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Ivan Alvareztwose - One of the best experts on this subject based on the ideXlab platform.
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kit d816v mutated bone marrow mesenchymal stem cells in Indolent Systemic Mastocytosis are associated with disease progression
Blood, 2015Co-Authors: Andres C Garciamontero, Ivan Alvareztwose, Laura Sanchezmunoz, Maria Jaraacevedo, Cristina Teodosio, Andrea Mayado, Almudena Matito, Javier I Munozgonzalez, Carmen Muniz, Carolina CaldasAbstract:Multilineage involvement of bone marrow (BM) hematopoiesis by the somatic KIT D816V mutation is present in a subset of adult Indolent Systemic Mastocytosis (ISM) patients in association with a poorer prognosis. Here, we investigated the potential involvement of BM mesenchymal stem cells (MSCs) from ISM patients by the KIT D816V mutation and its potential impact on disease progression and outcome. This mutation was investigated in highly purified BM MSCs and other BM cell populations from 83 ISM patients followed for a median of 116 months. KIT D816V-mutated MSCs were detected in 22 of 83 cases. All MSC-mutated patients had multilineage KIT mutation (100% vs 30%, P = .0001) and they more frequently showed involvement of lymphoid plus myeloid BM cells (59% vs 22%; P = .03) and a polyclonal pattern of inactivation of the X-chromosome of KIT-mutated BM mast cells (64% vs 0%; P = .01) vs other multilineage ISM cases. Moreover, presence of KIT-mutated MSCs was associated with more advanced disease features, a greater rate of disease progression (50% vs 17%; P = .04), and a shorter progression-free survival (P ≤ .003). Overall, these results support the notion that ISM patients with mutated MSCs may have acquired the KIT mutation in a common pluripotent progenitor cell, prior to differentiation into MSCs and hematopoietic precursor cells, before the X-chromosome inactivation process occurs. From a clinical point of view, acquisition of the KIT mutation in an earlier BM precursor cell confers a significantly greater risk for disease progression and a poorer outcome.
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detection of the kit d816v mutation in peripheral blood of Systemic Mastocytosis diagnostic implications
Modern Pathology, 2015Co-Authors: Maria Jaraacevedo, Ivan Alvareztwose, Laura Sanchezmunoz, Cristina Teodosio, Andrea Mayado, Carolina Caldas, Almudena Matito, Jose Mario Morgado, Javier I Munozgonzalez, Luis EscribanoAbstract:Recent studies have found the KIT D816V mutation in peripheral blood of virtually all adult Systemic Mastocytosis patients once highly sensitive PCR techniques were used; thus, detection of the KIT D816V mutation in peripheral blood has been proposed to be included in the diagnostic work-up of Systemic Mastocytosis algorithms. However, the precise frequency of the mutation, the biological significance of peripheral blood-mutated cells and their potential association with involvement of bone marrow hematopoietic cells other than mast cells still remain to be investigated. Here, we determined the frequency of peripheral blood involvement by the KIT D816V mutation, as assessed by two highly sensitive PCR methods, and investigated its relationship with multilineage involvement of bone marrow hematopoiesis. Overall, our results confirmed the presence of the KIT D816V mutation in peripheral blood of most Systemic Mastocytosis cases (161/190; 85%)--with an increasing frequency from Indolent Systemic Mastocytosis without skin lesions (29/44; 66%) to Indolent Systemic Mastocytosis with skin involvement (124/135; 92%), and more aggressive disease subtypes (11/11; 100%)--as assessed by the allele-specific oligonucleotide-qPCR method, which was more sensitive (P<.0001) than the peptide nucleic acid-mediated PCR approach (84/190; 44%). Although the presence of the KIT mutation in peripheral blood, as assessed by the allele-specific oligonucleotide-qPCR technique, did not accurately predict for multilineage bone marrow involvement of hematopoiesis, the allele-specific oligonucleotide-qPCR allele burden and the peptide nucleic acid-mediated-PCR approach did. These results suggest that both methods provide clinically useful and complementary information through the identification and/or quantification of the KIT D816V mutation in peripheral blood of patients suspected of Systemic Mastocytosis.
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nonaggressive Systemic Mastocytosis sm without skin lesions associated with insect induced anaphylaxis shows unique features versus other Indolent sm
The Journal of Allergy and Clinical Immunology, 2014Co-Authors: Ivan Alvareztwose, Roberta Zanotti, Patrizia Bonadonna, Laura Sanchezmunoz, Almudena Matito, Jose Mario Morgado, Arantza Vega, David Gonzalezdeolano, Omar Perbellini, Andres C GarciamonteroAbstract:Background Indolent Systemic Mastocytosis (ISM) without skin lesions (ISMs − ) shows a higher prevalence in males, lower serum baseline tryptase levels, and KIT mutation more frequently restricted to bone marrow (BM) mast cells (MCs) than ISM with skin lesions (ISMs + ). Interestingly, in almost one-half of ISMs − patients, MC-mediator release episodes are triggered exclusively by insects. Objective We aimed to determine the clinical and laboratory features of ISMs − associated with insect-induced anaphylaxis (insectISMs − ) versus other patients with ISM. Methods A total of 335 patients presenting with MC activation syndrome, including 143 insectISMs − , 72 ISMs − triggered by other factors (otherISMs − ), 56 ISMs + , and 64 nonclonal MC activation syndrome, were studied. Results Compared with otherISMs − and ISMs + patients, insectISMs − cases showed marked male predominance (78% vs 53% and 46%; P P ≤ .009). Moreover, insectISMs − less frequently presented BM MC aggregates (46% vs 70% and 81%; P ≤ .001), and they systematically showed MC-restricted KIT mutation. Conclusions ISMs − patients with anaphylaxis triggered exclusively by insects display clinical and laboratory features that are significantly different from other ISM cases, including other ISMs − and ISMs + patients, suggesting that they represent a unique subgroup of ISM with a particularly low BM MC burden in the absence of adverse prognostic factors.
