Materiały źródłowe

• #1 New Insights into the Pathogenesis of Systemic Mastocytosis

  https://www.mdpi.com/1422-0067/22/9/4900

  Mastocytosis is a type of myeloid neoplasm characterized by the clonal, neoplastic proliferation of morphologically and immunophenotypically abnormal mast cells that infiltrate one or more organ systems. […] Over 80% of patients with SM carry the KIT D816V mutation. However, the KIT D816V mutation serves as a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. […] The molecular mechanisms that underlie SM development are not well-understood. Over 80% of patients with SM harbor the KIT D816V mutation. However, KIT D816V mutation is a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. […] New developments, including the use of next-generation sequencing (NGS) panels and the increasingly sensitive detection of the KIT D816V mutation have improved our understanding of SM pathogenesis.

• #2 New Insights into the Pathogenesis of Systemic Mastocytosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8125314/

  Mastocytosis is a type of myeloid neoplasm characterized by the clonal, neoplastic proliferation of morphologically and immunophenotypically abnormal mast cells that infiltrate one or more organ systems. […] Over 80% of patients with SM carry the KIT D816V mutation. However, the KIT D816V mutation serves as a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. […] The molecular mechanisms that underlie SM development are not well-understood. Over 80% of patients with SM harbor the KIT D816V mutation. However, KIT D816V mutation is a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. […] New data suggested that KIT D816V is a late event in the pathogenesis of SM. […] Collectively, KIT mutations alone cannot explain the full clinical spectrum of SM.

• #3 IJMS | Special Issue : Pathogenesis and Management of Mastocytosis

  https://www.mdpi.com/journal/ijms/special_issues/Mastocytosis

  Mastocytosis is a type of myeloid neoplasm that is characterized by the clonal, neoplastic proliferation of morphologically and immunophenotypically abnormal mast cells in one or more organ systems. […] The molecular mechanisms that underlie the development of mastocytosis are not well understood. The KIT D816V mutation can be found in over 80% of patients with SM. However, the KIT D816V mutation is a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. […] Gaining a better understanding of the mechanisms underlying the development of SM may yield improved molecular therapies for its treatment.

• #4 Systemic Mastocytosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK544345/

  The pathogenesis of all types of mastocytosis is the result of chronic and episodic discharge of mast cell mediators and excessive accumulation of mast cells in one or more tissues. […] Mast cell production is under the regulation of a gene named KIT, which encodes CD117 transmembrane tyrosine kinase. CD117 helps in the growth, survival as well as the migration of mast cells. […] Activating and inactivating mutations of KIT are implicated in the pathogenesis of systemic mastocytosis. […] The precise mechanism by which KIT-activating mutations improve signaling is not thoroughly understood, but these errors lead to stem cell factor (SCF)-independent activation. […] KITD816V is the most common driver mutation for systemic mastocytosis. […] KIT mutations are mostly somatic, so they don’t seem to be inherited although, they might be present at birth. […] They are rarely present in the germline cells, hence not passed down to the next generation.

• #5 New Insights into the Pathogenesis of Systemic Mastocytosis

  https://www.mdpi.com/1422-0067/22/9/4900

  Mastocytosis is a type of myeloid neoplasm characterized by the clonal, neoplastic proliferation of morphologically and immunophenotypically abnormal mast cells that infiltrate one or more organ systems. […] Over 80% of patients with SM carry the KIT D816V mutation. However, the KIT D816V mutation serves as a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. […] The molecular mechanisms that underlie SM development are not well-understood. Over 80% of patients with SM harbor the KIT D816V mutation. However, KIT D816V mutation is a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. […] New developments, including the use of next-generation sequencing (NGS) panels and the increasingly sensitive detection of the KIT D816V mutation have improved our understanding of SM pathogenesis.

• #6 Systemic Mastocytosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/203948-overview

  Systemic mastocytosis (systemic mast cell disease) is characterized by mast cell infiltration of skin and extracutaneous organs. Mast cells typically infiltrate the bone marrow and consequently affect the peripheral blood and coagulation system. Mast cells are derived from CD34+/ KIT+ pluripotent hematopoietic cells in the bone marrow. The neoplastic clones of mast cells express abnormal cell surface markers CD25 and/or CD2. […] More than 95% of adults with systemic mastocytosis have exon 17 KIT mutations, most commonly the KIT D816V mutation. This gain of function mutation in the KIT receptor was detected by polymerase chain reaction (PCR) techniques in 68% of bone marrow specimens in patients with systemic mastocytosis. Additional molecular aberrations are frequently identified in TET2, SRSF2, ASXL1, CBL, RUNX1, DNMT3A, and in the RAS pathway.

• #7

  https://link.springer.com/article/10.1007/s40521-023-00349-2

  Mastocytosis is associated with a high risk of anaphylaxis, in part due to drug hypersensitivity reactions (DHR). […] The majority of mastocytosis are caused by activating mutations in the gene that codifies for the KIT-receptor/CD117 (i.e., KIT), with the KITD816V mutation being detected in over 90% of cases. […] Activating KIT mutations promote autophosphorylation and, or dimerization of the KIT receptor in a ligand-independent fashion, enhancing cell proliferation and survival, as well as IgE-mediated activation and may lower the threshold for non-IgE-mediated MC activation. […] In mastocytosis, MC activation symptoms can be unprovoked and provoked by triggers. […] Specific triggers include drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs), vaccines, opiates/opioids, neuromuscular blocking agents (NMBAs), radiocontrast media (RCM), quinolones, vancomycin, and Hymenoptera venoms, which may induce MC activation through several mechanisms.

• #8 Systemic mastocytosis: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/systemic-mastocytosis/

  Systemic mastocytosis occurs when white blood cells called mast cells, which are produced in bone marrow, abnormally accumulate in one or more tissues. In most cases of systemic mastocytosis, the accumulated mast cells have a mutation in a gene called KIT. The KIT gene provides instructions for making a protein that plays an important role in development and activity of mast cells. The KIT protein stimulates chemical signaling pathways that are involved in the growth and division (proliferation) of many types of cells, including mast cells. In systemic mastocytosis, KIT gene mutations are somatic, which means they are acquired during a person’s lifetime. These mutations result in a KIT protein that is always turned on (activated). As a result, signaling pathways are overactive, leading to increased production and accumulation of mast cells.

• #9 Azthena logo with the word Azthena

  https://www.news-medical.net/health/What-is-Systemic-Mastocytosis.aspx

  Systemic mastocytosis is usually linked to KIT somatic gain-of-function point mutations. […] The majority of adult SM patients have gain-of-function somatic mutations in the KIT tyrosine kinase domain, specifically the D816V mutation. […] Mutations produce a KIT protein that is always active. As a result, signaling pathways become hyperactive, resulting in increased mast cell production and accumulation.

• #10 New Insights into the Pathogenesis of Systemic Mastocytosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8125314/

  Mastocytosis is a type of myeloid neoplasm characterized by the clonal, neoplastic proliferation of morphologically and immunophenotypically abnormal mast cells that infiltrate one or more organ systems. […] Over 80% of patients with SM carry the KIT D816V mutation. However, the KIT D816V mutation serves as a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. […] The molecular mechanisms that underlie SM development are not well-understood. Over 80% of patients with SM harbor the KIT D816V mutation. However, KIT D816V mutation is a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. […] New data suggested that KIT D816V is a late event in the pathogenesis of SM. […] Collectively, KIT mutations alone cannot explain the full clinical spectrum of SM.

