المؤلفون: Dennis D. Weisenburger, Randy D. Gascoyne, Jan Delabie, Chih Jian Lih, Lisa M. Rimsza, Erlend B. Smeland, Elaine S. Jaffe, George E. Wright, Betty Glinsmann-Gibson, William D. Walsh, Louis M. Staudt, Andreas Rosenwald, German Ott, Kai Fu, Wing C. Chan, Joseph M. Connors, David W. Scott, Raymond R. Tubbs, P. Mickey Williams, Rita M. Braziel, James R. Cook, Anja Mottok, Elias Campo, Timothy C. Greiner

المصدر: Blood. 123:1214-1217

مصطلحات موضوعية: Adult, Male, Pathology, medicine.medical_specialty, Adolescent, Biopsy, Concordance, Cell of origin, Immunology, Tissue Banks, Biology, Biochemistry, Fixatives, Young Adult, hemic and lymphatic diseases, Formaldehyde, Gene expression, medicine, Humans, Cell Lineage, Aged, Aged, 80 and over, Paraffin Embedding, medicine.diagnostic_test, Germinal center, Cell Biology, Hematology, Middle Aged, medicine.disease, LYMPHOID NEOPLASIA, Lymphoma, Gene Expression Regulation, Neoplastic, Leukemia, Female, Lymphoma, Large B-Cell, Diffuse, Transcriptome, Diffuse large B-cell lymphoma

الوصف: The assignment of diffuse large B-cell lymphoma into cell-of-origin (COO) groups is becoming increasingly important with the emergence of novel therapies that have selective biological activity in germinal center B cell–like or activated B cell–like groups. The Lymphoma/Leukemia Molecular Profiling Project's Lymph2Cx assay is a parsimonious digital gene expression (NanoString)–based test for COO assignment in formalin-fixed paraffin-embedded tissue (FFPET). The 20-gene assay was trained using 51 FFPET biopsies; the locked assay was then validated using an independent cohort of 68 FFPET biopsies. Comparisons were made with COO assignment using the original COO model on matched frozen tissue. In the validation cohort, the assay was accurate, with only 1 case with definitive COO being incorrectly assigned, and robust, with >95% concordance of COO assignment between 2 independent laboratories. These qualities, along with the rapid turnaround time, make Lymph2Cx attractive for implementation in clinical trials and, ultimately, patient management.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d202c011d429fe0641090cb0389025beTest
https://doi.org/10.1182/blood-2013-11-536433Test

المؤلفون: Melinda G. Hollingshead, Paul M. Williams, Palmer Fliss, James H. Doroshow, Biswajit Das, Li Chen, Yvonne A. Evrard, Sean P. McDermott, Tomas Vilimas, Michelle Ahalt-Gottholm, Corrine E. Camalier, Shivaani Kummar, Vivekananda Datta, John Carter, Justine N. McCutcheon, Rajesh Patidar, William D. Walsh, Carrie Bonomi, Chris Karlovich, Kelly Dougherty, Amanda Peach

المصدر: Cancer Research. 78:1039-1039

مصطلحات موضوعية: Cancer Research, medicine.diagnostic_test, Combination therapy, MEK inhibitor, Cancer, Biology, medicine.disease_cause, medicine.disease, AKT3, Circulating tumor cell, Oncology, Liver biopsy, Cancer research, medicine, Copy-number variation, KRAS