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serum tryptase monitoring in Indolent Systemic Mastocytosis association with disease features and patient outcome
PLOS ONE, 2013Co-Authors: Almudena Matito, Ivan Alvareztwose, Laura Sanchezmunoz, Maria Jaraacevedo, Cristina Teodosio, Jose Mario Morgado, C E Pedreira, Paula Sanchezlopez, Elisa Fernandeznunez, Ricardo MorenoborqueAbstract:Background Serum baseline tryptase (sBT) is a minor diagnostic criterion for Systemic Mastocytosis (SM) of undetermined prognostic impact. We monitored sBT levels in Indolent SM (ISM) patients and investigated its utility for predicting disease behaviour and outcome. Methods In total 74 adult ISM patients who were followed for ≥48 months and received no cytoreductive therapy were retrospectively studied. Patients were classified according to the pattern of evolution of sBT observed. Results Overall 16/74 (22%) cases had decreasing sBT levels, 48 (65%) patients showed increasing sBT levels and 10 (13%) patients showed a fluctuating pattern. Patients with significantly increasing sBT (sBT slope ≥0.15) after 48 months of follow-up showed a slightly greater rate of development of diffuse bone sclerosis (13% vs. 2%) and hepatomegaly plus splenomegaly (16% vs. 5%), as well as a significantly greater frequency of multilineage vs. mast cells (MC)-restricted KIT mutation (p = 0.01) together with a greater frequency of cases with progression of ISM to smouldering and aggressive SM (p = 0.03), and a shorter progression-free survival (p = 0.03). Conclusions Monitoring of sBT in ISM patients is closely associated with poor prognosis disease features as well as with disease progression, pointing out the need for a closer follow-up in ISM patients with progressively increasing sBT values.
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clinical biological and molecular characteristics of clonal mast cell disorders presenting with Systemic mast cell activation symptoms
The Journal of Allergy and Clinical Immunology, 2010Co-Authors: Ivan Alvareztwose, Laura Sanchezmunoz, Almudena Matito, David Gonzalez De Olano, Maria I Estebanlopez, Maria Dolores Alonso Diaz De Durana, Arantza Vega, Maria Belen Mateo, Maria D Del Pozo Gil, Teresa CaballeroAbstract:Background Systemic mast cell activation disorders (MCADs) are characterized by severe and Systemic mast cell (MC) mediators–related symptoms frequently associated with increased serum baseline tryptase (sBt). Objective To analyze the clinical, biological, and molecular characteristics of adult patients presenting with Systemic MC activation symptoms/anaphylaxis in the absence of skin Mastocytosis who showed clonal (c) versus nonclonal (nc) MCs and to provide indication criteria for bone marrow (BM) studies. Methods Eighty-three patients were studied. Patients showing clonal BM MCs were grouped into Indolent Systemic Mastocytosis without skin lesions (ISMs - ; n = 48) and other c-MCADs (n = 3)—both with CD25 ++ BM MCs and either positive mast/stem cell growth factor receptor gene ( KIT ) mutation or clonal human androgen receptor assay (HUMARA) tests—and nc-MCAD (CD25-negative BM MCs in the absence of KIT mutation; n = 32) and compared for their clinical, biological, and molecular characteristics. Results Most clonal patients (48/51; 94%) met the World Health Organization criteria for Systemic Mastocytosis and were classified as ISMs - , whereas the other 3 c-MCAD and all nc-MCAD patients did not. In addition, although both patients with ISMs - and patients with nc-MCAD presented with idiopathic and allergen-induced anaphylaxis, the former showed a higher frequency of men, cardiovascular symptoms, and insect bite as a trigger, together with greater sBt. Based on a multivariate analysis, a highly efficient model to predict clonality before BM sampling was built that includes male sex ( P = .01), presyncopal and/or syncopal episodes ( P = .009) in the absence of urticaria and angioedema ( P = .003), and sBt >25 μg/L ( P = .006) as independent predictive factors. Conclusions Patients with c-MCAD and ISMs - display unique clinical and laboratory features different from nc-MCAD patients. A significant percentage of c-MCAD patients can be considered as true ISMs - diagnosed at early phases of the disease.
Laura Sanchezmunoz - One of the best experts on this subject based on the ideXlab platform.
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kit d816v mutated bone marrow mesenchymal stem cells in Indolent Systemic Mastocytosis are associated with disease progression
Blood, 2015Co-Authors: Andres C Garciamontero, Ivan Alvareztwose, Laura Sanchezmunoz, Maria Jaraacevedo, Cristina Teodosio, Andrea Mayado, Almudena Matito, Javier I Munozgonzalez, Carmen Muniz, Carolina CaldasAbstract:Multilineage involvement of bone marrow (BM) hematopoiesis by the somatic KIT D816V mutation is present in a subset of adult Indolent Systemic Mastocytosis (ISM) patients in association with a poorer prognosis. Here, we investigated the potential involvement of BM mesenchymal stem cells (MSCs) from ISM patients by the KIT D816V mutation and its potential impact on disease progression and outcome. This mutation was investigated in highly purified BM MSCs and other BM cell populations from 83 ISM patients followed for a median of 116 months. KIT D816V-mutated MSCs were detected in 22 of 83 cases. All MSC-mutated patients had multilineage KIT mutation (100% vs 30%, P = .0001) and they more frequently showed involvement of lymphoid plus myeloid BM cells (59% vs 22%; P = .03) and a polyclonal pattern of inactivation of the X-chromosome of KIT-mutated BM mast cells (64% vs 0%; P = .01) vs other multilineage ISM cases. Moreover, presence of KIT-mutated MSCs was associated with more advanced disease features, a greater rate of disease progression (50% vs 17%; P = .04), and a shorter progression-free survival (P ≤ .003). Overall, these results support the notion that ISM patients with mutated MSCs may have acquired the KIT mutation in a common pluripotent progenitor cell, prior to differentiation into MSCs and hematopoietic precursor cells, before the X-chromosome inactivation process occurs. From a clinical point of view, acquisition of the KIT mutation in an earlier BM precursor cell confers a significantly greater risk for disease progression and a poorer outcome.