• #11 New Insights into the Pathogenesis of Systemic Mastocytosis

  https://www.mdpi.com/1422-0067/22/9/4900

  Mastocytosis is a type of myeloid neoplasm characterized by the clonal, neoplastic proliferation of morphologically and immunophenotypically abnormal mast cells that infiltrate one or more organ systems. […] Over 80% of patients with SM carry the KIT D816V mutation. However, the KIT D816V mutation serves as a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. […] The molecular mechanisms that underlie SM development are not well-understood. Over 80% of patients with SM harbor the KIT D816V mutation. However, KIT D816V mutation is a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. […] New developments, including the use of next-generation sequencing (NGS) panels and the increasingly sensitive detection of the KIT D816V mutation have improved our understanding of SM pathogenesis.

• #12 Systemic Mastocytosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/203948-overview

  Systemic mastocytosis (systemic mast cell disease) is characterized by mast cell infiltration of skin and extracutaneous organs. Mast cells typically infiltrate the bone marrow and consequently affect the peripheral blood and coagulation system. Mast cells are derived from CD34+/ KIT+ pluripotent hematopoietic cells in the bone marrow. The neoplastic clones of mast cells express abnormal cell surface markers CD25 and/or CD2. […] More than 95% of adults with systemic mastocytosis have exon 17 KIT mutations, most commonly the KIT D816V mutation. This gain of function mutation in the KIT receptor was detected by polymerase chain reaction (PCR) techniques in 68% of bone marrow specimens in patients with systemic mastocytosis. Additional molecular aberrations are frequently identified in TET2, SRSF2, ASXL1, CBL, RUNX1, DNMT3A, and in the RAS pathway.

• #13

  https://haematologica.org/article/view/7840

  Systemic mastocytosis is a heterogeneous disease characterized by the accumulation of neoplastic mast cells in the bone marrow and other organ organs/tissues. Mutations in KIT, most frequently KIT D816V, are detected in over 80% of all systemic mastocytosis patients. […] Recent studies have also revealed additional somatic defects (apart from mutations in KIT) in a majority of patients with advanced systemic mastocytosis. These include TET2, SRSF2, ASXL1, RUNX1, JAK2, and/or RAS mutations, which may adversely impact prognosis and survival in particular systemic mastocytosis with an associated hematological neoplasm. […] Herein, we review the biology and pathogenesis of advanced systemic mastocytosis, with a special focus on novel molecular findings as well as current and evolving therapeutic options. […] The exact percentages vary, depending on disease subtypes (e.g. ISM vs. ASM) and cell source [e.g. BM vs. peripheral blood (PB)]. […] The presence of additional genetic defects in KIT D816V+ AdvSM patients may confer adverse prognosis as compared with patients without such abnormalities.

• #14 Systemic Mastocytosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/203948-overview

  The mechanism of bone loss is not yet fully elucidated, but stimulation of osteoclast activity through RANK-RANKL signaling appears to be most important. Histamine and other cytokines also play significant roles. […] The association between JAK2 V617F and systemic mastocytosis is weak and was noted in just 4% of patients with systemic mastocytosis (all had associated nonmast cell hematological disease). The incidence of TET2 mutations (reportedly as high as 29% in KIT-positive systemic mastocytosis) seems to influence the phenotype without affecting the prognosis. […] Another finding that may prove relevant to the pathogenesis of systemic mastocytosis is a constitutive expression of the stress-related survival factor heat-shock protein 32 (Hsp32) in a human mast cell tumor line.

• #15

  https://haematologica.org/article/view/7840

  Systemic mastocytosis is a heterogeneous disease characterized by the accumulation of neoplastic mast cells in the bone marrow and other organ organs/tissues. Mutations in KIT, most frequently KIT D816V, are detected in over 80% of all systemic mastocytosis patients. […] Recent studies have also revealed additional somatic defects (apart from mutations in KIT) in a majority of patients with advanced systemic mastocytosis. These include TET2, SRSF2, ASXL1, RUNX1, JAK2, and/or RAS mutations, which may adversely impact prognosis and survival in particular systemic mastocytosis with an associated hematological neoplasm. […] Herein, we review the biology and pathogenesis of advanced systemic mastocytosis, with a special focus on novel molecular findings as well as current and evolving therapeutic options. […] The exact percentages vary, depending on disease subtypes (e.g. ISM vs. ASM) and cell source [e.g. BM vs. peripheral blood (PB)]. […] The presence of additional genetic defects in KIT D816V+ AdvSM patients may confer adverse prognosis as compared with patients without such abnormalities.

• #16 New Insights into the Pathogenesis of Systemic Mastocytosis

  https://www.mdpi.com/1422-0067/22/9/4900

  Although KIT mutations, particularly KIT D816V, have been considered to serve as key mutations in mastocytosis, an increasing body of data has indicated that other events (e.g., tropomyosin-related kinase [TRK]) may play important roles in the pathogenesis of mastocytosis. […] The identification of early cooperating events for KIT mutations may improve our understanding of the pathogenesis of SM, leading to more efficient treatments and improved outcomes for SM patients. […] The roles played by TRK receptors and their respective ligands during normal and malignant hematopoiesis are not yet well-understood. […] However, we and others have obtained evidence suggesting an important role for NT signaling in leukemogenesis and mastocytosis. […] Taken together, we provided the first direct evidence to support SM development induced by the activation of TRKA or TRKB in HSC and progenitor cells in vivo.

• #17 New Insights into the Pathogenesis of Systemic Mastocytosis

  https://www.mdpi.com/1422-0067/22/9/4900

  Our data strongly supported the findings described by Peng et al. and their hypothesis, suggesting that TRKs have an important role in mastocytosis pathogenesis and the development of resistance to KIT inhibition. […] Collectively, these data suggested that TRKA signaling may improve neoplastic MC fitness, which would explain, at least in part, why the results of treatment with KIT inhibitors alone in SM patients have been disappointing in most studies. […] Identifying these genetic and epigenetic alterations and understanding their interactions and the molecular mechanisms involved in mastocytosis is of the utmost importance for developing rationally targeted therapies.

• #18 New Insights into the Pathogenesis of Systemic Mastocytosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8125314/

  The identification of early cooperating events for KIT mutations may improve our understanding of the pathogenesis of SM, leading to more efficient treatments and improved outcomes for SM patients. […] Moreover, TRK signaling has been suggested to be involved in other hematological malignancies, such as multiple myeloma. […] Taken together, we provided the first direct evidence to support SM development induced by the activation of TRKA or TRKB in HSC and progenitor cells in vivo. […] Our data strongly supported the findings described by Peng et al. and their hypothesis, suggesting that TRKs have an important role in mastocytosis pathogenesis and the development of resistance to KIT inhibition. […] Identifying these genetic and epigenetic alterations and understanding their interactions and the molecular mechanisms involved in mastocytosis is of the utmost importance for developing rationally targeted therapies.

• #19 New Insights into the Pathogenesis of Systemic Mastocytosis

  https://www.mdpi.com/1422-0067/22/9/4900

  Although KIT mutations, particularly KIT D816V, have been considered to serve as key mutations in mastocytosis, an increasing body of data has indicated that other events (e.g., tropomyosin-related kinase [TRK]) may play important roles in the pathogenesis of mastocytosis. […] The identification of early cooperating events for KIT mutations may improve our understanding of the pathogenesis of SM, leading to more efficient treatments and improved outcomes for SM patients. […] The roles played by TRK receptors and their respective ligands during normal and malignant hematopoiesis are not yet well-understood. […] However, we and others have obtained evidence suggesting an important role for NT signaling in leukemogenesis and mastocytosis. […] Taken together, we provided the first direct evidence to support SM development induced by the activation of TRKA or TRKB in HSC and progenitor cells in vivo.

• #20 New Insights into the Pathogenesis of Systemic Mastocytosis

  https://www.mdpi.com/1422-0067/22/9/4900

  Our data strongly supported the findings described by Peng et al. and their hypothesis, suggesting that TRKs have an important role in mastocytosis pathogenesis and the development of resistance to KIT inhibition. […] Collectively, these data suggested that TRKA signaling may improve neoplastic MC fitness, which would explain, at least in part, why the results of treatment with KIT inhibitors alone in SM patients have been disappointing in most studies. […] Identifying these genetic and epigenetic alterations and understanding their interactions and the molecular mechanisms involved in mastocytosis is of the utmost importance for developing rationally targeted therapies.