الوصف: Background: Patient-derived Xenograft (PDX) models are being widely used in preclinical studies to identify biomarkers of drug response and to enhance our understanding of cancer biology. Since patients with metastatic cancer have both intra-tumor and inter-site heterogeneity, PDX models generated from different tumor sites may provide a way to study tumor heterogeneity. Characterization of the genomic landscape in these models may also provide better insights into treatment response or resistance. It is rare to have multiple PDX models generated from a single patient over multiple time points during a treatment trajectory. Here, we report the genomic profiles of PDX models generated from 4 distinct tissue specimens over a 7-month period from a patient with metastatic colon adenocarcinoma. The first 2 PDX models were generated from circulating tumor cells (CTCs) and a liver biopsy prior to treatment with a combination pan-AKT + MEK inhibitor regimen. A third PDX model was generated from a liver biopsy while on-treatment and a fourth from an adrenal gland resection at progression. Clinically, all reported metastatic sites, except the adrenal gland, responded to the combination therapy. Results: Genomic characterization of the specimens obtained from these 4 PDX models led to the following observations: 1) PIK3CA E545K and KRAS G12D are present in all the specimens tested for all 4 models and are likely truncal driver mutations; 2) exclusive inter-model SNVs (single nucleotide variants) were identified, and may be model-specific variants representing inter-site heterogeneity in the patient; 3) variants involved in known resistance mechanisms to MEK inhibition were not present in any specimens; 4) overexpression of AKT3 has been reported as a resistance mechanism to a pan-AKT inhibitor and was observed in the adrenal tissue from the patient but not in any other PDX model derived from this patient; 5) intra-model and inter-model heterogeneity in whole genome CNV (copy number variant) profiles was observed between individual PDXs obtained from the pre-treatment CTC-derived model and the on-treatment liver biopsy model. Interestingly, one of the PDXs from the CTC-derived model presented a sub-clonal tumor fraction closely related to the on-treatment liver biopsy model. The multiple inter-model CNV profiles in the liver biopsy derived PDX models represent temporal heterogeneity within a tissue. Conclusions: We observed genomic heterogeneity in PDXs generated from specimens from a patient with metastatic colon adenocarcinoma. Both truncal and sub-clonal variants were identified representing various tumor fractions in these models. This case study illustrates how genomic profiling of multiple tumor sites at different times during course of treatment can provide insight into the complexity of tumor heterogeneity and tumor evolution in patients with metastatic disease. Citation Format: Biswajit Das, Chris Karlovich, Corrine E. Camalier, Rajesh Patidar, Li Chen, Vivekananda Datta, William D. Walsh, Sean P. McDermott, Tomas Vilimas, Palmer Fliss, Justine N. McCutcheon, Amanda Peach, Michelle Ahalt-Gottholm, Carrie Bonomi, Kelly Dougherty, John Carter, Shivaani Kummar, Yvonne A. Evrard, Melinda G. Hollingshead, Paul M. Williams, James H. Doroshow. PDX models generated from a patient with metastatic colon adenocarcinoma display both spatial and temporal tumor heterogeneity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1039.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::1a741c67ec47e58ff0eb9110c8087ca8Test
https://doi.org/10.1158/1538-7445.am2018-1039Test

المؤلفون: Aftab Ahmed, William D. Walsh, Dennis M. Wong, Regina R. Skelly, Kamal K. Mittal

المصدر: Human Immunology. 12:37-45

مصطلحات موضوعية: Cytotoxicity, Immunologic, medicine.drug_class, Ratón, Immunology, chemical and pharmacologic phenomena, Cross Reactions, Biology, Immunofluorescence, Monoclonal antibody, Antigen-Antibody Reactions, Mice, Antigen, medicine, Animals, Humans, Immunology and Allergy, Cytotoxic T cell, Lymphocytes, Murine monoclonal antibody, Gene, medicine.diagnostic_test, Histocompatibility Antigens Class II, Antibodies, Monoclonal, HLA-DR Antigens, General Medicine, Virology, Molecular biology, Cell culture, Spleen

الوصف: A murine monoclonal antibody, 12.7G3, directed against an Ia antigen encoded by genes in the I-A b subregion of the H-2 genetic complex, was found to be cytotoxic against human B lymphocytes. When tested against a random panel of normal human donors, the reactivity of 12.7G3 exhibited a correlation coefficient of 0.58–0.68 with cells expressing HLA-DR2. Antibody reactivity segregated with HLA-DR2 in two families studied. Binding of 12.7G3, as detected by immunofluorescence using flow microfluorometry, was positive for two human cell lines, GM 3161 and HFB-1, both expressing HLA-DR2, and negative for two other cell lines, GM 3104 (DR1,1) and GM 3164 (DR4,4).

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::23f7d49be1c159580d75dee121d10c72Test
https://doi.org/10.1016/0198-8859Test(85)90252-6