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detection of the kit d816v mutation in peripheral blood of Systemic Mastocytosis diagnostic implications
Modern Pathology, 2015Co-Authors: Maria Jaraacevedo, Ivan Alvareztwose, Laura Sanchezmunoz, Cristina Teodosio, Andrea Mayado, Carolina Caldas, Almudena Matito, Jose Mario Morgado, Javier I Munozgonzalez, Luis EscribanoAbstract:Recent studies have found the KIT D816V mutation in peripheral blood of virtually all adult Systemic Mastocytosis patients once highly sensitive PCR techniques were used; thus, detection of the KIT D816V mutation in peripheral blood has been proposed to be included in the diagnostic work-up of Systemic Mastocytosis algorithms. However, the precise frequency of the mutation, the biological significance of peripheral blood-mutated cells and their potential association with involvement of bone marrow hematopoietic cells other than mast cells still remain to be investigated. Here, we determined the frequency of peripheral blood involvement by the KIT D816V mutation, as assessed by two highly sensitive PCR methods, and investigated its relationship with multilineage involvement of bone marrow hematopoiesis. Overall, our results confirmed the presence of the KIT D816V mutation in peripheral blood of most Systemic Mastocytosis cases (161/190; 85%)--with an increasing frequency from Indolent Systemic Mastocytosis without skin lesions (29/44; 66%) to Indolent Systemic Mastocytosis with skin involvement (124/135; 92%), and more aggressive disease subtypes (11/11; 100%)--as assessed by the allele-specific oligonucleotide-qPCR method, which was more sensitive (P<.0001) than the peptide nucleic acid-mediated PCR approach (84/190; 44%). Although the presence of the KIT mutation in peripheral blood, as assessed by the allele-specific oligonucleotide-qPCR technique, did not accurately predict for multilineage bone marrow involvement of hematopoiesis, the allele-specific oligonucleotide-qPCR allele burden and the peptide nucleic acid-mediated-PCR approach did. These results suggest that both methods provide clinically useful and complementary information through the identification and/or quantification of the KIT D816V mutation in peripheral blood of patients suspected of Systemic Mastocytosis.
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nonaggressive Systemic Mastocytosis sm without skin lesions associated with insect induced anaphylaxis shows unique features versus other Indolent sm
The Journal of Allergy and Clinical Immunology, 2014Co-Authors: Ivan Alvareztwose, Roberta Zanotti, Patrizia Bonadonna, Laura Sanchezmunoz, Almudena Matito, Jose Mario Morgado, Arantza Vega, David Gonzalezdeolano, Omar Perbellini, Andres C GarciamonteroAbstract:Background Indolent Systemic Mastocytosis (ISM) without skin lesions (ISMs − ) shows a higher prevalence in males, lower serum baseline tryptase levels, and KIT mutation more frequently restricted to bone marrow (BM) mast cells (MCs) than ISM with skin lesions (ISMs + ). Interestingly, in almost one-half of ISMs − patients, MC-mediator release episodes are triggered exclusively by insects. Objective We aimed to determine the clinical and laboratory features of ISMs − associated with insect-induced anaphylaxis (insectISMs − ) versus other patients with ISM. Methods A total of 335 patients presenting with MC activation syndrome, including 143 insectISMs − , 72 ISMs − triggered by other factors (otherISMs − ), 56 ISMs + , and 64 nonclonal MC activation syndrome, were studied. Results Compared with otherISMs − and ISMs + patients, insectISMs − cases showed marked male predominance (78% vs 53% and 46%; P P ≤ .009). Moreover, insectISMs − less frequently presented BM MC aggregates (46% vs 70% and 81%; P ≤ .001), and they systematically showed MC-restricted KIT mutation. Conclusions ISMs − patients with anaphylaxis triggered exclusively by insects display clinical and laboratory features that are significantly different from other ISM cases, including other ISMs − and ISMs + patients, suggesting that they represent a unique subgroup of ISM with a particularly low BM MC burden in the absence of adverse prognostic factors.
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serum tryptase monitoring in Indolent Systemic Mastocytosis association with disease features and patient outcome
PLOS ONE, 2013Co-Authors: Almudena Matito, Ivan Alvareztwose, Laura Sanchezmunoz, Maria Jaraacevedo, Cristina Teodosio, Jose Mario Morgado, C E Pedreira, Paula Sanchezlopez, Elisa Fernandeznunez, Ricardo MorenoborqueAbstract:Background Serum baseline tryptase (sBT) is a minor diagnostic criterion for Systemic Mastocytosis (SM) of undetermined prognostic impact. We monitored sBT levels in Indolent SM (ISM) patients and investigated its utility for predicting disease behaviour and outcome. Methods In total 74 adult ISM patients who were followed for ≥48 months and received no cytoreductive therapy were retrospectively studied. Patients were classified according to the pattern of evolution of sBT observed. Results Overall 16/74 (22%) cases had decreasing sBT levels, 48 (65%) patients showed increasing sBT levels and 10 (13%) patients showed a fluctuating pattern. Patients with significantly increasing sBT (sBT slope ≥0.15) after 48 months of follow-up showed a slightly greater rate of development of diffuse bone sclerosis (13% vs. 2%) and hepatomegaly plus splenomegaly (16% vs. 5%), as well as a significantly greater frequency of multilineage vs. mast cells (MC)-restricted KIT mutation (p = 0.01) together with a greater frequency of cases with progression of ISM to smouldering and aggressive SM (p = 0.03), and a shorter progression-free survival (p = 0.03). Conclusions Monitoring of sBT in ISM patients is closely associated with poor prognosis disease features as well as with disease progression, pointing out the need for a closer follow-up in ISM patients with progressively increasing sBT values.