• #21 Role of sclerostin in mastocytosis bone disease | Scientific Reports

  https://www.nature.com/articles/s41598-024-83851-0

  Mastocytosis is a heterogeneous group of disorders, characterized by accumulation of clonal mast cells which can infiltrate several organs, most often spine (70%). The pathogenesis of mastocytosis bone disease is poorly understood. […] The pathogenesis of bone alterations in SM remains unclear. Bone infiltration by mast cells and the influence of inflammatory mediators are considered. Histamine, tryptase and heparin may directly activate osteoclasts. […] Sclerostin may serve as a marker of more advanced disease and bone disease in mastocytosis. […] Sclerostin is involved in the pathogenesis of many bone diseases, although its exact functions are not yet clearly understood. […] In our study, we demonstrated that unstimulated, neoplastic mast cells (HMC-1.2 cell line) are capable of secreting sclerostin and that stimulation with IL-6 (at a concentration of 100ng/ml) results in a significant increase in SOST gene expression. This would suggest the potential role of sclerostin and the Wnt pathway as one of the components of the pathomechanism of bone damage in mastocytosis.

• #22 Role of sclerostin in mastocytosis bone disease | Scientific Reports

  https://www.nature.com/articles/s41598-024-83851-0

  Mastocytosis is a heterogeneous group of disorders, characterized by accumulation of clonal mast cells which can infiltrate several organs, most often spine (70%). The pathogenesis of mastocytosis bone disease is poorly understood. […] The pathogenesis of bone alterations in SM remains unclear. Bone infiltration by mast cells and the influence of inflammatory mediators are considered. Histamine, tryptase and heparin may directly activate osteoclasts. […] Sclerostin may serve as a marker of more advanced disease and bone disease in mastocytosis. […] Sclerostin is involved in the pathogenesis of many bone diseases, although its exact functions are not yet clearly understood. […] In our study, we demonstrated that unstimulated, neoplastic mast cells (HMC-1.2 cell line) are capable of secreting sclerostin and that stimulation with IL-6 (at a concentration of 100ng/ml) results in a significant increase in SOST gene expression. This would suggest the potential role of sclerostin and the Wnt pathway as one of the components of the pathomechanism of bone damage in mastocytosis.

• #23 Systemic Mastocytosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/203948-overview

  The mechanism of bone loss is not yet fully elucidated, but stimulation of osteoclast activity through RANK-RANKL signaling appears to be most important. Histamine and other cytokines also play significant roles. […] The association between JAK2 V617F and systemic mastocytosis is weak and was noted in just 4% of patients with systemic mastocytosis (all had associated nonmast cell hematological disease). The incidence of TET2 mutations (reportedly as high as 29% in KIT-positive systemic mastocytosis) seems to influence the phenotype without affecting the prognosis. […] Another finding that may prove relevant to the pathogenesis of systemic mastocytosis is a constitutive expression of the stress-related survival factor heat-shock protein 32 (Hsp32) in a human mast cell tumor line.

• #24 Skin and bones: systemic mastocytosis and bone in: Endocrinology, Diabetes & Metabolism Case Reports Volume 2023 Issue 2 (2023)

  https://edm.bioscientifica.com/view/journals/edm/2023/2/EDM22-0408.xml

  SM is recognised as a rare cause of secondary osteoporosis, whereby the release of mast cell mediators such as histamine, tryptase, heparin and interleukins may promote osteoclasts and inhibit osteoblasts, leading to bone resorption. […] There is a complex interplay between the balance of osteoclastic and osteoblastic drivers, and depending on disease manifestations, some patients may present with osteosclerosis rather than osteoporosis. […] Upon activation, mast cells secrete numerous mediators, either promoting osteoclastic (e.g. histamine, heparin, tumour necrosis factor, and interleukin-6) or inhibiting osteoblastic activity (e.g. interleukin-1, interleukin-6 and tumour necrosis factor). Conversely, mediators may also promote osteoblastic (e.g. transforming growth factor-) or inhibit osteoclastic activity (e.g. interleukin-12, interferon-) under different conditions.

• #25 Skin and bones: systemic mastocytosis and bone in: Endocrinology, Diabetes & Metabolism Case Reports Volume 2023 Issue 2 (2023)

  https://edm.bioscientifica.com/view/journals/edm/2023/2/EDM22-0408.xml

  Increase in osteoprotegerin and RANKL levels were also noted in SM, suggesting the involvement of the RANKL/RANK/OPG pathway. […] The prevalence of SM in patients with osteoporosis is unknown but is likely underdiagnosed. […] Thus, mediators favouring osteoclastogenesis may predominate with a moderate increase in mast cells, whereas mediators favouring osteoblastogenesis prevail with a higher mast cell burden. […] Studies have shown that while osteoporosis is a common feature in indolent SM, increased bone density is frequently encountered in advanced cases and associated with poorer prognosis. […] Bone marrow mast cell infiltration and serum tryptase levels were both significantly lower in patients with compared to those without osteoporosis. […] An increased bone mineral density is an adverse prognostic factor in patients with systemic mastocytosis.

• #26

  https://medicaljournalssweden.se/actadv/article/view/350

  Pruritus is widely observed in many dermatoses, including mastocytosis, a rare disease characterized by abnormal accumulation of mast cells, which can involve skin, bone marrow, and other organs. […] Increasing evidence highlights the role of mast cells in neurogenic inflammation and itching. […] Mast cells release various pruritogenic mediators, initiating subsequent mutual communication with specific nociceptors on sensory nerve fibres. […] Among important mediators released by mast cells that induce pruritus, one can distinguish histamine, serotonin, proteases, as well as various cytokines. […] During neuronal-induced inflammation, mast cells may respond to numerous mediators, including neuropeptides, such as substance P, neurokinin A, calcitonin gene-related peptide, endothelin 1, and nerve growth factor. […] Currently, treatment of pruritus in mastocytosis is focused on alleviating the effects of mediators secreted by mast cells. […] However, a deeper understanding of the intricacies of the neurobiology of this disease could help to provide better treatment options for patients.

• #27 Central Role of Mast Cells in Mastocytosis, Hereditary α-Tryptasemia, Mast Cell Activation Syndrome, Urticaria, and Angioedema – European Medical Journal

  https://www.emjreviews.com/allergy-immunology/article/central-role-of-mast-cells-in-mastocytosis-hereditary-%CE%B1-tryptasemia-mast-cell-activation-syndrome-urticaria-and-angioedema-j01121/

  Mast cells are the central cells in the pathogenesis of many conditions that are associated with mediator release. […] Some conditions such as mastocytosis have a confirmed genetic background; however, the genetic background of hereditary -tryptasemia has only recently been described, and routine testing is yet to be set up in genetic laboratories. […] Mast cell activation syndrome is a more prevalent, heterogeneous condition with an unclear aetiology, but has clinically similar symptoms associated with an impaired tolerance of mast cells. […] The ethology and mechanisms of chronic mast cell dysregulation are not well understood, with many clinical studies emphasising the role of the epithelium or the presence of acute inflammation, which leads to mast cell activation. […] The overactivity of mast cells and subsequent parthenogenesis can affect the connective tissue.

