scholarly journals Rare and unknown canine systemic mastocytosis: clinical and laboratory features of an aberrant c-Kit mutation neoplasia

2021 ◽  
Vol 58 ◽  
pp. e175896
Author(s):  
Carla Sofia Soares ◽  
Leonor Delgado ◽  
Sónia Morgado ◽  
Pedro Pires Carvalho ◽  
Luís Carlos Barros
Keyword(s):  
Systemic Mastocytosis ◽  
Myeloproliferative Neoplasms ◽  
World Health ◽  
Base Pairs ◽  
Kit Mutation ◽  
Laboratory Features ◽  
Exon 11 ◽  
Serra Da Estrela ◽  
Health Organization ◽  
Reported Data

Systemic mastocytosis (SM) pathology is extremely rare in canine practice, with insufficient reported data. The knowledge of the clinical behavior of this pathology is scarce. In human medicine, SM has been widely investigated, being defined as a rare hematopoietic disorder by the World Health Organization (2016), within the type of myeloproliferative neoplasms. Herein, we describe a systemic mastocytosis case in a Portuguese Serra-da-Estrela dog, where a cutaneous grade III/high-grade MCT was also diagnosed. The clinical decline of the animal and owner’s insistence throughout anamnesis that the dog was markedly different after the cytologic exam performed in another clinic, along with both severe eosinophilia and hepatomegaly, led to the clinical suspicion of SM. The animal passed away 7 days later. Post-mortem investigation confirmed SM pathology, and a deletion of 15 base pairs change on c-Kit gene exon 11 was identified. Contemplating the low number of cases described in the literature, this publication aims to disclose clinical and laboratory features of rare and poorly described canine SM, taking into consideration human outcomes described in the literature.

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.

scholarly journals A review of current knowledge of myeloproliferative disorders in the horse

2021 ◽  
Vol 63 (1) ◽  
Author(s):  
Katy Satué ◽  
Juan Carlos Gardon ◽  
Ana Muñoz
Keyword(s):  
Bone Marrow ◽  
Myeloid Leukemia ◽  
Current Knowledge ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Disorders ◽  
World Health ◽  
Chronic Granulocytic Leukemia ◽  
Current State ◽  
Multiple Cell ◽  
Health Organization

AbstractMyeloid disorders are conditions being characterized by abnormal proliferation and development of myeloid lineage including granulocytes (neutrophils, eosinophils and basophils), monocytes, erythroids, and megakaryocytes precursor cells. Myeloid leukemia, based on clinical presentation and proliferative rate of neoplastic cells, is divided into acute (AML) and myeloproliferative neoplasms (MPN). The most commonly myeloid leukemia reported in horses are AML-M4 (myelomonocytic) and AML-M5 (monocytic). Isolated cases of AML-M6B (acute erythroid leukemia), and chronic granulocytic leukemia have also been reported. Additionally, bone marrow disorders with dysplastic alterations and ineffective hematopoiesis affecting single or multiple cell lineages or myelodysplastic diseases (MDS), have also been reported in horses. MDSs have increased myeloblasts numbers in blood or bone marrow, although less than 20%, which is the minimum level required for diagnosis of AML. This review performed a detailed description of the current state of knowlegde of the myeloproliferative disorders in horses following the criteria established by the World Health Organization.

Haematopathology of classic myeloproliferative neoplasms

2020 ◽  
pp. 45-62
Author(s):  
Hans Michael Kvasnicka ◽  
Jürgen Thiele
Keyword(s):  
Continuous Improvement ◽  
Who Classification ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
World Health ◽  
Polycythaemia Vera ◽  
The World ◽  
Health Organization ◽  
Diagnostic Importance

The classification of the World Health Organization (WHO) continues to advocate the diagnostic importance of bone marrow (BM) morphology in the diagnostic workup of myeloproliferative neoplasms (MPN). In this regard, distinctive histological BM patterns characterize specific subtypes of MPN and are the key to a meaningful clinical and molecular-defined risk stratification of patients. In this regard, the morphological denominator includes a characteristic megakaryocytic proliferation along with variable changes in the granulopoiesis and erythropoiesis. Importantly, diagnosis of MPN requires absence of relevant dysgranulopoiesis or dyserythropoiesis. In terms of clinical practice, the concept of precursor stages provides the possibility of an early intervention by appropriate therapeutic regimens that might prevent fatal complications like thrombosis and haemorrhage, especially in early stages of polycythaemia vera or in primary myelofibrosis. However, the WHO classification is not aimed to capture all biological true cases of MPN or guarantee a complete diagnostic specificity and thus might be in need of continuous improvement following clinical experience.

