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OBJECTIVE: To assess the frequency and types of visits related to modifications in the intensity of asthma medications. PATIENTS AND METHODS: We retrospectively reviewed the medical records of adults (aged 18-40 years) and children (aged 6-17 years) living in Olmsted County, Minnesota, to evaluate changes in asthma medications by dose and drug class and site and type of visit (routine vs unscheduled) at the time of changes. All records from all visits were reviewed for each patient to identify asthma-related visits at all sites of care from January 1, 2002, through December 31, 2003. RESULTS: The study consisted of 397 adults and children. In 255 patients, 597 asthma medication changes occurred. Step-up changes usually occurred because of an exacerbation or loss of control of asthma and adhered to the medication hierarchy in the national asthma guidelines. Twenty step-up changes involved skipping inhaled corticosteroid (ICS) monotherapy and moving directly to combined ICSs plus a long-acting beta-agonist (LABA). Lack of documentation of asthma symptom frequency or interference with activities made it impossible to determine whether these 'skips' were appropriate. Only 78 physician-directed step-down changes were documented, usually to a lower dose of combined ICSs and LABAs or a move from combined ICSs and LABAs to anti-inflammatory monotherapy. Patients initiated additional step-down changes between encounters. Step-down changes occurred at routine or follow-up asthma visits, but the limited number of such visits provided few opportunities for step-down care. CONCLUSION: The continuing episodic-style treatment of asthma aimed at exacerbation management facilitates step-up changes in asthma therapy. The dearth of asthma evaluation visits limited opportunities to step down use of asthma medications and to provide long-term asthma management. [ABSTRACT FROM AUTHOR]

Mastocytosis is a clonal myeloid disorder defined by an increase and accumulation of mast cells (MCs) in one or multiple organ systems. The complex pathology of mastocytosis results in variable clinical presentations, courses, and outcomes. The World Health Organization (WHO) divides the disease into cutaneous mastocytosis (CM), several forms of systemic mastocytosis (SM), and MC sarcoma. In most patients with SM, a somatic KIT mutation, usually D816V, is identified. Patients diagnosed with CM or nonadvanced SM, including indolent SM, have a near-normal life expectancy, whereas those with advanced SM, including aggressive SM and MC leukemia, have limited life expectancy. Since 2001, a multidisciplinary consensus group consisting of experts from the European Competence Network on Mastocytosis and the American Initiative in Mast Cell Diseases has supported the field by developing diagnostic criteria for mastocytosis. These criteria served as the basis for the WHO classification of mastocytosis over 2 decades. More recently, an International Consensus Classification group proposed slightly modified diagnostic criteria and a slightly revised classification. In this article, these changes are discussed. Furthermore, we propose harmonization among the proposals of the American Initiative in Mast Cell Diseases/European Competence Network on Mastocytosis consensus group, WHO, and the International Consensus Classification Group. Such harmonization will facilitate comparisons of retrospective study results and the conduct of prospective trials., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Mast cell activation syndrome (MCAS) is a term applied to several clinical entities that have gained increased attention from patients and medical providers. Although several descriptive publications about MCAS exist, there are many gaps in knowledge, resulting in confusion about this clinical syndrome. Whether MCAS is a primary syndrome or exists as a constellation of symptoms in the context of known inflammatory, allergic, or clonal disorders associated with systemic mast cell activation is not well understood. More importantly, the underlying mechanisms and pathways that lead to mast cell activation in MCAS patients remain to be elucidated. Here we summarize the known literature, identify gaps in knowledge, and highlight research needs. Covered topics include contextualization of MCAS and MCAS-like endotypes and related diagnostic evaluations; mechanistic research; management of typical and refractory symptoms; and MCAS-specific education for patients and health care providers., Competing Interests: Disclosure statement M.C.C. and D.D.M. were supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH). The content is solely the