• #28

  https://medicaljournalssweden.se/actadv/article/view/350

  Pruritus is widely observed in many dermatoses, including mastocytosis, a rare disease characterized by abnormal accumulation of mast cells, which can involve skin, bone marrow, and other organs. […] Increasing evidence highlights the role of mast cells in neurogenic inflammation and itching. […] Mast cells release various pruritogenic mediators, initiating subsequent mutual communication with specific nociceptors on sensory nerve fibres. […] Among important mediators released by mast cells that induce pruritus, one can distinguish histamine, serotonin, proteases, as well as various cytokines. […] During neuronal-induced inflammation, mast cells may respond to numerous mediators, including neuropeptides, such as substance P, neurokinin A, calcitonin gene-related peptide, endothelin 1, and nerve growth factor. […] Currently, treatment of pruritus in mastocytosis is focused on alleviating the effects of mediators secreted by mast cells. […] However, a deeper understanding of the intricacies of the neurobiology of this disease could help to provide better treatment options for patients.

• #29 Central Role of Mast Cells in Mastocytosis, Hereditary α-Tryptasemia, Mast Cell Activation Syndrome, Urticaria, and Angioedema – European Medical Journal

  https://www.emjreviews.com/allergy-immunology/article/central-role-of-mast-cells-in-mastocytosis-hereditary-%CE%B1-tryptasemia-mast-cell-activation-syndrome-urticaria-and-angioedema-j01121/

  Mast cell activation syndrome is characterised by aberrant inappropriate release of mast cell mediators. […] The suspected mechanisms lead to pruritus, pain, abdominal cramping, vomiting, nausea, and flushing include increased mast cell proliferation, accumulation of altered or mutated mast cells, and decreased apoptosis. […] Although the pathogenesis of CSU and angioedema is not yet fully understood, they occur due to the release and effects of mast cell mediators following mast cell activation in the skin.

• #30 The stromal composition of mast cell aggregates in systemic mastocytosis | Modern Pathology

  https://www.nature.com/articles/modpathol200953

  Systemic mastocytosis is a stem cell disorder characterized histologically by the presence of multifocal compact aggregates of mast cells in at least one extracutaneous organ with or without evidence of skin lesions. […] These findings indicate that systemic mastocytosis exhibits a distinct pattern of stromal change, and suggest that the fibrogenetic mechanism in systemic mastocytosis is most likely different from that of other bone marrow neoplasms which are also associated with fibrosis. […] In this study, we demonstrated that the degree of reticulin and collagen fibrosis within the mast cell lesions of systemic mastocytosis is pronounced and similar to that seen in advanced primary myelofibrosis and in cases of metastatic malignancy associated with fibrosis. […] The presence of diminished vascularity was further confirmed by the paucity of CD34-positive microvessels observed in these lesions.

• #31 The stromal composition of mast cell aggregates in systemic mastocytosis | Modern Pathology

  https://www.nature.com/articles/modpathol200953

  In conclusion, the fibrotic lesions of systemic mastocytosis show abundant mature collagen, reduced vascularization as evidenced by scarce collagen IV, laminin, and CD34 expression, and the paucity of cells expressing low-affinity nerve growth factor receptor and stromal cells showing myofibroblastic differentiation. This pattern of stromal change is uncommonly seen in other bone marrow disorders characterized by fibrosis. These observations suggest that the pathogenetic mechanism leading to fibrosis in systemic mastocytosis may differ from that of other fibrotic neoplasms of the bone marrow.

• #32 Mast Cell Activation Syndrome (MCAS)

  https://www.aaaai.org/conditions-treatments/related-conditions/mcas

  Mast cells can also be activated by other substances, such as medications, infections, insect or reptile venoms. […] Sometimes mast cells become defective and release mediators because of abnormal internal signals. Certain mutations in mast cells can produce populations of identical mast cells called clones that overproduce and spontaneously release mediators. […] These abnormal cells can grow uncontrollably and are unusually sensitive to activation in a condition called mastocytosis. […] The episodes are called idiopathic which means that the mechanism is unknown – that is, not caused by allergic antibody or secondary to other known conditions that activate normal mast cells. […] The improvement with treatment using inhibitors of mast cell mediators completes the diagnosis. […] The patients blood should be tested for mutation of mast cell growth receptor KIT, called KIT D816V. If positive, it indicates a clonal mast cell disorder. […] If the bone marrow biopsy is negative for abnormal and clonal mast cells, it establishes the diagnosis of idiopathic mast cell activation syndrome.

• #33 Mastocytosis: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1057932-overview

  Although pediatric mastocytosis can spontaneously regress, it is a clonal disease most commonly associated with D816V and other activating c-kit mutations. […] Associated systemic manifestations are believed to reflect the release of mast cell-derived mediators, such as histamine, prostaglandins, heparin, neutral proteases, and acid hydrolases. Symptoms and signs induced by mediators may include headache, neuropsychiatric symptoms (cognitive disorganization), flushing, dizziness, tachycardia, hypotension, syncope, anorexia, nausea, vomiting, abdominal pain, and diarrhea. The skeletal, hematopoietic, gastrointestinal (GI), cardiopulmonary, and central nervous systems may be involved either directly, via mast cell infiltration, or indirectly, via mast cell mediator release.

• #34 Mastocytosis: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1057932-overview

  Although pediatric mastocytosis can spontaneously regress, it is a clonal disease most commonly associated with D816V and other activating c-kit mutations. […] Associated systemic manifestations are believed to reflect the release of mast cell-derived mediators, such as histamine, prostaglandins, heparin, neutral proteases, and acid hydrolases. Symptoms and signs induced by mediators may include headache, neuropsychiatric symptoms (cognitive disorganization), flushing, dizziness, tachycardia, hypotension, syncope, anorexia, nausea, vomiting, abdominal pain, and diarrhea. The skeletal, hematopoietic, gastrointestinal (GI), cardiopulmonary, and central nervous systems may be involved either directly, via mast cell infiltration, or indirectly, via mast cell mediator release.

• #35 Mastocytosis: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1057932-overview

  Although pediatric mastocytosis can spontaneously regress, it is a clonal disease most commonly associated with D816V and other activating c-kit mutations. […] Associated systemic manifestations are believed to reflect the release of mast cell-derived mediators, such as histamine, prostaglandins, heparin, neutral proteases, and acid hydrolases. Symptoms and signs induced by mediators may include headache, neuropsychiatric symptoms (cognitive disorganization), flushing, dizziness, tachycardia, hypotension, syncope, anorexia, nausea, vomiting, abdominal pain, and diarrhea. The skeletal, hematopoietic, gastrointestinal (GI), cardiopulmonary, and central nervous systems may be involved either directly, via mast cell infiltration, or indirectly, via mast cell mediator release.

• #36

  https://link.springer.com/article/10.1007/s40521-023-00349-2

  Mastocytosis is associated with a high risk of anaphylaxis, in part due to drug hypersensitivity reactions (DHR). […] The majority of mastocytosis are caused by activating mutations in the gene that codifies for the KIT-receptor/CD117 (i.e., KIT), with the KITD816V mutation being detected in over 90% of cases. […] Activating KIT mutations promote autophosphorylation and, or dimerization of the KIT receptor in a ligand-independent fashion, enhancing cell proliferation and survival, as well as IgE-mediated activation and may lower the threshold for non-IgE-mediated MC activation. […] In mastocytosis, MC activation symptoms can be unprovoked and provoked by triggers. […] Specific triggers include drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs), vaccines, opiates/opioids, neuromuscular blocking agents (NMBAs), radiocontrast media (RCM), quinolones, vancomycin, and Hymenoptera venoms, which may induce MC activation through several mechanisms.