Immunogenicity and Safety of the Measles Vaccine in HIV-Infected Children: An Updated Systematic Review

2019 ◽  
Author(s):  
Nicky J Mehtani ◽  
Lori Rosman ◽  
William J Moss
Keyword(s):  
Latin American ◽  
Prevalence Ratio ◽  
Vaccine Safety ◽  
World Health ◽  
Measles Vaccine ◽  
Serious Adverse Events ◽  
Increased Risk ◽  
Hiv Exposed ◽  
Health Organization ◽  
Reported Data

Abstract Children infected with human immunodeficiency virus (HIV) are at increased risk of measles morbidity and mortality. We searched abstracts from the PubMed, Embase, and Latin American and Caribbean Center on Health Sciences Information databases for articles published from the earliest date available through September 26, 2017. The primary outcome of interest was serological responses to measles vaccine, stratified by HIV infection status. A total of 2,858 potentially eligible articles were identified, and the final review included 12 studies published between 1992 and 2013, 9 of which reported data on vaccine safety. The studies we included represented 3,573 children, of whom at least 335 were infected with HIV, 788 were HIV-exposed but not infected, and 1,478 were unexposed to HIV. Four of the 12 studies found statistically significant reductions in seropositivity among HIV-infected children compared with HIV-uninfected children within 4 months of vaccination (prevalence ratio range, 0.44–0.70), and forest plots provided visual trends of decreasing immunity over time among HIV-infected children in 2 additional studies. No vaccine-related deaths or serious adverse events were reported. This updated review demonstrated limitations of the existing published literature but supported evidence of reduced immunogenicity of measles vaccine among HIV-infected children, supporting the World Health Organization recommendation to revaccinate HIV-infected children against measles following immune reconstitution with combination antiretroviral therapy.

scholarly journals Multidisciplinary Challenges in Mastocytosis and How to Address with Personalized Medicine Approaches

2019 ◽  
Vol 20 (12) ◽  
pp. 2976 ◽  
Author(s):  
Peter Valent ◽  
Cem Akin ◽  
Karoline V. Gleixner ◽  
Wolfgang R. Sperr ◽  
Andreas Reiter ◽  
...  
Keyword(s):  
Mast Cell ◽  
Personalized Medicine ◽  
Current Knowledge ◽  
Systemic Mastocytosis ◽  
Daily Practice ◽  
World Health ◽  
Survival Times ◽  
Tryptase Level ◽  
Organ Systems ◽  
Health Organization

Mastocytosis is a hematopoietic neoplasm defined by abnormal expansion and focal accumulation of clonal tissue mast cells in various organ-systems. The disease exhibits a complex pathology and an equally complex clinical behavior. The classification of the World Health Organization (WHO) divides mastocytosis into cutaneous forms, systemic variants, and localized mast cell tumors. In >80% of patients with systemic mastocytosis (SM), a somatic point mutation in KIT at codon 816 is found. Whereas patients with indolent forms of the disease have a normal or near-normal life expectancy, patients with advanced mast cell neoplasms, including aggressive SM and mast cell leukemia, have a poor prognosis with short survival times. In a majority of these patients, multiple somatic mutations and/or an associated hematologic neoplasm, such as a myeloid leukemia, may be detected. Independent of the category of mastocytosis and the serum tryptase level, patients may suffer from mediator-related symptoms and/or osteopathy. Depending on the presence of co-morbidities, the symptomatology in such patients may be mild, severe or even life-threatening. Most relevant co-morbidities in such patients are IgE-dependent allergies, psychiatric, psychological or mental problems, and vitamin D deficiency. The diagnosis and management of mastocytosis is an emerging challenge in clinical practice and requires vast knowledge, a multidisciplinary approach, and personalized medicine procedures. In this article, the current knowledge about mastocytosis is reviewed with special emphasis on the multidisciplinary aspects of the disease and related challenges in daily practice.

