerabilities by providing datasets at scale, cutting-edge computational tools, and sophisticated visualization tools that together have accelerated the discovery of novel targets and biomarkers. Please visit Depmap.org to access the public portal.

  Study phs003444

• KDM6A Loss Triggers an Epigenetic Switch that Disrupts Urothelial Identity and Drives Cell Proliferation in Bladder Cancer

  Disruption of KDM6A, a histone lysine demethylase, is one of the most common somatic alternations in bladder cancer. How mutations of this chromatin modifier impact the epigenetic landscape to promote carcinogenesis is poorly understood. Here, we demonstrate that KDM6A loss triggers an epigenomic switch that disrupts urothelial identity and induces a neoplastic state characterized by increased cell proliferation. In bladder cancer cells with intact KDM6A, FOXA1 binds KDM6A at enhancers to activate genes instructing urothelial differentiation. In KDM6A-deficient cells, we observed simultaneous loss of FOXA1 target binding and genome-wide redistribution of the bZIP transcription factor ATF3, which in turn represses FOXA1 target genes and activates cell-cycle progression genes. Importantly, ATF3 depletion reverses the cell proliferation phenotype. These data establish that KDM6A loss creates an epigenetic state that drives tumor growth in an ATF3-dependent manner, forging a molecular vulnerability that can be targeted by novel therapeutic strategies.

  Study phs002801

• Inherited Genetic Susceptibility in Langerhans Cell Histiocytosis

  We recruited cases of Langerhans cell histiocytosis (LCH) who were recruited to the Children's Oncology Group Childhood Cancer Research Network, Project:EveryChild projects, or to a local patient biobank to conduct an expanded genome-wide association study for risk variants and to perform post-GWAS analysis of a previous hit in the SMAD6 gene. Publicly available control data were used for our analyses; however, here we provide the SNP array data and targeted SMAD6 sequence data for the LCH cases and some non-LCH cases included in the analysis.

  Study phs004547

• MP2PRT: Evaluation of an Inflammation Polygenic Risk Score (iPRS) to Predict Cancer Related Cognitive Impairment and Fatigue in Patients Receiving Chemotherapy for Non-Metastatic Breast Cancer in URCC0701 and URCC10055

  This study is a secondary analysis of cancer related cognitive impairment (CRCI) and cancer related fatigue (CRF) among participants in URCC0701 and URCC10055 from the University of Rochester NCI Community Oncology Research Program (NCORP) Research Base. CRCI and CRF are common, troublesome, and dose-limiting toxicities reported by patients undergoing breast cancer chemotherapy that have an etiologic basis linked to low-grade systemic inflammation. Chronic, low-grade systemic inflammation is, in part, genetically determined with common single nucleotide polymorphisms (SNPs) capturing variation across individuals. This study aimed to 1) determine whether an inflammation polygenic risk score (iPRS) is associated with CRCI or CRF, 2) determine whether the relationship between the iPRS and CRCI or CRF is modified by exercise at the time of cancer treatment, 3) identify SNPs associated with serum cytokines measured at the time of cancer treatment, and 4) identify novel CRCI- and CRF-associated risk SNPs via genome-wide association analyses. We found that there was a significant inverse correlation between the iPRS and change in fatigue score from pre-chemotherapy to post-chemotherapy while there was no statistically significant association between the iPRS and cognitive impairment score. The inverse relationship between the iPRS and fatigue may be explained in part by the finding that the iPRS was also significantly associated with greater pre-chemotherapy fatigue, suggesting that women with a genetic predisposition to low-grade systemic inflammation (i.e., high iPRS) have more fatigue at the time of breast cancer diagnosis and, therefore, are less likely to worsen over the course of treatment. In contrast, women with a low iPRS had significantly less fatigue pre-chemotherapy and a significant worsening of fatigue from pre- to post-chemotherapy. The relationship between the iPRS and fatigue remained after adjustment for patient and cancer treatment covariates and was most pronounced in women who reported regularly exercising for at least 6 months prior to starting their cancer treatment. Exploratory genome-wide analysis identified a novel risk locus on chromosome chr6q27, tagged by rs9365961, associated with CRCI. This locus is upstream of TBXT, which encodes an embryonic nuclear transcription factor previously associated with susceptibility to neural tube defects. The genome-wide SNP data, patient-reported CRCI and CRF outcome measures, and covariate data used in this analysis are available through dbGaP.

  Study phs003688

• Metabolic Biomarkers in Thoracic Cancers

  Here we present RNA sequencing (RNA-Seq) of non-small cell lung cancer (NSCLC) and adjacent lung tissue. These samples were acquired from primarily untreated, surgically resected primary tumors. The first analysis published with this data was to determine the metabolic signatures between primary tumors and adjacent lung tissue.The associated clinical trial (NCT02095808) includes patients with many kinds of thoracic cancers, including NSCLC and other diseases, such as thymoma and esophageal adenocarcinoma. However, the current dbGaP data is focused on the NSCLCs described in the associated paper.

