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systemic mastocytosis Pathogenesis

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https://www.readbyqxmd.com/read/27694501/advanced-systemic-mastocytosis-from-molecular-and-genetic-progress-to-clinical-practice
#1
REVIEW
Celalettin Ustun, Michel Arock, Hanneke C Kluin-Nelemans, Andreas Reiter, Wolfgang R Sperr, Tracy George, Hans-Peter Horny, Karin Hartmann, Karl Sotlar, Gandhi Damaj, Olivier Hermine, Srdan Verstovsek, Dean D Metcalfe, Jason Gotlib, Cem Akin, Peter Valent
Systemic mastocytosis is a heterogeneous disease characterized by the accumulation of neoplastic mast cells in the bone marrow and other organ organs/tissues. Mutations in KIT, most frequently KIT D816V, are detected in over 80% of all systemic mastocytosis patients. While most systemic mastocytosis patients suffer from an indolent disease variant, some present with more aggressive variants, collectively called "advanced systemic mastocytosis", which include aggressive systemic mastocytosis, systemic mastocytosis with an associated hematologic, clonal non mast cell-lineage disease, and mast cell leukemia...
October 2016: Haematologica
https://www.readbyqxmd.com/read/27355533/efficacy-and-safety-of-midostaurin-in-advanced-systemic-mastocytosis
#2
MULTICENTER STUDY
Jason Gotlib, Hanneke C Kluin-Nelemans, Tracy I George, Cem Akin, Karl Sotlar, Olivier Hermine, Farrukh T Awan, Elizabeth Hexner, Michael J Mauro, David W Sternberg, Matthieu Villeneuve, Alice Huntsman Labed, Eric J Stanek, Karin Hartmann, Hans-Peter Horny, Peter Valent, Andreas Reiter
BACKGROUND: Advanced systemic mastocytosis comprises rare hematologic neoplasms that are associated with a poor prognosis and lack effective treatment options. The multikinase inhibitor midostaurin inhibits KIT D816V, a primary driver of disease pathogenesis. METHODS: We conducted an open-label study of oral midostaurin at a dose of 100 mg twice daily in 116 patients, of whom 89 with mastocytosis-related organ damage were eligible for inclusion in the primary efficacy population; 16 had aggressive systemic mastocytosis, 57 had systemic mastocytosis with an associated hematologic neoplasm, and 16 had mast-cell leukemia...
June 30, 2016: New England Journal of Medicine
https://www.readbyqxmd.com/read/27104187/a-scientific-treatment-approach-for-acute-mast-cell-leukemia-using-a-strategy-based-on-next-generation-sequencing-data
#3
Jeonghwan Youk, Youngil Koh, Ji-Won Kim, Dae-Yoon Kim, Hyunkyung Park, Woo June Jung, Kwang-Sung Ahn, Hongseok Yun, Inho Park, Choong-Hyun Sun, Seungmook Lee, Sung-Soo Yoon
BACKGROUND: Mast cell leukemia (MCL) is the most aggressive form of systemic mastocytosis disorders. Owing to its rarity, neither pathogenesis nor standard treatment is established for this orphan disease. Hence, we tried to treat a patient with MCL based on the exome and transcriptome sequencing results of the patient's own DNA and RNA. METHODS: First, tumor DNA and RNA were extracted from bone marrow at the time of diagnosis. Germline DNA was extracted from the patient's saliva 45 days after induction chemotherapy and used as a control...
March 2016: Blood Research
https://www.readbyqxmd.com/read/27070304/mastocytosis-a-comprehensive-insight
#4
Dirk VAN Gysel, Hannelore DE Maeseneer, Arnold P Oranje
Mastocytosis refers to a heterogeneous group of clinical disorders characterized by an abnormal accumulation of mast cells (MCs) in various tissues. The skin is the organ most frequently involved, but all organs may be affected. The clinical signs and symptoms are produced by the functional effects of mast cell-derived mediators and the anatomical distribution of the mast cells. The 2008 WHO-classification defines 7 categories of mastocytosis. Skin disease, with or without systemic involvement, is by far the most common form of childhood mastocytosis...
August 2016: Giornale Italiano di Dermatologia e Venereologia: Organo Ufficiale, Società Italiana di Dermatologia e Sifilografia
https://www.readbyqxmd.com/read/26892042/prevalence-pathogenesis-and-treatment-options-for-mastocytosis-related-osteoporosis
#5
REVIEW
M Rossini, R Zanotti, G Orsolini, G Tripi, O Viapiana, L Idolazzi, A Zamò, P Bonadonna, V Kunnathully, S Adami, D Gatti
Mastocytosis is a rare condition characterized by abnormal mast cell proliferation and a broad spectrum of manifestations, including various organs and tissues. Osteoporosis is one of the most frequent manifestations of systemic mastocytosis, particularly in adults. Osteoporosis secondary to systemic mastocytosis is a cause of unexplained low bone mineral density that should be investigated when accompanied by suspicious clinical elements. Bone involvement is often complicated by a high recurrence of fragility fractures, mainly vertebral, leading to severe disability...
