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Bidirectional interactions between eosinophils and mast cells (MCs) have been reported in various allergic diseases. Bone marrow (BM) eosinophilia, and to a lesser extent blood eosinophilia, is common in systemic mastocytosis (SM), but its significance remains unknown. We described blood and BM eosinophil characteristics in SM. A large collection of BM biopsy samples was analyzed using immunohistochemical staining and whole-slide imaging. Eosinophil and extracellular granules were detected by eosinophil peroxidase (EPX) staining and MCs by KIT staining. Complementary analyses were conducted using flow cytometry and immunofluorescence. Eosinophil infiltrates and large areas of eosinophil degranulation were observed within or around BM MC infiltrates in SM. EPX staining surface, highlighting intact eosinophils and eosinophil degranulation, was higher in nonadvanced SM (n = 37 BM biopsy samples) compared with both controls (n = 8, P =.0003) and advanced SM (n = 24, P =.014). In nonadvanced SM, positive correlations were observed between serum tryptase levels and percentages of eosinophil counts in BM aspirations (Spearman r coefficient r = 0.38, P =.038), eosinophils count in BM biopsy samples (r = 0.45, P =.007), EPX staining (r = 0.37, P =.035), and eosinophil degranulation (r = 0.39, P =.023). Eosinophil counts in BM biopsy samples also correlated with MC counts (r = 0.47, P =.006) and KIT staining surface (r = 0.49, P =.003). BM MCs expressed IL-5 receptor and other usual eosinophil cytokine/chemokine receptors, and blood eosinophils displayed several increased surface markers compared with controls, suggesting an activated state. Our data suggest possible cross talk between MCs and eosinophils, supporting MC tryptase release and MC activation-related symptoms. This suggests a rationale for targeting eosinophils in nonadvanced SM not fully controlled by other therapies. [ABSTRACT FROM AUTHOR]

Mast cell sarcoma (MCS) is an extremely rare and aggressive form of mastocytosis characterized by highly atypical mast cells with local invasion, metastatic potential, and poor prognosis. MCS is predominantly a de novo process without recurrent molecular findings or predisposing lesions including various myeloid neoplasms. However, there have been rare case reports of MCS with preceding or concurrent systemic mastocytosis (SM) or cutaneous mastocytosis (CM), which is suggestive of an uncommon progression from SM/CM to MCS. We hereby report a case of MCS in an 84-year-old male with a KIT p.D816V mutation and concurrent SM. KIT p.D816V point mutation is well known as the canonical variant in SM. In our case, MCS with KIT p.D816V mutation is a unique finding in the setting of concurrent SM, highlighting the potential relatedness of these two entities and the progression from SM to MCS, a currently poorly understood phenomenon. [ABSTRACT FROM AUTHOR]

Systemic mastocytosis (SM) is a rare hematologic disorder characterized by clonal proliferation of mast cells in the bone marrow and/or other organs. SM‐associated hematologic neoplasm (SM‐AHN) is one of the advanced SM variants that usually confer a poor prognosis. We present a case of a 75‐year‐old female patient with SM‐AHN, specifically myelodysplastic syndrome (MDS), that harbored a unique KIT mutation KIT V560D, not previously described in the literature in this setting. We describe the clinical course and the outcome with the use of avapritinib, midostaurin, and decitabine‐cedazuridine. Trial Registration: ClinicalTrials.gov identifier: NCT00782067 [ABSTRACT FROM AUTHOR]

Background: Mastocytosis (MS) is a rare disease that can involve various organs, including the bone. Given the incidence of the disease in the global population, MS poses a challenge for physicians, and early therapeutic intervention in the initial stages could significantly impact the quality of life of affected patients. Objective: The aim of this scoping review was to provide an overview of secondary osteoporosis in systemic mastocytosis (SM), focusing on the heterogeneity of its manifestations, the benefits of early diagnosis, and appropriate pharmacological treatment. Design: A technical expert panel (TEP) consisting of 8 physicians with expertise in metabolic bone diseases conducted the review following the PRISMA-ScR model. A strength of this study is that it provides various therapeutic approaches for patients with bone involvement in SM, although the limited available literature on the topic constituted a limitation. The TEP sought evidence regarding the following diagnostic and therapeutic modalities in the management of SM: "bisphosphonate therapy", "zoledronic acid therapy", "denosumab therapy", "IFN-alpha therapy", and "IFN-alpha therapy in combination with pamidronate". Results: Clinical data showed a correlation between densitometric outcomes, serum tryptase levels, and mast cell infiltration in the bone marrow, between increased bone mineral density and the presence of osteosclerosis in cases of advanced SM, between the severity of osteoporosis and hypertryptasemia, and also provided results on the long-term effects of bisphosphonate therapy, the therapeutic efficacy of zoledronic acid administration, the positive effect of denosumab on the reduction of serum tryptase levels (even if is proved in a limited numbers of cases) and the prevention of new fractures, and the effect of IFN-alpha in more severe cases of SM, either alone or in combination with pamidronate. Conclusions: Studies have demonstrated the effectiveness of various treatments depending on the form of mastocytosis, whether indolent systemic or advanced systemic, in the prognosis of the disease. However, this role should be further investigated in additional clinical studies, considering the limited data on the use of these interventions. [ABSTRACT FROM AUTHOR]

More than 90% of patients affected by mastocytosis are characterized by a somatic point mutation of KIT, which induces ligand-independent activation of the receptor and downstream signal triggering, ultimately leading to mast cell accumulation and survival. The most frequent mutation is KIT p.D816V, but other rarer mutations can also be found. These mutations often have a very low variant allele frequency (VAF), well below the sensitivity of common next-generation sequencing (NGS) methods used in routine diagnostic panels. Highly sensitive methods are developing for detecting mutations. This review summarizes the current indications on the recommended methods and on how to manage and interpret molecular data for the diagnosis and follow-up of patients with mastocytosis. [ABSTRACT FROM AUTHOR]

We describe the case of a 72-year-old male with a history of systemic mastocytosis scheduled for on-pump aortic valve replacement for severe aortic insufficiency. Anesthesia and peri-operative management included avoidance of histamine-releasing drugs, methylprednisolone and clemastin prophylaxis. Furthermore, a CytoSorb® cartridge has been added to the bypass circuit and hemoadsorption was performed throughout the entire cardiopulmonary bypass (CPB) duration. CytoSorb® is a hemoadsorption device designed to remove various cytokines and drugs from the blood. The use of CytoSorb® during CPB in our case was not associated with adverse events, and the patient did not present any allergic or anaphylactic reaction. [ABSTRACT FROM AUTHOR]

Objectives Systemic mastocytosis (SM) is a neoplasm of mast cells (MCs) characterized by their proliferation in extracutaneous organs. Systemic mastocytosis includes several entities with different clinical courses and prognoses. The rarity of this disease and the diversity of clinical and morphologic presentation make the diagnosis of SM very challenging. The aim of this review is to share our approach to the diagnosis of SM. Methods We present 4 cases that highlight the spectrum of clinical and laboratory features of SM and outline the diagnostic process with an emphasis on morphology. Results Pathology and laboratory medicine play a key role in investigation of SM, as correct diagnosis requires integration of morphologic, molecular, and serologic findings. In addition to awareness of microscopic findings in SM, a pathologist must keep abreast with an expanding menu of ancillary studies, particularly molecular testing. Conclusions Systemic mastocytosis is a challenging diagnosis that requires not only a demonstration of a clonal proliferation of MCs but also a correct subclassification based on the recently updated criteria. [ABSTRACT FROM AUTHOR]

We describe the case of a 72-year-old male with a history of systemic mastocytosis scheduled for on-pump aortic valve replacement for severe aortic insufficiency. Anesthesia and peri-operative management included avoidance of histamine-releasing drugs, methylprednisolone and clemastin prophylaxis. Furthermore, a CytoSorb® cartridge has been added to the bypass circuit and hemoadsorption was performed throughout the entire cardiopulmonary bypass (CPB) duration. CytoSorb® is a hemoadsorption device designed to remove various cytokines and drugs from the blood. The use of CytoSorb® during CPB in our case was not associated with adverse events, and the patient did not present any allergic or anaphylactic reaction.