• #37

  https://link.springer.com/article/10.1007/s40521-023-00349-2

  Mastocytosis is associated with a high risk of anaphylaxis, in part due to drug hypersensitivity reactions (DHR). […] The majority of mastocytosis are caused by activating mutations in the gene that codifies for the KIT-receptor/CD117 (i.e., KIT), with the KITD816V mutation being detected in over 90% of cases. […] Activating KIT mutations promote autophosphorylation and, or dimerization of the KIT receptor in a ligand-independent fashion, enhancing cell proliferation and survival, as well as IgE-mediated activation and may lower the threshold for non-IgE-mediated MC activation. […] In mastocytosis, MC activation symptoms can be unprovoked and provoked by triggers. […] Specific triggers include drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs), vaccines, opiates/opioids, neuromuscular blocking agents (NMBAs), radiocontrast media (RCM), quinolones, vancomycin, and Hymenoptera venoms, which may induce MC activation through several mechanisms.

• #38

  https://link.springer.com/article/10.1007/s40521-023-00349-2

  In mastocytosis, vaccines contain adjuvants which modulate both innate and adaptive immune responses and excipients to stabilize and preserve formulations. […] Anaphylaxis to vaccines is rare in the general population, amounting to an overall rate of 1.31 per million vaccine doses, and is increased tenfold for SARS-COV-2 vaccines. […] In mastocytosis, MC activation episodes related to vaccination have been reported in children and in adults. […] The data support the safe vaccination of all pediatric and adult mastocytosis patients as recommended by worldwide agencies. […] There is a perception by patients and providers that general anesthesia is a high-risk procedure for mastocytosis patients. […] However, in a large retrospective study of patients with mastocytosis, the risk of DHR during the perioperative period was shown to be low.

• #39

  https://link.springer.com/article/10.1007/s40521-023-00349-2

  Neuromuscular blocking agents are the most frequent elicitors of perioperative anaphylaxis in the general population, which may be caused by IgE-mediated and MRGPRX2-related MC activation. […] Opiates/opioids, including morphine, pethidine/meperidine, codeine, and others, are avoided by mastocytosis patients based on in vivo and in vitro data showing direct MC activation. […] Mastocytosis has been associated with an increased risk of DHR to a wide array of drugs, including NSAIDs, drugs used in the perioperative setting, opiates and opioids, vaccines, RCM, antibiotics such as quinolones, and vancomycin and identifying patients at risk is paramount to prevent unnecessary avoidance of critical drugs.

• #40

  https://link.springer.com/article/10.1007/s40521-023-00349-2

  Avoidance of such drugs is frequently unnecessary as the associated risk of MC activation is often low and similar to the risk in the general population. […] The prevalence of anaphylaxis in mastocytosis patients is considerably higher than in the general population and may reach up to 50%. […] Mastocytosis patients at higher risk for anaphylaxis include those presenting without skin lesions, atopy, high total IgE, and lower serum baseline tryptase (sBT). […] In mastocytosis, the reported prevalence of NSAID hypersensitivity is 14% in adults and 9% in pediatric patients, and NSAID-induced anaphylaxis is found in 2 to 11% of adult patients and 2% of children and adolescents. […] Patients who tolerate NSAIDs before and after the onset of mastocytosis do not require testing, and avoidance is not indicated.

• #41 ASCIA Position Paper – Diagnosis and Investigation of Mast Cell Activation Disorders and Syndrome – Australasian Society of Clinical Immunology and Allergy (ASCIA)

  https://www.allergy.org.au/hp/papers/testing-for-mast-cell-activation-disorders-and-syndrome

  Mast cell activation syndrome (MCAS) can be defined as a heterogenous group of disorders presenting with episodic symptoms involving multiple systems that are attributable to mast cell mediator release (e.g. flushing, pruritus, wheeze, gastrointestinal symptoms). […] Pathologic activation of mast cells can occur in two key settings: (1) Increased numbers or increased function in the absence of usual triggers; or (2) activation and release of mediators out of proportion to a stimulus e.g. infections, venom, allergens. […] Mast cell activation syndrome (MCAS) has been defined as a heterogenous group of disorders of varied causes that present with episodic symptoms involving multiple systems that are attributable to mast cell mediator release. […] It is agreed that MCAS should be considered a diagnosis of exclusion.

• #42 ASCIA Position Paper – Diagnosis and Investigation of Mast Cell Activation Disorders and Syndrome – Australasian Society of Clinical Immunology and Allergy (ASCIA)

  https://www.allergy.org.au/hp/papers/testing-for-mast-cell-activation-disorders-and-syndrome

  Mast cell activation syndrome (MCAS) can be defined as a heterogenous group of disorders presenting with episodic symptoms involving multiple systems that are attributable to mast cell mediator release (e.g. flushing, pruritus, wheeze, gastrointestinal symptoms). […] Pathologic activation of mast cells can occur in two key settings: (1) Increased numbers or increased function in the absence of usual triggers; or (2) activation and release of mediators out of proportion to a stimulus e.g. infections, venom, allergens. […] Mast cell activation syndrome (MCAS) has been defined as a heterogenous group of disorders of varied causes that present with episodic symptoms involving multiple systems that are attributable to mast cell mediator release. […] It is agreed that MCAS should be considered a diagnosis of exclusion.

• #43 Mastocytosis and Mast Cell Activation Syndrome – Immunology; Allergic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/immunology-allergic-disorders/allergic-autoimmune-and-other-hypersensitivity-disorders/mastocytosis-and-mast-cell-activation-syndrome

  Mastocytosis is mast cell proliferation with infiltration of skin or other tissues and organs. […] Pathology results mainly from release of mast cell mediators, including histamine, heparin, leukotrienes, and various inflammatory cytokines. […] Etiology in many cases of mastocytosis involves an activating mutation (D816V) in the gene coding for the stem cell factor receptor c-kit, which is present on mast cells. The result is autophosphorylation of the receptor, which causes uncontrolled mast cell proliferation. […] Mast cell activation syndrome is characterized by increased and inappropriate activation of mast cells with mediator release but without clonal proliferation or organ infiltration by mast cells. […] Most cases do not involve clonal proliferation of mast cells but are due to a lower threshold for mast cells to degranulate. […] It is unclear whether mast cell activation syndrome can progress to systemic mastocytosis or another form of mast cell disease and, if so, how many patients are affected.

• #44 Mast Cell Activation

  https://worldallergy.org/component/content/article/mast-cell-activation?catid=17&Itemid=101

  It appears that non IgE- mediated food mechanisms do not involve mast cell activation, except for the possibility in the spectrum of systemic mastocytosis. […] However, in pathologic hyperactive mast cell conditions, such as systemic mastocytosis or inflammatory bowel disease, clinical symptoms of mast cell release could be triggered by food molecules -and other diverse stimuli too- in the absence of IgE-mediated mechanisms. […] Furthermore, recent studies show that after infectious gastroenteritis, mast cells in the murine gut can react to food given at the time of infection. […] There is indirect evidence through the measurement of mast cell mediators that GI mast cells can be activated by certain foods in patient with mastocytosis and MCAS.

• #45 Mast cell activation may explain many cases of chemical intolerance | Environmental Sciences Europe | Full Text

  https://enveurope.springeropen.com/articles/10.1186/s12302-021-00570-3

  Mast cell activation may explain many cases of chemical intolerance. […] We present data suggesting that xenobiotic activation of mast cells may underlie CI/TILT. […] The close correspondence between QEESI scores and symptom patterns for MCAS and TILT patients supports xenobiotic-driven mast cell activation and mediator release (i.e., MCAS) as a plausible unifying biological mechanism for CI/TILT, with profound implications for medicine, public health, and regulatory toxicology. […] We propose mast cell mediator release, initiated and triggered by xenobiotics, as a plausible biological mechanism underlying many, if not most, cases of CI and TILT. […] Our findings suggest that a vast assortment of chemical exposures may initiate or escalate TILT/CI via chronic, aberrant MC activation.