August 2016: Osteoporosis International
https://www.readbyqxmd.com/read/26775802/cardiovascular-symptoms-in-patients-with-systemic-mast-cell-activation-disease
#6
REVIEW
Ulrich W Kolck, Britta Haenisch, Gerhard J Molderings
Traditionally, mast cell activation disease (MCAD) has been considered as just one rare (neoplastic) disease, mastocytosis, focused on the mast cell (MC) mediators tryptase and histamine and the suggestive, blatant symptoms of flushing and anaphylaxis. Recently another form of MCAD, the MC activation syndrome, has been recognized featuring inappropriate MC activation with little to no neoplasia and likely much more heterogeneously clonal and far more prevalent than mastocytosis. Increasing expertise and appreciation has been established for the truly very large menagerie of MC mediators and their complex patterns of release, engendering complex, nebulous presentations of chronic and acute illness best characterized as multisystem polymorbidity of generally inflammatory ± allergic theme...
August 2016: Translational Research: the Journal of Laboratory and Clinical Medicine
https://www.readbyqxmd.com/read/26562302/mutational-hotspot-of-tet2-idh1-idh2-srsf2-sf3b1-kras-and-nras-from-human-systemic-mastocytosis-are-not-conserved-in-canine-mast-cell-tumors
#7
Eleonora Zorzan, Katia Hanssens, Mery Giantin, Mauro Dacasto, Patrice Dubreuil
INTRODUCTION: Both canine cutaneous mast cell tumor (MCT) and human systemic mastocytosis (SM) are characterized by abnormal proliferation and accumulation of mast cells in tissues and, frequently, by the presence of activating mutations in the receptor tyrosine kinase V-Kit Hardy-Zuckerman 4 Feline Sarcoma Viral Oncogene Homolog (c-KIT), albeit at different incidence (>80% in SM and 10-30% in MCT). In the last few years, it has been discovered that additional mutations in other genes belonging to the methylation system, the splicing machinery and cell signaling, contribute, with c-KIT, to SM pathogenesis and/or phenotype...
2015: PloS One
https://www.readbyqxmd.com/read/26543328/cytokine-regulation-of-microenvironmental-cells-in-myeloproliferative-neoplasms
#8
REVIEW
Gregor Hoermann, Georg Greiner, Peter Valent
The term myeloproliferative neoplasms (MPN) refers to a heterogeneous group of diseases including not only polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), but also chronic myeloid leukemia (CML), and systemic mastocytosis (SM). Despite the clinical and biological differences between these diseases, common pathophysiological mechanisms have been identified in MPN. First, aberrant tyrosine kinase signaling due to somatic mutations in certain driver genes is common to these MPN...
2015: Mediators of Inflammation
https://www.readbyqxmd.com/read/26162709/mast-cell-activation-disease-an-underappreciated-cause-of-neurologic-and-psychiatric-symptoms-and-diseases
#9
REVIEW
Lawrence B Afrin, Dieter Pöhlau, Martin Raithel, Britta Haenisch, Franz L Dumoulin, Juergen Homann, Uwe M Mauer, Sabrina Harzer, Gerhard J Molderings
Neurologists and psychiatrists frequently encounter patients whose central and/or peripheral neurologic and/or psychiatric symptoms (NPS) are accompanied by other symptoms for which investigation finds no unifying cause and for which empiric therapy often provides little to no benefit. Systemic mast cell activation disease (MCAD) has rarely been considered in the differential diagnosis in such situations. Traditionally, MCAD has been considered as just one rare (neoplastic) disease, mastocytosis, generally focusing on the mast cell (MC) mediators tryptase and histamine and the suggestive, blatant symptoms of flushing and anaphylaxis...
November 2015: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/26017288/kit-d816v-and-jak2-v617f-mutations-are-seen-recurrently-in-hypereosinophilia-of-unknown-significance
#10
Juliana Schwaab, Roland Umbach, Georgia Metzgeroth, Nicole Naumann, Mohamad Jawhar, Karl Sotlar, Hans-Peter Horny, Timo Gaiser, Wolf-Karsten Hofmann, Susanne Schnittger, Nicholas C P Cross, Alice Fabarius, Andreas Reiter
Myeloproliferative neoplasms with eosinophilia are commonly characterized by a normal karyotype and remain poorly defined at the molecular level. We therefore investigated 426 samples from patients with hypereosinophilia of unknown significance initially referred for screening of the FIP1L1-PDGFRA (FP) fusion gene also for KIT D816V and JAK2 V617F mutations. Overall, 86 (20%) patients tested positive: FP+ in 55 (12%), KIT D816V+ in 14 (3%), and JAK2 V617F+ in 17 (4%) patients, respectively. To gain better insight into clinical characteristics, we compared these cases with 31 additional and well-characterized KIT D816V+ eosinophilia-associated systemic mastocytosis (SM-eo) patients enrolled within the "German Registry on Disorders of Eosinophils and Mast cells...