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clinical biological and molecular characteristics of clonal mast cell disorders presenting with Systemic mast cell activation symptoms
The Journal of Allergy and Clinical Immunology, 2010Co-Authors: Ivan Alvareztwose, Laura Sanchezmunoz, Almudena Matito, David Gonzalez De Olano, Maria I Estebanlopez, Maria Dolores Alonso Diaz De Durana, Arantza Vega, Maria Belen Mateo, Maria D Del Pozo Gil, Teresa CaballeroAbstract:Background Systemic mast cell activation disorders (MCADs) are characterized by severe and Systemic mast cell (MC) mediators–related symptoms frequently associated with increased serum baseline tryptase (sBt). Objective To analyze the clinical, biological, and molecular characteristics of adult patients presenting with Systemic MC activation symptoms/anaphylaxis in the absence of skin Mastocytosis who showed clonal (c) versus nonclonal (nc) MCs and to provide indication criteria for bone marrow (BM) studies. Methods Eighty-three patients were studied. Patients showing clonal BM MCs were grouped into Indolent Systemic Mastocytosis without skin lesions (ISMs - ; n = 48) and other c-MCADs (n = 3)—both with CD25 ++ BM MCs and either positive mast/stem cell growth factor receptor gene ( KIT ) mutation or clonal human androgen receptor assay (HUMARA) tests—and nc-MCAD (CD25-negative BM MCs in the absence of KIT mutation; n = 32) and compared for their clinical, biological, and molecular characteristics. Results Most clonal patients (48/51; 94%) met the World Health Organization criteria for Systemic Mastocytosis and were classified as ISMs - , whereas the other 3 c-MCAD and all nc-MCAD patients did not. In addition, although both patients with ISMs - and patients with nc-MCAD presented with idiopathic and allergen-induced anaphylaxis, the former showed a higher frequency of men, cardiovascular symptoms, and insect bite as a trigger, together with greater sBt. Based on a multivariate analysis, a highly efficient model to predict clonality before BM sampling was built that includes male sex ( P = .01), presyncopal and/or syncopal episodes ( P = .009) in the absence of urticaria and angioedema ( P = .003), and sBt >25 μg/L ( P = .006) as independent predictive factors. Conclusions Patients with c-MCAD and ISMs - display unique clinical and laboratory features different from nc-MCAD patients. A significant percentage of c-MCAD patients can be considered as true ISMs - diagnosed at early phases of the disease.
Patrizia Bonadonna - One of the best experts on this subject based on the ideXlab platform.
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Hymenoptera Anaphylaxis and C-kit Mutations: An Unexpected Association
Current Allergy and Asthma Reports, 2015Co-Authors: Patrizia Bonadonna, Massimiliano Bonifacio, Carla Lombardo, Roberta ZanottiAbstract:Clinical manifestations of Mastocytosis in adults comprise signs and symptoms linked to mast cell (MC) activation, including anaphylaxis. Depending on MC burden, adults can be diagnosed with Systemic Mastocytosis, when the WHO criteria are fulfilled, or with other clonal MC disorders, characterized by MC mediator symptoms and demonstration of activating KIT mutations and/or expression of CD25 on MCs. There is a specific link between Mastocytosis and hymenoptera venom allergy (HVA): the reported frequency of HVA in Mastocytosis is 20–50 % and raises to 60–80 % in patients affected by Indolent Systemic Mastocytosis without skin lesions. The presentation of HVA characterized by severe hypotension in the absence of urticarial or angioedema is typical in patient with an underlying MC disorder, even in the presence of normal baseline serum tryptase levels.
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nonaggressive Systemic Mastocytosis sm without skin lesions associated with insect induced anaphylaxis shows unique features versus other Indolent sm
The Journal of Allergy and Clinical Immunology, 2014Co-Authors: Ivan Alvareztwose, Roberta Zanotti, Patrizia Bonadonna, Laura Sanchezmunoz, Almudena Matito, Jose Mario Morgado, Arantza Vega, David Gonzalezdeolano, Omar Perbellini, Andres C GarciamonteroAbstract:Background Indolent Systemic Mastocytosis (ISM) without skin lesions (ISMs − ) shows a higher prevalence in males, lower serum baseline tryptase levels, and KIT mutation more frequently restricted to bone marrow (BM) mast cells (MCs) than ISM with skin lesions (ISMs + ). Interestingly, in almost one-half of ISMs − patients, MC-mediator release episodes are triggered exclusively by insects. Objective We aimed to determine the clinical and laboratory features of ISMs − associated with insect-induced anaphylaxis (insectISMs − ) versus other patients with ISM. Methods A total of 335 patients presenting with MC activation syndrome, including 143 insectISMs − , 72 ISMs − triggered by other factors (otherISMs − ), 56 ISMs + , and 64 nonclonal MC activation syndrome, were studied. Results Compared with otherISMs − and ISMs + patients, insectISMs − cases showed marked male predominance (78% vs 53% and 46%; P P ≤ .009). Moreover, insectISMs − less frequently presented BM MC aggregates (46% vs 70% and 81%; P ≤ .001), and they systematically showed MC-restricted KIT mutation. Conclusions ISMs − patients with anaphylaxis triggered exclusively by insects display clinical and laboratory features that are significantly different from other ISM cases, including other ISMs − and ISMs + patients, suggesting that they represent a unique subgroup of ISM with a particularly low BM MC burden in the absence of adverse prognostic factors.