Myeloid neoplasms include myeloproliferative and myelodysplastic neoplasms and acute myeloid leukaemia. Historically, these diseases have been diagnosed based on clinicopathological features with sometimes arbitrary thresholds that have persisted even as molecular features were gradually incorporated into their classification. As such, although current diagnostic approaches can classify the majority of myeloid neoplasms accurately using a combination of molecular and clinicopathological features, some areas of overlap persist and occasionally pose diagnostic challenges. These include overlap across BCR::ABL1‐negative myeloproliferative neoplasms; between clonal cytopenia of undetermined significance and myelodysplastic neoplasms; myelodysplastic/myeloproliferative neoplasms; and, detection of KIT mutations in myeloid neoplasms other than mastocytosis, raising the prospect of systemic mastocytosis. Molecular testing has become state of the art in the diagnostic work‐up of myeloid neoplasms, and molecular patterns can inherently help to classify overlapping entities if considered within a framework of haematological presentations. For future development, molecular testing will likely include whole genome and transcriptome sequencing, and primarily molecular classifications of myeloid neoplasms have already been suggested. As such, genetically defined groups should still constitute the basis for our understanding of disease development from early onset to progression, while clinicopathological features could then be used to describe the stage of the disease rather than the specific type of myeloid neoplasm. [ABSTRACT FROM AUTHOR]

Douglas Tremblay,1 Nicole E Wagner,2 John Mascarenhas1 1Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 2Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USACorrespondence: John Mascarenhas, Myeloproliferative Disorders Program, Tisch Cancer Institute, Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1079, New York, NY, 10029, USA, Tel +1 212 241 3417, Fax +12128765276, Email john.mascarenhas@mssm.eduAbstract: Advanced systemic mastocytosis (AdvSM) is a rare hematologic malignancy with organ damage and compromised life expectancy arising from organ accumulation of neoplastic mast cells. Identification of the gain-of-function KITD816V in the majority of cases has accelerated pharmaceutical development culminating with the development of selective KIT inhibitors such as avapritinib. While the advent of these therapies has improved the quality and quantity of life in patients with AdvSM, current challenges remain in the management of this disease. In this review, we summarize the present and future therapeutics landscape of AdvSM, highlighting the development of novel KIT inhibitors including elenestinib and bezuclastinib. We also explore the continued role of additional treatment modalities including allogeneic stem cell transplantation before discussing unresolved clinical challenges in the management of AdvSM.Keywords: systemic mastocytosis, KITD816V, avapritinib, midostaurin

Mastocytosis is a rare disorder due to the abnormal proliferation of clonal mast cells. Mast cells exist in most tissues, mature in situ from hematopoietic stem cells and develop unique characteristics of local effector cells. It manifests as two main categories: cutaneous mastocytosis and systemic mastocytosis (SM). Patients presenting with SM-acute myeloid leukaemia (AML) often have the worst outcome. Here we present a patient with the simultaneous diagnosis of SM associated with t (8;21) (q22;q22) acute myeloid leukaemia,M2 subtype in theFrench-American-British (FAB) classification, carrying a population ofimmature mast cell precursors. Initially, she was diagnosed with AML with t (8;21) (q22;q22) and was started on induction chemotherapy. Subsequent trephine biopsy evaluation post-induction chemotherapy showed no increase in blast cells. However, abnormal mast cells were seen distributed throughout the marrow spaces, which expressed mast cell tryptase, CD117 and CD68. She was then diagnosed as SM associated with t(8;21) (q22;q22) AML. Unfortunately, she succumbed to death due to severe neutropenic sepsis postinduction chemotherapy. By sharing the knowledge, hopefully it will help the clinicians as the diagnosis of SM is difficult to establish because the associated malignancy may obscure the morphological features of SM. However, a reduction in blast cell percentage at the time of a post-induction marrow evaluation helps in diagnosis. [ABSTRACT FROM AUTHOR]

Background: Systemic mastocytosis (SM) is a heterogeneous disease characterized by an expansion of KIT‐mutated mast cells (MC). KIT‐mutated MC display activated features and release MC mediators that might act on the tumour microenvironment and other immune cells. Here, we investigated the distribution of lymphocyte subsets in blood of patients with distinct subtypes of SM and determined its association with other disease features. Methods: We studied the distribution of TCD4+ and TCD4− cytotoxic cells and their subsets, as well as total NK‐ and B cells, in blood of 115 SM patients—38 bone marrow mastocytosis (BMM), 67 indolent SM (ISM), 10 aggressive SM (ASM)‐ and 83 age‐matched healthy donors (HD), using spectral flow cytometry and the EuroFlow Immunomonitoring panel, and correlated it with multilineage KITD816V, the alpha‐tryptasemia genotype (HαT) and the clinical manifestations of the disease. Results: SM patients showed decreased counts (vs. HD) of TCD4− cytotoxic cells, NK cells and several functional subsets of TCD4+ cells (total Th1, Th2‐effector memory, Th22‐terminal effector and Th1‐like Tregs), together with increased T‐follicular‐helper and Th1/Th17‐like Treg counts, associated with different immune profiles per diagnostic subtype of SM, in multilineal versus MC‐restricted KITD816V and in cases with a HαT+ versus HαT− genotype. Unique immune profiles were found among BMM and ISM patients with MC‐restricted KITD816V who displayed HαT, anaphylaxis, hymenoptera venom allergy, bone disease, pruritus, flushing and GI symptoms. Conclusion: Our results reveal altered T‐ and NK‐cell immune profiles in blood of SM, which vary per disease subtype, the pattern of involvement of haematopoiesis by KITD816V, the HαT genotype and specific clinical manifestations of the disease. [ABSTRACT FROM AUTHOR]

Anaphylaxis can induce life-threatening coagulopathy by releasing various mediators from activated mast cells. These mediators directly affect coagulation and fibrinolytic pathways, increasing the bleeding risk. Diagnosis and management of anaphylaxis-induced coagulopathy remain challenging. We report a unique case of a 44-year-old man with undiagnosed systemic mastocytosis who developed peanut-induced anaphylactic shock, resulting in cardiac arrest. Laboratory tests revealed elevated serum tryptase and severe coagulopathy. Thromboelastography, a point-of-care viscoelastic monitoring (VEM) test identified the presence of heparin-like anticoagulants within minutes. Bone marrow examination subsequently confirmed isolated mastocytosis. This case highlights the potential of VEM for rapid diagnosis and management of coagulopathy in patients with anaphylaxis, potentially aiding in the identification of mast cell degranulation in undifferentiated shock. We suggest that VEM should be considered in the investigation of patients with suspected anaphylaxis-induced coagulopathy.

