16513 results for "sec+and+unspecified+malignant+neoplasm"

in 15.28 milliseconds.

• A Phase II Neoadjuvant Study of Palbociclib in Combination with Letrozole and Trastuzumab as Neoadjuvant Treatment of Stage II-III ER+ HER2+ Breast Cancer (PALTAN)

  Women with early stage ER+/HER2+ breast cancer (BC) are less likely to achieve pathological complete response (pCR) after chemotherapy with standard of care dual HER2 blockade than patients with ER-/HER2+ BC. Additionally, the toxicity burden of standard systemic therapy is high. Thus, this single arm phase 2 clinical trial investigated a novel de-escalation regimen with trastuzumab, letrozole, and palbociclib in those with early stage ER+/HER2+ BC. The aim was to determine if this treatment regimen will achieve similar pCR rates as conventional treatment and spare women the toxicity burden of regular treatments. The primary endpoint was pCR after 16 weeks of treatment with trastuzumab, letrozole, and palbociclib. Patients with newly diagnosed ER+ HER2+ invasive BC with clinical stages II and III were eligible for this protocol. Research biopsies were performed during the treatment course for whole exome and RNA sequencing, PAM50 molecular subtyping, and Ki67 assessment using immunohistochemistry for complete cell cycle arrest (CCCA: Ki67 ≤2.7%). Results showed a pCR of 7.7% and a rate of residual cancer burden at 0 or I of 38.5%. CCCA was observed in 85% at Cycle 1 day 15 post palbociclib, trastuzumab, and letrozole treatment (C1D15), compared to 27% at surgery after palbociclib was discontinued. PAM50 subtyping identified 31.2% HER2-E, 43.8% Luminal B, 25% Luminal A. 161 genes were differentially expressed comparing C1D15 to baseline. Whole exome and RNA sequencing data will be available through dbGaP.

  Study phs003147

• Somatic Genome Dynamics of Barrett's Esophagus Patients with Non-Cancer and Cancer Outcomes

  A case-control study was designed with 80 participants diagnosed with Barrett's Esophagus (BE) selected from a larger case-cohort study (Li et al., 2014, PMID: 24253313) within the Seattle Barrett's Esophagus Program (SBEP) at the Fred Hutchinson Cancer Research Center. The study included 40 cases with BE with non-cancer outcomes, "NCO", who did not progress to esophageal adenocarcinoma (EA), and 40 controls who progressed to an endoscopically detected, incident EA (cancer outcome, "CO"). For each patient, two timepoints were evaluated (T1 and T2). NCO were matched to CO based on age at T1 (T1=first endoscopy with sufficient sample availability), and time between T1 and T2 (T2 in CO=time of diagnosis of incident EA). In 10 NCO, a third time point (T3), a mean of 13.2 years after T1, was also sequenced. Mapped endoscopic biopsies, at 1/3 and 2/3 annotated distances from the gastroesophageal junction within the Barrett's segment, were sampled per patient at each timepoint. Each biopsy was purified to separate BE epithelium from stroma, and DNA was extracted from purified epithelium for 60X WGS and 2.5M SNP array; normal control blood (N=62) or normal gastric sample (N=18) were analyzed by 30X WGS and 2.5M SNP array. An additional seven normal gastric biopsy samples in seven patients with normal control blood were also sequenced at 60X as controls. All research participants contributing clinical data and esophageal samples to this study provided written informed consent, subject to oversight by the Fred Hutchinson Cancer Research Center IRB Committee D (Reg ID 5619).

  Study phs001912

• High-Resolution Clonal Mapping of Multi-Organ Metastasis, and Resistance to Neoadjuvant Chemotherapy, in Triple Negative Breast Cancer