New TET2, ASXL1 and CBL Mutations Have Poor Prognostic Impact In Systemic Mastocytosis and Related Disorders

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3076-3076
Author(s):  
Fabiola Traina ◽  
Ania Jankowska ◽  
Hideki Makishima ◽  
Fred H. Hsieh ◽  
Yingchun Han ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Systemic Mastocytosis ◽  
Single Nucleotide Polymorphism Array ◽  
Myeloproliferative Neoplasms ◽  
Uniparental Disomy ◽  
Prognostic Impact ◽  
Biallelic Mutation ◽  
Prognostic Information ◽  
Kit Mutation ◽  
Disease Spectrum

Abstract Abstract 3076 Mastocytosis is a heterogeneous hematopoietic neoplasm characterized by proliferation and organ infiltration by clonal mast cells (MC). The disease spectrum encompasses chronic indolent forms such as cutaneous mastocytosis (CM)/indolent systemic mastocytosis (ISM) to more aggressive types such as SM with associated clonal hematologic non-mast-cell disease (SM-AHNMD), the latter most closely related to myeloproliferative neoplasms (MPN) or MDS/MPN overlap syndromes. Molecular pathogenesis of mastocytosis involves acquisition of c-KIT mutations, particularly D816V, which is present in many cases and confers resistance to imatinib. TET2 mutations are often found in MPN and MDS/MPN and also in ∼20% of SM patients without noticeable impact on survival. We have hypothesized that analysis of molecular defects in mastocytosis may shed light on disease pathogenesis and possibly convey prognostic information that may help in diagnosis and selection of rational therapies. To investigate these molecular events, we have applied single nucleotide polymorphism array-based karyotyping (SNP-A) (Affymetrix 6.0) to identify recurrent areas of loss of heterozygosity and performed a broad screen for mutations which could be present in mastocytosis including c-KIT, TET2, CBL gene family (CBL, CBLB, CBLC), ASXL1, IDH1/IDH2, which have been found in hematologic disorders related to or associated with SM. Overall survival (OS) was analyzed using the Kaplan-Meier method (Log-Rank). We studied a total of 35 mastocytosis patients classified using WHO criteria (CM, N=9; ISM, N=14; SM-AHNMD, N=9; [CMML, N=6; AML, N=1; NHL, N=2], aggressive SM (ASM) N=2; MC sarcoma, N=1). Median age of the cohort was 51 yrs (13-71). SNP-A showed a total of 20 new lesions (13 gains, 3 losses and 4 uniparental disomy [UPD]) in 10 patients (CM=1, ISM=4, SM-AHNMD=4, ASM=1). The most frequently affected chromosomes were 2, 7, 12, 13, 14 and X. UPD was only found in SM-AHNMD and ASM and it involved chromosomes 2p, 4q, 7p and 13q. No OS difference were observed between patients with new SNP lesions compared to those without (47 mo vs. 38 mo; p=.84). c-KIT sequencing showed D816V in 29% of patients (ISM=29%; SM-AHNMD=44%, ASM=100%). A total of 15 additional mutations were found in 9/35 patients. TET2 mutations were found in 8/35 (23%), including 2 patients with biallelic mutations (3 frameshift, 2 nonsense and 5 missense). TET2 mutational frequencies for CM, ISM and SM-AHNMD (only CMML) were 22% (2/9), 7% (1/14) and 56% (5/9). Majority of TET2 mutations were heterozygous, except one that was homozygous. These mutations have not been previously described in mastocytosis. We have also detected ASXL1 mutations in 3/35 (9%) patients, with biallelic mutation seen in one patient (1 frameshift, 1 nonsense and 2 missense). ASXL1 mutations were seen in 1/14 ISM and 2/9 SM-AHNMD (with CMML). To our knowledge, ASXL1 mutations have not been described in mastocytosis. A heterozygous CBL mutation was found in 1/35 patients with SM-AHNMD (CMML). No mutations were found in CBLB, CBLC and IDH1/IDH2. Interestingly, 5 patients were found to have >1 mutation, c-KIT and TET2 in 2, c-KIT/TET2/ASXL1 in 2 and TET2/CBL in 1 patient. The median OS of the cohort was 18 mo (1-85). As expected, for patients with only SM (excluding CM cases), c-KIT mutants had a worse OS than wild type (WT) c-KIT patients (17 mo vs. 52 mo; p=.02). SM patients with TET2, ASXL1 or CBL mutations, independently of c-KIT, had a worse OS than those with WT genes (17 mo vs. 52; p=.01). SM patients with c-KIT mutation who carry additional mutations had a worse OS, c-KIT + any mutation [11 mo] vs. TET2/ASXL1/CBL mutant [32 mo] vs. c-KIT mutant alone [NR] vs. WT [NR]; p<.0001. Similarly, when TET2 and c-KIT mutations were analyzed independent of CBL and ASXL1, patients with mutant c-KIT and TET2 had the poorest OS in the group (c-KIT plus TET2 [10 mo] vs. TET2 alone [32 mo] vs. c-KIT alone [NR] vs. WT [NR]; p<.0001). All patients with CM were still alive at the time of analysis. In conclusion, SNP-A lesions including UPD are karyotypic changes also seen in mastocytosis. TET2 mutations are frequently found in mastocytosis, particularly in SM-AHNMD (CMML). Novel molecular mutations frequently found in MDS and MPN, as ASXL1 and CBL, are also found in mastocytosis but at lower frequencies. More importantly, these new mutations may affect prognosis, as demonstrated by poor OS in patients who carry these mutations independently of c-KIT. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Reevaluation of the University of Wisconsin 2-Year Protocol for Treating Canine Lymphosarcoma