Background: Mastocytosis (MS) is a rare disease that can involve various organs, including the bone. Given the incidence of the disease in the global population, MS poses a challenge for physicians, and early therapeutic intervention in the initial stages could significantly impact the quality of life of affected patients. Objective: The aim of this scoping review was to provide an overview of secondary osteoporosis in systemic mastocytosis (SM), focusing on the heterogeneity of its manifestations, the benefits of early diagnosis, and appropriate pharmacological treatment. Design: A technical expert panel (TEP) consisting of 8 physicians with expertise in metabolic bone diseases conducted the review following the PRISMA-ScR model. A strength of this study is that it provides various therapeutic approaches for patients with bone involvement in SM, although the limited available literature on the topic constituted a limitation. The TEP sought evidence regarding the following diagnostic and therapeutic modalities in the management of SM: “bisphosphonate therapy”, “zoledronic acid therapy”, “denosumab therapy”, “IFN-alpha therapy”, and “IFN-alpha therapy in combination with pamidronate”. Results: Clinical data showed a correlation between densitometric outcomes, serum tryptase levels, and mast cell infiltration in the bone marrow, between increased bone mineral density and the presence of osteosclerosis in cases of advanced SM, between the severity of osteoporosis and hypertryptasemia, and also provided results on the long-term effects of bisphosphonate therapy, the therapeutic efficacy of zoledronic acid administration, the positive effect of denosumab on the reduction of serum tryptase levels (even if is proved in a limited numbers of cases) and the prevention of new fractures, and the effect of IFN-alpha in more severe cases of SM, either alone or in combination with pamidronate. Conclusions: Studies have demonstrated the effectiveness of various treatments depending on the form of mastocytosis, whether indolent systemic or advanced systemic, in the prognosis of the disease. However, this role should be further investigated in additional clinical studies, considering the limited data on the use of these interventions.

Relapse acute leukemia is defined as the reappearance of more than 5% blast in the bone marrow. In most instances, blast expresses the specific lineage (myeloid or lymphoid), similar to a diagnosis. However, it rarely converts to a different lineage, either myeloid shifting to lymphoid or vice versa, during relapse. Thus, it is labelled as switching lineage acute leukemia, after excluding the criteria for mixed phenotypic acute leukemia, which can be a challenge to diagnose. We describe a 24-year-old gentleman with a known case of acute myeloid leukemia associated with systemic mastocytosis (SM); eight months later and after two complete cycles of chemotherapy, relapse occurred with a switched lineage to B-acute lymphoblastic leukemia. The laboratory investigation approaches and the challenges in the diagnosis are also discussed in this case report. [ABSTRACT FROM AUTHOR]

Background. Mastocytosis is a heterogeneous group of diseases that are characterized by excessive proliferation and accumulation of clonal (neoplastic) mast cells in one or more organs. Advanced variants of systemic mastocytosis (aggressive systemic mastocytosis, systemic mastocytosis associated with hematological neoplasm, and mast cell leukemia) are characterized by infiltration of organs by mast cells, which leads to organs dysfunction. Such patients require a more active approach and the use of cytoreductive therapy. Available therapeutic options include imatinib, interferon-alpha, cladribine. Only one of the targeted drugs is registered in Russia – midostaurin. Midostaurin is a potent multikinase inhibitor that is active against KIT regardless of mutation status. Midostaurin has shown its effectiveness in clinical trials, however, we know that data from real clinical practice often differ from clinical studies due to the characteristics of patients (preserved comorbid status, stable disease parameters) traditionally included in clinical trials.Aim. To evaluate the effectiveness and safety of midostaurin in patients with advanced variants of systemic mastocytosis in real clinical practice.Materials and methods. This work analyzed 13 patients (7 (54 %) men and 6 (46 %) women) who received midostaurin therapy for systemic mastocytosis (aggressive systemic mastocytosis – 9 (69 %), systemic mastocytosis associated with a hematological neoplasm – 4 (31 %)). The median age of patients when the diagnosis was verified was 73 (61–87) years, the median age when midostaurin was prescribed was 74 (61–88) years. According to the International prognostic scoring system for mastocytosis (IPSM) based on clinical variables, patients are classified as follows groups: SM1 – 1 (8 %) patient, SM2 – 3 (23 %), SM3 – 8 (61 %), SM4 – 1 (8 %).Results. As a result of therapy, clinical improvement was achieved in 10 (77 %) patients, and stabilization in 3 (23 %) patients. During midostaurin therapy, grade I–II adverse events were noted from the gastrointestinal tract: nausea in 5 patients (38 %), vomiting in 2 (15 %), diarrhea in 6 (46 %). Hematological toxicity of grade I–II was also observed: anemia in 6 (46 %) patients, thrombocytopenia in 5 (38 %) patients. The median overall survival in the group was not achieved. The 2-year overall survival rate was 75 %.Conclusion. The study results suggest the potential efficacy and safety of midostaurin in patients with aggressive systemic mastocytosis and systemic mastocytosis associated with hematological malignancies.

Mast Cell Activation Syndrome (MCAS) is a severe relapsing disease requiring inpatient treatment, with clinical pattern including the features of anaphylaxis. The article presents diagnostic criteria aimed for differentiation of MCAS from similar severe conditions as well as discusses local forms of mast cell activation. The consensus group has established distinct criteria for diagnosing MCAS. The agreed criteria include episodic (recurrent) occurrence of typical systemic symptoms caused by release of mast cell mediators and involve, at least, two organs; an increase in serum tryptase level by, at least, 20% over individual baseline tryptase plus 2 ng/mL tryptase during 3-4 hours of the pathological reaction; a positive response to drugs that either target mast cells mediators, or their effects. In principle, the classification of MCAS is based on its etiology being subdivided into primary (clonal) MCAS, secondary MCAS, and idiopathic MCAS. The primary MCAS is determined by clonal expansion of mast cells and is considered systemic mastocytosis. In secondary MCAS, normal mast cells are activated by the known triggers, e.g., IgE. If neither clonal expansion nor a trigger for mast cells activation are identified, the condition is defined as idiopathic MCAS.The new COVID-19 infection has attracted particular interest in MCAS, since the severe course of COVID-19 was thought to develop due to latent MCAS, but the criteria for MCAS in these patients were not reproduced. In the presence of local symptoms, such as urticaria, or in cases of single-organ involvement, e.g., isolated gastrointestinal symptoms, and suspected mast cell activation being basic to pathogenesis, the term mast cell activation disorder was introduced. Moreover, the article discusses several different mediators that are proposed as markers in the diagnosis of MCAS.However, over-diagnosis of MCAS entails the risk of missing the underlying pathology, which is not associated with MCAS, and requires differential diagnosis with a number of diseases. In the absence of severe attacks (with hypotension and shock), the likelihood of MCAS is generally very low. Of course, the patients with mastocytosis and/or confirmed IgE-dependent allergy are at higher risk of developing MCAS, but a key diagnostic marker is an event-related increase in mast cells tryptase from baseline determined over the asymptomatic period. The diagnosis of MCAS is highly likely if the tryptase level rises above a certain threshold (20% of baseline plus 2 ng/mL).

Key Clinical Message Low dose Avapritinib is a new medication that is a potential treatment option not just for advanced systemic mastocytosis, but also for the indolent form.