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improved detection of the kit d816v mutation using a real time pcr assay allows a finer recognition of patients with Indolent Systemic Mastocytosis
Blood, 2011Co-Authors: Massimiliano Bonifacio, Patrizia Bonadonna, Anna Artuso, Giovanna De Matteis, Caterina De Benedittis, Elisa Paviati, Omar Perbellini, Alberto Zamo, Simona Soverini, Giovanni PizzoloAbstract:Abstract 5163 The somatic D816V mutation of the KIT gene is present in the large majority of patients (>90%) with Systemic Mastocytosis (SM) and, therefore, is considered as one of the minor criteria for its diagnosis by the 2008 World Health Organization (WHO) classification. Patients with Indolent SM (ISM) without skin involvement frequently have a low mast cell burden in the bone marrow so they do not satisfy the major criterion for diagnosis of SM (i.e. the presence of multifocal dense mast cell infiltrates in extracutaneous organs). A finer detection of clonality markers in mast cells through highly sensitive diagnostic tools is necessary for the correct individuation of SM patients. To improve detection of D816V KIT mutation, we tested bone marrow (BM) cells from 97 adult patients with a suspicion for SM referred to our Multidisciplinary Outpatient Clinic for Mastocytosis in Verona from May 2009 to June 2011 using both a traditional PCR/RFLP assay and a mismatch amplification real time PCR technique. All patients underwent to a BM evaluation with histology/cytology and flow cytometry, as described (Bonadonna et al, 2009). For D816V KIT mutation analyses, RNA was extracted on BM mononuclear cell fraction and split in two equal amounts for traditional PCR and real time PCR respectively. In the traditional technique a PCR product of 287 bp, corresponding to the second tyrosine kinase domain (TKDII), was digested with the restriction enzyme HinfI to detect the nucleotide change at codon 816, leading to D816V mutation, and screened by RFLP assay. Concurrently mutation detection was conducted by a real time PCR in combination with mismatched forward primer for D816V mutation (Amplification Refractory Mutation System, ARMS) and Taqman probe; also WT primer was used to control RNA quality and compare samples. According to the 2008 WHO criteria, a diagnosis of ISM was made in 73 out of 97 patients (38 males, median age 50 years). Forty-two patients (57.3%) did not present skin involvement. The major histological criterion was fulfilled in 24 patients (32.8%), while in the remaining patients the diagnosis was made for the presence of at least 3 minor criteria. The presence of the D816V mutation was detected by real time PCR in 100% of 73 patients with ISM as well as the presence of CD25+ aberrant mast cells by flow cytometry. All the other patients, not suffering from Mastocytosis, were negative both at flow cytometry and real time PCR, so determining a 100% concordance between these two highly sensitive techniques. Conversely, traditional PCR assay could demonstrate D1816V mutation only in 47 patients (64%) with SM. These patients had significantly higher levels of serum tryptase (median 27.5 vs 19.5 ng/mL, p=0.04) and higher amount of CD25+ aberrant mast cells by flow cytometry (median percentage of mast cells on total mononuclear cells 0.06 vs 0.018, p<0.001) as compared to patients negative by traditional PCR assay. Among the 28 patients with serum tryptase <20 ng/mL, 13 (46.4%) did not display KIT mutation by traditional PCR and 11/13 did not meet the major criterion: applying a conventional PCR technique only, these patients would have not fulfilled at least three minor criteria, thus missing a right diagnosis. We suggest that a real time PCR technique for D816V KIT mutation analysis, along with a highly sensitive flow cytometry assay, could improve the recognition of patients with ISM, particularly those with a very low mast cell burden and absence of skin lesions. Disclosures: No relevant conflicts of interest to declare.
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bone mineral density bone turnover markers and fractures in patients with Indolent Systemic Mastocytosis
Bone, 2011Co-Authors: Maurizio Rossini, Roberta Zanotti, Patrizia Bonadonna, Anna Artuso, Beatrice Caruso, Donatella Schena, Decio Vecchiato, Massimiliano Bonifacio, Ombretta Viapiana, Davide GattiAbstract:Abstract Objective We systematically assessed bone mineral density (BMD), bone turnover markers (BTM), and fractures in a large cohort of patients with Indolent Systemic Mastocytosis (ISM). Methods Eighty-two patients (mean age 48 years, 37 women) with ISM were studied. BMD was measured by dual X-ray absorptiometry at the lumbar spine and proximal hip. The serum markers of bone turnover included bone-specific alkaline phosphatase, C-telopeptides of type I collagen, and serum osteocalcin. Previous clinical fractures were registered and spine X-ray was obtained from all patients. Results Three women were excluded for concomitant diseases associated to osteoporosis. Osteoporosis according with the WHO classification (T-score − 2 or not valuable at the spine. No significant difference was found in the prevalence of Mastocytosis-related low BMD and/or vertebral fractures between patients with or without skin involvement. Two patients had radiographic and densitometric osteosclerosis-like characteristics. In osteoporotic patients higher, normal or lower serum BTM were found, without correlations with serum tryptase levels, while in patients with osteosclerosis both BTM and serum tryptase values were particularly increased. Conclusions Vertebral osteoporosis and fractures are frequent in patients with ISM. Spine X-ray and densitometric examination are warranted in all patients, also without skin involvement and particularly in males; Z-score other than T-score BMD must be evaluated. Patients with idiopathic osteoporosis should be evaluated for mast cell disease. Both high than low BTM can be observed in patients with osteoporosis while osteosclerosis is characterized by high bone turnover and serum tryptase levels.
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clonal mast cell disorders in patients with Systemic reactions to hymenoptera stings and increased serum tryptase levels
The Journal of Allergy and Clinical Immunology, 2009Co-Authors: Patrizia Bonadonna, Beatrice Caruso, Sabrina Colarossi, Omar Perbellini, Giovanni Passalacqua, Daniela Dal Fior, Luca Castellani, Chiara Bonetto, Francesco Frattini, A DamaAbstract:Background Anaphylaxis after Hymenoptera stings has been reported in subjects with Mastocytosis, but few data exist regarding disease prevalence in populations allergic to these insects. Objective The incidence of clonal mast cell (MC) disorders in subjects with both Systemic reactions to Hymenoptera stings and increased serum baseline tryptase (sBT) levels was assessed by using bone marrow (BM) aspirates and biopsy specimens. Methods Subjects with a history of a Systemic reaction caused by a Hymenoptera sting underwent the standard diagnostic work-up for Hymenoptera allergy, and sBT levels were measured. Subjects with an increased sBT level had BM evaluation that included histology/cytology, flow cytometry, and detection of KIT mutations. Results Forty-four (11.6%) of 379 subjects with Systemic reactions had increased sBT levels (>11.4 ng/mL), and 31 (70.5%) of these had a history of anaphylaxis. Thirty-four subjects with increased sBT levels underwent a BM analysis. Histology detected diagnostic or subdiagnostic MC infiltrates in 22 (65%) of 34 patients. Abnormal MCs were identified by means of flow cytometry and cytology in 26 (78.8%) of 33 and 20 (58.8%) of 34 subjects, respectively. A KIT mutation was detected in 17 (54.8%) of 31 subjects. The diagnosis was Indolent Systemic Mastocytosis in 21 (61.7%) of 34 subjects and monoclonal MC activation syndrome in 9 (26.5%) of 34 subjects. All subjects with anaphylaxis had one of those 2 disorders. Conclusion The concomitant presence of Systemic reactions (especially anaphylaxis) after Hymenoptera stings and increased sBT levels strongly suggests that a BM examination is indicated for the diagnosis of clonal MC disease.