  Study phs003880

• Healthy Communities Study (HCS-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives: To examine the relationships between characteristics of community programs and policies that are designed to prevent childhood obesity and are focused on Body Mass Index, diet, and physical activity in children.Background: Childhood obesity is a major public health issue in the U.S. with 18.5% of children aged 2-19 having obesity (Hales, Caroll, Fryer, and Ogden, 2017). Children who have obesity are more likely to have cardiovascular risk factors (Freedman, Mei, Srinivasan, Berenson, & Dietz, 2007; Koskinen et al., 2018), type 2 diabetes (Goran, Ball, & Cruz, 2003) and are at increased risk for morbidity and mortality as adults (Reilly & Kelly, 2011) including increased risk of developing several types of cancer (World Cancer Research Fund/American Institute for Cancer Research, 2007).Community programs and policies targeting childhood obesity are being implemented across the country, but their approaches have not been systematically studied. There is natural variation in many aspects of community programs and policies, including intensity level, duration, funding, target population, and how they are implemented. However, no previous studies have examined these variations and how such aspects of community programs and policies are related to childhood obesity outcomes. The Healthy Communities Study (HCS) was initiated to address the need for a study of community programs and policies and their relationship with childhood obesity.The three aims of HCS are to: 1) determine the associations between characteristics of community programs and policies and obesity outcomes in children; 2) identify factors that modify or mediate the associations; and 3) examine the association between characteristics of program and policies and obesity outcomes in communities that have a high proportion of African American or Hispanic residents. This study was not designed to evaluate any one specific program, policy or community, but was designed to systematically assess if components or characteristics of programs/policies in communities across the country are related to BMI, diet, and physical activity in children.Design: Community selection: For the purposes of HCS, a community was defined as a high school catchment area, and child participants were students at public elementary and middle schools (kindergarten through eighth grade) within the catchment areas. Communities were selected using a hybrid sampling approach. Some of the communities were “certainty” communities, which had implemented promising program and policies targeting childhood obesity. Other communities were sampled using a stratified national probability-based sample, using weights proportional to the number of children aged 4-15 in each Census Tract.Participant recruitment At the school level, children were recruited from two public elementary and two public middle schools in each community. Materials were distributed to children in these schools and families who completed the forms were contacted by the study.The HCS employed a complex study design that included a diverse sample of communities across the country and combines current/cross-sectional and retrospective data. Data were collected at multiple levels including at the child/household, schools, and community levels.Cross-sectional component: Interviews conducted in households along with community and school assessments were the primary data collection activities for HCS. Cross-sectional data were collected on a) children and their families, b) schools, and c) communities:a. Children and households: All children participated in the Standard Protocol measure consisting of: medical history, height, weight, and waist circumference measurements of the child; height and weight measurements (or self-reported measurements) of the two parent(s)/caregiver(s); general demographic and background questions; brief nutrition and physical activity behavior questionnaires; and a modified Windshield Survey of the home. A subset of children (approximately 14% of the children in the 130 communities) received an Enhanced Protocol, which included: all of the Standard Protocol measures listed previously plus (2) 24-hour dietary recalls during both of the home visits, the use of an accelerometer for a one-week period between the first and second home visit, and a previous day physical activity assessment questionnaire at the end of the second visit.b. Schools: School assessments were comprised of web-based surveys and observations of the 4 participating schools. Observations in the 2 elementary and 2 middle schools included lunchroom observations, an interview of the physical education instructor, and a Physical Activity Resource Assessment (PARA) was administered to observe the school's outdoor physical activity resources. Web-based surveys were administered to the district food service administrator/manager and a staff member from each school. The school staff completed a survey on school policies and practices related to physical activity and nutrition, whereas, the district –level personnel completed a food environment questionnaire for each of the recruited schools that were in their district.c. Communities: In each community, interviews were conducted with key informants (10-14 persons per community) to review and gather characteristics on current community policies and programs and for communities programs and policies for up to 10 years prior.Retrospective component:a. Among children, medical records were abstracted for going back up to 10 years in approximately 65-70% the sample to develop longitudinal BMI trajectories.b. Communities: Data were collected from key informants in each community on characteristics of programs and polices going back up to 10 years to assess how programs and policies unfolded over time in each community.Demographics:Communities: A total of 130 diverse communities participated in the HCS. Communities were diverse with respect to low income (38.5%), urbanicity (38.5% urban, 38.5% suburban, 23.1% rural), and geographic region (42.3% South, 22.3% West, 20% Midwest, 15.4% Northeast). Communities with a high proportion of race-ethnic groups also were oversampled (32.3% Hispanic, 26.2% African American, 41.5% other). Data were collected in a total of 436 schools; 227 elementary (52%), 53 elementary/middle (12%), and 158 middle schools (36%).There were 1,421 key informants interviewed across the 130 communities. Through the key informant interviews and document abstraction, 9,681 community programs and policies (CPPs) over the ten year retrospective study period were identified and characterized.Participants: A total of 5,138 children and their parent(s)/caregiver(s) from 130 diverse communities across the country were recruited for the HCS study. Child participants were evenly distributed across ages 4–15 years and gender; 21.5% were African American and 43.5% were Hispanic. Nearly a third of households reported an annual income below $20,000.

  Study phs004494

• Childhood Cancer Data Initiative (CCDI): A Cohort of Hispanic Children with Acute Lymphoblastic Leukemia; Bloom Syndrome in a Mexican American Family with Rhabdomyosarcoma

  Retrospective case-control genetic study of Hispanic children with acute lymphoblastic leukemia (ALL) treated 1994-2013, comparing 14 treatment-related pancreatitis (TRP) cases to 46 treatment-matched controls without pancreatitis. Targeted sequencing of 23 genes (pancreatitis-related and asparagine-metabolism genes) was performed from post-remission blood DNA; select HLA types were inferred from whole-exome data in cases. CFTR and ASNS variants were enriched in TRP (notably CFTR V470M, OR 4.27, p=0.025).

  Study phs002823

• Impact of HLA Aberrations on Tumor Neoepitope Presentation

  TP53 mutations may encode tumor-specific truncal neoantigens for targeting cytotoxic T lymphocyte (CTL). Using mass spectrometry followed by X-ray crystallographic analysis of HLA-bound p53 neoantigens, clinical tumor database analyses, and functional studies of neoantigen-directed T cell receptors (TCRs), we have built a comprehensive p53 immunopeptidome. As a component of this study, we noted that tumors with neoantigens displayable on HLA-A*02:01 or HLA-B*07:02, and structurally divergent from p53 wild-type peptide-HLA complexes, may exploit an allele's absence for growth in patients. The data deposited highlights that in brain metastasis of an ovarian cancer, that a damaged HLA-A*02:01 allele resulted in inability to present the p53 I195F neoepitope (GLAPPQHLFRV). Conversely, a simultaneously processed glioblastoma sample, sequenced as a control (and bearing a p53 R248W mutation on an A*24:02/A*32:01 background), revealed full exome genomic reads and transcript reads of the HLA-A locus. This indicated that biallelic HLA-A loss in the 10-417-1023 tumor was not a technical issue but represented damage to the 5' encoding exons of HLA-A.