Background: Systemic mastocytosis (SM) is a clonal disorder of mast cells in which the KIT Asp816Val mutation can be detected not only in mature mast cells but also in the hematopoietic stem cell and in non–mast cell lineages. Current treatment with tyrosine kinase inhibitors provides improved clinical responses in patients with advanced mastocytosis but no cures. Targeting of cancer stem cells (CSCs) resistant to chemotherapy and radiation therapy potentially could improve clinical outcomes in mastocytosis. In recent years, nonchemotherapeutic medications such as metformin have been repurposed for this role because of their ability to destroy CSCs from both solid tumors and leukemias and also because of their ability to act as chemosensitizers. Objective: We sought to determine whether those patients with both type 2 diabetes mellitus (DM2) and SM who were receiving metformin, which has been reported to inhibit CSCs, experienced clinical or laboratory benefit to their SM from this agent. Methods: Mayo Clinic databases were searched for patients with diagnoses of DM plus SM. The clinical courses of mastocytosis for patients with DM2 were compared among patients treated with metformin or by other means. Effects of metformin on human mast cell (HMC) leukemia line (HMC-1.1 and HMC-1.2) cell proliferation were tested in vitro. Results: No patient treated with metformin before SM was diagnosed developed advanced forms of disease. A lower percentage of these patients had splenomegaly compared with other groups not treated with metformin, and none of these patients developed Janus kinase 2, tet methylcytosine dioxygenase 2, or serine and arginine–rich splicing factor 2 mutations. In vitro results showed that metformin inhibited the proliferation of both cell lines; HMC-1.1 cells were more sensitive to metformin. Conclusions: These preliminary findings suggest that early use of metformin to target CSCs has the possibility to complement current treatments available for SM.

Key Clinical Message: Additional investigations for systemic involvement should be initiated once the diagnosis of cutaneous mastocytosis has been established in an adult patient. A serum tryptase can serve as a screening test for systemic mastocytosis, and persistent elevations should prompt further investigations, such as bone marrow studies. Urticaria pigmentosa (UP) is the most common form of cutaneous mastocytosis, presenting as a wide variety of macroscopic appearances. Cutaneous mastocytosis in pediatric patients usually does not present with systemic involvement, but more than half of adult patients with cutaneous mastocytosis demonstrate systemic involvement. Currently, there is no guidance surrounding systemic testing in patients with UP. A 50‐year‐old Caucasian male was referred to the Clinical Immunology and Allergy clinic with a history of a rash. He initially presented to hospital 12 years prior with group A beta hemolytic streptococcus bacteremia treated with multiple different antibiotics. One week following discharge, he developed erythematous brown spots on his right leg which were flat, non‐pruritic, and not painful. The rash later expanded to his trunk and extremities. A skin biopsy performed 2 years prior to referral to our clinic demonstrated urticaria pigmentosa. The CD117 immunohistochemical stain showed increased perivascular and interstitial mast cells in the superficial dermis. Darier's sign was negative on physical examination, and venom testing was also negative. Although he had no symptoms of systemic involvement, his serum tryptase was elevated at 47.6 ng/mL in the context of normal kidney and liver function. A skeletal survey was normal, and an abdominal ultrasound ruled out splenomegaly. Bone marrow biopsy demonstrated a mild increase in paratrabecular and perivascular atypical mast cells, in keeping with systemic mastocytosis. Adult patients with cutaneous mastocytosis have a high likelihood of having an underlying systemic mast cell disorder. Therefore, any patient presenting with characteristic skin findings should be investigated as having a cutaneous manifestation of systemic mastocytosis. This case demonstrates the utility of serum tryptase and its role in triggering additional investigations and guiding appropriate therapy. [ABSTRACT FROM AUTHOR]

Systemic mastocytosis (SM) is a disorder of excessive mast cell accumulation in tissues due to a somatic gain-of-function mutation, commonly in the KIT gene, which prevents apoptosis of mast cells. Whereas bone marrow, skin, lymph nodes, spleen and gastrointestinal tract are commonly involved, kidneys are rarely involved directly by SM. However, there are increasing reports of indirect kidney involvement in patients with SM. Novel anti-neoplastic agents to treat advanced forms of SM include non-specific tyrosine kinase inhibitors, which are reported to be associated with kidney dysfunction in some patients. SM is also associated with immune-mediated glomerulonephritis (GN) such as mesangioproliferative GN, membranous nephropathy and diffuse proliferative GN. Kidney injury, in the form of monoclonal deposition disease and primary light chain amyloidosis, is reported in SM associated with plasma cell dyscrasia. In this narrative review we discuss the various ways kidneys (and the urinary tract) are involved in patients with SM. [ABSTRACT FROM AUTHOR]

Neonatal diffuse cutaneous mastocytosis (NDCM) is defined as the infiltration of the epidermis by a clonal proliferation of mast cells, observed at birth, without initial signs of systemic involvement. The typical driver mutation is in the KIT gene. We report a rare case of a boy, born at term, already presenting at birth with generalized subcutaneous nodules on the face, scalp, trunk, back, hands, and feet. The spleen, liver, and inflammatory markers were normal at birth. Tryptase was significantly elevated. A bone marrow biopsy showed no mast cell involvement at age 2 months. A punch biopsy at age 2 months revealed CD117-positive cells diffusely infiltrating the skin, with subsequent DNA NGS sequencing for the formalin-fixed paraffin embedded tissue (FFPE) identifying the pathogenic NM_000222.3:c.1504_1509dup; p.(Ala502_Tyr503dup) variant in the KIT gene previously associated with cutaneous mastocytosis. At 2 years follow-up, he had splenomegaly and multiple cervical and inguinal adenopathy, while the skin nodules persisted, especially on the scalp with accompanying pruritus. He received oral and local sodium cromoglycate, oral antihistamines, antibiotic cream for skin infection, and iron supplementation; however, compliance to treatment was relatively low. The prognosis is difficult to predict, as he developed systemic involvement, failure to thrive, and mild psychomotor delay. A case aggregation of NDCM reported in the literature was performed to provide a comprehensive overview of this rare pathology, to better understand the prognosis. NDCM is a life-threatening disease with severe complications. Almost half had severe complications, such as mast hepatosplenomegaly, adenopathy, bacterial infections, mast cell leukaemia, and systemic involvement. [ABSTRACT FROM AUTHOR]

Bacground: The pathogenesis of systemic mastocytosis with associated haematological neoplasm (SMAHN) is not well understood. Both diagnoses heavily rely on morphological evaluation because SM is rarely suspected in clinical practise. Objective: This case highlighted a possible delay in diagnosis due to underlying conditions or diseases. Case Report: We present a case of a patient with acute myeloid leukaemia (AML), acute myelomonocytic subtype, and concurrent mastocytosis according to World Health Organization (WHO) classification. Due to an extensive accumulation of AML blast cells that obscured the mast cell infiltrates, mastocytosis was not evident at the first diagnosis. Discussion and conclusion: The diagnosis, in this case, was established only in the third bone marrow biopsy after chemotherapy. A high index of suspicion with morphological and immunohistochemical evaluations for neoplastic mast cell populations should be considered. The optimal treatment approach should be chosen based on these two disease entities. [ABSTRACT FROM AUTHOR]

Purpose: Patients with mastocytosis have an increased risk of anaphylaxis during surgical procedures with general anesthesia. Therefore, we reviewed the anesthesia course of a large cohort of patients with mastocytosis. Methods: We retrospectively reviewed adult and pediatric patients with mastocytosis who underwent surgical procedures with general anesthesia at Mayo Clinic from January 1, 2000, through June 30, 2021. We also included any procedures with general anesthesia that occurred during the 3-year period preceding mastocytosis diagnosis and designated the patients who underwent these procedures as having an unknown diagnosis at the time of their surgical procedure. We analyzed whether patients received chronic antimediator treatment for mastocytosis and/or prophylactic medications before the procedures. We also determined whether medications indicative of mastocytosis-related adverse events were intraoperatively administered. Results: We identified 113 patients who underwent 219 procedures during the study period; 25 procedures were performed before mastocytosis diagnosis. Of 194 procedures in patients with known mastocytosis, patients received chronic antimediator therapy and/or perioperative prophylactic medications for 178 (91.8%) procedures. Among these procedures, 10 were potentially complicated by mast cell activation, which was inferred from administration of inhaled albuterol (n = 3) or intravenous diphenhydramine (n = 8). In addition, there was only one case of intraoperative anaphylaxis which occurred in a patient who underwent anesthesia before mastocytosis diagnosis and therefore did not receive prophylaxis. Conclusion: Intraoperative anaphylaxis can be the first presenting sign of mastocytosis. Patients with mastocytosis who received chronic antimediator therapy and/or preoperative prophylactic medications had an uneventful surgical course. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Low dose Avapritinib is a new medication that is a potential treatment option not just for advanced systemic mastocytosis, but also for the indolent form. [ABSTRACT FROM AUTHOR]