  Clonal dynamics during metastasis were studied in two patient-derived xenograft (PDX) models established from treatment-naive primary breast tumors from TNBC patients diagnosed with concurrent metastatic disease. Genomic sequencing and barcode-mediated clonal tracking revealed robust alterations in clonal architecture between primary tumors and metastases. Polyclonal seeding and maintenance of low-abundance subclones was observed in each metastatic lesion examined. Lung, liver, and brain metastases were enriched for an identical population of subclones. Clones dominating multi-organ metastases shared a genomic lineage. Thus, properties of rare mammary tumor subclones enabled the seeding and colonization of metastases in multiple secondary organ sites. In this study, patient-derived xenograft (PDX) models of treatment-naive TNBC and serial biopsies from TNBC patients undergoing NACT were used to elucidate mechanisms of chemoresistance in the neoadjuvant setting. Barcode-mediated clonal tracking and genomic sequencing of PDX tumors revealed that residual tumors remaining after chemotherapy maintained the subclonal architecture of untreated tumors yet their transcriptomes, proteomes, and histologic features were distinct from those of untreated tumors. Once treatment was halted, residual tumors gave rise to chemotherapy-sensitive tumors with similar transcriptomes, proteomes, and histological features to those of untreated tumors. Taken together, these results demonstrated that tumors can adopt a reversible drug-tolerant state that does not involve clonal selection as a chemotherapy resistance mechanism. Serial biopsies obtained from patients with TNBC undergoing NACT revealed similar histologic changes as well as maintenance of stable subclonal architecture, demonstrating that PDXs capture molecular features characteristic of human TNBC chemoresistance.

  Study phs001742

• Circulating tumor DNA dynamics reveal KRAS G12C mutation heterogeneity and response to treatment with the KRAS G12C inhibitor divarasib in solid tumors

  Purpose: To inform prognosis, treatment response, disease biology, and KRAS G12C mutation heterogeneity, we conducted exploratory circulating tumor DNA (ctDNA) profiling on 134 patients with solid tumors harboring a KRAS G12C mutation treated with single-agent divarasib (GDC-6036) in a phase 1 study. Experimental design: Plasma samples were collected for serial ctDNA profiling at baseline (Cycle 1 Day 1 prior to treatment) and multiple on-treatment time points (Cycle 1 Day 15 and Cycle 3 Day 1). Results: KRAS G12C ctDNA was detectable from plasma samples in 72.9% (43/59) and 92.6% (50/54) of patients with non-small cell lung cancer and colorectal cancer, respectively, the majority of whom were eligible for study participation based on a local test detecting the KRAS G12C mutation in tumor tissue. Baseline ctDNA tumor fraction was associated with tumor type, disease burden, and metastatic sites. A decline in ctDNA level was observed as early as Cycle 1 Day 15. Serial assessment showed a decline in ctDNA tumor fraction associated with response and progression-free survival. Except for a few cases of KRAS G12C sub-clonality, on-treatment changes in KRAS G12C variant allele frequency mirrored changes in the overall ctDNA tumor fraction. Conclusion: Across tumor types, the KRAS G12C mutation likely represents a truncal mutation in the majority of patients. Rapid and deep decline in ctDNA tumor fraction was observed in patients responding to divarasib treatment. Early on-treatment dynamics of ctDNA were associated with patient outcomes and tumor response to divarasib treatment.

  Study EGAS50000000315

• Coding and regulatory somatic profiling of triple-negative breast cancer in Sub-Saharan African patients

  The burden of triple-negative breast cancer (TNBC) may be shaped by genetic factors, particularly inherited and somatic mutation profiles. However, data on this topic remain limited, especially for the African continent, where a higher TNBC incidence is observed. In the age of precision medicine, cataloguing TNBC diversity in African patients becomes imperative. We performed whole exome sequencing, including untranslated regions, on 30 samples from Angola and Cape Verde, which allowed to ascertain on potential regulatory mutations in TNBC for the first time. A high somatic burden was observed for the African cohort, with 86% of variants being so far unreported. Recurring to predictive functional algorithms, 17% of the somatic single nucleotide variants were predicted to be deleterious at the protein level, and 20% overlapped with candidate cis-regulatory elements controlling gene expression. Several of these somatic functionally-impactful mutations and copy number variation (mainly in 1q, 8q, 6 and 10p) occur in known BC- and all cancer-driver genes, enriched for several cancer mechanisms, including response to radiation and related DNA repair mechanisms. TP53 is the top of these known BC-driver genes, but our results identified possible novel TNBC driver genes that may play a main role in the African context, as TTN, CEACAM7, DEFB132, COPZ2 and GAS1. These findings emphasize the need to expand cancer omics screenings across the African continent, the region of the globe with highest genomic diversity, accelerating the discovery of new somatic mutations and cancer-related pathways.