  Study phs004529

• Childhood Cancer Data Initiative (CCDI): Metastatic Osteosarcoma snMultiome Profiling

  Metastatic osteosarcoma is an aggressive bone malignancy affecting pediatric, adolescent, and young adults. While recent research has increasingly focused on understanding the complex biology of the osteosarcoma microenvironment, the tumor vasculature is understudied, especially in the context of metastatic disease. To address this, we performed single-nuclei multi-ome (RNA+ATAC) sequencing on a cohort of 24 human metastatic osteosarcoma specimens. Our data shows that endothelial cells universally exhibit a hybrid endothelial–mesenchymal state consistent with endothelial-to-mesenchymal transition (EndMT). Additionally, we uncovered that a subset of diploid endothelial cells adopts an osteoblastic cell fate as evidenced by gene expression and gene regulatory network (GRN) analysis. Joint copy-number analysis of our dataset identified a subset of osteosarcoma cells with endothelial transcriptional programs and GRNs, indicative of vascular mimicry. In vitro assays and in vivo lineage tracing experiments using syngeneic murine models validated both vascular mimicry and endothelial to-osteoblastic transdifferentiation. Collectively, these findings highlight the remarkable plasticity and lineage infidelity of both endothelial and osteosarcoma cells in patient specimens and a metastatic syngeneic murine model, provide novel insights into the functional role of endothelial cells in the metastatic osteosarcoma microenvironment, and challenge current understanding of osteosarcoma biology.

  Study phs004490

• Childhood Cancer Data Initiative (CCDI): Frameshift Mutation Profiling of Constitutional Mismatch Repair Deficiency Syndrome Patients

  Samples from patients with Constitutional Mismatch Repair Deficiency Syndrome (CMMRD) were sequenced using the Archer NextSeq platform to detect frameshift mutations in cell-free DNA (cfDNA), matched tumor samples, and other tissue types. The goal of the study is to evaluate whether a frameshift mutation biomarker panel can be used for disease monitoring. Limited treatment information is included when available. The listed genes represent those in which recurrent frameshift mutations were identified and evaluated as candidate biomarkers for disease monitoring in CMMRD.

  Study phs004017

• Blood and Marrow Transplant Clinical Trials Network - Randomized Multicenter Trial Comparing Sirolimus Plus Prednisone and Sirolimus/Calcineurin Inhibitor Plus Prednisone for the Treatment of Chronic Graft-versus-Host Disease (BMT-CTN-0801-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. ObjectivesFor the phase II component, to compare the responses of patients with graft-versus-host disease who received sirolimus/calcineurin inhibitor plus prednisone versus sirolimus plus prednisone after 6 months of therapy. For the phase III component, to compare the proportion of subjects with complete resolution of all reversible manifestations at 24 months after starting therapy.BackgroundChronic graft-versus-host disease (cGVHD) is the major treatment-related complication among patients who survive after allogeneic hematopoietic cell transplantation (HCT). Standard immunosuppressive therapy (IST) with prednisone ± a calcineurin inhibitor (CNI) has not changed for three decades, but most patients respond inadequately with slow and most often incomplete control of their disease. Renewed understanding of regulatory T cells (Tregs) led to the hypothesis that experimental therapies permissive of Treg expansion would better abrogate GVHD than CNI-containing (control) IST. Sirolimus and extracorporeal photopheresis (ECP) are permissive of Treg expansion. Because of their acceptance in clinical practice, sirolimus and ECP were considered good candidates for adding to prednisone in clinical trials in cGVHD.ParticipantsAdult and pediatric allogeneic HCT recipients were eligible if they had classic cGVHD ± acute GVHD (overlap subtype) that met 2005 NIH diagnostic consensus criteria. This included newly diagnosed patients, defined as individuals who had received One hundred patients were evaluated for the phase II primary endpoint after all had completed 6 months of follow-up. All 151 enrolled subjects were followed for phase III endpoints. 77 patients were randomized to the prednisone/sirolimus arm and 74 patients to the prednisone/sirolimus/CNI arm.DesignThe trial was designed as an adaptive phase II/III randomized, open-label, prospective study of three treatments for chronic GVHD. Phase II was to include two parallel, 100-patient, randomized trials, comparing prednisone/sirolimus or prednisone/sirolimus/ECP versus identical (prednisone/sirolimus/CNI) comparator arms, where centers selected only one trial in which to participate. However, the prednisone/sirolimus/ECP arm was closed prematurely due to poor accrual. Comparison of complete/partial response rates did not support proceeding to phase III and further accrual was suspended.The starting dose of prednisone (or prednisone-equivalent) was 1 mg/kg once daily, unless contraindicated, in which case the prednisone dose began at 0.5–1 mg/kg once daily. It was recommended that the dose of prednisone was tapered down, over 4–8 weeks to reach a dose of 0.5–1 mg/kg every other day, with the tapering starting within 2 weeks after the first evidence of GVHD improvement. Once an every-other-day prednisone (or equivalent) regimen was achieved, this dose remained constant for 10–12 weeks until all reversible chronic GVHD manifestations resolved. The sirolimus therapy began at a dose of 2 mg orally once daily (1 mg/m2 per day if the patient weighed Health-related quality of life was measured by self-report instruments, including the Functional Assessment of Cancer Therapy Bone Marrow Transplantation (FACT-BMT), Short Form-36 (SF-36).For phase II, the primary outcome was complete or partial response after 6 months of therapy. For phase III, the primary outcome was complete response at 24 months.ConclusionsInitial therapy of chronic GVHD with prednisone/sirolimus is an acceptable alternative and better tolerated than therapy with prednisone/sirolimus/CNI.Carpenter PA, Logan BR, Lee SJ, et al. A phase II/III randomized, multicenter trial of prednisone/sirolimus versus prednisone/ sirolimus/calcineurin inhibitor for the treatment of chronic graft-versus-host disease: BMT CTN 0801 (Carpenter PA et al. Haematologica, 2018).

  Study phs004641

• RNA Sequencing Analysis of Patient-Derived Xenograft Tissue PIM-084 Treated with L-NMMA+Alpelisib vs Vehicle Control

  This dataset contains RNA-seq analysis of vehicle control compared to L-NMMA+alpelisib treated metaplastic breast cancer PDX PIM084 tumors (RNA sequencing and analysis performed by Novogene). The submitted data contains the gene ID, gene name, normalized read counts from all samples from control group and combination treatment group, log2-fold change derived from DESeq2 R/EdgeR package, p-value, adjusted p-value, read counts from each group, and gene FPKM from the each sample in the group. Due to patient privacy, we are submitting only the processed and desensitized RNA sequencing analysis to this repository.