Key Clinical Message Additional investigations for systemic involvement should be initiated once the diagnosis of cutaneous mastocytosis has been established in an adult patient. A serum tryptase can serve as a screening test for systemic mastocytosis, and persistent elevations should prompt further investigations, such as bone marrow studies. Abstract Urticaria pigmentosa (UP) is the most common form of cutaneous mastocytosis, presenting as a wide variety of macroscopic appearances. Cutaneous mastocytosis in pediatric patients usually does not present with systemic involvement, but more than half of adult patients with cutaneous mastocytosis demonstrate systemic involvement. Currently, there is no guidance surrounding systemic testing in patients with UP. A 50‐year‐old Caucasian male was referred to the Clinical Immunology and Allergy clinic with a history of a rash. He initially presented to hospital 12 years prior with group A beta hemolytic streptococcus bacteremia treated with multiple different antibiotics. One week following discharge, he developed erythematous brown spots on his right leg which were flat, non‐pruritic, and not painful. The rash later expanded to his trunk and extremities. A skin biopsy performed 2 years prior to referral to our clinic demonstrated urticaria pigmentosa. The CD117 immunohistochemical stain showed increased perivascular and interstitial mast cells in the superficial dermis. Darier's sign was negative on physical examination, and venom testing was also negative. Although he had no symptoms of systemic involvement, his serum tryptase was elevated at 47.6 ng/mL in the context of normal kidney and liver function. A skeletal survey was normal, and an abdominal ultrasound ruled out splenomegaly. Bone marrow biopsy demonstrated a mild increase in paratrabecular and perivascular atypical mast cells, in keeping with systemic mastocytosis. Adult patients with cutaneous mastocytosis have a high likelihood of having an underlying systemic mast cell disorder. Therefore, any patient presenting with characteristic skin findings should be investigated as having a cutaneous manifestation of systemic mastocytosis. This case demonstrates the utility of serum tryptase and its role in triggering additional investigations and guiding appropriate therapy.

Background: Mast cell activation syndrome (MCAS) is a clinically heterogeneous disease with allergy-like symptoms and abdominal complaints. Its etiology is only partially understood and it is often overlooked. Aims: The aim of this study was to identify subgroups of MCAS patients to facilitate diagnosis and allow a personalized therapy. Methods: Based on data from 250 MCAS patients, hierarchical and two-step cluster analyses as well as association analyses were performed. The data used included data from a MCAS checklist asking about symptoms and triggers and a set of diagnostically relevant laboratory parameters. Results: Using a two-step cluster analysis, MCAS patients could be divided into three clusters. Physical trigger factors were particularly decisive for the classification as they showed remarkable differences between the three clusters. Cluster 1, labeled high responders, showed high values for the triggers heat and cold, whereas cluster 2, labeled intermediate responders, presented with high values for the trigger heat and low values for cold. The third cluster, labeled low responders, did not react to thermal triggers. The first two clusters showed more divers clinical symptoms especially with regard to dermatological and cardiological complaints. Subsequent association analyses revealed relationships between triggers and clinical complaints: Abdominal discomfort is mainly triggered by histamine consumption, dermatological discomfort by exercise, and neurological symptoms are related to physical exertion and periods of starvation. The reasons for the occurrence of cardiological complaints are manifold and triggers for respiratory complaints still need better identification. Conclusion: Our study identified three distinct clusters on the basis of physical triggers, which also differ significantly in their clinical symptoms. A trigger-related classification can be helpful in clinical practice for diagnosis and therapy. Longitudinal studies should be conducted to further understand the relationship between triggers and symptoms. [ABSTRACT FROM AUTHOR]

Prevention of fatal side effects during cancer therapy of cancer patients with high‐dosed pharmacological inhibitors is to date a major challenge. Moreover, the development of drug resistance poses severe problems for the treatment of patients with leukemia or solid tumors. Particularly drug‐mediated dimerization of RAF kinases can be the cause of acquired resistance, also called "paradoxical activation." In the present work we re‐analyzed the effects of different tyrosine kinase inhibitors (TKIs) on the proliferation, metabolic activity, and survival of the Imatinib‐resistant, KIT V560G, D816V‐expressing human mast cell (MC) leukemia (MCL) cell line HMC‐1.2. We observed that low concentrations of the TKIs Nilotinib and Ponatinib resulted in enhanced proliferation, suggesting paradoxical activation of the MAPK pathway. Indeed, these TKIs caused BRAF‐CRAF dimerization, resulting in ERK1/2 activation. The combination of Ponatinib with the MEK inhibitor Trametinib, at nanomolar concentrations, effectively suppressed HMC‐1.2 proliferation, metabolic activity, and induced apoptotic cell death. Effectiveness of this drug combination was recapitulated in the human KIT D816V MC line ROSAKIT D816V and in KIT D816V hematopoietic progenitors obtained from patient‐derived induced pluripotent stem cells (iPS cells) and systemic mastocytosis patient samples. In conclusion, mutated KIT‐driven Imatinib resistance and possible TKI‐induced paradoxical activation can be efficiently overcome by a low concentration Ponatinib and Trametinib co‐treatment, potentially reducing the negative side effects associated with MCL therapy. [ABSTRACT FROM AUTHOR]

[Display omitted] Systemic mastocytosis (SM) is a heterogeneous group of mast cell–driven diseases diagnosed by bone marrow sampling. However, there are a limited number of available blood disease biomarkers. Our aim was to identify mast cell–derived proteins that could potentially serve as blood biomarkers for indolent and advanced forms of SM. We performed a plasma proteomics screening coupled with single-cell transcriptomic analysis in SM patients and healthy subjects. Plasma proteomics screening identified 19 proteins upregulated in indolent disease compared to healthy, and 16 proteins in advanced disease compared to indolent. Among these, 5 proteins, CCL19, CCL23, CXCL13, IL-10, and IL-12Rβ1, were higher in indolent relative to healthy and in advanced disease compared to indolent. Single-cell RNA sequencing demonstrated that CCL23, IL-10, and IL-6 were selectively produced by mast cells. Notably, plasma CCL23 levels correlated positively with known markers of SM disease severity, namely tryptase levels, percentage bone marrow mast cell infiltration, and IL-6. CCL23 is produced predominantly by mast cells in SM, and CCL23 plasma levels are associated with disease severity, correlating positively with established markers of disease burden, thus suggesting that CCL23 is a specific SM biomarker. In addition, the combination of CCL19, CCL23, CXCL13, IL-10, and IL-12Rβ1 may be useful for defining disease stage. [ABSTRACT FROM AUTHOR]