  Study EGAS50000001013

• Target sequencing of 27 cancer-predisposing genes and 13 renal cell carcinoma-related genes in Japanese renal cell carcinoma patients

  Identifying causative genes via genetic testing is useful for the screening, prevention, and treatment of cancer. Several hereditary syndromes are known to occur in renal cell carcinoma (RCC). However, these evidences came from the European population; it remains unclear how the RCC-related genes and other cancer-predisposing genes contribute to the development RCC in the Japanese population. A case-control study of 14 RCC-related genes and 26 cancer-predisposing genes was performed using 1,563 Japanese patients with RCC and 6,016 controls. Patients were divided into two major histological subtypes of clear cell RCC (ccRCC) or non-clear cell RCC (nccRCC). Gene-based analysis of germline pathogenic variants in patients with each subtype and cancer-free subjects was performed. Following quality control, 1,532 patients with RCC and 5,996 controls were further analyzed. For ccRCC, 52 of 1,283 (4.05%) patients carried pathogenic variants mainly in the cancer-predisposing genes such as TP53 (P = 1.73 �� 10-4; OR, 5.8; 95% CI, 2.2���15.7). Approximately 80% of patients with pathogenic variants in TP53 had p.Ala189Val that was specific in East Asian population. For nccRCC, 14 of 249 (5.62%) patients carried pathogenic variants mainly in the RCC-related genes such as BAP1 (P = 6.27 �� 10-5; OR, Inf; 95% CI, 10.0���Inf), and FH (P = 6.27 �� 10-5; OR, Inf; 95% CI, 10.0���Inf). Our study showed different and population-specific contributions of risk genes between ccRCC and nccRCC in Japanese for better-personalized medicine.

  Study JGAS000414

• Gene expression of human Th17 cells before and after activation

  Although gene expression of human Th17 clones has been studies, to date, molecular mechanisms for human Th17 development remain unclear. We have analyzed gene expression of human Th17 cells before and after activation. Th17-cell clones from peripheral blood CD4 T cells cultured with LPS-stimulated dendritic cells derived from monocytes stimulated by TNF were established by a limited dilution method. One of the Th17 clones was proliferated significantly, and high percentages (>70%) of Th17 cells in the cultured cells were maintained by addition of monocytes, IL-1b, and IL-15. CD161+CXCR3- cells (CD161+Th17) in the cultures were sorted and purified up to approximately 97% of IL-17-producing cells after treatment with PMA/ionomycin. Furthermore, these cells were treated with TCR-stimuli, IL-1b, and IL-23 for 2 days, and IL-17-producing Th17 cells (active-Th17) detected by IL-17-catch-up antibodies were sorted. Total RNA sampled from 1x 106 CD161+Th17, active-Th17, na?ve CD4 T cells, or CXCR3+ Th1 cells from combined CD4 T and dendritic cell cultures was used for SAGE. SAGE was performed by using SOLID TM SAGETM kit with barcoding adaptor molecules (Applied Biosystems). DNA sequence was analyzed by using AB5500 Genetic Analyzer (Applied Biosystems), and gene expression was analyzed by using SOLID? SAGETM software (Applied Biosystems). Our data shows high levels of IL-17A-mRNA expression by active-Th17; however, but only slight expression by CD161+Th17. Therefore, the data could provide alteration of gene expression by Th17 cells before and after stimulation.

  Study JGAS000005

• Neoadjuvant immunotherapy leads to pathological responses in MMR proficient and MMR deficient early stage colon cancers