  Study phs003814

• The Study of Somatic LINE1 Activity in Cancers

  This study focuses exclusively on the quantification of LINE1 mobilization. We analyzed a recent whole genome sequencing data release from multiple Cancer Genome Atlas (TCGA) sub-projects. In addition to the somatic LINE1 insertions (present in tumor and having no support in the matched normal) there are "pseudo-germline" non-reference LINE1 elements identified in tumor tissue and having some support in the matched normal. This dataset reports such "pseudo-germline" LINE1 retrotranspositions. Individual level data for TCGA can be accessed by requesting access to phs000178.

  Study phs003888

• NCI's Collection of Studies for General Cancer Research

  This collection contains all of NCIs authorized individual-level genomic datasets currently in dbGaP that are approved for Cancer Research (DS-CA) use only and limitations outlined in the model Data Use Certification Agreement. Access to this study will include any additional authorized individual-level DS-CA datasets that become available. Renewal of this study is required annually. To request access to this study collection, select phs003967.v1.p1 in the dbGaP Authorized Access System.

  Study phs003967

• Involvement of the FGF8/FGF Receptor Signaling Pathway in the Maintenance and Progression of Fusion-Positive Rhabdomyosarcoma

  In our previous work, we used a myoblast model of fusion-positive rhabdomyosarcoma (FP-RMS) to demonstrate that FGF8, a target of the PAX3-FOXO1 (P3F) transcription factor, is essential for tumorigenicity driven by P3F. When aberrantly expressed, FGF8 can also sustain tumorigenicity in recurrent tumors that are independent of P3F. In this study, we report that FGF8, along with its receptors FGFR1 and FGFR4, is often highly expressed in FP-RMS tumors. We found that high levels of FGF8 expression in FP-RMS cells correlate with increased sensitivity to an FGFR4 inhibitor and a pan-FGFR inhibitor. Conversely, downregulating FGF8 led to a loss of sensitivity to these inhibitors. Interestingly, when FGF8 was upregulated in myoblasts, it resulted in decreased FGFR4 expression and sensitized the cells to an FGFR1 inhibitor and a pan-FGFR inhibitor. The downregulation of FGFR4 expression mediated by FGF8 could be reversed by inhibiting FGFR1, MEK, or ERK, thereby defining a signaling pathway through which FGF8 exerts its regulatory effects. Additionally, we discovered that high FGF8 expression in P3F-independent recurrent tumors is due to a rearrangement of viral long terminal repeat (LTR) sequences into the 3' untranslated region (UTR) of FGF8, leading to increased stability of FGF8 mRNA. These findings indicate that FGF8 plays an oncogenic role in FP-RMS through FGFR4 and may also exert oncogenic effects in P3F-independent relapses via FGFR1. Our study highlights the functional significance of FGF8 in FP-RMS and supports the rationale for preclinical investigations of FGFR inhibitors in treating this type of cancer.

  Study phs004009

• Human Cancer-Targeted Immunity via Transgenic Hematopoietic Stem Cell Progeny

  Analysis of a patient biopsy from the clinical trial (NCT03240861), a first-in-human study of transgenic NY-ESO-1 TCR- T cells and NY-ESO-1 TCR+ sr39tk autologous hematopoietic stem cells tandem therapy for solid tumors after myeloablative conditioning chemotherapy with busulfan and fludarabine. Single-cell RNAseq and single-cell ATACseq analysis from peripheral blood mononuclear cells obtained from subject NYSCT-03.

  Study phs003898

• CDK2 Inhibition Demonstrates RB-Independent Efficacy in CDK4/6 Inhibitor-Resistant HR-Positive/HER2-Negative Breast Cancer

  Preliminary clinical data from hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative metastatic breast cancer (MBC) patients with resistance to CDK4/6 inhibitors treated with the CDK2 inhibitor PF-07104091 as monotherapy indicate that therapeutic efficacy correlates with TP53 status, but not with RB expression or phosphorylation. Using a panel of HR+/HER2- MBC patient-derived (PD) cell lines, including both CDK4/6 inhibitor-naïve and resistant models, we found that CDK2, unlike CDK4/6, is dispensable for RB phosphorylation. Notably, in models derived from tumors that had progressed on CDK4/6 inhibitor therapy, as well as in models with acquired in vitro resistance, CDK2 inhibition reduced DNA replication rate, induced DNA damage, and inhibited mitotic entry in an RB-independent manner. Data available through this dbGaP submission include whole-exome sequencing (WES) from four CDK4/6 inhibitor-naïve HR+/HER2- MBC PD cell lines (MGH10035.1, MGH10035.2, MGH358.1, and MGH358.2), their corresponding isogenic derivatives with acquired in vitro resistance to the CDK4/6 inhibitor palbociclib, and one PD cell line (MGH321.4) derived from a letrozole/ribociclib-resistant HR+/HER2- MBC tumor. MGH10035.1 and MGH10035.2 were derived from the same patient at different stages of treatment, as were MGH358.1 and MGH358.2.

  Study phs004466

• NCTN: Phase III Trial of Tamoxifen Alone vs. Tamoxifen Plus Radiation Therapy for Good Risk Duct Carcinoma In-Situ (DCIS) of the Female Breast (RTOG-98-04)

  Study ID: RTOG-98-04 NCT Number: NCT00003857 NRG Oncology Submitted in collaboration with the NCTN/NCORP Data Archive Trial Title: NCTN: Phase III Trial of Tamoxifen Alone vs. Tamoxifen plus Radiation Therapy for Good Risk Duct Carcinoma In-Situ (DCIS) of the Female Breast (RTOG-98-04) Trial Description: RATIONALE: Radiation therapy uses high-energy x-rays to damage tumor cells. Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using tamoxifen may fight breast cancer by blocking the uptake of estrogen by the tumor cells. It is not yet known if radiation therapy is more effective than observation, with or without tamoxifen, in treating ductal carcinoma in situ. PURPOSE: Randomized phase III trial to compare the effectiveness of radiation therapy with that of observation, with or without tamoxifen, in treating women who have ductal carcinoma in situ.Clinical data presented in the following publication(s): • PMID 25605856 Disease type(s): Breast Neoplasm - Breast Neoplasm, Miscellaneous Clinical Dataset(s) included: • NCT00003857-D1 (PMID 25605856): This dataset is for RTOG-98-04's primary publication 25605856. The dataset contains reasons for exclusion, baseline characteristics, survival, local failure, distant metastasis, salvage mastectomy, and toxicity data. You are encouraged to view the PDF data dictionaries found in the “Documents” tab of the dbGaP study page, which may contain additional information regarding the data or the associated publication(s).