Abstract Background Systemic mastocytosis (SM), a rare myeloid neoplasm, is defined as a clonal and neoplastic proliferation of mast cells in at least one extracutaneous organ(s). The pathologic diagnosis and treatment of SM are challenging. Case presentation We presented a 44-year-old male patient who had endured abdomen discomfort for 4 years and diarrhea for 5 months. Colonoscopy and PET/CT found a protuberant lesion in the cecum with adjacent lymphadenopathy. Histopathology of the cecum biopsy showed diffuse infiltration of medium-sized round/oval cells in lamina propria with immunohistochemical expressions of CD45, CD117, CD25, CD68, CD123, CD56, CD4, and CD35, mimicking blastic plasmacytoid dendritic cell neoplasm. Sanger sequencing revealed missense mutation (D816V) in the exon 17 of KIT gene. Serum tryptase level was 38.56 ng/ml. No abnormality was found in skin examination and bone marrow biopsy. No primitive cells were observed in bone marrow smear and peripheral blood smear. The diagnosis of aggressive SM with intestinal tract involvement was established. The patient received avapritinib treatment at an initial dosage of 200 mg once daily and exhibited dramatic clinical improvement but memory impairment within 1 month. No recurrence was observed in 1-year follow-up at the adjusted avapritinib dose (75 mg once daily). Conclusions SM is very rare and should be considered in patients with long-term diarrhea symptoms and hematopoietic/lymphoid-appearing tumors. KIT D816V mutation contributes to the differentiation of CD123, CD4, and CD56 immunoreactive SM from blastic plasmacytoid dendritic cell neoplasm. The rare side-effect of memory impairment in this case helps to accumulate the experience of avapritinib in treating KIT D816V-mutant SM.

Abstract Background Pediatric Mastocytosis is a rare and heterogeneous disease, characterized by accumulation of mast cells in the skin (Cutaneous Mastocytosis) and/or, less frequently, in other organs, mainly liver, spleen, bone marrow, lymph nodes and gastrointestinal tract (Systemic Mastocytosis). Patients affected by Systemic Mastocytosis show symptoms caused by a massive release of mast cell mediators: itching, flushing, abdominal pain, generalized weakness, fatigue and neuropsychiatric disorders. Moreover, children with Systemic Mastocytosis are at greater risk of anaphylactic/anaphylactoid reactions, often poorly controlled by the conventional therapy with antihistamines, mast cells stabilizers and steroids. As a result, children affected by Systemic Mastocytosis have a poor quality of life and suffer the consequence of prolonged steroidal treatment. Case presentation A child with Systemic Mastocytosis and severe symptoms, refractory to symptomatic and steroidal therapy, has been successfully treated with Omalizumab, an anti-IgE monoclonal antibody usually employed in allergic patients with severe asthma and orticaria. The onset of clinical benefit of Omalizumab therapy was extraordinarily rapid, but proved to be strictly dependent on drug administration. The child has become completely and steadily asymptomatic. No other anaphylactic episodes have been reported. Steroid treatment could be definitively withdrawn after the second dose of Omalizumab, and all the other medications were later reduced. Twenty months after beginning, Omalizumab therapy is still ongoing with good symptomatology control; no side effects have been observed so far. Conclusions In our experience, Omalizumab is an effective treatment for children affected by Systemic Mastocytosis not responding to conventional medical treatments. The main strengths of this therapy are its rapid and extraordinary efficacy to control the severe mast cells mediator-related symptoms, the lack of side effects and its steroid-sparing effect. However, more extensive and controlled studies in pediatric patients affected by Systemic Mastocytosis are needed to substantiate these promising findings.

Mast cells are residents of the tubular gastrointestinal (GI) tract, where they play an important role in host defence and other vital functions. Dysregulation of mast cells has been implicated in the pathogenesis of several neoplastic, inflammatory, and functional disorders, some of which may manifest with GI symptoms. Surgical pathologists must therefore confront when and how to evaluate GI biopsies for mast cells, and whether such decisions should be based on morphologic criteria, clinical context, or direct request from clinical colleagues. The pathologist's role in evaluation of mast cell infiltrates is best defined in the diagnosis of systemic mastocytosis, where the utility of morphologic assessment coupled with ancillary studies is well established. In contrast, in nonneoplastic mast cell disorders such as mast cell activation syndrome, irritable bowel syndrome, or so‐called 'mastocytic enterocolitis', a role for histopathology, if any, is controversial. Despite this, pathologists have seen a sharp increase in requests for mast cell quantification in the latter setting, despite these requests not being supported by published evidence. Moreover, what constitutes a 'normal' number of mast cells in a luminal GI biopsy is not well established. As a result, there is considerable variation in how these requests are handled in practice. This review evaluates and summarizes the published evidence relating to mast cell evaluation in endoscopic GI biopsies in various clinical scenarios, with a goal of providing practical, evidence‐based guidance for the surgical pathologist when approached with requests for mast cell quantification in GI biopsies. [ABSTRACT FROM AUTHOR]

Background: Cutaneous mastocytosis (CM) occurs when abnormal mast cells accumulate in the skin, whereas in systemic mastocytosis (SM), accumulation also occurs in other tissues. A transition from CM to SM is an atypical occurrence in pediatric patients. Case Presentation: An 8-month-old female presented with a 3-month history of whole body hyperpigmented macules with a normal serum tryptase level, consistent with a diagnosis of CM. At age 2.5 years, cutaneous lesions increased and repeat serum tryptase levels were elevated. Subsequent positive peripheral blood KIT D816V mutation testing furthered concern for a monoclonal mast cell disorder; therefore, prompting a bone marrow biopsy which was consistent with a diagnosis of SM. Conclusion: Our case depicts the possible transition from CM to SM in a pediatric patient. Despite an initial presentation consistent with a diagnosis of CM, watchful monitoring for signs and symptoms indicative of systemic involvement may be warranted in some pediatric patients. [ABSTRACT FROM AUTHOR]

Abstract Background Among various anaphylactic conditions resulting in acute abdomen, mast cell activation disorders, although rare, are included in the differential diagnosis. Case presentation This report describes a 63-year-old Caucasian man who was brought to the emergency room with sudden onset abdominal pain, vomiting, and diarrhea, with breathing difficulty, and with facial swelling after quarrelling with an acquaintance. Computed tomography showed edematous and swollen intestines, consistent with splenomegaly. Physical findings included maculopapular cutaneous mastocytosis. He also had a long history of repeated episodes of anaphylaxis requiring occasional epinephrine auto-injector administration; however, the precise cause of anaphylaxis was previously undetermined. Blood tests showed high serum concentrations of soluble IL-2R and tryptase, suggesting mast cell-related disease. Subsequent biopsies of his bone marrow and cutaneous rash confirmed the diagnosis of systemic mastocytosis (SM). Conclusion SM was diagnosed in a patient with acute abdomen who visited the emergency room.