Andres C Garciamontero - One of the best experts on this subject based on the ideXlab platform.
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kit d816v mutated bone marrow mesenchymal stem cells in Indolent Systemic Mastocytosis are associated with disease progression
Blood, 2015Co-Authors: Andres C Garciamontero, Ivan Alvareztwose, Laura Sanchezmunoz, Maria Jaraacevedo, Cristina Teodosio, Andrea Mayado, Almudena Matito, Javier I Munozgonzalez, Carmen Muniz, Carolina CaldasAbstract:Multilineage involvement of bone marrow (BM) hematopoiesis by the somatic KIT D816V mutation is present in a subset of adult Indolent Systemic Mastocytosis (ISM) patients in association with a poorer prognosis. Here, we investigated the potential involvement of BM mesenchymal stem cells (MSCs) from ISM patients by the KIT D816V mutation and its potential impact on disease progression and outcome. This mutation was investigated in highly purified BM MSCs and other BM cell populations from 83 ISM patients followed for a median of 116 months. KIT D816V-mutated MSCs were detected in 22 of 83 cases. All MSC-mutated patients had multilineage KIT mutation (100% vs 30%, P = .0001) and they more frequently showed involvement of lymphoid plus myeloid BM cells (59% vs 22%; P = .03) and a polyclonal pattern of inactivation of the X-chromosome of KIT-mutated BM mast cells (64% vs 0%; P = .01) vs other multilineage ISM cases. Moreover, presence of KIT-mutated MSCs was associated with more advanced disease features, a greater rate of disease progression (50% vs 17%; P = .04), and a shorter progression-free survival (P ≤ .003). Overall, these results support the notion that ISM patients with mutated MSCs may have acquired the KIT mutation in a common pluripotent progenitor cell, prior to differentiation into MSCs and hematopoietic precursor cells, before the X-chromosome inactivation process occurs. From a clinical point of view, acquisition of the KIT mutation in an earlier BM precursor cell confers a significantly greater risk for disease progression and a poorer outcome.
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the impact of sensitive kit d816v detection on recognition of Indolent Systemic Mastocytosis
Leukemia Research, 2015Co-Authors: Giovanna De Matteis, Roberta Zanotti, Beatrice Caruso, Massimiliano Bonifacio, Andres C Garciamontero, Sabrina Colarossi, Caterina De Benedittis, Marta Sartori, Fiorenza Aprili, Elisa PaviatiAbstract:Patients with Systemic Mastocytosis (SM) need a highly sensitive diagnostic test for D816V detection of the KIT receptor gene. Along with histology/cytology and flow cytometry evaluation, bone marrow (BM) from 110 consecutive adult patients referred with a suspicion of SM to Multidisciplinary Outpatient Clinic for Mastocytosis in Verona were tested both by Amplification Refractory Mutation System Reverse Transcriptase quantitative real time Polymerase Chain Reaction (ARMS-RT-qPCR) and RT-PCR+Restriction Fragment Length Polymorphism (RFLP) followed by Denaturing-High Performance Liquid Chromatography (D-HPLC) and Sanger sequencing. ARMS-RT-qPCR identified D816V mutation in 77 patients, corresponding to 100% of cases showing CD25(+) mast cells (MCs) whereas RT-PCR+RFLP/D-HPLC+sequencing revealed D816V mutations in 47 patients. According to the 2008 WHO criteria 75 SM, 1 Cutaneous Mastocytosis (CM), 1 monoclonal MC activation syndrome (MMAS), and 1 SM Associated with Haematologic Non-Mast Cell Disorder (SM-AHNMD) were diagnosed. Seventeen out 75 SM patients (23%) would have not satisfied sufficient WHO criteria on the basis of the sole RT-PCR+RFLP: these patients had significantly lower serum tryptase levels and amount of CD25(+) MCs. Therefore, ARMS-RT-qPCR might result particularly useful, in patients that do not fulfil major BM histological criterion, for the recognition of Indolent SM with a very low MC burden.
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nonaggressive Systemic Mastocytosis sm without skin lesions associated with insect induced anaphylaxis shows unique features versus other Indolent sm
The Journal of Allergy and Clinical Immunology, 2014Co-Authors: Ivan Alvareztwose, Roberta Zanotti, Patrizia Bonadonna, Laura Sanchezmunoz, Almudena Matito, Jose Mario Morgado, Arantza Vega, David Gonzalezdeolano, Omar Perbellini, Andres C GarciamonteroAbstract:Background Indolent Systemic Mastocytosis (ISM) without skin lesions (ISMs − ) shows a higher prevalence in males, lower serum baseline tryptase levels, and KIT mutation more frequently restricted to bone marrow (BM) mast cells (MCs) than ISM with skin lesions (ISMs + ). Interestingly, in almost one-half of ISMs − patients, MC-mediator release episodes are triggered exclusively by insects. Objective We aimed to determine the clinical and laboratory features of ISMs − associated with insect-induced anaphylaxis (insectISMs − ) versus other patients with ISM. Methods A total of 335 patients presenting with MC activation syndrome, including 143 insectISMs − , 72 ISMs − triggered by other factors (otherISMs − ), 56 ISMs + , and 64 nonclonal MC activation syndrome, were studied. Results Compared with otherISMs − and ISMs + patients, insectISMs − cases showed marked male predominance (78% vs 53% and 46%; P P ≤ .009). Moreover, insectISMs − less frequently presented BM MC aggregates (46% vs 70% and 81%; P ≤ .001), and they systematically showed MC-restricted KIT mutation. Conclusions ISMs − patients with anaphylaxis triggered exclusively by insects display clinical and laboratory features that are significantly different from other ISM cases, including other ISMs − and ISMs + patients, suggesting that they represent a unique subgroup of ISM with a particularly low BM MC burden in the absence of adverse prognostic factors.