  Study phs004264

• Blood and Marrow Clinical Trials Network (BMT CTN) A Phase III Randomized, Multicenter Trial Comparing Sirolimus/Tacrolimus With Tacrolimus/Methotrexate as Graft-versus-Host Disease Prophylaxis After HLA-Matched, Related Peripheral Blood Stem Cell Transplantation (BMT-CTN-0402-BioLINCC)

  ObjectivesThe primary objective was to determine if the combination of tacrolimus and sirolimus (Tac/Sir) was more effective than tacrolimus and methotrexate (Tac/Mtx) in preventing acute graft-versus-host disease and early mortality after allogeneic related donor hematopoietic cell transplantation.BackgroundStem cell transplantation is a standard therapy for leukemia and myelodysplastic disorders. Recipients of human leukocyte antigen (HLA)-matched, related donor (MRD) stem cell transplants are at risk for a number of infections and complications. One of these complications is a condition known as acute graft-versus-host disease (GVHD). Recipients of HLA-MRD stem cell transplants for the treatment of myelodysplastic disorders and leukemia experience a 35% incidence of GVHD. Furthermore, GVHD contributes significantly to 1-year early treatment-related mortality (TRM) estimates of approximately 20%.The standard prophylaxis regimen for GVHD is a calcineurin inhibitor combined with methotrexate. Calcineurin inhibitors block calcineurin, a protein phosphatase that catalyzes some of the intracellular processes associated with T-lymphocyte activation. Inhibition is achieved by binding to immunophilins. The result is reduced production of interleukin-2 and reduced proliferation of T-cells. Methotrexate, an antineoplastic antimetabolite, has immunosuppressant properties that prevents the synthesis of tetrahydrofolate. Tetrahydrofolate is necessary for synthesis of thymidylate, an essential component of DNA. Of particular clinical concern is the theory that the injury caused by methotrexate to tissues could play a contributory role in initiation of the cytokine cascade associated with GVHD.The standard prophylaxis regimen for GVHD was established in the mid-1980s. Minor alterations to the standard regimen have shown limited effect on TRM outcomes in spite of the improvements that have been made to allogeneic hematopoietic cell transplantation (HCT) outcomes. Sirolimus, a rapamycin inhibitor, has been suggested as an alternative for methotrexate. Previous studies have suggested that sirolimus use results in decreased incidence of acute GVHD and treatment-related toxicity after HLA-MRD and unrelated donor transplantation, at the expense of higher rates of endothelial injury syndromes. Sirolimus has additional immunomodulatory properties that include effects on antigen-presenting cells, the thymus, and preservation of regulatory T-cell subsets after transplantation. The purpose of this study was to determine if sirolimus, in place of methotrexate, would produce improved outcomes in GVHD and TRM.ParticipantsEligible participants were 2 to 60 years of age, of either gender, and were undergoing transplantation for one of the following conditions: acute leukemia in remission, myelodysplastic disorder, or chronic myeloid leukemia in chronic or accelerated phase. All participants were required to have a 6/6 Class I HLA-A and B and molecular Class II DRB1 matched sibling donor medically able and willing to donate peripheral blood stem cells that also met institutional criteria for stem cell donation.Participants were excluded from participating in the trial for the following: prior allogenic or autologous transplant, HIV or another uncontrolled active infection, pregnant or breast-feeding, known allergy to sirolimus, requiring voriconazole at time of study entry, currently receiving another investigational drug (unless cleared by protocol officer or chair), or participants with a history of cancer.Participants were excluded from continuation for the following laboratory criteria if measured within 4 weeks of study entry: measured creatinine clearance 500mg/dL; forced vital capacity (FVC) or forced expiratory volume (FEV1) 45% in adults or A total of 304 participants were enrolled in the study. 151 participants were randomized to the tacrolimus/sirolimus (Tac/Sir) treatment, which 149 completed and 2 did not undergo transplantation. 153 participants were randomized to the tacrolimus/methotrexate (Tac/Mtx) treatment, which 152 completed and 1 did not undergo transplantation.DesignBMT 0402 was an interventional study with the purpose of determining the best combination of medications for the prevention of GVHD after HLA-MRD peripheral blood stem cell transplantation. Two GVHD prophylaxis conditioning regimens were tested: tacrolimus/sirolimus (Tac/Sir) and tacrolimus/methotrexate (Tac/Mtx). The study was Phase III, and designed to be multicenter, randomized, open label, and with parallel assignment treatment arms. Randomization occurred within 7 days of initiation of pretransplantation conditioning therapy, and was performed in a 1:1 ratio with the use of random block sites, stratified by transplantation center. The transplant physician selection of treatment occurred prior to participant's assignment to the study. All parties involved in the trial knew the treatment arm assigned to each participant.Participants received pretransplantation myeloablative conditioning with total body irradiation in combination with either cyclophosphamide or etoposide. Initially, a conditioning regimen comprised of myeloablative doses of busulfan with CY was permitted, however this was removed due to excess toxicity and veno-occulusive disease of the liver. The participants that received busulfan-based conditioning were not included in the primary outcome analyses. PBSC donors received filgrastim and underwent large volume apheresis with a goal of collecting 2 to 10 × 106/kg CD34+ stem cells. No graft manipulation was allowed prior to the infusion of the stem-cell product.For GVHD prophylaxis, tacrolimus was begun on day −3 for all participants at a dose of 0.02 mg/kg/day by continuous IV infusion, adjusted to maintain a serum concentration of 5 to 10 ng/mL. For participants in the Tac/Sir group, sirolimus was started on day −3 with a 12 mg oral loading dose, followed by daily oral doses of 4 mg, adjusted to maintain a serum trough concentration of 3 to 12 ng/mL. For participants in the Tac/Mtx group, methotrexate was IV administered on day +1 (15 mg/m2), +3, +6, and +11 (10 mg/m2 each day).The primary endpoint of grades II-IV acute GVHD-free survival was assessed 114 days from the time of randomization based on intention-to-treat. The study had 80% power to detect a 15% difference between the 2 prophylaxis strategies based on the standardized difference in Kaplan-Meier estimates with a 2-sided α of 5%. A committee of investigators blinded to GVHD prophylaxis assignment reviewed all case records, focusing on the incidence of acute and chronic GVHD, relapse, toxicity, and causes of death. Participants were followed for two years after transplantation for evaluation of secondary endpoints, which included cumulative incidence of acute GVHD, time to neutrophil and platelet engraftment, mucositis severity, rate of veno-occlusive disease, thrombotic microangiopathy infection, cytomegalovirus reactivation, treatment-related mortality, malignant disease relapse, all infections, overall survival, and time to discharge after transplant.ConclusionsParticipants who received Tac/Sir engrafted significantly earlier and had significantly less severe oropharyngeal mucositis after transplantation; however, no difference was observed in the primary end point of GVHD-free survival at 114 days post randomization between participants treated with Tac/Sir and Tac/Mtx (Cutler C. et al., Blood 2014).