responsibility of the authors and does not represent the official views of the NIH. Disclosure of potential conflict of interest: M. Castells has received research funding and consulting fees from Blueprint Medicines and consulting fees from Cogent Biosciences. M. P. Giannetti has received research funding and consulting fees from Blueprint Medicines and consulting fees from Cogent Biosciences. M. J. Hamilton has received consulting fees from Blueprint Medicines. P. Novak has received funding from Mona Taliaferro/Bay Shore Recycling, the National Heart, Lung, and Blood Institute (NHLNI; 1OT2HL156812-01), and FBRI (2022A018462); is current or previous shareholder of Moderna, Edidas Medicine, Novavax, and Pfizer; and has received royalties from Oxford University Press. J. Nicoloro-SantaBarbara has received consulting fees from Cogent Biosciences and Blueprint Medicines. S. C. Glover received consulting fees from Blueprint Medicine, Janssen, BMS, AbbVie, and Takeda. S. J. Galli has received research funding from and is scientific advisor to Evommune; and is on the scientific advisory board of Jasper Therapeutics. A. White is on the speakers bureau at Blueprint Medicines; and received consulting fees from Cogent Biosciences and Blueprint Medicines. P. Valent received funding from BMS/Celgene and AOP Orphan; and consultancy fees from Novartis, BMS/Celgene, Blueprint, Pfizer, Cogent, and Stemline. J. H. Butterfield has received a fee for the licensing of HMC-1 cell lines. D. D. Metcalfe has received consulting fees from Visterra. J. D. Milner has received consulting fees from Blueprint Medicines. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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., (© 2023 The Author(s).)

Physiological levels of basal serum tryptase vary among healthy individuals, depending on the numbers of mast cells, basal secretion rate, copy numbers of the TPSAB1 gene encoding alpha tryptase, and renal function. Recently, there has been a growing debate about the normal range of tryptase because individuals with the hereditary alpha tryptasemia (HαT) trait may or may not be symptomatic, and if symptomatic, uncertainty exists as to whether this trait directly causes clinical phenotypes or aggravates certain conditions. In fact, most HαT-positive cases are regarded as asymptomatic concerning mast cell activation. To address this point, experts of the European Competence Network on Mastocytosis (ECNM) and the American Initiative in Mast Cell Diseases met at the 2022 Annual ECNM meeting and discussed the physiological tryptase range. Based on this discussion, our faculty concluded that the normal serum tryptase range should be defined in asymptomatic controls, inclusive of individuals with HαT, and based on 2 SDs covering the 95% confidence interval. By applying this definition in a literature screen, the normal basal tryptase in asymptomatic controls (HαT-positive persons included) ranges between 1 and 15 ng/mL. This definition should avoid overinterpretation, unnecessary referrals, and unnecessary anxiety or anticipatory fear of illness in healthy individuals., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (© 2023. The Author(s) under exclusive licence to Japanese Society of Anesthesiologists.)

Background: One requirement for diagnosing mast cell activation syndrome (MCAS) is an increase, above an established baseline level, in serum tryptase by 20% plus 2 ng/mL. However, there is no consensus of what constitutes excretion of a substantial increase in metabolites from prostaglandin D 2 , histamine, or leukotriene E 4 in MCAS., Objective: Ratios of acute/baseline levels for each urinary metabolite that accompanied tryptase increases of 20% plus 2 ng/mL were determined., Methods: Mayo Clinic databases of patients with systemic mastocytosis with or without MCAS were reviewed. Patients with the requisite increase in serum tryptase during MCAS were examined for those who also had acute/baseline measurements of urinary mediator metabolite(s)., Results: Ratios of acute/baseline levels for tryptase and for each urinary metabolite were calculated. For all patients, the average acute/baseline ratio (SD) for tryptase was 4.88 (3.77). Average ratios of urinary mediator metabolites were: leukotriene E 4 : 35.98 (50.59), 2,3-dinor-11β-prostaglandin F2α: 7.28 (6.89), and N-methyl histamine: 3.2 (2.31). The lowest acute-baseline ratios for each of the three metabolites accompanying a tryptase increase of 20% plus 2 ng/mL were similar, with values of about 1.3., Conclusions: To the author's knowledge, this is the largest series of mast cell mediator metabolite measurements during episodes of MCAS that were verified by the