scholarly journals The new tool “KIT” in advanced systemic mastocytosis

Hematology ◽  
2018 ◽  
Vol 2018 (1) ◽  
pp. 127-136 ◽  
Author(s):  
William Shomali ◽  
Jason Gotlib
Keyword(s):  
Cell Activation ◽  
Systemic Mastocytosis ◽  
Symptom Burden ◽  
Organ Damage ◽  
Mast Cell Activation ◽  
World Health ◽  
Hematologic Neoplasm ◽  
Health Organization ◽  
Kit D816v

AbstractMastocytosis is a rare disease characterized by KIT-driven expansion and accumulation of neoplastic mast cells in various tissues. Although mediator symptoms related to mast cell activation can impose a symptom burden in cutaneous disease and across the spectrum of systemic mastocytosis subtypes, the presence of an associated hematologic neoplasm and/or organ damage denotes advanced disease and the potential for increased morbidity and mortality. In addition to the revised 2016 World Health Organization classification of mastocytosis, a new diagnostic and treatment toolkit, tethered to enhanced molecular characterization and monitoring, is poised to transform the management of patients with advanced systemic mastocytosis (advSM). Although the efficacy of midostaurin and novel selective KIT D816V inhibitors, such as avapritinib (BLU-285), have validated KIT as a therapeutic target, the clinical and biologic heterogeneity of advSM requires that we reimagine the blueprint for tackling these diseases and use tools that move beyond KIT-centric approaches.

Mast cell leukemia

Blood ◽  
2013 ◽  
Vol 121 (8) ◽  
pp. 1285-1295 ◽  
Author(s):  
Sophie Georgin-Lavialle ◽  
Ludovic Lhermitte ◽  
Patrice Dubreuil ◽  
Marie-Olivia Chandesris ◽  
Olivier Hermine ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
De Novo ◽  
Systemic Mastocytosis ◽  
Mast Cell Activation ◽  
Cell Leukemia ◽  
Mast Cell Leukemia ◽  
Kit D816v

Abstract Mast cell leukemia (MCL) is a very rare form of aggressive systemic mastocytosis accounting for < 1% of all mastocytosis. It may appear de novo or secondary to previous mastocytosis and shares more clinicopathologic aspects with systemic mastocytosis than with acute myeloid leukemia. Symptoms of mast cell activation—involvement of the liver, spleen, peritoneum, bones, and marrow—are frequent. Diagnosis is based on the presence of ≥ 20% atypical mast cells in the marrow or ≥ 10% in the blood; however, an aleukemic variant is frequently encountered in which the number of circulating mast cells is < 10%. The common phenotypic features of pathologic mast cells encountered in most forms of mastocytosis are unreliable in MCL. Unexpectedly, non-KIT D816V mutations are frequent and therefore, complete gene sequencing is necessary. Therapy usually fails and the median survival time is < 6 months. The role of combination therapies and bone marrow transplantation needs further investigation.

scholarly journals Response Criteria in Advanced Systemic Mastocytosis: Evolution in the Era of KIT Inhibitors

2021 ◽  
Vol 22 (6) ◽  
pp. 2983
Author(s):  
William Shomali ◽  
Jason Gotlib
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Systemic Mastocytosis ◽  
Myeloproliferative Neoplasms ◽  
Organ Damage ◽  
Response Criteria ◽  
Molecular Response ◽  
Tryptase Level ◽  
Hematologic Neoplasm ◽  
Kit D816v

Systemic mastocytosis (SM) is a rare clonal hematologic neoplasm, driven, in almost all cases, by the activating KIT D816V mutation that leads to the growth and accumulation of neoplastic mast cells. While patients with advanced forms of SM have a poor prognosis, the introduction of KIT inhibitors (e.g., midostaurin, and avapritinib) has changed their outlook. Because of the heterogenous nature of advanced SM (advSM), successive iterations of response criteria have tried to capture different dimensions of the disease, including measures of mast cell burden (percentage of bone marrow mast cells and serum tryptase level), and mast cell-related organ damage (referred to as C findings). Historically, response criteria have been anchored to reversion of one or more organ damage finding(s) as a minimal criterion for response. This is a central principle of the Valent criteria, Mayo criteria, and International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (IWG-MRT-ECNM) consensus criteria. Irrespective of the response criteria, an ever-present challenge is how to apply response criteria in patients with SM and an associated hematologic neoplasm, where the presence of both diseases complicates assignment of organ damage and adjudication of response. In the context of trials with the selective KIT D816V inhibitor avapritinib, pure pathologic response (PPR) criteria, which rely solely on measures of mast cell burden and exclude consideration of organ damage findings, are being explored as more robust surrogate of overall survival. In addition, the finding that avapritinib can elicit complete molecular responses of KIT D816V allele burden, establishes a new benchmark for advSM and motivates the inclusion of definitions for molecular response in future criteria. Herein, we also outline how the concept of PPR can inform a proposal for new response criteria which use a tiered evaluation of pathologic, molecular, and clinical responses.

