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Ioanna Triviai, Silke Zeschke, Jan Rentel, Marios Spanakis, Theo Scherer, Razif Gabdoulline, Victoria Panagiota, Felicitas Thol, Michael Heuser, Carol Stocking, Nicolaus Kröger
Primary myelofibrosis (PMF) is a hematopoietic stem cell (HSC) disease, characterized by aberrant differentiation of all myeloid lineages and profound disruption of the bone marrow niche. PMF samples carry several mutations, but their cell origin and hierarchy in regulating the different waves of clonal and aberrant myeloproliferation from the prime HSC compartment is poorly understood. Genotyping of >2000 colonies from CD133+HSC and progenitors from PMF patients confirmed the complex genetic heterogeneity within the neoplastic population...
June 15, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Victoria V Prassek, Maja Rothenberg-Thurley, Maria C Sauerland, Tobias Herold, Hanna Janke, Bianka Ksienzyk, Nikola P Konstandin, Dennis Goerlich, Utz Krug, Andreas Faldum, Wolfgang E Berdel, Bernhard Wörmann, Jan Braess, Stephanie Schneider, Marion Subklewe, Stephan K Bohlander, Wolfgang Hiddemann, Karsten Spiekermann, Klaus H Metzeler
Acute myeloid leukemia is a disease of the elderly (median age at diagnosis, 65-70 years). The prognosis of older acute myeloid leukemia patients is generally poor. While genetic markers have become important tools for risk stratification and treatment selection in young and middle-aged acute myeloid leukemia patients, their applicability in very old patients is less clear. We sought to validate existing genetic risk classifications systems and identify additional factors associated with outcomes in intensively treated acute myeloid leukemia patients aged ≥75 years...
June 14, 2018: Haematologica
Thomas Ernst, Melinda Busch, Jenny Rinke, Jana Ernst, Claudia Haferlach, James F Beck, Andreas Hochhaus, Bernd Gruhn
No abstract text is available yet for this article.
June 13, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Jason R Schwartz, Michael P Walsh, Jing Ma, Tamara Lamprecht, Shuoguo Wang, Gang Wu, Susana Raimondi, Brandon Triplett, Jeffery Klco
Donor-derived hematologic malignancies are rare complications of hematopoietic cell transplantation (HCT). Although these are commonly either a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), in general, they are a heterogeneous group of diseases and a unified mechanism for their development has remained elusive. Here we report next generation sequencing, including whole exome sequencing (WES), whole genome sequencing (WGS), and targeted sequencing, of a case of donor-derived MDS (dMDS) following HCT for high-risk B-lymphoblastic leukemia (B-ALL) in an adolescent...
June 11, 2018: Cold Spring Harbor Molecular Case Studies
Mrinal M Patnaik, Ayalew Tefferi
DISEASE OVERVIEW: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms, with an inherent risk for leukemic transformation (∼15%-20% over 3-5 years). DIAGNOSIS: Diagnosis is based on the presence of sustained (>3 months) peripheral blood monocytosis (≥1 × 109 /L; monocytes ≥10%), along with bone marrow dysplasia. Clonal cytogenetic abnormalities occur in ∼ 30% of patients, while >90% have gene mutations...
June 2018: American Journal of Hematology
Catherine C Coombs, Nancy K Gillis, Xianming Tan, Jonathan S Berg, Markus C Ball, Maria E Balasis, Nathan D Montgomery, Kelly Bolton, Joel S Parker, Tania E Mesa, Sean J Yoder, Michele C Hayward, Nirali M Patel, Kristy L Richards, Christine M Walko, Todd C Knepper, John T Soper, Jared Weiss, Juneko E Grilley-Olson, William Y Kim, Shelton Earp, Ross Levine, Elli Papaemmanuil, Ahmet Zehir, D Neil Hayes, Eric Padron
PURPOSE: In this era of precision-based medicine, for optimal patient care, results reported from commercial next-generation sequencing assays should adequately reflect the burden of somatic mutations in the tumor being sequenced. Here, we sought to determine the prevalence of clonal hematopoiesis leading to possible misattribution of tumor mutation calls on unpaired FoundationMedicine® next-generation sequencing assays. EXPERIMENTAL DESIGN: This was a retrospective cohort study of individuals undergoing next-generation sequencing of solid tumors from two large cancer centers...