requisite tryptase increase above baseline. Unexpectedly, leukotriene E 4 showed the greatest average increase. Acute/baseline increase of 1.3 or greater in any of these mediators could be useful for corroborating a diagnosis of MCAS., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Hypereosinophilic syndrome (HES) encompasses a group of diseases with blood hypereosinophilia and eosinophil-mediated organ dysfunction. HES-associated skin abnormalities, termed cutaneous HES (cHES) here, may influence diagnosis of HES. We sought to better define clinical and histopathological features of cHES., Methods: We retrospectively reviewed clinical records and cutaneous histopathology of adult patients with HES evaluated at our institution from 2007 to 2018., Results: Forty-one percent (61/150) patients with HES had cHES. The most common clinical morphologies were urticarial (30%) and eczematous (26%). Skin specimens most often showed a spongiotic pattern (31%) with abundant inflammation (50%) including eosinophils (85%). Two specimens (8%) showed interstitial granulomatous dermatitis, and two specimens showed eosinophilic fasciitis (8%). Vasculitis was not identified in any specimen. Eighty-four percent of patients with cHES had ≥1 other organ system involved: pulmonary 41%, ENT 26%, and nervous 23%. Sixty percent (53/89) of non-cHES patients had at least two organ systems involved. Cardiac or gastrointestinal involvement was more common in non-cHES than cHES (p < 0.05)., Conclusion: Our review confirms that there are no specific clinical or histopathological cHES patterns, but HES should be considered in patients who have eczematous or urticarial reactions of unknown etiology and persistent peripheral hypereosinophilia., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Eosinophilia and eosinophil activation are recurrent features in various reactive states and certain hematologic malignancies. In patients with hypereosinophilia (HE), HE-induced organ damage is often encountered and may lead to the diagnosis of a hypereosinophilic syndrome (HES). A number of known mechanisms and etiologies contribute to the development of HE and HES. Based on these etiologies and the origin of eosinophils, HE and HES are divided into primary forms where eosinophils are clonal cells, reactive forms where an underlying reactive or neoplastic condition is detected and eosinophils are considered to be "non-clonal" cells, and idiopathic HE and HES in which neither a clonal nor a reactive underlying pathology is detected. Since 2012, this classification and the related criteria have been widely accepted and regarded as standard. However, during the past few years, new developments in the field and an increasing number of markers and targets have created a need to update these criteria and the classification of HE and HES. To address this challenge, a Working Conference on eosinophil disorders was organized in 2021. In this conference, a panel of experts representing the relevant fields, including allergy, dermatology, hematology, immunology, laboratory medicine, and pathology, met and discussed new markers and concepts as well as refinements in definitions, criteria and classifications of HE and HES. The outcomes of this conference are presented in this article and should assist in the diagnosis and management of patients with HE and HES in daily practice and in the preparation and conduct of clinical trials., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Patients with systemic mastocytosis often have symptoms of mast cell activation, which is associated with elevated levels of urinary mast cell mediator metabolites. Patients with hereditary α-tryptasemia (HαT) may present with symptoms of mast cell activation. Whether levels of mast cell mediators are elevated in this patient population is not known., Objective: The purpose of this study was to determine whether patients with HαT and symptoms of mast cell activation have elevated levels of urinary mediators and compare the levels with those in patients with systemic mastocytosis., Methods: We retrospectively analyzed mast cell mediators in 63 patients with a confirmed diagnosis of HαT, 20 patients with a confirmed diagnosis of indolent systemic mastocytosis (ISM), and 23 healthy controls. All patients were referred to the Brigham and Women's Hospital Mastocytosis Center or the Mayo Clinic for evaluation of mast cell activation disorders., Results: Our population was predominantly female (85.7%) with an average age of 53.8 years. The average baseline serum tryptase level was significantly higher in patients with ISM than in those with HαT (65.9 vs 19.3 ng/mL [P &lt; .01]). When compared with patients