  Study phs004629

• NCTN: A Phase III Trial Evaluating the Addition of Trastuzumab to Trimodality Treatment of HER2-Overexpressing Esophageal Adenocarcinoma (RTOG-1010)

  Study ID: RTOG-1010NCT Number: NCT01196390 NRG OncologySubmitted in collaboration with the NCTN/NCORP Data ArchiveTrial Title: NCTN: A Phase III Trial Evaluating the Addition of Trastuzumab to Trimodality Treatment of HER2-Overexpressing Esophageal Adenocarcinoma (RTOG-1010)Trial Description: This randomized phase III trial studies how well radiation therapy, paclitaxel, and carboplatin with or without trastuzumab work in treating patients with esophageal cancer. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as trastuzumab, may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving radiation therapy and combination chemotherapy together with or without trastuzumab is more effective in treating esophageal cancer. Clinical data presented in the following publication(s):PMID 35038433Disease type(s): Gastrointestinal Neoplasm - Gastroesophageal CancerClinical Dataset(s) included:NCT01196390-D1 (PMID 35038433): There are three datasets for RTOG-1010's primary publication 35038433 (-D1 through -D3). This dataset, NCT01196390-D1, contains the baseline characteristics, treatment, reasons for treatment discontinuation, surgery information, survival, and toxicity data. NCT01196390-D2 (PMID 35038433): There are three datasets for RTOG-1010's primary publication 35038433 (-D1 through -D3). This dataset, NCT01196390-D2, contains the treatment-related adverse event data. NCT01196390-D3 (PMID 35038433): There are three datasets for RTOG-1010's primary publication 35038433 (-D1 through -D3). This dataset, NCT01196390-D3, contains the treatment-related serious adverse event data. You are encouraged to view the PDF data dictionaries found in the “Documents” tab of the dbGaP study page, which may contain additional information regarding the data or the associated publication(s).

  Study phs004237

• Ongoing Replication Stress Tolerance and Clonal T Cell Responses Distinguish Liver and Lung Recurrence and Patient Outcomes in Pancreatic Ductal Adenocarcinoma

  Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) survive longer when disease spreads to the lung but not to the liver. We generated overlapping, multi-omic datasets to identify molecular and cellular features that distinguish patients whose disease develops liver metastasis (liver cohort) from those whose disease progression results in lung metastasis without liver metastases (lung cohort). Lung cohort patients generally survived longer than liver cohort patients, independent of tumor subtype. We developed a pORG gene signature that distinguishes primary tumors in the liver and lung cohorts. We identified ongoing replication stress (RS) response pathways in high pORG/liver cohort tumors, while low pORG/lung cohort tumors had greater densities of lymphocytes and shared T cell clonal responses. Our study demonstrates that liver-avid PDAC is associated with tolerance to ongoing RS, limited tumor immunity, and less favorable outcomes; whereas low RS, lung-avid/liver-averse tumors are associated with active tumor immunity that may account for favorable outcomes. As expected, we found high frequencies of KRAS, TP53, CDKN2A, and SMAD4 gene alterations in our tumor samples. High pORG activity (GSVA scores) in our primary tumors appear to be positively correlated with alteration frequencies in both TP53 and CDKN2A. We did not see a correlation with alterations in KRAS as almost all the tumor samples have KRAS alterations. From a de-identified dataset of 1,873 patients diagnosed with and/or treated for PDAC at our institution between 2004 and 2020, we identified 422 patients for which we had specimens with sequencing data (N=374) and/or specific evidence of disease metastasis site(s) from the OHSU cancer registry or disease-relevant computed tomography (CT) scans to allow cohort classification. Note that our study includes RNA-Seq, DNA-Seq panel, and TCR-Seq (T-cell Receptor Sequencing) data, but that this dbGaP submission just includes the patients/samples with RNA-Seq and/or DNA-Seq panel data. Therefore, this submission includes 290 samples from 278 patients. TCR sequence data is available on the Adaptive Biotechnologies platform. Clinical course timepoints, patient demographics, stage, grade, nodal involvement, resection margins, and angiolymphatic invasion were provided as deidentified data by the OHSU cancer registry with quality control data verification in a subset by pathologists (BB and TM). We reviewed all available computed tomography (CT) scans for all patients with primary tumor resection dates recorded by the cancer registrar, with tumor samples analyzed by RNA-seq, DNA-seq, or TCR-seq, and/or with additional information indicating metastatic spread (e.g., metastatic samples received for related studies). We abstracted the site of all lesions proven to be metastatic by biopsy and/or that clearly increased in size during progression or decreased in size during treatment as long as a radiologist described the lesion as “likely”, “suspicious for”, “concerning for”, or “favor” metastasis. Clinical imaging was reviewed by a radiologist (AG) to validate patient assignments to the liver, lung, and neither liver nor lung (other recurrence site) cohorts. Time to recurrence was calculated from the earliest of either the recurrence date provided by the OHSU cancer registry, or the date of earliest lesion abstracted from CT reports. The subject attributes reported in this submission were up to date at the time of our data freeze, which occurred July 2021.

  Study phs003597

• Childhood Cancer Data Initiative (CCDI): Pediatric In Vivo Testing Program - Neuroblastoma

  The goal of NCI's Pediatric In Vivo Testing Consortium (PIVOT) is to advance the development of effective treatments for pediatric cancers through preclinical in vivo testing of novel therapeutic agents. To design impactful experiments that can be rapidly translated to the clinic, PIVOT investigators require comprehensive genomic characterization of the patient-derived xenograft (PDX) models used across the consortium. This robust experimental design enhances collaboration with industry partners by providing proof-of-concept data for drugs in development. As part of this effort, neuroblastoma PDX models are being molecularly characterized to identify promising therapeutic candidates. The molecular profiling includes whole exome sequencing (WES), RNA-seq, MethylEPIC array, CytoSNP array, and DNA fingerprinting for quality control. Additionally, demographic and clinical data (e.g., diagnosis, disease site, disease status) are shared. These characterized PDX models, matched with patient tumors, guide model selection for preclinical drug testing.