  PD-1 plus CTLA-4 blockade is highly effective in advanced-stage, mismatch repair (MMR)-deficient (dMMR) colorectal cancers, yet not in MMR-proficient (pMMR) tumors. We postulated a higher efficacy of neoadjuvant immunotherapy in early-stage colon cancers. In the exploratory NICHE study (ClinicalTrials.gov: NCT03026140), patients with dMMR or pMMR tumors received a single dose of ipilimumab and two doses of nivolumab before surgery, the pMMR group with or without celecoxib. The primary objective was safety and feasibility; 40 patients with 21 dMMR and 20 pMMR tumors were treated, and 3 patients received nivolumab monotherapy in the safety run-in. Treatment was well tolerated and all patients underwent radical resections without delays, meeting the primary endpoint. Of the patients who received ipilimumab + nivolumab (20 dMMR and 15 pMMR tumors), 35 were evaluable for efficacy and translational endpoints. Pathological response was observed in 20/20 (100%; 95% exact confidence interval (CI): 86–100%) dMMR tumors, with 19 major pathological responses (MPRs, ≤10% residual viable tumor) and 12 pathological complete responses. In pMMR tumors, 4/15 (27%; 95% exact CI: 8–55%) showed pathological responses, with 3 MPRs and 1 partial response. CD8+PD-1+ T cell infiltration was predictive of response in pMMR tumors. These data indicate that neoadjuvant immunotherapy may have the potential to become the standard of care for a defined group of colon cancer patients when validated in larger studies with at least 3 years of disease-free survival data.

  Study EGAS00001004160

• Spatial and temporal evolution of distal 10q deletion, a prognostically unfavorable event in diffuse low-grade gliomas

  Background: The disease course of patients with diffuse low-grade glioma is notoriously unpredictable. Temporal and spatially distinct samples may provide insight into the evolution of clinically relevant copy number aberrations (CNAs). The purpose of this study is to identify CNAs that are indicative of aggressive tumor behaviour and can thereby complement the prognostically favorable 1p/19q co-deletion. Results: Genome-wide, 50 base pair single-end, sequencing was performed to detect CNAs in a clinically well-characterized cohort of 98 formalin-fixed paraffin-embedded low-grade gliomas. CNAs are correlated with overall survival as an endpoint. Seventy-five additional samples from spatially distinct regions and paired recurrent tumors of the discovery cohort were analysed to interrogate the intratumoral heterogeneity and spatial evolution. Loss of 10q25.2-qter is a frequent subclonal event and significantly correlates with an unfavorable prognosis. A significant correlation is furthermore observed in a validation set of 126 and confirmation set of 184 patients. Loss of 10q25.2-qter arises in a longitudinal manner in paired recurrent tumor specimens, whereas the prognostically favorable 1p/ 19q co-deletion is the only CNA that is stable across spatial regions and recurrent tumors. Conclusions: CNAs in low-grade gliomas display extensive intratumoral heterogeneity. Distal loss of 10q is a late onset event and a marker for reduced overall survival in low-grade glioma patients. Intratumoral heterogeneity and higher frequencies of distal 10q loss in recurrences suggest this event is involved in outgrowth to the recurrent tumor.

  Study EGAS00001000643

• Versatile workflow for cell-type resolved transcriptional and epigenetic profiles from cryopreserved human lung

  The complexity of the lung microenvironment and changes in cellular composition during disease progression make it exceptionally hard to understand molecular mechanisms leading to the development of chronic lung diseases. Although recent advances in cell-type resolved and single-cell sequencing approaches hold great promise for studying complex diseases, their implementation relies on local access to fresh tissue, as traditional tissue storage methods do not allow viable cell isolation. To overcome these hurdles, we developed a novel, versatile workflow that allows long-term storage of human lung tissue with high cell viability, permits thorough sample quality check before cell isolation, and is compatible with sequencing-based profiling, including single-cell approaches. We demonstrate that cryopreservation is suitable for the isolation of multiple cell types from human lung and is applicable to both healthy and diseased tissue, including COPD and tumour samples. Basal cells isolated from cryopreserved airways retain the ability to differentiate, indicating that cellular identity is not altered by cryopreservation. Importantly, using RNA sequencing and EPIC Array, we show that genome-wide gene expression and DNA methylation signatures are preserved upon cryopreservation, emphasizing the suitability of our workflow for -omics profiling of human lung cells. In addition, we obtained high-quality single-cell RNA sequencing data of cells isolated from the cryopreserved human lung, demonstrating that cryopreservation empowers single-cell approaches. Overall, thanks to its simplicity, our cryopreservation workflow is well-suited for prospective tissue collection by academic collaborators and biobanks, opening worldwide access to human tissue.

  Study EGAS00001004477