with HαT, those with ISM had statistically significant increases in their levels of urinary N-methylhistamine (P &lt; .01) and 2,3-dinor-11β-prostaglandin F2α (P &lt; .05)., Conclusion: Patients with symptomatic HαT do not have elevations of mast cell urinary metabolites, suggesting that granule- and membrane-derived mediators may not drive symptoms in HαT., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Mastocytosis is a myeloid neoplasm defined by expansion and focal accumulation of clonal mast cells (MCs) in one or more organs. The disease exhibits a complex pathology and may be complicated by MC activation, bone abnormalities, neurological problems, gastrointestinal symptoms, and/or hematologic progression. The World Health Organization divides mastocytosis into cutaneous forms, systemic mastocytosis (SM) and MC sarcoma. In most patients with SM, somatic mutations in KIT are detected. Patients with indolent SM have a normal to near-normal life expectancy, whereas patients with advanced SM, including aggressive SM and MC leukemia, have a poor prognosis. In those with advanced SM, multiple somatic mutations and an associated hematologic neoplasm may be detected. Mediator-related symptoms can occur in any type of mastocytosis. Symptoms may be mild, severe, or even life-threatening. In patients with severe acute symptoms, an MC activation syndrome may be diagnosed. In these patients, relevant comorbidities include IgE-dependent and IgE-independent allergies. Management of patients with SM is an emerging challenge in daily practice and requires in-depth knowledge and a multidisciplinary and personalized approach with selection of appropriate procedures and interventions. In this article, we review the current knowledge on SM and MC activation syndrome, with emphasis on multidisciplinary aspects in diagnosis and patient-specific management. In addition, we provide a user's guide for application of markers, algorithms, prognostic scores, and treatments for use in daily practice., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Indolent systemic mastocytosis (ISM) has a favorable prognosis and normal life expectancy. However, many patients suffer from mast cell (MC) mediator-related symptoms, which significantly affect quality of life (QoL). Cutaneous, gastrointestinal, and neurological complaints, musculoskeletal pain, and the presence of skin lesions, anaphylaxis, and osteoporosis are the main symptoms and signs in ISM and must be assessed in all patients before and during treatment. Validated mastocytosis-specific patient-reported outcome measures (PROMs) should be used for this purpose. Serum tryptase and KIT D816V allele burden are recommended as secondary outcome parameters, noting that they do not reflect the severity of signs, symptoms, and related QoL impairment, but indirectly express MC burden. Changes from baseline of 90%, 60%, and 30% indicate complete response >90%, major response 60% to 90%, partial response 30% to 60%, and no response <30% to treatment. To conclude, we recommend the use of PROMs as primary outcome parameters to define treatment response in patients with ISM in clinical trials and in everyday clinical practice., (Copyright © 2022. Published by Elsevier Inc.)

Advanced systemic mastocytosis (AdvSM) is characterized by the presence of KIT D816V and other somatic mutations (eg, in SRSF2, ASXL1, and RUNX1) in 95% and 60% to 70% of patients, respectively. The biological and clinical consequences of AdvSM include multilineage involvement (eg, associated hematologic neoplasm) in 60% to 80% of patients, variable infiltration and damage (C-findings) of predominantly bone marrow and visceral organs through affected mast cell (MC) and non-MC lineages, and elevated levels of serum tryptase. Recently, the treatment landscape has substantially changed with the introduction of the multikinase/KIT inhibitor midostaurin and the selective KIT D816V inhibitor avapritinib. In this review, we discuss the evolution of AdvSM response criteria that have been developed to better capture clinical benefit (eg, improved responses and progression-free and overall survival). We propose refined response criteria from European Competence Network on Mastocytosis and American Initiative in Mast Cell Diseases investigators that use a tiered approach to segregate the effects of histopathologic (eg, bone marrow MC burden, tryptase), molecular (eg, KIT D816V variant allele frequency), clinical (eg, C-findings), and symptom response on long-term outcomes. These response criteria require evaluation in future prospective clinical trials of selective KIT inhibitors and other novel agents., (Copyright © 2022. Published by Elsevier Inc.)