• #46 Mast cell activation may explain many cases of chemical intolerance | Environmental Sciences Europe | Full Text

  https://enveurope.springeropen.com/articles/10.1186/s12302-021-00570-3

  Mast cell activation may explain many cases of chemical intolerance. […] We present data suggesting that xenobiotic activation of mast cells may underlie CI/TILT. […] The close correspondence between QEESI scores and symptom patterns for MCAS and TILT patients supports xenobiotic-driven mast cell activation and mediator release (i.e., MCAS) as a plausible unifying biological mechanism for CI/TILT, with profound implications for medicine, public health, and regulatory toxicology. […] We propose mast cell mediator release, initiated and triggered by xenobiotics, as a plausible biological mechanism underlying many, if not most, cases of CI and TILT. […] Our findings suggest that a vast assortment of chemical exposures may initiate or escalate TILT/CI via chronic, aberrant MC activation.

• #47 Mast cell activation may explain many cases of chemical intolerance | Environmental Sciences Europe | Full Text

  https://enveurope.springeropen.com/articles/10.1186/s12302-021-00570-3

  Our proposal that MCAS could be the biological mechanism for TILT arises out of recent recognition that the spectrum of MC disease extends beyond clinically recognizable allergic phenomena (e.g., allergy, anaphylaxis, urticaria, angioedema, atopic dermatitis or eczema) and differs from the rare MC malignancy called mastocytosis. […] The symptoms and findings in TILT patients may be best understood in the context of MCs and the mediators they release. […] Thus, MCA can provoke nearby neurons, inducing their associated symptoms; similarly, neurons can provoke nearby MCs, inducing their associated symptoms. […] Our logistic regression model demonstrated that as the likelihood of patients having MCAS increases, their likelihood of having CI/TILT similarly increases, to a near-perfect correspondence at the high ends of these scales. […] The strikingly similar symptom and intolerance patterns for the MCAS and TILT populations suggest that xenobiotics can disrupt mast cells, resulting in either or both of these challenging conditions.

• #48

  https://www.scielo.br/j/spmj/a/7qTvTzbMkTNnkWYQyYzhQkL/?lang=en

  Several c-kit mutations have been reported in cases of systemic mastocytosis, although the most common one consists of substitution of valine for aspartate in codon 816 (Asp816Val), thus resulting in constitutive activation of the c-kit receptor. […] The diagnosis of SM is based on a set of diagnostic criteria, requiring the presence of one major criterion plus one minor criterion or a combination of three minor diagnostic criteria. […] In this case report, one major criterion [multifocal dense infiltrates of MCs in bone marrow or other extracutaneous organs (> 15 MCs aggregating)] and one minor criterion [MCs in bone marrow or other extracutaneous organs with an abnormal (spindling) morphology (> 25%)] were fulfilled. […] Once a diagnosis of SM has been made, patients are categorized further according to the presence of B and C findings, which assess disease burden and disease aggressiveness.

• #49 Systemic mastocytosis – a diagnostic challenge | Hematology, Transfusion and Cell Therapy

  http://www.htct.com.br/en-systemic-mastocytosis-diagnostic-challenge-articulo-resumen-S1516848414000048

  Mastocytosis refers to a group of disorders characterized by the infiltration of clonally derived mast cells to the skin or extracutaneous tissues resulting in a heterogeneous clinical picture. […] Its molecular pathogenesis is incompletely understood. […] The molecular pathogenesis is incompletely understood but it is believed that activating mutations in the c-KIT receptor or CD117, essential for normal development and expansion of mast cells from hematopoietic progenitors, leads to a clonal hyperproliferation of atypical mast cells. The Asp816Val mutation is the most common. […] The diagnosis is histopathological and should include a bone marrow evaluation because, in most cases, infiltration occurs. […] According to the WHO, diagnostic criteria for CM include skin lesions with compatible biopsy results, while for SM the presence of one major (multifocal clusters greater than 15 mast cells) and one minor criterion or three minor criteria (atypical morphology or spindle shapes in greater than 25% of the mast cells, c-KIT gene mutation, mast cells expressing the CD2 or CD25 surface markers or both, and increased serum tryptase levels greater than 20ng/mL) are required.

• #50 Systemic mastocytosis – a diagnostic challenge | Hematology, Transfusion and Cell Therapy

  http://www.htct.com.br/en-systemic-mastocytosis-diagnostic-challenge-articulo-resumen-S1516848414000048

  Mastocytosis refers to a group of disorders characterized by the infiltration of clonally derived mast cells to the skin or extracutaneous tissues resulting in a heterogeneous clinical picture. […] Its molecular pathogenesis is incompletely understood. […] The molecular pathogenesis is incompletely understood but it is believed that activating mutations in the c-KIT receptor or CD117, essential for normal development and expansion of mast cells from hematopoietic progenitors, leads to a clonal hyperproliferation of atypical mast cells. The Asp816Val mutation is the most common. […] The diagnosis is histopathological and should include a bone marrow evaluation because, in most cases, infiltration occurs. […] According to the WHO, diagnostic criteria for CM include skin lesions with compatible biopsy results, while for SM the presence of one major (multifocal clusters greater than 15 mast cells) and one minor criterion or three minor criteria (atypical morphology or spindle shapes in greater than 25% of the mast cells, c-KIT gene mutation, mast cells expressing the CD2 or CD25 surface markers or both, and increased serum tryptase levels greater than 20ng/mL) are required.

• #51

  https://www.scielo.br/j/spmj/a/7qTvTzbMkTNnkWYQyYzhQkL/?lang=en

  Several c-kit mutations have been reported in cases of systemic mastocytosis, although the most common one consists of substitution of valine for aspartate in codon 816 (Asp816Val), thus resulting in constitutive activation of the c-kit receptor. […] The diagnosis of SM is based on a set of diagnostic criteria, requiring the presence of one major criterion plus one minor criterion or a combination of three minor diagnostic criteria. […] In this case report, one major criterion [multifocal dense infiltrates of MCs in bone marrow or other extracutaneous organs (> 15 MCs aggregating)] and one minor criterion [MCs in bone marrow or other extracutaneous organs with an abnormal (spindling) morphology (> 25%)] were fulfilled. […] Once a diagnosis of SM has been made, patients are categorized further according to the presence of B and C findings, which assess disease burden and disease aggressiveness.

• #52 Systemic mastocytosis – a diagnostic challenge | Hematology, Transfusion and Cell Therapy

  http://www.htct.com.br/en-systemic-mastocytosis-diagnostic-challenge-articulo-resumen-S1516848414000048

  Mastocytosis refers to a group of disorders characterized by the infiltration of clonally derived mast cells to the skin or extracutaneous tissues resulting in a heterogeneous clinical picture. […] Its molecular pathogenesis is incompletely understood. […] The molecular pathogenesis is incompletely understood but it is believed that activating mutations in the c-KIT receptor or CD117, essential for normal development and expansion of mast cells from hematopoietic progenitors, leads to a clonal hyperproliferation of atypical mast cells. The Asp816Val mutation is the most common. […] The diagnosis is histopathological and should include a bone marrow evaluation because, in most cases, infiltration occurs. […] According to the WHO, diagnostic criteria for CM include skin lesions with compatible biopsy results, while for SM the presence of one major (multifocal clusters greater than 15 mast cells) and one minor criterion or three minor criteria (atypical morphology or spindle shapes in greater than 25% of the mast cells, c-KIT gene mutation, mast cells expressing the CD2 or CD25 surface markers or both, and increased serum tryptase levels greater than 20ng/mL) are required.

• #53

  https://www.scielo.br/j/spmj/a/7qTvTzbMkTNnkWYQyYzhQkL/?lang=en

  Several c-kit mutations have been reported in cases of systemic mastocytosis, although the most common one consists of substitution of valine for aspartate in codon 816 (Asp816Val), thus resulting in constitutive activation of the c-kit receptor. […] The diagnosis of SM is based on a set of diagnostic criteria, requiring the presence of one major criterion plus one minor criterion or a combination of three minor diagnostic criteria. […] In this case report, one major criterion [multifocal dense infiltrates of MCs in bone marrow or other extracutaneous organs (> 15 MCs aggregating)] and one minor criterion [MCs in bone marrow or other extracutaneous organs with an abnormal (spindling) morphology (> 25%)] were fulfilled. […] Once a diagnosis of SM has been made, patients are categorized further according to the presence of B and C findings, which assess disease burden and disease aggressiveness.