  Study phs003163

• Spindle Assembly Checkpoint Competency Determines Sensitivity to KIF18A Inhibition in Small-Cell Lung Cancer

  This study examined the biological determinants of response to KIF18A inhibition in small-cell lung cancer (SCLC), a chromosomal instability-high cancer. The study used patient tumor datasets, SCLC cell line models, genomic and transcriptomic profiling, drug sensitivity testing, live-cell imaging, genetic perturbation, and pharmacologic inhibition to assess chromosomal instability, mitotic regulation, and spindle assembly checkpoint function. Although KIF18A expression was elevated in SCLC and associated with chromosomal instability, proliferation, and neuroendocrine transcriptional programs, these features did not predict drug sensitivity. Instead, response to KIF18A inhibition was primarily determined by spindle assembly checkpoint competency, with SAC-proficient cells undergoing sustained mitotic arrest and apoptosis and SAC-defective cells showing resistance. The dbGaP-accessible data will include de-identified RNA-seq-derived expression data and associated sample metadata for the NIH/NCI patient-derived SCLC cell line component of the study. These data were used to assess selected gene expression features, including KIF18A-related expression and a neuroendocrine-related score based on Neuroendocrine-associated genes. No direct participant identifiers will be included.

  Study phs004869

• Subtyping of Small Cell Lung Cancer Using ChIP-Seq of Plasma Cell-Free Nucleosomes and Matched Tumor Transcriptomes

  We undertook an observational study using plasma collected from patients with small cell cancer who received care at the National Cancer Institute (NCI). Human subjects committee at NCI approved the studies; all patients provided written informed consent for plasma, tumor, and matched normal sample sequencing. Sequence data for 8 samples in phs003628 are available under phs004200.

  Study phs003628

• Blockade of TGF Beta Drive Hyper Progression on Small Cell Lung Cancer

  To uncover mechanisms underlying divergent outcomes in patients with small cell lung cancer (SCLC), a highly aggressive neuroendocrine malignancy, we performed bulk transcriptomics of pre-treatment tumor biopsies from patients enrolled in a clinical trial of bintrafusp alfa, a bifunctional fusion protein targeting PD-L1 and TGF-β. We identified marked elevation of IFN-γ signaling and MHC class II expression. In contrast, Hyperprogressive disease (HPD) was associated with systemic immune suppression, impaired cytotoxicity, and, unexpectedly, tumor-intrinsic activation of TGF-β signaling and stemness. Functional studies confirmed that intact TGFβR2-mediated signaling is required for the hyperproliferative response to TGF-β blockade, revealing a context-dependent tumor-suppressive role for TGF-β.Although TGF-β is widely regarded as an immunosuppressive driver in advanced cancers, our findings reveal a tumor-intrinsic, growth-constraining role for TGF-β signaling in SCLC. Disrupting this restraint can accelerate tumor progression, providing a mechanistic basis for HPD and highlighting the need for biomarker-driven strategies that account for tumor-intrinsic signaling when applying stromal-targeted immunotherapies.

  Study phs004200

• Whole Genome Sequencing for Metastatic Mutational Burden in Extraskeletal Myxoid Chondrosarcoma

  Extraskeletal myxoid chondrosarcoma (EMC) is an ultra-rare cancer. Though it has a favorable prognosis and an indolent course, it has high rates of local recurrence and metastasis to the lungs. EMC is most often characterized by a translocation involving the NR4A3 gene most often fusing with EWSR1, leading to constitutive expression of NR4A3, the biological significance of which is unknown. Our study presents a case of EMC with case-matched lung and advanced pelvic metastases. We conducted Whole Genome Sequencing to examine differences in the mutational landscape at two different stages of metastasis. This is the first study to our knowledge to analyze mega-base scale structural variants (SVs) in EMC. Our data validates copy number variants (CNVs) found in previous studies. While the primary tumor and lung metastasis had similar somatic variations and CNVs, the pelvic metastasis had more SVs with especially increased mutational burden of SVs in chromosome 2. This suggests that different molecular drivers appear in more advanced, relapsing EMC compared with the primary tumor and early lung metastasis. The sequencing data is available through dbGaP.

  Study phs003305

• Childhood Cancer Data Initiative (CCDI): Enhancement of Data Sharing in Pediatric, Adolescent and Young Adult Cancers

  NCI's Childhood Cancer Data Initiative (CCDI) is building a community centered around childhood cancer care and research data. Through enhanced data sharing, we can improve our understanding of cancer biology to improve preventive measures, treatment, quality of life, and survivorship, as well as ensure that researchers learn from every child with cancer. While childhood cancers represent the leading cause of death in children over the age of 1, they are collectively rare, comprising approximately 1%‒3% of cancers diagnosed annually in the United States. Information on diagnosis, treatment, and outcomes is often stored at the hospital or institution where a child is treated, making it difficult to answer scientific questions about childhood cancer. Sharing clinical care and research data generated by children's hospitals, clinics, or networks broadly with the community can help us learn faster and, on a scale much larger than any single institution caring for children can learn on its own. To exploit the rapid advances in high-throughput DNA sequencing technologies and realize the goals of precision cancer medicine, the UMICH Cancer Center established the Michigan Oncology Sequencing Center (MI-ONCOSEQ). This UMICH Cancer Center provisions genomic data derived from the Michigan Oncology Sequencing Center (MI-ONCOSEQ) clinical sequencing assay for patients that fall within the inclusion criteria of the CCDI data sharing initiative. An "integrative sequencing approach" carried out in a CLIA-certified laboratory is utilized to provide a comprehensive landscape of the genetic alterations in individual tumor specimens for the purpose of identifying informative and/or actionable mutations. Using a number of computational pipelines that we have developed in-house or have adapted from the public domain, candidate molecular aberrations are nominated and then analyzed by scientists for clinical significance and/or relevance. This approach enables the detection of point mutations, insertions/deletions, gene fusions and rearrangements, amplifications/deletions, and outlier expressed genes. Furthermore, we can identify certain germline alterations that may also be relevant.