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prognosis in adult Indolent Systemic Mastocytosis a long term study of the spanish network on Mastocytosis in a series of 145 patients
The Journal of Allergy and Clinical Immunology, 2009Co-Authors: Luis Escribano, Rosa Nunez, Ivan Alvareztwose, Laura Sanchezmunoz, Andres C Garciamontero, Julia Almeida, Maria Jaraacevedo, Cristina Teodosio, Monica Garciacosio, Carmen BellasAbstract:Background Indolent Systemic Mastocytosis is a group of rare diseases for which reliable predictors of progression and outcome are still lacking. Objective Here we investigate the prognostic impact of the clinical, biological, phenotypic, histopathological, and molecular disease characteristics in adults with Indolent Systemic Mastocytosis, who were followed using conservative therapy. Methods A total of 145 consecutive patients were prospectively followed between January 1983 and July 2008; in addition, from 1967 to 1983, 20 patients were retrospectively studied. Results Multivariate analysis showed that serum β2-microglobulin ( P = .003) together with the presence of mast/stem cell growth factor receptor gene ( KIT ) mutation in mast cells plus myeloid and lymphoid hematopoietic lineages ( P = .02) was the best combination of independent parameters for predicting disease progression (cumulative probability of disease progression of 1.7% ± 1.2% at 5-10 years and of 8.4% ± 5.0% at 20-25 years). Regarding overall survival, the best predictive model included age >60 years ( P = .005) and development of an associated clonal hematological non–mast cell disorder ( P = .03) with a cumulative probability of death of 2.2% ± 1.3% at 5 years and of 11% ± 5.9% at 25 years. Conclusions Indolent Systemic Mastocytosis in adults has a low disease progression rate, and the great majority of patients have a normal life expectancy, with the presence of KIT mutation in all hematopoietic lineages and increased serum β2-microglobulin the most powerful independent parameters for predicting transformation into a more aggressive form of the disease.
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safety and effectiveness of immunotherapy in patients with Indolent Systemic Mastocytosis presenting with hymenoptera venom anaphylaxis
The Journal of Allergy and Clinical Immunology, 2008Co-Authors: David Gonzalez De Olano, Ivan Alvareztwose, Laura Sanchezmunoz, Andres C Garciamontero, Maria I Estebanlopez, Maria Dolores Alonso Diaz De Durana, Arantza Vega, E Gonzalezmancebo, Teresa Belver, Maria D HerrerogilAbstract:Background Anaphylaxis after Hymenoptera sting has been described in patients with Mastocytosis. Venom immunotherapy (VIT) is a safe and effective way to treat patients with Hymenoptera anaphylaxis, but few studies have addressed its usefulness in patients with Systemic Mastocytosis. Objective To study the effectiveness and safety of VIT in patients with Systemic Mastocytosis having anaphylaxis after Hymenoptera sting. Methods A total of 21 Mastocytosis patients—4 women (19%) and 17 men (81%) with a median age of 50 years (range, 29-74 years)—with Hymenoptera sting anaphylaxis who were treated with VIT and followed for a median of 52 months (range, 2-250 months) were studied. Results In 18 of 21 patients—16 of them lacking skin involvement—anaphylaxis was the presenting symptom. Six patients (29%) experienced adverse reactions during VIT, 3 during initiation and 3 during maintenance. Twelve patients (57%) were restung while undergoing VIT; 9 (75%) presented local reactions and 3 (25%) Systemic reactions, 1 of which required intubation. The Hymenoptera specific IgE decreased from 4.15 kU/L (range, 0.44-100 kU/L) before immunotherapy to 1.2 kU/L (range, 0.34-69.4 kU/L) after 4 years ( P Conclusion Venom immunotherapy is effective to treat IgE-mediated Hymenoptera anaphylaxis in patients with Mastocytosis. Its use is recommended despite a relatively high risk of adverse reactions during the build-up phase because it provides protection from anaphylaxis in around 3/4 of the patients.
Almudena Matito - One of the best experts on this subject based on the ideXlab platform.
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Serum Tryptase Monitoring in Indolent Systemic Mastocytosis: Association with Disease Features and Patient Outcome
2016Co-Authors: Almudena Matito, Cristina Teodosio, Ricardo Moreno-borque, Alberto Orfao, Jose ́ Mario Morgado, Eduardo Pedreira, Luis EscribanoAbstract:Background: Serum baseline tryptase (sBT) is a minor diagnostic criterion for Systemic Mastocytosis (SM) of undetermined prognostic impact. We monitored sBT levels in Indolent SM (ISM) patients and investigated its utility for predicting disease behaviour and outcome. Methods: In total 74 adult ISM patients who were followed for $48 months and received no cytoreductive therapy were retrospectively studied. Patients were classified according to the pattern of evolution of sBT observed. Results: Overall 16/74 (22%) cases had decreasing sBT levels, 48 (65%) patients showed increasing sBT levels and 10 (13%) patients showed a fluctuating pattern. Patients with significantly increasing sBT (sBT slope $0.15) after 48 months of follow-up showed a slightly greater rate of development of diffuse bone sclerosis (13 % vs. 2%) and hepatomegaly plus splenomegaly (16 % vs. 5%), as well as a significantly greater frequency of multilineage vs. mast cells (MC)-restricted KIT mutation (p = 0.01) together with a greater frequency of cases with progression of ISM to smouldering and aggressive SM (p = 0.03), and a shorter progression-free survival (p = 0.03). Conclusions: Monitoring of sBT in ISM patients is closely associated with poor prognosis disease features as well as wit
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Advances in the understanding and clinical management of Mastocytosis and clonal mast cell activation syndromes [version 1; referees: 2 approved]
F1000 Research Ltd, 2016Co-Authors: David González-de-olano, Almudena Matito, Alberto Orfao, Luis EscribanoAbstract:Clonal mast cell activation syndromes and Indolent Systemic Mastocytosis without skin involvement are two emerging entities that sometimes might be clinically difficult to distinguish, and they involve a great challenge for the physician from both a diagnostic and a therapeutic point of view. Furthermore, final diagnosis of both entities requires a bone marrow study; it is recommended that this be done in reference centers. In this article, we address the current consensus and guidelines for the suspicion, diagnosis, classification, treatment, and management of these two entities