• #54 Systemic mastocytosis – a diagnostic challenge | Hematology, Transfusion and Cell Therapy

  http://www.htct.com.br/en-systemic-mastocytosis-diagnostic-challenge-articulo-resumen-S1516848414000048

  Mastocytosis refers to a group of disorders characterized by the infiltration of clonally derived mast cells to the skin or extracutaneous tissues resulting in a heterogeneous clinical picture. […] Its molecular pathogenesis is incompletely understood. […] The molecular pathogenesis is incompletely understood but it is believed that activating mutations in the c-KIT receptor or CD117, essential for normal development and expansion of mast cells from hematopoietic progenitors, leads to a clonal hyperproliferation of atypical mast cells. The Asp816Val mutation is the most common. […] The diagnosis is histopathological and should include a bone marrow evaluation because, in most cases, infiltration occurs. […] According to the WHO, diagnostic criteria for CM include skin lesions with compatible biopsy results, while for SM the presence of one major (multifocal clusters greater than 15 mast cells) and one minor criterion or three minor criteria (atypical morphology or spindle shapes in greater than 25% of the mast cells, c-KIT gene mutation, mast cells expressing the CD2 or CD25 surface markers or both, and increased serum tryptase levels greater than 20ng/mL) are required.

• #55 Diagnostic Workup for Advanced Forms of Mastocytosis – TMS – The Mast Cell Disease Society, IncAccessibilityIncrease TextDecrease TextGrayscaleHigh ContrastNegative ContrastLight BackgroundLinks UnderlineReadable FontReset

  https://tmsforacure.org/expert-information/diagnostic-workup-advanced-forms-mastocytosis/

  Mastocytosis denotes a heterogeneous group of disorders characterized by abnormal growth and accumulation of mast cells (MCs) that has a variable prognosis and course of disease. […] The major criterion is multifocal mast cell infiltration in the bone marrow (BM) or in an extracutaneous organ, as assessed by histology. […] To diagnose an advanced form of mastocytosis, the presence of B-findings, C-findings, or an AHN is of importance. […] It is of particular importance that organ damage caused by MC infiltration only counts as an SM-related C-finding. […] The most important molecular marker to show monoclonality in SM is the KIT point mutation D816V that can be analyzed in the bone marrow and the peripheral blood. […] In the majority of patients with SM, neoplastic MCs harbor this mutation. […] This suggests that additional genetic alterations, together with KIT D816V, result in neoplastic proliferation of MCs in advanced SM and thus are responsible for consecutive organ destruction by mast cell infiltration.

• #56 Mast Cell Activation Syndrome (MCAS)

  https://www.aaaai.org/conditions-treatments/related-conditions/mcas

  Mast cells can also be activated by other substances, such as medications, infections, insect or reptile venoms. […] Sometimes mast cells become defective and release mediators because of abnormal internal signals. Certain mutations in mast cells can produce populations of identical mast cells called clones that overproduce and spontaneously release mediators. […] These abnormal cells can grow uncontrollably and are unusually sensitive to activation in a condition called mastocytosis. […] The episodes are called idiopathic which means that the mechanism is unknown – that is, not caused by allergic antibody or secondary to other known conditions that activate normal mast cells. […] The improvement with treatment using inhibitors of mast cell mediators completes the diagnosis. […] The patients blood should be tested for mutation of mast cell growth receptor KIT, called KIT D816V. If positive, it indicates a clonal mast cell disorder. […] If the bone marrow biopsy is negative for abnormal and clonal mast cells, it establishes the diagnosis of idiopathic mast cell activation syndrome.

• #57

  https://www.scielo.br/j/spmj/a/7qTvTzbMkTNnkWYQyYzhQkL/?lang=en

  Several c-kit mutations have been reported in cases of systemic mastocytosis, although the most common one consists of substitution of valine for aspartate in codon 816 (Asp816Val), thus resulting in constitutive activation of the c-kit receptor. […] The diagnosis of SM is based on a set of diagnostic criteria, requiring the presence of one major criterion plus one minor criterion or a combination of three minor diagnostic criteria. […] In this case report, one major criterion [multifocal dense infiltrates of MCs in bone marrow or other extracutaneous organs (> 15 MCs aggregating)] and one minor criterion [MCs in bone marrow or other extracutaneous organs with an abnormal (spindling) morphology (> 25%)] were fulfilled. […] Once a diagnosis of SM has been made, patients are categorized further according to the presence of B and C findings, which assess disease burden and disease aggressiveness.

• #58 Systemic mastocytosis – a diagnostic challenge | Hematology, Transfusion and Cell Therapy

  http://www.htct.com.br/en-systemic-mastocytosis-diagnostic-challenge-articulo-resumen-S1516848414000048

  After establishing the diagnosis it is necessary to define the disease category and the presence of B findings, corresponding to organ enlargement without organ dysfunction, or C findings that denote organ function impairment due to excessive mast cell infiltration; this latter is associated to a poorer prognosis. […] Currently, there are no curative therapies for SM and treatment is intended to reduce symptoms and improve quality of life. […] The prognosis of aggressive SM is variable, with some patients experiencing a rapidly declining course over one to two years, while others follow a slower course with several years of survival.

• #59

  https://www.scielo.br/j/spmj/a/7qTvTzbMkTNnkWYQyYzhQkL/?lang=en

  Several c-kit mutations have been reported in cases of systemic mastocytosis, although the most common one consists of substitution of valine for aspartate in codon 816 (Asp816Val), thus resulting in constitutive activation of the c-kit receptor. […] The diagnosis of SM is based on a set of diagnostic criteria, requiring the presence of one major criterion plus one minor criterion or a combination of three minor diagnostic criteria. […] In this case report, one major criterion [multifocal dense infiltrates of MCs in bone marrow or other extracutaneous organs (> 15 MCs aggregating)] and one minor criterion [MCs in bone marrow or other extracutaneous organs with an abnormal (spindling) morphology (> 25%)] were fulfilled. […] Once a diagnosis of SM has been made, patients are categorized further according to the presence of B and C findings, which assess disease burden and disease aggressiveness.

• #60 Systemic mastocytosis – a diagnostic challenge | Hematology, Transfusion and Cell Therapy

  http://www.htct.com.br/en-systemic-mastocytosis-diagnostic-challenge-articulo-resumen-S1516848414000048

  After establishing the diagnosis it is necessary to define the disease category and the presence of B findings, corresponding to organ enlargement without organ dysfunction, or C findings that denote organ function impairment due to excessive mast cell infiltration; this latter is associated to a poorer prognosis. […] Currently, there are no curative therapies for SM and treatment is intended to reduce symptoms and improve quality of life. […] The prognosis of aggressive SM is variable, with some patients experiencing a rapidly declining course over one to two years, while others follow a slower course with several years of survival.