  Study phs002431

• GENomics of CAncer DisparitiEs (GENCADE)

  Genetic ancestry-concordant RNA splicing events in men with prostate cancer (PCa) involve cancer promoting genes and associate with disease recurrence after radical prostatectomy. Patients diagnosed with PCa who were scheduled to undergo radical prostatectomy or biopsy were enrolled in the GENCADE study, according to the Institutional Review Board (IRB)-approved protocol Pro00053535 (NCT02229565). With respect to NCT02229565, the descriptors “African American” and “Caucasian American” refer to the same patients described as “Black” and “White”, respectively, herein. Patients were also co-enrolled to the Duke BioRepository & Precision Pathology Center (BRPC) protocol (Pro00035974) to facilitate tissue collection.

  Study phs003731

• Cardiovascular Cell Therapy Research Network - A Phase I, First-in-Human, Multicenter, Randomized, Double-Blinded, Placebo-Controlled Study of the Safety and Efficacy of Allogeneic Mesenchymal Stem Cells in Cancer Survivors With Anthracycline-Induced Cardiomyopathy (CCTRN-SENECA-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions.Objectives: To examine the safety and feasibility of delivering allogeneic human mesenchymal stem cells (allo-MSCs) by transendocardial injection to cancer survivors with left ventricular (LV) dysfunction secondary to anthracycline-induced cardiomyopathy (AIC).Background: Anthracycline-based chemotherapies are effective in treating various forms of cancer. The risk of anthracycline-induced cardiomyopathy (AIC) has been primarily related to the lifetime cumulative dose and every exposure to an anthracycline carried some risk of inducing cardiac dysfunction. Historically, AIC has been irreversible with poor prognosis and most prevalent in young persons and females. Previous studies have determined that patients with AIC have approximately 3.5-higher relative risk of death within 5 years compared to ischemic or nonischemic cardiomyopathy. There is currently no effective treatment for AIC.There are several shared pathological features between AIC and heart failure (HF). A promising approach to treatment of HF is the administration of bone marrow–derived mesenchymal stromal cells (MSCs). The SENECA trial was the first-in-human study of allo-MSCs in patients with LV dysfunction secondary to AIC.Participants: Male and female cancer survivors aged 18 to 79 years, with a diagnosis of AIC, were recruited for the SENECA trial. Inclusion criteria included: initial diagnosis of AIC at least 6 months prior to consent; left ventricular ejection fraction (LVEF) ≤45%; receiving stable, optimally tolerated therapy with beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, and/or aldosterone antagonists unless contraindicated; no evidence of ischemic heart disease; cancer-free for at least 2 years with a low likelihood of recurrence (a 5-year risk of recurrence estimated at ≤30%).Participants were excluded for any condition that, in the judgment of the Investigator or Sponsor, would be a contraindication to enrollment, study product administration, or follow-up.Design: The primary objectives of SENECA were the safety of allo-MSC administration, the feasibility of delivering the cells to the subjects, and collecting outcome measures. The secondary objectives were to determine the effects of allo-MSC administration on LV function and functional status from baseline to 6 months and from baseline to 12 months after treatment.The trial was initiated with a 6-subject, open-label lead-in phase. Between September 2016 and December 2016, 6 candidates consented to participate and received 20 transendocardial, electromechanically-guided injections of allo-MSCs. A complete safety report of the 6 subjects was provided for review by the data safety monitoring board and FDA. Subsequently, the study was allowed to proceed to the randomization phase.Baseline evaluations to determine eligibility included: cardiac magnetic resonance imaging (CMR), 6-min walk test (6MWT), Minnesota Living with Heart Failure Questionnaire (MLHFQ), and a comprehensive laboratory panel that included N-terminal pro-brain natriuretic peptide (NT-proBNP).Between March 2017 and October 2018, 31 eligible subjects were randomized 1:1. There were 14 subjects enrolled in the treatment arm and 17 subjects in the placebo arm. Participants received either 1 × 108 allo-MSCs in 8 ml of Buminate 5% solution or a placebo (8 ml of cell-free Buminate solution) delivered via 20 transendocardial injections (0.4 ml each).All subjects were followed for 1 year, with evaluations at: day 0 (day of injection), day 1, day 7, day 30, day 180, and day 365. A physical examination, electrocardiogram, and laboratory evaluations were conducted at each visit, along with the assessment of adverse events and review of medications. In addition, at 6 months and 1 year, subjects performed the following tests: 6MWT, MLHFQ, and CMR. Serum samples were collected at baseline and 1, 6, and 12 months after treatment to determine whether there were any significant changes in panel reactive antibody (PRA).Conclusions: The SENECA trial demonstrated that allo-MSCs are well-tolerated and that transendocardial injections of allo-MSCs are feasible in patients with AIC. Although the SENECA trial was not designed to test efficacy, a subset of participants was included in secondary endpoint analysis. The only statistically significant differences observed were with the MLHFQ and 6MWT assessments which favored the intervention. Larger studies will be required to determine the efficacy of allo-MSCs treatment.

  Study phs004712

• FORCE Trial: Resistance Training Intervention Among Colon Cancer Patients

  Our study population was composed of participants of the FORCE clinical trial, which was a randomized resistance training intervention study for Stage II and III colon cancer patients undergoing chemotherapy. Patients were recruited from Kaiser Permanente of Northern California, the Penn State Cancer Institute, and the Dana Farber Cancer Institute and were assigned to resistance training or usual care within the first weeks of adjuvant chemotherapy. Lean mass was evaluated at the beginning and the end of the study, and participants were monitored for toxicities associated with chemotherapy and chemotherapy dose modifications. Genome-wide DNA methylation was assayed using peripheral blood collected at the FORCE trial baseline and the post-intervention visit using the Infinium MethylationEPIC v1.0 (EPIC) BeadChips (Illumina). EPIC array signal intensities were preprocessed and used to estimate site-specific DNA methylation levels, which were used for the estimation of several epigenetic clocks. Our study hypothesized that those with accelerated epigenetic age at the beginning of chemotherapy would be more likely to have modifications to their assigned chemotherapy regimen driven by a higher burden of chemotoxicities. We also hypothesized that epigenetic age acceleration would significantly increase over the course of chemotherapy and that a resistance training intervention would reduce the rate of change.

  Study phs003671