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kit d816v mutated bone marrow mesenchymal stem cells in Indolent Systemic Mastocytosis are associated with disease progression
Blood, 2015Co-Authors: Andres C Garciamontero, Ivan Alvareztwose, Laura Sanchezmunoz, Maria Jaraacevedo, Cristina Teodosio, Andrea Mayado, Almudena Matito, Javier I Munozgonzalez, Carmen Muniz, Carolina CaldasAbstract:Multilineage involvement of bone marrow (BM) hematopoiesis by the somatic KIT D816V mutation is present in a subset of adult Indolent Systemic Mastocytosis (ISM) patients in association with a poorer prognosis. Here, we investigated the potential involvement of BM mesenchymal stem cells (MSCs) from ISM patients by the KIT D816V mutation and its potential impact on disease progression and outcome. This mutation was investigated in highly purified BM MSCs and other BM cell populations from 83 ISM patients followed for a median of 116 months. KIT D816V-mutated MSCs were detected in 22 of 83 cases. All MSC-mutated patients had multilineage KIT mutation (100% vs 30%, P = .0001) and they more frequently showed involvement of lymphoid plus myeloid BM cells (59% vs 22%; P = .03) and a polyclonal pattern of inactivation of the X-chromosome of KIT-mutated BM mast cells (64% vs 0%; P = .01) vs other multilineage ISM cases. Moreover, presence of KIT-mutated MSCs was associated with more advanced disease features, a greater rate of disease progression (50% vs 17%; P = .04), and a shorter progression-free survival (P ≤ .003). Overall, these results support the notion that ISM patients with mutated MSCs may have acquired the KIT mutation in a common pluripotent progenitor cell, prior to differentiation into MSCs and hematopoietic precursor cells, before the X-chromosome inactivation process occurs. From a clinical point of view, acquisition of the KIT mutation in an earlier BM precursor cell confers a significantly greater risk for disease progression and a poorer outcome.
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detection of the kit d816v mutation in peripheral blood of Systemic Mastocytosis diagnostic implications
Modern Pathology, 2015Co-Authors: Maria Jaraacevedo, Ivan Alvareztwose, Laura Sanchezmunoz, Cristina Teodosio, Andrea Mayado, Carolina Caldas, Almudena Matito, Jose Mario Morgado, Javier I Munozgonzalez, Luis EscribanoAbstract:Recent studies have found the KIT D816V mutation in peripheral blood of virtually all adult Systemic Mastocytosis patients once highly sensitive PCR techniques were used; thus, detection of the KIT D816V mutation in peripheral blood has been proposed to be included in the diagnostic work-up of Systemic Mastocytosis algorithms. However, the precise frequency of the mutation, the biological significance of peripheral blood-mutated cells and their potential association with involvement of bone marrow hematopoietic cells other than mast cells still remain to be investigated. Here, we determined the frequency of peripheral blood involvement by the KIT D816V mutation, as assessed by two highly sensitive PCR methods, and investigated its relationship with multilineage involvement of bone marrow hematopoiesis. Overall, our results confirmed the presence of the KIT D816V mutation in peripheral blood of most Systemic Mastocytosis cases (161/190; 85%)--with an increasing frequency from Indolent Systemic Mastocytosis without skin lesions (29/44; 66%) to Indolent Systemic Mastocytosis with skin involvement (124/135; 92%), and more aggressive disease subtypes (11/11; 100%)--as assessed by the allele-specific oligonucleotide-qPCR method, which was more sensitive (P<.0001) than the peptide nucleic acid-mediated PCR approach (84/190; 44%). Although the presence of the KIT mutation in peripheral blood, as assessed by the allele-specific oligonucleotide-qPCR technique, did not accurately predict for multilineage bone marrow involvement of hematopoiesis, the allele-specific oligonucleotide-qPCR allele burden and the peptide nucleic acid-mediated-PCR approach did. These results suggest that both methods provide clinically useful and complementary information through the identification and/or quantification of the KIT D816V mutation in peripheral blood of patients suspected of Systemic Mastocytosis.
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nonaggressive Systemic Mastocytosis sm without skin lesions associated with insect induced anaphylaxis shows unique features versus other Indolent sm
The Journal of Allergy and Clinical Immunology, 2014Co-Authors: Ivan Alvareztwose, Roberta Zanotti, Patrizia Bonadonna, Laura Sanchezmunoz, Almudena Matito, Jose Mario Morgado, Arantza Vega, David Gonzalezdeolano, Omar Perbellini, Andres C GarciamonteroAbstract:Background Indolent Systemic Mastocytosis (ISM) without skin lesions (ISMs − ) shows a higher prevalence in males, lower serum baseline tryptase levels, and KIT mutation more frequently restricted to bone marrow (BM) mast cells (MCs) than ISM with skin lesions (ISMs + ). Interestingly, in almost one-half of ISMs − patients, MC-mediator release episodes are triggered exclusively by insects. Objective We aimed to determine the clinical and laboratory features of ISMs − associated with insect-induced anaphylaxis (insectISMs − ) versus other patients with ISM. Methods A total of 335 patients presenting with MC activation syndrome, including 143 insectISMs − , 72 ISMs − triggered by other factors (otherISMs − ), 56 ISMs + , and 64 nonclonal MC activation syndrome, were studied. Results Compared with otherISMs − and ISMs + patients, insectISMs − cases showed marked male predominance (78% vs 53% and 46%; P P ≤ .009). Moreover, insectISMs − less frequently presented BM MC aggregates (46% vs 70% and 81%; P ≤ .001), and they systematically showed MC-restricted KIT mutation. Conclusions ISMs − patients with anaphylaxis triggered exclusively by insects display clinical and laboratory features that are significantly different from other ISM cases, including other ISMs − and ISMs + patients, suggesting that they represent a unique subgroup of ISM with a particularly low BM MC burden in the absence of adverse prognostic factors.