June 4, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Ayalew Tefferi, Naseema Gangat, Mythri Mudireddy, Terra L Lasho, Christy Finke, Kebede H Begna, Michelle A Elliott, Aref Al-Kali, Mark R Litzow, C Christopher Hook, Alexandra P Wolanskyj, William J Hogan, Mrinal M Patnaik, Animesh Pardanani, Darci L Zblewski, Rong He, David Viswanatha, Curtis A Hanson, Rhett P Ketterling, Jih-Luh Tang, Wen-Chien Chou, Chien-Chin Lin, Cheng-Hong Tsai, Hwei-Fang Tien, Hsin-An Hou
OBJECTIVE: To develop a new risk model for primary myelodysplastic syndromes (MDS) that integrates information on mutations, karyotype, and clinical variables. PATIENTS AND METHODS: Patients with World Health Organization-defined primary MDS seen at Mayo Clinic (MC) from December 28, 1994, through December 19, 2017, constituted the core study group. The National Taiwan University Hospital (NTUH) provided the validation cohort. Model performance, compared with the revised International Prognostic Scoring System, was assessed by Akaike information criterion and area under the curve estimates...
June 1, 2018: Mayo Clinic Proceedings
Zhi-Ping Guo, Yan-Hong Tan, Jian-Lan Li, Zhi-Fang Xu, Xiu-Hua Chen, Lian-Rong Xu
The development of acute lymphoblastic leukemia (ALL) from myelodysplastic syndrome (MDS) is a very rare event. The current report presents a rare case of a 33-year-old man who was diagnosed with MDS with multiple-lineage dysplasia (MDS-MLD) that transformed into pro-B-ALL. A missense mutation (S1231F) of the additional sex combs like 1, transcriptional regulator gene was identified, which may have a substantial role in the progression, however does not act as an unfavorable prognostic marker. The patient died during induction chemotherapy...
June 2018: Oncology Letters
Manuel Buscarlet, Sylvie Provost, Yassamin Feroz Zada, Vincent Bourgoin, Luigina Mollica, Marie-Pierre Dubé, Lambert Busque
We analyzed DNA from PMN (granulocytes), CD14+ (monocytes), CD19+ (B-cells) and CD3+ (T-cells) of 107 individuals with clonal hematopoiesis of indeterminate potential (CHIP) to perform lineage restriction analysis of different gene mutations. Individuals were aged 55 to 96 (mean age: 70.0). Three lineage categories were defined: myeloid (PMN±monocytes), myelolympho-B (myeloid and B-cells), multipotent (myeloid, B and T-cells). Six individuals with aberrant patterns were excluded from analysis. Fifty-six had a single DNMT3A mutation, 24 had a single TET2 mutation, 7 had a single mutation in other genes (JAK2, ASXL1, CBL or TP53), and 14 had multiple mutations...
May 15, 2018: Blood
Duarte Mendes Oliveira, Gianluca Santamaria, Carmelo Laudanna, Simona Migliozzi, Pietro Zoppoli, Michael Quist, Catie Grasso, Chiara Mignogna, Laura Elia, Maria Concetta Faniello, Cinzia Marinaro, Rosario Sacco, Francesco Corcione, Giuseppe Viglietto, Donatella Malanga, Antonia Rizzuto
The objective of this study was to determine the feasibility to detect copy number alterations in colon cancer samples using Next Generation Sequencing data and to elucidate the association between copy number alterations in specific genes and the development of cancer in different colon segments. We report the successful detection of somatic changes in gene copy number in 37 colon cancer patients by analysis of sequencing data through Amplicon CNA Algorithm. Overall, we have found a total of 748 significant copy number alterations in 230 significant genes, of which 143 showed CN losses and 87 showed CN gains...