September 2015: American Journal of Hematology
https://www.readbyqxmd.com/read/26002753/nilotinib-in-patients-with-systemic-mastocytosis-analysis-of-the-phase-2-open-label-single-arm-nilotinib-registration-study
#11
Andreas Hochhaus, Michele Baccarani, Francis J Giles, Philipp D le Coutre, Martin C Müller, Andreas Reiter, Helene Santanastasio, Mimi Leung, Steven Novick, Hagop M Kantarjian
PURPOSE: Activating KIT mutations are part of the pathogenesis of systemic mastocytosis (SM). Nilotinib is a tyrosine kinase inhibitor that potently inhibits activated forms of KIT. This phase 2, open-label, single-arm study (CAMN107A2101; www.clinicaltrials.gov NCT00109707) evaluated nilotinib in patients with SM. METHODS: Patients with SM [aggressive SM (ASM), indolent SM, or other] received nilotinib 400 mg twice daily. C-findings were collected retrospectively to assess response using criteria proposed after trial initiation...
November 2015: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/25694784/cutaneous-and-gastrointestinal-symptoms-in-two-patients-with-systemic-mastocytosis-successfully-treated-with-omalizumab
#12
Sofie Lieberoth, Simon Francis Thomsen
The pathogenesis of mastocytosis is not well defined and thus treatment remains challenging and remains on a palliative basis. We present two cases (a 48-year-old woman and a 57-year-old man) with indolent systemic mastocytosis in whom omalizumab (anti-IgE) reduced gastrointestinal and cutaneous symptoms significantly. This observation provides additional insight into the effects of omalizumab on systemic mastocytosis.
2015: Case Reports in Medicine
https://www.readbyqxmd.com/read/25386256/telangiectasia-macularis-eruptiva-perstans-more-than-skin-deep
#13
REVIEW
Casey E Watkins, Winston B Bokor, Stuart Leicht, George Youngberg, Guha Krishnaswamy
Systemic mastocytosis is a rare disease involving the infiltration and accumulation of active mast cells within any organ system. By far, the most common organ affected is the skin. Cutaneous manifestations of mastocytosis, including Urticaria Pigmentosa (UP), cutaneous mastocytoma or telangiectasia macularis eruptive perstans (TMEP), may indicate a more serious and potentially life-threatening underlying disease. The presence of either UP or TMEP in a patient with anaphylactic symptoms should suggest the likelihood of systemic mastocytosis, with the caveat that systemic complications are more likely to occur in patients with UP...
January 31, 2011: Dermatology Reports
https://www.readbyqxmd.com/read/25315185/diagnostic-procedures-for-improving-of-the-kit-cd117-expressed-allele-burden-for-the-liver-metastases-from-uterus-mast-cell-tumors-prognostic-value-of-the-metastatic-pattern-and-tumor-biology
#14
Ehsan Hosseini, Behnam Pedram, Ali Mohammad Bahrami, Seyed Rashid Touni, Hamed Zamankhan Malayeri, Aram Mokarizadeh, Mehdi Pourzaer, Maryam Pourzaer, Shahram Zehtabian, Sheida Mohajer, Sharareh Ahmadi
The activating KIT marker plays a central role in the pathogenesis, diagnosis, and targeted treatment of systemic mastocytosis (SM). Recent studies have identified the KIT (CD117) as a marker that distinguishes nonneoplastic from neoplastic mast cells in human systemic mastocytosis. In this study, we conclude that immunohistopathology assays for KIT staining pattern are useful complimentary tools for diagnosis and evaluation of prognosis in uterus mast cell tumor (MCT) metastasis to the liver in 10 patients...
February 2015: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/25115556/mast-cells-in-a-murine-lung-ischemia-reperfusion-model-of-primary-graft-dysfunction
#15
John R Greenland, Xiang Xu, David M Sayah, Feng Chun Liu, Kirk D Jones, Mark R Looney, George H Caughey
Primary graft dysfunction (PGD), as characterized by pulmonary infiltrates and high oxygen requirements shortly after reperfusion, is the major cause of early morbidity and mortality after lung transplantation. Donor, recipient and allograft-handling factors are thought to contribute, although new insights regarding pathogenesis are needed to guide approaches to prevention and therapy. Mast cells have been implicated in ischemic tissue injury in other model systems and in allograft rejection, leading to the hypothesis that mast cell degranulation contributes to lung injury following reperfusion injury...