2007 ◽  
Vol 43 (2) ◽  
pp. 85-92 ◽  
Author(s):  
Claire Inderbinen Kaiser ◽  
Janean L. Fidel ◽  
Malgorzata Roos ◽  
Barbara Kaser-Hotz
Keyword(s):  
Stage Iv ◽  
World Health ◽  
Treatment Delays ◽  
Prior Therapy ◽  
University Of Wisconsin ◽  
Chemotherapy Protocol ◽  
First Remission ◽  
Health Organization ◽  
Reported Data ◽  
The University

This retrospective study investigated a population of 96 dogs with newly diagnosed malignant lymphosarcoma that were treated with the commonly used University of Wisconsin-Madison (UW-M) chemotherapy protocol. Pretreatment characteristics were analyzed to determine prognostic factors. Dogs with higher World Health Organization (WHO) stages (including stage IV) and dogs with hypercalcemia were at significantly higher risk of relapse (P=0.018 and P=0.016, respectively). Dose reduction, treatment delays, and prior therapy with cortico-steroids were not associated with clinical outcome. First remission duration of 270 days was similar to historically reported data. Overall survival time of 218 days was much shorter than historical data.

scholarly journals Cutaneous Mastocytosis in a 61-year-old Female from a Dermatological and Histopathological Perspective

2020 ◽  
pp. 01-06
Author(s):  
Erisa Kola ◽  
Jorida Memini ◽  
Ina Kola ◽  
Daniela Nakuci ◽  
John Ekladous ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Mast Cells ◽  
Lymph Nodes ◽  
Systemic Mastocytosis ◽  
World Health ◽  
Systemic Involvement ◽  
Cutaneous Mastocytosis ◽  
Health Organization ◽  
Cell Disorder

First described by Nettleship et al. in 1869 [1], mastocytoses are a heterogeneous group of disorders characterized by the pathologic accumulation of mast cells in various tissues [2-5]. Mastocytosis can be confined to the skin as in cutaneous mastocytosis (CM), or it can involve extracutaneous tissues such as the liver, spleen, bone marrow and lymph nodes, as in systemic mastocytosis [6]. Mastocytosis is a World Health Organization-defined clonal mast cell disorder characterized by significant clinicopathologic heterogeneity [7]. Keywords: Cutaneous mastocytosis; Systemic mastocytosis; Systemic involvement; Mast cells; Mastocytosis.

scholarly journals The Smart Solution for DNA Removal in Biopharmaceutical Production by Benzonase Endonuclease

2013 ◽  
Vol 2 (1) ◽  
Author(s):  
Zhu Yang ◽  
Mingxin Li ◽  
Wen Chen ◽  
Alexander Peters
Keyword(s):  
Mammalian Cells ◽  
Rna World ◽  
Rapid Development ◽  
World Health ◽  
Base Pairs ◽  
Biological Products ◽  
Continuous Cell Lines ◽  
Dna And Rna ◽  
Biomedical Technologies ◽  
Health Organization

<p>More and more mammalian cells especially continuous cell lines were used to produce vaccines and therapeutic biological products with the rapid development of biomedical technologies. Therefore, more attention should be paid from drug regulatory authorities to the safety of biological products especially quality control of residual DNA and RNA. World Health Organization has evaluated the methods commonly used in vaccine manufacture for their ability to reduce the biological activity of DNA. Benzonase endonuclease is frequently used during the production of vaccines and can degrade all nucleic acid sequences down to oligonucleotides of approximately 3 to 5 base pairs.</p>

Sign in / Sign up

Export Citation Format

Share Document