April 17, 2018: Oncotarget
Ying Guo, Hui Yang, Shi Chen, Peng Zhang, Rong Li, Stephen D Nimer, J William Harbour, Mingjiang Xu, Feng-Chun Yang
No abstract text is available yet for this article.
April 2, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Matthieu Duchmann, Fevzi F Yalniz, Alessandro Sanna, David Sallman, Catherine C Coombs, Aline Renneville, Olivier Kosmider, Thorsten Braun, Uwe Platzbecker, Lise Willems, Lionel Adès, Michaela Fontenay, Raajit Rampal, Eric Padron, Nathalie Droin, Claude Preudhomme, Valeria Santini, Mrinal M Patnaik, Pierre Fenaux, Eric Solary, Raphael Itzykson
Somatic mutations contribute to the heterogeneous prognosis of chronic myelomonocytic leukemia (CMML). Hypomethylating agents (HMAs) are active in CMML, but analyses of small series failed to identify mutations predicting response or survival. We analyzed a retrospective multi-center cohort of 174 CMML patients treated with a median of 7 cycles of azacitidine (n = 68) or decitabine (n = 106). Sequencing data before treatment initiation were available for all patients, from Sanger (n = 68) or next generation (n = 106) sequencing...
April 25, 2018: EBioMedicine
Yan-Bo Nie, Meng Sun, Colin K He, Man-Kai Ju, Fu-Ling Zhou, San-Yun Wu, Yi Zhou, Li Liu, Hui Shen, Ting-Ting Huang, Pan Liu, Ying Xu, Liang Shao, Xue-Lan Zuo
Essential thrombocythemia (ET) is characterized by thrombotic and hemorrhagic events. The association of clinical characteristics of Chinese ET patients and additional sex combs like 1 (ASXL1) mutations in these patients has remained to be elucidated. In the present study, 72 newly diagnosed Chinese ET patients were enrolled to determine ASXL1 mutations. Mutations in ASXL1, Janus kinase (JAK)2, calreticulin (CALR) and myeloproliferative leukemia (MPL) genes were detected using Sanger sequencing, and data were statistically analyzed...
May 2018: Experimental and Therapeutic Medicine
Tiphanie Picot, Carmen Mariana Aanei, Pascale Flandrin Gresta, Pauline Noyel, Sylvie Tondeur, Emmanuelle Tavernier Tardy, Denis Guyotat, Lydia Campos Catafal
Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm, characterized by persistent monocytosis and dysplasia in at least one myeloid cell lineage. This persistent monocytosis should be distinguished from the reactive monocytosis which is sometimes observed in a context of infections or solid tumors. In 2015, Selimoglu-Buet et al. observed an increased percentage of classical monocytes (CD14+ /CD16- >94%) in the peripheral blood (PB) of CMML patients. In this study, using multiparametric flow cytometry (MFC), we assessed the monocytic distribution in PB samples and in bone marrow aspirates from 63 patients with monocytosis or CMML suspicion, and in seven follow-up blood samples from CMML patients treated with hypomethylating agents (HMA)...
2018: Frontiers in Oncology
Veronika Reidel, Johanna Kauschinger, Richard T Hauch, Catharina Müller-Thomas, Niroshan Nadarajah, Rainer Burgkart, Burkhard Schmidt, Dirk Hempel, Anne Jacob, Julia Slotta-Huspenina, Ulrike Höckendorf, Christian Peschel, Wolfgang Kern, Torsten Haferlach, Katharina S Götze, Stefanie Jilg, Philipp J Jost
Somatic mutations in genes such as ASXL1 , RUNX1 , TP53 or EZH2 adversely affect the outcome of patients with myelodysplastic syndromes (MDS). Since selective BCL-2 inhibition is a promising treatment strategy in hematologic malignancies, we tested the therapeutic impact of ABT-199 on MDS patient samples bearing an adverse mutational profile. By gene expression, we found that the level of pro-apoptotic BIM significantly decreased during MDS disease progression in line with an acquired resistance to cell death...