• #61 Diagnostic Workup for Advanced Forms of Mastocytosis – TMS – The Mast Cell Disease Society, IncAccessibilityIncrease TextDecrease TextGrayscaleHigh ContrastNegative ContrastLight BackgroundLinks UnderlineReadable FontReset

  https://tmsforacure.org/expert-information/diagnostic-workup-advanced-forms-mastocytosis/

  Mastocytosis denotes a heterogeneous group of disorders characterized by abnormal growth and accumulation of mast cells (MCs) that has a variable prognosis and course of disease. […] The major criterion is multifocal mast cell infiltration in the bone marrow (BM) or in an extracutaneous organ, as assessed by histology. […] To diagnose an advanced form of mastocytosis, the presence of B-findings, C-findings, or an AHN is of importance. […] It is of particular importance that organ damage caused by MC infiltration only counts as an SM-related C-finding. […] The most important molecular marker to show monoclonality in SM is the KIT point mutation D816V that can be analyzed in the bone marrow and the peripheral blood. […] In the majority of patients with SM, neoplastic MCs harbor this mutation. […] This suggests that additional genetic alterations, together with KIT D816V, result in neoplastic proliferation of MCs in advanced SM and thus are responsible for consecutive organ destruction by mast cell infiltration.

• #62 Systemic mastocytosis – a diagnostic challenge | Hematology, Transfusion and Cell Therapy

  http://www.htct.com.br/en-systemic-mastocytosis-diagnostic-challenge-articulo-resumen-S1516848414000048

  After establishing the diagnosis it is necessary to define the disease category and the presence of B findings, corresponding to organ enlargement without organ dysfunction, or C findings that denote organ function impairment due to excessive mast cell infiltration; this latter is associated to a poorer prognosis. […] Currently, there are no curative therapies for SM and treatment is intended to reduce symptoms and improve quality of life. […] The prognosis of aggressive SM is variable, with some patients experiencing a rapidly declining course over one to two years, while others follow a slower course with several years of survival.

• #63 Systemic Mastocytosis: Classification, Pathogenesis, Diagnosis, and Treatment | MDedge

  https://www.mdedge.com/cutis/article/67785/systemic-mastocytosis-classification-pathogenesis-diagnosis-and-treatment

  Mastocytosis is a heterogeneous entity that may present as either a cutaneous or systemic disease. […] A gain-of-function mutation in codon 816 of c-kit is frequently present in mast cells of patients with systemic mastocytosis (SM). […] Mast cell proliferation and differentiation from stem cell precursors depend on a number of factors, including a mast cell tyrosine kinase receptor (kit) and its ligand (the stromal cell–derived cytokine stem cell factor). […] The treatment is directed toward avoidance of triggers of mast cell mediator release and management of symptoms. […] Research has been directed at more specific treatment modalities, including specific kit tyrosine kinase inhibitors.

• #64 Systemic Mastocytosis: Classification, Pathogenesis, Diagnosis, and Treatment | MDedge

  https://www.mdedge.com/cutis/article/67785/systemic-mastocytosis-classification-pathogenesis-diagnosis-and-treatment

  Mastocytosis is a heterogeneous entity that may present as either a cutaneous or systemic disease. […] A gain-of-function mutation in codon 816 of c-kit is frequently present in mast cells of patients with systemic mastocytosis (SM). […] Mast cell proliferation and differentiation from stem cell precursors depend on a number of factors, including a mast cell tyrosine kinase receptor (kit) and its ligand (the stromal cell–derived cytokine stem cell factor). […] The treatment is directed toward avoidance of triggers of mast cell mediator release and management of symptoms. […] Research has been directed at more specific treatment modalities, including specific kit tyrosine kinase inhibitors.

• #65 Pathogenesis and Pathology of Mastocytosis | CoLab

  https://colab.ws/articles/10.1146%2Fannurev-pathol-052016-100312

  Systemic mastocytosis is a clonal disorder of mast cells that may variably present with characteristic skin lesions, episodes of mast cell mediator release, and disturbances of hematopoiesis. […] Recent advances in the molecular understanding of the pathophysiology of systemic mastocytosis have provided new therapeutic considerations, including new and novel tyrosine kinase inhibitors.

• #66 Indolent Systemic Mastocytosis – AB Science

  https://www.ab-science.com/pipeline/masitinib-overview/indolent-systemic-mastocytosis/

  Mastocytosis is a rare disease characterized by proliferation and accumulation of mast cells in various tissues, causing a wide variety of clinical symptoms. […] Masitinibs anti-mast cell properties appear particularly well-adapted to the treatment of indolent systemic mastocytosis. A reduction of mast cell activity is generated via its inhibitory action on wild-type c-Kit, Lyn and Fyn tyrosine kinases. […] Masitinib also demonstrated significant activity on objective markers of mast cell activation and burden (i.e. level of tryptase, body surface area with urticaria pigmentosa, and presence of Dariers sign).

• #67 Leukemia and Other Blood Cancers: Systemic Mastocytosis | Memorial Sloan Kettering Cancer Center

  https://www.mskcc.org/cancer-care/types/leukemias/types/systemic-mastocytosis

  Mastocytosis happens when too many mast cells build up in the body. […] In systemic mastocytosis, however, there are too many mast cells throughout the body, including in the gastrointestinal tract and the bone marrow. […] A targeted drug called midostaurin (Rydapt) is approved to treat more-aggressive cases of systemic mastocytosis. […] Our scientists are researching new drugs for people with systemic mastocytosis that carries certain mutations.

• #68 Mastocytosis: Types, Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/5908-mastocytosis

  Mastocytosis happens when mast cells that protect your body from allergens and bacteria mutate (change) and become abnormal cells that set up a continuous allergic response. […] Mastocytosis is an acquired genetic disorder, meaning you dont inherit the condition. It happens when KIT genes mutate (change). KIT genes play a role in developing certain cell types, including blood cells and mast cells. In mastocytosis, mutated KIT genes order mast cells to multiply uncontrollably. […] Mastocytosis is considered an incurable disease that healthcare providers manage with treatments to ease symptoms and treat complications. […] The only potential cure for mastocytosis is an allogeneic stem cell (bone marrow) transplantation. Providers may recommend stem cell transplantation for people who have very aggressive or advanced mastocytosis.

• #69 New Insights into the Pathogenesis of Systemic Mastocytosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8125314/

  The identification of early cooperating events for KIT mutations may improve our understanding of the pathogenesis of SM, leading to more efficient treatments and improved outcomes for SM patients. […] Moreover, TRK signaling has been suggested to be involved in other hematological malignancies, such as multiple myeloma. […] Taken together, we provided the first direct evidence to support SM development induced by the activation of TRKA or TRKB in HSC and progenitor cells in vivo. […] Our data strongly supported the findings described by Peng et al. and their hypothesis, suggesting that TRKs have an important role in mastocytosis pathogenesis and the development of resistance to KIT inhibition. […] Identifying these genetic and epigenetic alterations and understanding their interactions and the molecular mechanisms involved in mastocytosis is of the utmost importance for developing rationally targeted therapies.

• #70 New Insights into the Pathogenesis of Systemic Mastocytosis

  https://www.mdpi.com/1422-0067/22/9/4900

  Our data strongly supported the findings described by Peng et al. and their hypothesis, suggesting that TRKs have an important role in mastocytosis pathogenesis and the development of resistance to KIT inhibition. […] Collectively, these data suggested that TRKA signaling may improve neoplastic MC fitness, which would explain, at least in part, why the results of treatment with KIT inhibitors alone in SM patients have been disappointing in most studies. […] Identifying these genetic and epigenetic alterations and understanding their interactions and the molecular mechanisms involved in mastocytosis is of the utmost importance for developing rationally targeted therapies.

• #71 IJMS | Special Issue : Pathogenesis and Management of Mastocytosis

  https://www.mdpi.com/journal/ijms/special_issues/Mastocytosis

  Mastocytosis is a type of myeloid neoplasm that is characterized by the clonal, neoplastic proliferation of morphologically and immunophenotypically abnormal mast cells in one or more organ systems. […] The molecular mechanisms that underlie the development of mastocytosis are not well understood. The KIT D816V mutation can be found in over 80% of patients with SM. However, the KIT D816V mutation is a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. […] Gaining a better understanding of the mechanisms underlying the development of SM may yield improved molecular therapies for its treatment.

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