scholarly journals ASXL1 and CBL Mutations Are Independently Predictive of Inferior Survival in Advanced Systemic Mastocytosis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 828-828 ◽  
Author(s):  
Animesh Pardanani ◽  
Terra L. Lasho ◽  
Christy Finke ◽  
Darci Zblewski ◽  
Ramy Abdelrahman ◽  
...  
Keyword(s):  
Deep Sequencing ◽  
Prognostic Value ◽  
Systemic Mastocytosis ◽  
Myeloproliferative Neoplasm ◽  
Clinical Manifestations ◽  
World Health ◽  
Kit Mutation ◽  
Specific Pcr ◽  
Health Organization ◽  
Kit D816v

Abstract Background: KIT D816V is considered the driver mutation in systemic mastocytosis (SM) however this mutation alone does not explain the diverse clinical manifestations of SM. While mutations in other myeloid-relevant genes have been reported in SM, their pattern(s) of co-segregation and prognostic value, independent of age and SM subtype, have not been fully defined in a mature dataset. Objectives: In this pilot study of advanced SM patients, we sequenced a panel of myeloid-relevant genes for known pathogenic mutations, to ascertain: (i) the frequency of individual mutations; (ii) the pattern(s) of mutation co-segregation; and (iii) the prognostic value of mutations, both individually and in combination, on overall- (OS) and leukemia-free survival (LFS). Methods: The current study was approved by the Mayo Clinic institutional review board. SM was classified as per World Health Organization criteria. DNA was isolated from archived bone marrow (BM) cell pellets. Next-generation deep sequencing by HiSeq SBS chemistry (Illumina) was performed to investigate the coding regions of 22 genes: KIT, JAK2, CALR, SRSF2, U2AF1, SF3B1, ASXL1, TET2, EZH2, SETBP1, DNMT3A, IDH-1/2, SUZ12, CBL, NRAS, FLT3, PTPN11, RUNX1, CEBPA, TP53 and NPM1. Results: We studied 19 patients with advanced SM; 6 had aggressive SM (ASM) and 13 had SM with an associated hematological disease (SM-AHD). Of the latter, 5 patients (38%) had myeloproliferative neoplasm-unclassified (MPN-u), 3 (23%) chronic myelomonocytic leukemia (CMML), 2 (15%) acute myeloid leukemia (AML), and 1 (8%) each polycythemia vera, myelodysplastic syndrome, and multiple myeloma. The median follow up from diagnosis was 20 months (range 2 to 84). Over this period, 5 patients (26%) developed leukemic transformation and 12 patients (63%) have died. KIT D816V was identified in 9 (47%) patients; 9 of 10 patients who tested negative by deep sequencing were screened by allele-specific PCR (sensitivity ~0.01%), with 8 additional patients testing positive. Thus, overall KIT D816V frequency was 89%. Fourteen (74%) patients harbored at least one additional non-KIT mutation; of these 7 patients had one additional mutation (ASXL1/TET2/SF3B1 = 2 each and JAK2 =1), 3 patients each had two and three additional mutations, and 1 patient had 4 additional mutations. The most frequently mutated genes (other than KIT) were ASXL1/TET2 (5 patients each, 26%), CBL (4 patients, 21%), SETBP1/SF3B1/DNMT3A (2 patients each, 11%) and JAK2/CALR/FLT3/IDH-1/RUNX1/TP53 (1 patient each, 5%). There was no overlap between patients harboring TET2 and ASXL1 mutations however 2 and 1 CBL-mutated patients concurrently harbored TET2 and ASXL1 mutations, respectively. SETBP1 and SF3B1 but not DNMT3A mutations occurred independently of TET2 and ASXL1 mutations. The distribution of mutations was similar between ASM and SM-AHD subgroups. When considered individually, the following non-KIT mutated genes (present in at least 2 patients) were associated with significantly inferior OS: ASXL1, CBL and SETBP1 (p<0.05). When the 3 mutated genes were considered together, only ASXL1 and CBL maintained their significance, independent of age and SM subtype, for inferior OS (Hazard ratio (95% confidence interval)=34.8 (3.1-393.9) and 59.7 (4.1-861.5), respectively). Patients harboring ASXL1 and/or CBL mutations (n=8, 8 deaths, median OS=11 months) had a significantly worse OS as compared to those without either mutation (n=11, 4 deaths, median OS=84 months) (p=0.0002) (Fig 1). When considering the number of non-KIT mutations (zero, one, two, three and four mutations in 5, 7, 3, 3 and 1 patients, respectively), the group with ≥3 mutations (n=4, 4 deaths, median OS=7 months) had a significantly inferior OS as compared to those with <3 mutations (n=15, 8 deaths, median OS=48 months) (p=0.01) (Fig 2). Presence of mutations was not correlated with LFS in this analysis. Conclusions: In this cohort of advanced SM patients, non-KIT mutations were frequent (prevalence 74%). TET2, ASXL1, SETBP1 and SF3B1, but not CBL or DNMT3A, mutations were mutually exclusive. Presence of ASXL1 and CBL mutations was associated with significantly inferior OS (HR=35 and 60, respectively), independent of known prognostic factors. An increasing number of non-KIT mutations (≥3, HR=5.9) was also associated with a significantly worse survival outcome. Sequencing results from a larger cohort will be presented at the meeting. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Pardanani: Stemline: Research Funding.