April 3, 2018: Oncotarget
Kiyomi Morita, Hagop M Kantarjian, Feng Wang, Yuanqing Yan, Carlos Bueso-Ramos, Koji Sasaki, Ghayas C Issa, Sa Wang, Jeffrey Jorgensen, Xingzhi Song, Jianhua Zhang, Samantha Tippen, Rebecca Thornton, Marcus Coyle, Latasha Little, Curtis Gumbs, Naveen Pemmaraju, Naval Daver, Courtney D DiNardo, Marina Konopleva, Michael Andreeff, Farhad Ravandi, Jorge E Cortes, Tapan Kadia, Elias Jabbour, Guillermo Garcia-Manero, Keyur P Patel, P Andrew Futreal, Koichi Takahashi
Purpose The aim of the current study was to determine whether the degree of mutation clearance at remission predicts the risk of relapse in patients with acute myeloid leukemia (AML). Patients and Methods One hundred thirty-one previously untreated patients with AML who received intensive induction chemotherapy and attained morphologic complete remission (CR) at day 30 were studied. Pretreatment and CR bone marrow were analyzed using targeted capture DNA sequencing. We analyzed the association between mutation clearance (MC) on the basis of variant allele frequency (VAF) at CR (MC2...
April 27, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
José A Páramo Fernández
Recent research has revealed that clonal hematopoyesis of indeterminate potential (CHIP) characterized by the acquisition of somatic mutations in hematopoietic stem cells, is not only a common age-related disorder and a premalignant condition, but it is also associated with the development of atherosclerotic vascular diseases. Mutations in DNMT3A, TET2 and ASXL1 were each individually associated with coronary heart disease, stroke and coronary calcification. Therefore, CHIP emerges as a new risk factor for atherosclerotic vascular pathologies and its detection may be relevant as a new therapeutic target in order to modify the natural course of the disease...
April 23, 2018: Clínica e Investigación en Arteriosclerosis
Masaya Kibe, Satoshi Ibara, Hidehito Inagaki, Takema Kato, Hiroki Kurahashi, Toshiro Ikeda
Bohring-Opitz syndrome (BOS) is a rare disease with a number of characteristic features, including hypertelorism, prominent metopic suture, exophthalmos, cleft palate, abnormal posture, and developmental retardation. Here, we report a BOS patient presenting with lethal persistent pulmonary hypertension of the newborn (PPHN) and inspiratory respiratory failure. The female infant was treated with nitric oxide and vasodilator, which did not improve her condition. The inspiratory respiratory failure required management with deep sedation...
May 2018: American Journal of Medical Genetics. Part A
Emma Bedoukian, Deborah Copenheaver, Sherri Bale, Matthew Deardorff
Bohring-Opitz syndrome (BOS) is characterized clinically by severe developmental delays, microcephaly, failure to thrive, and characteristic facial features (prominent eyes, facial nevus simplex [flammeus], and others). Most patients meeting the clinical criteria for BOS (MIM: 605039) have a de novo nonsense or frameshift variant in ASXL1. We report a case of BOS caused by a pathogenic ASXL1 variant inherited from a germline mosaic mother. The ASXL1 mutation was detected via trio exome sequencing. The sequencing data demonstrated that the variant was inherited maternally but that the maternal variant was underrepresented in comparison to the normal allele...
May 2018: American Journal of Medical Genetics. Part A
Y Liu, Y Cao, Y Lin, W-M Dong, R-R Lin, Q Gu, X-B Xie, W-Y Gu
The presence of recurrent gene mutations is increasingly important in acute myeloid leukemia (AML) and sheds new insights into the understanding of leukemogenesis, prognostic evaluation, and clinical therapeutic efficacy. Until now, ten-eleven translocation 2 (TET2) and isocitrate dehydrogenase 2 (IDH2) mutations were reported to be mutually exclusive in AML patients. Similarly, nucleophosmin (NPM1) and additional sex comb-like 1 (ASXL1) mutations were rarely coexisted in AML. A 47-year-old man diagnosed with high-risk AML presented simultaneous mutations of TET2-IDH2 and NPM1-ASXL1 revealed by next-generation sequencing...
April 2018: Transplantation Proceedings
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