2014: Respiratory Research
https://www.readbyqxmd.com/read/25088577/novel-thiazole-amine-class-tyrosine-kinase-inhibitors-induce-apoptosis-in-human-mast-cells-expressing-d816v-kit-mutation
#16
Yanli Jin, Ke Ding, Deping Wang, Mengjie Shen, Jingxuan Pan
Gain-of-function mutations of receptor tyrosine kinase KIT play a critical role in the pathogenesis of systemic mastocytosis (SM) and gastrointestinal stromal tumors. D816V KIT mutation, found in ∼80% of SM, is resistant to the currently available tyrosine kinase inhibitors (TKIs) (e.g. imatinib mesylate). Therefore, development of promising TKIs for the treatment of D816V KIT mutation is still urgently needed. We synthesized thiazole amine compounds and chose one representative designated 126332 to investigate its effect on human mast cells expressing KIT mutations...
October 10, 2014: Cancer Letters
https://www.readbyqxmd.com/read/25039926/the-presence-of-mast-cell-clonality-in-patients-with-unexplained-anaphylaxis
#17
T Gülen, H Hägglund, B Sander, B Dahlén, G Nilsson
BACKGROUND: The mechanisms by which mast cells in patients with unexplained anaphylaxis (UEA) are triggered remain elusive. Onset of episodes is unpredictable and often recurrent. The substantial overlap between the clinical manifestations of UEA and clonal mast cell disorders (CMD) suggests an association between these rare disorders. The two forms of CMD characterized to date are systemic mastocytosis (SM) and monoclonal mast cell activation syndrome (MMAS). OBJECTIVE: To examine the hypothesis that the pathogenesis of UEA reflects the presence of aberrant subpopulations of mast cells...
September 2014: Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/25032071/modelling-of-a-genetically-diverse-evolution-of-systemic-mastocytosis-with-chronic-myelomonocytic-leukemia-sm-cmml-by-next-generation-sequencing
#18
Markus Rechsteiner, Rouven Müller, Tanja Reineke, Jeroen Goede, Annette Bohnert, Qing Zhong, Markus G Manz, Holger Moch, Peter J Wild, Dieter R Zimmermann, Marianne Tinguely
BACKGROUND: Systemic mastocytosis (SM) is a heterogenous, clonal mast cell (MC) proliferation, rarely associated with clonal hematologic non-mast cell lineage disease (SM-AHNMD). KIT (D816V) is regarded as driver-mutation in SM-AHNMD. METHODS: DNA isolated from peripheral blood (PB) of an SM-CMML patient was investigated with targeted next generation sequencing. Variants were verified by Sanger sequencing and further characterized in the SM part of the bone marrow trephine (BMT), normal tissue, and FACS sorted PB cell subpopulations...
2014: Experimental Hematology & Oncology
https://www.readbyqxmd.com/read/25031064/systemic-mastocytosis-a-diagnostic-challenge
#19
Ana Cristina Amorim Oliveira Gaia Lladó, Claudia Elena Mihon, Madalena Silva, Antonio Galzerano
Mastocytosis refers to a group of disorders characterized by the infiltration of clonally derived mast cells to the skin or extracutaneous tissues resulting in a heterogeneous clinical picture. It is a rare hematologic disorder in all its forms. The exact incidence is unknown; it affects patients of any age and males and females equally. Its molecular pathogenesis is incompletely understood. The clinical features of mastocytosis result from both chronic and episodic mast cell mediator release, signs and symptoms arising from diffuse or focal tissue infiltration, and, occasionally, the presence of an associated non-mast cell clonal hematologic disease...
May 2014: Revista Brasileira de Hematologia e Hemoterapia
https://www.readbyqxmd.com/read/24760514/the-mouse-cyclophosphamide-model-of-bladder-pain-syndrome-tissue-characterization-immune-profiling-and-relationship-to-metabotropic-glutamate-receptors
#20
Anna V Golubeva, Alexander V Zhdanov, Giuseppe Mallel, Timothy G Dinan, John F Cryan
Abstract Painful bladder syndrome/Interstitial cystitis (PBS/IC) is a chronic disorder characterized clinically by recurring episodes of pelvic pain and increased urination frequency, significantly impairing patients' quality of life. Despite this, there is an unmet medical need in terms of effective diagnostics and treatment. Animal models are crucial in this endeavor. Systemic chronic administration of cyclophosphamide (CYP) in mice has been proposed as a relevant preclinical model of chronic bladder pain...
2014: Physiological Reports
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