Sixth Edition: the New Standard

2008 ◽  
Vol 13 (1) ◽  
pp. 1-12
Author(s):  
Christopher R. Brigham ◽  
Robert D. Rondinelli ◽  
Elizabeth Genovese ◽  
Craig Uejo ◽  
Marjorie Eskay-Auerbach
Keyword(s):  
Review Process ◽  
Peer Review Process ◽  
World Health ◽  
International Classification Of Functioning ◽  
Revision Process ◽  
Sixth Edition ◽  
Impairment Ratings ◽  
Health Organization ◽  
Impairment Severity

Abstract The AMA Guides to the Evaluation of Permanent Impairment (AMA Guides), Sixth Edition, was published in December 2007 and is the result of efforts to enhance the relevance of impairment ratings, improve internal consistency, promote precision, and simplify the rating process. The revision process was designed to address shortcomings and issues in previous editions and featured an open, well-defined, and tiered peer review process. The principles underlying the AMA Guides have not changed, but the sixth edition uses a modified conceptual framework based on the International Classification of Functioning, Disability, and Health (ICF), a comprehensive model of disablement developed by the World Health Organization. The ICF classifies domains that describe body functions and structures, activities, and participation; because an individual's functioning and disability occur in a context, the ICF includes a list of environmental factors to consider. The ICF classification uses five impairment classes that, in the sixth edition, were developed into diagnosis-based grids for each organ system. The grids use commonly accepted consensus-based criteria to classify most diagnoses into five classes of impairment severity (normal to very severe). A figure presents the structure of a typical diagnosis-based grid, which includes ranges of impairment ratings and greater clarity about choosing a discreet numerical value that reflects the impairment.

The Historical Development of Burden of Treatment Compliance

2014 ◽  
Vol 19 (5) ◽  
pp. 13-15
Author(s):  
Stephen L. Demeter
Keyword(s):  
Internal Medicine ◽  
Treatment Compliance ◽  
World Health ◽  
International Classification Of Functioning ◽  
Sixth Edition ◽  
Burden Of Treatment ◽  
Specific Goal ◽  
Surrogate Measure ◽  
Health Organization

Abstract A long-standing criticism of the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides) has been the inequity between the internal medicine ratings and the orthopedic ratings; in the comparison, internal medicine ratings appear inflated. A specific goal of the AMA Guides, Sixth Edition, was to diminish, where possible, those disparities. This led to the use of the International Classification of Functioning, Disability, and Health from the World Health Organization in the AMA Guides, Sixth Edition, including the addition of the burden of treatment compliance (BOTC). The BOTC originally was intended to allow rating internal medicine conditions using the types and numbers of medications as a surrogate measure of the severity of a condition when other, more traditional methods, did not exist or were insufficient. Internal medicine relies on step-wise escalation of treatment, and BOTC usefully provides an estimate of impairment based on the need to be compliant with treatment. Simplistically, the need to take more medications may indicate a greater impairment burden. BOTC is introduced in the first chapter of the AMA Guides, Sixth Edition, which clarifies that “BOTC refers to the impairment that results from adhering to a complex regimen of medications, testing, and/or procedures to achieve an objective, measurable, clinical improvement that would not occur, or potentially could be reversed, in the absence of compliance.