Pathology plays a central role in the diagnosis of systemic mastocytosis (SM), its delineation from other neoplasms and reactive conditions, and in monitoring of SM under therapy. The morphologic hallmark of SM is the accumulation of spindle-shaped, hypogranulated mast cells (MCs) in bone marrow (BM) and other extracutaneous tissues. Four of the 5 World Health Organization-defined diagnostic criteria (ie, compact MC aggregates [=major criterion]; atypical MC morphology; activating KIT point mutations; aberrant expression of CD25 and/or CD2 and/or CD30 in MCs [=minor criteria]) can be addressed by the pathologist. The final classification of SM variants as either BM mastocytosis, indolent SM, smoldering SM, aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), or MC leukemia (MCL) has important prognostic significance and requires the integration of certain morphological, clinical, radiological, and biochemical data, referred to as B- and C-findings. Substantial diagnostic challenges may be posed to the pathologist and clinician especially in the so-called advanced SM variants, that is, ASM, MCL, and SM-AHN. In this article, updated recommendations of the EU-US Cooperative Group regarding standards of pathology in the diagnosis of SM, presented during the year 2020 Working Conference held in September in Vienna, are reported., (Copyright © 2022. Published by Elsevier Inc.)

Quantitation of urinary metabolites of histamine, prostaglandin D 2 , and leukotriene E 4 can fill the gap in our current efforts to improve diagnosis and management of symptomatic patients with systemic mastocytosis, and/or mast cell activation syndrome, In addition, patients symptomatic due to mast cell activation but who do not meet all the criteria for mast cell activation syndrome can have elevated baseline mediator metabolites. Serum tryptase levels have been the workhorse in diagnosing these disorders, but it has several drawbacks including the need to obtain acute and baseline samples, which require 2 visits to health care facilities and 2 venipunctures. Recently, increased baseline tryptase level has been reported in hereditary alpha tryptasemia, complicating diagnostic possibilities of an increased baseline tryptase level. Furthermore, no treatment can specifically be targeted at tryptase itself. In contrast, the finding of 1 or more elevated urinary levels of histamine, prostaglandin D 2 , and/or leukotriene E 4 metabolites (1) greatly narrows diagnostic possibilities for causes of symptoms; (2) informs the practitioner what specific metabolic pathways are involved; and (3) targets the treatment in a specific, direct fashion. As a bonus, baseline spot/random urine samples can be obtained by the patients themselves and repeated at exactly the correct time when symptoms occur., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Mastocytosis comprises rare heterogeneous diseases characterized by an increased accumulation of abnormal mast cells in various organs/tissues. The pathogenesis of mastocytosis is strongly linked to the presence of KIT-activating mutations. In systemic mastocytosis (SM), the most frequent mutation encountered is KIT p.D816V, whose presence constitutes one of the minor diagnostic criteria. Different techniques are used to search and quantify the KIT p.D816V mutant; however, allele-specific quantitative PCR and droplet digital PCR are today the most sensitive. The analysis of the KIT p.D816V allele burden has undeniable interest for diagnostic, prognostic, and therapeutic monitoring. The analysis of non-mast cell hematological compartments in SM is similarly important because KIT p.D816V multilineage involvement is associated with a worse prognosis. In addition, in advanced forms of SM, mutations in genes other than KIT are frequently identified and affect negatively disease outcome and response to therapy. Thus, combined quantitative and sensitive analysis of KIT mutations and next-generation sequencing of other recurrently involved myeloid genes make it possible to better characterize the extent of the affected cellular compartments and additional molecular aberrations, providing a more detailed overview of the complex mutational landscape of SM, in relation with the clinical heterogeneity of the disease. In this article, we report the latest recommendations of the EU-US Cooperative Group presented in September 2020 in Vienna during an international working conference, on the techniques we consider standard to detect and quantify the KIT p.D816V mutant in SM and additional myeloid mutations found in SM subtypes., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Mast cell activation (MCA) is common and occurs in a number of pathologic conditions, including IgE-dependent and independent allergic reactions, atopic disorders, autoimmune processes, and mastocytosis. In a subset of patients, no underlying disease and no known trigger of MCA are found. When the symptoms are severe, systemic, and recurrent, and accompanied by a diagnostic increase in the serum tryptase level or other mast cell mediators, an MCA syndrome (MCAS) may be diagnosed. In these patients, the symptoms