Simple Summary: Mast cell leukemia (MCL) is a rare and aggressive subtype of systemic mastocytosis (SM). MCL diagnosis requires fulfillment of diagnostic criteria for SM plus at least 20% immature/atypical mast cells on bone marrow smear. Based on different clinicopathological characteristics, MCL is subdivided into the following variants: primary (de novo) or secondary (from a prior SM form); acute with C-findings (where C-findings represent organ damage requiring cytoreductive treatment) or chronic without C-findings; and finally, MCL with or without an associated hematological neoplasm. The latter category was renamed MCL with an associated myeloid neoplasm in the 2022 International Consensus Classification (ICC). The relevance of the distinction between the leukemic and aleukemic forms, based on the percentage of circulating mast cells, is under discussion. In this study, we review the current knowledge on MCL with the aim of increasing clinicians' and pathologists' awareness of this rare, still incompletely understood disease with a grim prognosis. Mast cell leukemia (MCL) is the leukemic form of SM with at least 20% mostly immature mast cells on bone marrow aspirate. MCL may develop de novo, in the absence of a prior SM, or it may represent a progression from a previous SM. MCL may be sub-divided into the more frequent, aggressive acute form with signs of organ damage (C-findings) and the chronic form lacking C-findings and presenting a more stable course, although over time, progression to acute MCL is common. The 2022 WHO subtype of MCL with an associated hematological neoplasm was renamed MCL with an associated myeloid neoplasm in the 2022 International Consensus Classification (ICC). The relevance of the distinction between the leukemic and aleukemic forms based on the percentage of circulating mast cells is a matter of debate. The current knowledge on MCL is restricted mainly to single reports or case series with a limited number of larger studies. Our aim is to provide a comprehensive overview of this rare disease in terms of clinical manifestations, morphology, phenotype, molecular characteristics, differential diagnosis, outcome and treatment. A general overview on mastocytosis is also included. [ABSTRACT FROM AUTHOR]

Mast cells (MCs) represent a population of hematopoietic cells with a key role in innate and adaptive immunity and are well known for their detrimental role in allergic responses. Yet, MCs occur in low abundance, which hampers their detailed molecular analysis. Here, we capitalized on the potential of induced pluripotent stem (iPS) cells to give rise to all cells in the body and established a novel and robust protocol for human iPS cell differentiation toward MCs. Relying on a panel of systemic mastocytosis (SM) patient-specific iPS cell lines carrying the KIT D816V mutation, we generated functional MCs that recapitulate SM disease features: increased number of MCs, abnormal maturation kinetics and activated phenotype, CD25 and CD30 surface expression and a transcriptional signature characterized by upregulated expression of innate and inflammatory response genes. Therefore, human iPS cell-derived MCs are a reliable, inexhaustible, and close-to-human tool for disease modeling and pharmacological screening to explore novel MC therapeutics. [ABSTRACT FROM AUTHOR]

Background: Systemic mastocytosis (SM), a rare myeloid neoplasm, is defined as a clonal and neoplastic proliferation of mast cells in at least one extracutaneous organ(s). The pathologic diagnosis and treatment of SM are challenging. Case presentation: We presented a 44-year-old male patient who had endured abdomen discomfort for 4 years and diarrhea for 5 months. Colonoscopy and PET/CT found a protuberant lesion in the cecum with adjacent lymphadenopathy. Histopathology of the cecum biopsy showed diffuse infiltration of medium-sized round/oval cells in lamina propria with immunohistochemical expressions of CD45, CD117, CD25, CD68, CD123, CD56, CD4, and CD35, mimicking blastic plasmacytoid dendritic cell neoplasm. Sanger sequencing revealed missense mutation (D816V) in the exon 17 of KIT gene. Serum tryptase level was 38.56 ng/ml. No abnormality was found in skin examination and bone marrow biopsy. No primitive cells were observed in bone marrow smear and peripheral blood smear. The diagnosis of aggressive SM with intestinal tract involvement was established. The patient received avapritinib treatment at an initial dosage of 200 mg once daily and exhibited dramatic clinical improvement but memory impairment within 1 month. No recurrence was observed in 1-year follow-up at the adjusted avapritinib dose (75 mg once daily). Conclusions: SM is very rare and should be considered in patients with long-term diarrhea symptoms and hematopoietic/lymphoid-appearing tumors. KIT D816V mutation contributes to the differentiation of CD123, CD4, and CD56 immunoreactive SM from blastic plasmacytoid dendritic cell neoplasm. The rare side-effect of memory impairment in this case helps to accumulate the experience of avapritinib in treating KIT D816V-mutant SM. [ABSTRACT FROM AUTHOR]

(1) Background: Systemic mastocytosis is a rare, non-curable disease with potential life-threatening complications in patients receiving cardiac surgery. (2) Methods: This systematic review of the literature was prompted by the case of a life-threatening anaphylactic reaction during cardiac surgery related to systemic mastocytosis. The search of all types of studies, using several databases (Pubmed, Scopus and Web of Science), was conducted through September 2022 to identify the relevant studies. (3) Results: Twelve studies were included describing cases of patients undergoing cardiac surgery who were diagnosed with systemic mastocytosis. An adverse effect, namely anaphylaxis, has happened in three cases. Different strategies of premedication, intraoperative and postoperative management were used. In our case, the patient was admitted for elective biological aortic valve replacement due to severe aortic stenosis. Intraoperatively, the patient developed an anaphylactic shock during the administration of protamine after separation from the cardiopulmonary bypass. This anaphylaxis reaction was a complication of the pre-existing systemic mastocytosis and could be successfully managed by the administration of epinephrine, antihistamines and corticosteroids. (4) Conclusions: This systematic literature search and case report highlight the importance of careful preoperative planning, as well as coordination between cardiac surgeons, anesthesiologists and hemato-oncological specialists, in patients with rare but complication-prone diseases such as systemic mastocytosis. [ABSTRACT FROM AUTHOR]

Mast cells and basophils degranulate upon activation, releasing preformed mediators from intracellular granules into the extracellular environment, of which tryptase and histamine are the two most common and best characterized mediators. Despite the large number of mediators synthesized by mast cells, the non-tryptase biomarkers used to evaluate systemic mastocytosis and mast cell activation syndrome do not include the metabolites of the prestored amine histamine and the de novo synthesized phospholipids prostaglandin D2 and leukotriene C4. Currently, these markers are not used as criteria for the diagnosis of mastocytosis and mast cell activation syndrome. However, consensus groups foster the use of increases in measured baseline levels of these metabolites as potential diagnostic criteria. Metabolites of arachidonic acid such as prostaglandin D2 or leukotriene C4 play a role in the development of symptoms in systemic mastocytosis and mast cell activation syndrome. In this review, the metabolites of arachidonic acid and the detection of the metabolites of leukotrienes and prostaglandins in mastocytosis are highlighted. Measurement of these metabolites remains a major challenge because they are not widely available in daily clinical practice. However, new insights have been gained in recent years, and their application in the clinic has progressed. [ABSTRACT FROM AUTHOR]

Background. Mastocytosis is a disease characterized by the presence of mast cells in various organs. The skin is affected most often. Almost every patient diagnosed with mastocytosis has skin lesions. This disease is characterized by redness, itching, abdominal pain, diarrhea, musculoskeletal pain, hypotension. These features result from the release of the mast cell mediator and its infiltration into the target organs. Materials and methods. This article describes the symptoms and signs of each and systemic mastocytosis, the principles of their diagnosis, based on recently published іnternational recommendations. Results. According to the 2016 World Health Organization classification, mastocytosis can be divided into cutaneous mastocytosis, systemic mastocytosis and mast cell sarcoma. Cutaneous mastocytosis is divided into three subtypes: maculopapular cutaneous mastocytosis, diffuse cutaneous mastocytosis and cutaneous mastocytoma. Permanent telangiectasia of the macular eruptive form is no longer considered a separate unit. Systemic mastocytosis, in turn, is also divided into indolent, smoldering, aggressive and associated with hematological tumors. Conclusions. Cutaneous manifestations of mastocytosis may vary with age. The classification of cutaneous mastocytosis has recently been updated. As a rule, in patients with mastocytosis in childhood the disease occurs as cutaneous mastocytosis and spontaneously regresses during puberty. On the contrary, in adult patients, despite skin lesions, systemic lesions are often observed, and the course of the disease is usually chronic. That is, patients of any age can be affected. The article describes the causes and pathoge­nesis of mastocytosis with an overview of clinical features, approach to diagnosis and therapy depending on age and severity of the di­sease. Clinical cases for visual acquaintance with a clinical picture of various forms of mastocytosis are resulted.