scholarly journals Morphological Characteristics, Classifications and Difficulties in the Use of Diagnostic Criteria for Serrated Lesions of the Large Intestine

2021 ◽  
Author(s):  
Cesar de Souza Bastos Junior ◽  
Vera Lucia Nunes Pannain ◽  
Adriana Caroli-Bottino
Keyword(s):  
Diagnostic Criteria ◽  
Morphological Characteristics ◽  
World Health ◽  
Diagnostic Tools ◽  
Serrated Adenoma ◽  
The Past ◽  
The World ◽  
Serrated Lesions ◽  
Health Organization

Abstract Introduction Colorectal carcinoma (CRC) is the most common gastrointestinal neoplasm in the world, accounting for 15% of cancer-related deaths. This condition is related to different molecular pathways, among them the recently described serrated pathway, whose characteristic entities, serrated lesions, have undergone important changes in their names and diagnostic criteria in the past thirty years. The multiplicity of denominations and criteria over the last years may be responsible for the low interobserver concordance (IOC) described in the literature. Objectives The present study aims to describe the evolution in classification of serrated lesions, based on the last three publications of the World Health Organization (WHO) and the reproducibility of these criteria by pathologists, based on the evaluation of the IOC. Methods A search was conducted in the PubMed, ResearchGate and Portal Capes databases, with the following terms: sessile serrated lesion; serrated lesions; serrated adenoma; interobserver concordance; and reproducibility. Articles published since 1990 were researched. Results and Discussion The classification of serrated lesions in the past thirty years showed different denominations and diagnostic criteria. The reproducibility and IOC of these criteria in the literature, based on the kappa coefficient, varied in most studies, from very poor to moderate. Conclusions Interobserver concordance and the reproducibility of microscopic criteria may represent a limitation for the diagnosis and appropriate management of these lesions. It is necessary to investigate diagnostic tools to improve the performance of the pathologist's evaluation, for better concordance, and, consequently, adequate diagnosis and treatment.

scholarly journals Classification Maps for TDS Concentrations in the GIS Along Euphrates River, Iraq

2021 ◽  
Vol 232 (8) ◽  
Author(s):  
Ali Chabuk ◽  
Zahraa Ali Hammood ◽  
Nadhir Al-Ansari ◽  
Salwan Ali Abed ◽  
Jan Laue
Keyword(s):  
Water Quality ◽  
Drinking Water ◽  
World Health Organization ◽  
World Health ◽  
Euphrates River ◽  
Poor Water Quality ◽  
Quality Category ◽  
Health Organization ◽  
Dissolved Salts

AbstractIraq currently undergoing the problem of water shortage, although Iraq has two Rivers (Euphrates and Tigris) pass throughout most of its areas, and they have represented a major source of water supply. In the current research, to evaluate the quality of the Euphrates river in Iraq based on the values of total dissolved salts (TDS), the TDS concentrations were collected from sixteen sections along the river in the three succeeding years (2011, 2012, and 2013). The evaluation of the river was done depending on the classification of (W.H.O. (World Health Organization). (2003). Total Dissolved Salts in Drinking-water: Background document for development of W.H.O. Guidelines for Drinking-water Quality. World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland). of rivers for drinking uses. Inverse Distance Weighting Technique (IDWT) as a tool in the GIS was employed to establish the maps of the river that using interpolation/prediction for the TDS concentrations to each selected year and the average values of TDS for these 3 years. Based on the five categories of rivers’ classification of the TDS concentrations according to the (W.H.O. (World Health Organization). (2003). Total Dissolved Salts in Drinking-water: Background document for development of W.H.O. Guidelines for Drinking-water Quality. World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland), the Euphrates river was classified, and the maps of classification for the years 2011, 2012 and 2013 and the average values for 3 years were created. The average values for 3 years of TDS along the Euphrates river indicated that the sections from SC-1 to SC-4 as moderate-water-quality-Category-3, the sections from SC-5 to SC-10 as poor-water-quality-Category-4, while the sections between SC-11 to SC-16 as very poor-water-quality-Category-5. The interpolation maps showed that the Euphrates river in Iraq was ranged from moderate water quality (Category-3) to very poor water quality (Category-5).

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