typically respond to drugs suppressing MCA, mediator production in mast cells, or mediator effects. In each case, diagnostic consensus criteria must be fulfilled to diagnose MCAS. In other patients, MCA may be local, less severe, or less acute, or may be suspected but not confirmed, so that the diagnostic criteria of MCAS are not fulfilled. In these patients, it may be difficult to prove MCA, for example, by measuring multiple mast cell mediators or basophil activation, the latter as a surrogate of IgE-dependent hypersensitivity. However, validated diagnostic criteria for implicating suspected MCA behind such conditions are lacking, even if some of these conditions have recently been assigned to an International Classification of Diseases-10-Clinical Modification code (ICD-10-CM). In this article, we discuss diagnostic features and criteria and propose a ICD-10-CM-adjusted classification for disorders associated with MCA, herein referred to as MCA disorders (MCADs), with special emphasis on the delineation between confirmed MCAS, MCAD not fulfilling MCAS criteria, and suspected MCAD that is not present. In addition, we discuss the discrimination between overt MCAD and predisposing conditions, such as atopic states, mastocytosis, and hereditary alpha tryptasemia., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

In recent years, knowledge about mechanisms underlying mast cell activation (MCA) and accumulation in various pathologic conditions increased substantially. In addition, criteria and a classification of MCA syndromes (MCASs) have been set forth. MCAS is defined by typical clinical symptoms, a substantial increase in serum tryptase level during an attack over the patient's baseline tryptase, and a response of the symptoms to drugs targeting mast cells, mediator production, and/or mediator effects. Alternative diagnostic criteria of MCAS have also been suggested, but these alternative criteria often lack specificity and validation. In this report, we critically review the contemporary literature relating to MCAS and compare the specificity, sensitivity, and strength of MCAS-related parameters within proposals to diagnose and classify MCAS and its variants. Furthermore, we highlight the need to apply specific consensus criteria in the evaluation and classification of MCAS in individual patients. This is an urgent and important medical necessity because as an increasing number of patients are being given a misdiagnosis of MCAS based on nonspecific criteria, which contributes to confusion and frustration by patients and caregivers and sometimes may delay recognition and treatment of correct medical conditions that often turn out to be unrelated to MCA., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Mastocytosis is a hematologic neoplasm characterized by expansion and focal accumulation of neoplastic mast cells (MC) in diverse organs, including the skin, bone marrow (BM), spleen, liver, and gastrointestinal tract. The World Health Organization classification divides the disease into prognostically distinct variants of cutaneous mastocytosis (CM) and systemic mastocytosis (SM). Although this classification remains valid, recent developments in the field and the advent of new diagnostic and prognostic parameters created a need to update and refine definitions and diagnostic criteria in MC neoplasms. In addition, MC activation syndromes (MCAS) and genetic features predisposing to SM and MCAS have been identified. To discuss these developments and refinements in the classification, we organized a Working Conference comprised of experts from Europe and the United States in August 2020. This article reports on outcomes from this conference. Of particular note, we propose adjustments in the classification of CM and SM, refinements in diagnostic criteria of SM variants, including smoldering SM and BM mastocytosis (BMM), and updated criteria for MCAS and other conditions involving MC. CD30 expression in MC now qualifies as a minor SM criterion, and BMM is now defined by SM criteria, absence of skin lesions and absence of B- and C-findings. A basal serum tryptase level exceeding 20 ng/mL remains a minor SM criterion, with recognition that hereditary alpha-tryptasemia and various myeloid neoplasms may also cause elevations in tryptase. Our updated proposal will support diagnostic evaluations and prognostication in daily practice and the conduct of clinical trials in MC disorders., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Aspirin-exacerbated respiratory disease and some cases of chronic idiopathic urticaria are disorders in which increased baseline urinary excretion of leukotriene(LT)E4 further increases following aspirin administration. Increased urinary excretion of the metabolites of prostaglandin D2, 11β-prostaglandin(PG)F2α and (2,3-dinor)-11β-PGF2α, have been documented in systemic mastocytosis (SM) and in mast cell activation syndrome (MCAS). Symptoms due to increased baseline and/or episodic release of PGD2 can be prevented with aspirin, an inhibitor of cyclooxygenase (COX)1 and COX2. Here by retrospective chart review we discovered 8 of 10 patients with SM in whom