We report a case of myeloid/lymphoid neoplasm with ZMYM2::FGFR1 rearrangement (MLNZMYM2::FGFR1) exhibiting a complex disease evolution. This neoplasm initially presented as T-lymphoblastic lymphoma (T-LBL) in lymph node and myeloproliferative neoplasm (MPN) with eosinophilia in bone marrow, then transitioned to systemic mastocytosis (SM) likely accompanied by additional JAK3 and other mutations and finally transformed to acute myeloid leukemia (AML) accompanied by additional/secondary genetic abnormality (gain of chromosome 21, der(13)t(8;13), and RUNX1 mutation). To our knowledge, this is the first case of MLNZMYM2::FGFR1 with a complex trilineage/phenotypic [T-cell (T-LBL), mast cell (SM), and myeloid (MPN and AML)] lineage evolution.

Systemic mastocytosis is a neoplastic proliferation of mast cells that most frequently involves cutaneous sites. Mastocytosis involves various extracutaneous sites, but the lymph node is rare. We present an interesting image of systemic mastocytosis in the lymph node with marked eosinophilia. It is a rare subtype of systemic mastocytosis requiring high suspicion levels for the correct diagnosis. [ABSTRACT FROM AUTHOR]

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Systemic mastocytosis with associated hematological neoplasm (SM-AHN) poses diagnostic challenges because of the coexistence of atypical mast cell proliferation and hematological neoplasms. We assessed the presence of SM-AHN in patients with acute myeloid leukemia (AML) with RUNX1::RUNX1T1 from 2014 to 2020. Bone marrow (BM) samples were evaluated for mast cell aggregates using CD117 and CD25 immunohistochemical (IHC) staining. The KIT D816V variant burden at diagnosis and post induction was assessed using droplet digital PCR. Among 23 patients diagnosed as having AML with RUNX1::RUNX1T1, four (17.4%) were also diagnosed as having SM-AHN. No significant differences in clinical characteristics or overall survival (P =0.565) were observed between patients with or without SM-AHN, except for the presence of KIT variants (P =0.040). After induction therapy, IHC staining revealed the presence of mast cell aggregates in the BM, and the KIT D816V variant burden decreased with decreasing blast count and was similar in BM aspirates, smear slides, and sections. Concomitant SM-AHN was not infrequent in AML patients with RUNX1::RUNX1T1. This study showed the importance of CD117 and CD25 IHC staining after induction chemotherapy for SM-AHN screening, especially in patients with KIT variants. [ABSTRACT FROM AUTHOR]

Background: Systemic mastocytosis (SM) is a rare clonal neoplasm driven by the KIT D816V mutation and has a broad range of debilitating symptoms. In this study, the authors evaluated SM disease perceptions and management strategies among US health care providers (HCPs).Methods: Hematologist/oncologist (H/O) HCPs and allergist/immunologist (A/I) HCPs who were treating four or more patients with SM completed an online, 51-item TouchStone HCP Survey, which queried provider characteristics, perceptions of disease burden, and current management. Descriptive analyses by specialty and SM subtype were performed.Results: Of 304 HCPs contacted, 111 (37%) met eligibility criteria, including 51% A/I specialists and 49% H/O specialists. On average, the HCPs had 14 years of practice experience and cared for 20 patients with SM. A/I HCPs saw more patients with nonadvanced SM (78%) compared with H/O HCPs, who saw similar proportions of patients with nonadvanced SM (54%) and advanced SM (46%). HCPs reported testing 75% of patients for the KIT D816V mutation and found an estimated prevalence of 47%. On average, HCPs estimated 8 months between symptom onset and SM diagnosis. HCPs reported that 62% of patients with indolent SM felt depressed or discouraged because of symptoms. In terms of treatment goals for SM, both types of specialists prioritized symptom improvement for nonadvanced SM and improved survival for advanced SM while also prioritizing improving patient quality of life.Conclusions: Both A/I and H/O specialists highlighted unmet needs for patients with SM. The HCPs surveyed reported a lower rate of KIT D816V mutations and a perceived shorter time between symptom onset and SM diagnosis compared with published estimates.Lay Summary: Specialists treating systemic mastocytosis (SM) completed a 51-item questionnaire about their clinical practices and perceptions of disease impact. The study included 111 hematology, oncology, allergy, and immunology physicians. Physicians reported that most patients had nonadvanced disease, yet SM symptoms significantly disrupted their patients' lives. Physicians estimated that SM is diagnosed within months of symptom onset, in contrast with published reports of years' long delays reported by patients with SM. This study identified unmet needs that can inform educational and patient management priorities in this rare disease. [ABSTRACT FROM AUTHOR]

Background: Systemic mastocytosis (SM) is a rare clonal neoplasm driven by KIT D816V and other mutations. Data were collected from the patient perspective on disease burden and included an SM-specific symptom assessment tool.Methods: US adults aged 18 years and older with a self-reported SM diagnosis completed an online TouchStone SM Patient Survey of 100 items, including the 12-item Short-Form Health Survey, the Indolent Systemic Mastocytosis Symptom Assessment Form, and the Work Productivity and Activity Impairment Questionnaire, as well as questions about SM diagnosis, the impact of SM on daily activities, work impairment, and health care use. The results were analyzed using descriptive statistics.Results: Fifty-six individuals completed the survey (89% women; median age, 48 years; mean time since diagnosis, 6.7 years), reporting indolent SM (66%), aggressive SM (9%), smoldering SM (5%), and unknown SM subtype (18%). Over a 1-year recall, respondents reported seeking emergency care for anaphylaxis (30%) and taking three or more prescription medications (52%) for SM. Over one half of patients (54%) reduced their work hours because of SM, and 64% avoided leaving home because of symptoms. A majority of respondents (93%) had experienced ≥10 SM-related symptoms, noting that the most bothersome were anaphylactic episodes (18%), abdominal/stomach pain (16%), diarrhea/loose stools (13%), and fatigue (11%). Whereas an Indolent Systemic Mastocytosis Symptom Assessment Form-derived total symptom score of 28 is used to indicate moderate-to-severe symptoms, the mean total symptom score was 52.7. Mental and physical component summary scores from the 12-item Short-Form Health Survey were below population norms.Conclusions: Patients who were surveyed reported substantial symptom burden and unmet needs because of SM, as evidenced by seeking emergency care and reporting bothersome symptoms, poor quality of life, and reduced work hours and productivity.Lay Summary: The objective of this research was to understand the burden and unmet needs in the rare disease of systemic mastocytosis (SM) to guide future care. Fifty-six patients completed an online survey containing questions about their diagnosis, medications, health care use, quality of life, and SM symptoms. The results demonstrated that SM is associated with severe and burdensome symptoms, anaphylactic events, emergency department visits, use of multiple medications, reduced ability to work, and poor physical and psychological quality of life. These findings suggest the need for future advances to address unmet needs in patients affected by SM. [ABSTRACT FROM AUTHOR]

Despite much of the past 2 years being engulfed by the devastating consequences of the SAR‐CoV‐2 pandemic, significant progress, even breathtaking, occurred in the field of chronic myeloid malignancies. Some of this was show‐cased at the 15th Post‐American Society of Hematology (ASH) and the 25th John Goldman workshops on myeloproliferative neoplasms (MPN) held on 9th‐10th December 2020 and 7th‐10th October 2021, respectively. The inaugural Post‐ASH MPN workshop was set out in 2006 by John Goldman (deceased) and Tariq Mughal to answer emerging translational hematology and therapeutics of patients with these malignancies. Rather than present a resume of the discussions, this perspective focuses on some of the pivotal translational hematology and therapeutic insights in these diseases. [ABSTRACT FROM AUTHOR]