normalization of an elevated urinary (2,3-dinor)-11β-PGF2α occurred with aspirin therapy also had a parallel increased excretion of LTE4 by an average of nearly 13-fold. How widespread this phenomenon occurs in SM is unknown; however, this occurrence needs to be considered when interpreting changes in these urinary mast cell mediator metabolites during aspirin therapy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Mastocytosis is a neoplasm characterized by an accumulation of mast cells in various organs and increased risk for severe anaphylaxis in patients with concomitant allergies. Coronavirus disease 2019 (COVID-19) is a pandemic that is associated with a relatively high rate of severe lung disease and mortality. The mortality is particularly high in those with certain comorbidities and increases with age. Recently, several companies have developed an effective vaccination against COVID-19. Although the reported frequency of severe side effects is low, there is an emerging discussion about the safety of COVID-19 vaccination in patients with severe allergies and mastocytosis. However, even in these patients, severe adverse reactions are rare. We therefore recommend the broad use of COVID-19 vaccination in patients with mastocytosis on a global basis. The only well-established exception is a known or suspected allergy against a constituent of the vaccine. Safety measures, including premedication and postvaccination observation, should be considered in all patients with mastocytosis, depending on the individual personal risk and overall situation in each case. The current article provides a summary of published data, observations, and expert opinion that form the basis of these recommendations., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The syndrome of episodic angioedema with eosinophilia, first reported over 40 years ago, is a hypereosinophilic disorder that, uniquely, is not associated with end-organ pathology. However, patients develop a constellation of symptoms that include angioedema, urticaria, fatigue, and fever. Episodes are accompanied by massive hypereosinophilia and weight gain. Type II serum cytokine levels (IL-5, IL-13, IL-9, and IL-10) show cyclic variations peaking at or just prior to the peak of eosinophilia and an abnormal Th2 cell phenotype has been reported. Attacks may occur with predictable regularity and have been described in both adults and children. Glucocorticoid therapy reliably reverses symptoms with accompanying diuresis, defervesce, and normalization of the eosinophil count. In this report, a patient who had the syndrome of episodic angioedema with eosinophilia exceeding 20 years is reported. He has had no end-organ damage to date. Testing for the CHIC 2 deletion, a surrogate for the FIP1L1-PDGFRA fusion, was negative. Use of imatinib mesylate, initially as a steroid-sparing agent, and subsequently as a maintenance medication, plus low-dose prednisone has provided long-term control of hypereosinophilia and all clinical manifestations.

The coronavirus disease 2019 (COVID-19) (caused by severe acute respiratory syndrome coronavirus 2) pandemic has massively distorted our health care systems and caused catastrophic consequences in our affected communities. The number of victims continues to increase, and patients at risk can only be protected to a degree, because the virulent state may be asymptomatic. Risk factors concerning COVID-19-induced morbidity and mortality include advanced age, an impaired immune system, cardiovascular or pulmonary diseases, obesity, diabetes mellitus, and cancer treated with chemotherapy. Here, we discuss the risk and impact of COVID-19 in patients with mastocytosis and mast cell activation syndromes. Because no published data are yet available, expert opinions are, by necessity, based on case experience and reports from patients. Although the overall risk to acquire the severe acute respiratory syndrome coronavirus 2 may not be elevated in mast cell disease, certain conditions may increase the risk of infected patients to develop severe COVID-19. These factors include certain comorbidities, mast cell activation-related events affecting the cardiovascular or bronchopulmonary system, and chemotherapy or immunosuppressive drugs. Therefore, such treatments should be carefully evaluated on a case-by-case basis during a COVID-19 infection. In contrast, other therapies, such as anti-mediator-type drugs, venom immunotherapy, or vitamin D, should be continued. Overall, patients with mast cell disorders should follow the general and local guidelines in the COVID-19 pandemic and advice from their medical provider., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Although 4 mast cell mediators can be routinely measured, the results of initial testing to evaluate symptoms of mast cell activation have not been widely reported., Objective: We examined the results of mast cell mediator tests used to assess patients with mast cell activation symptoms during a 5-year time span., Methods: After excluding patients with alternative diagnoses, records of 108 patients were reviewed for initial mediator test results. Mediators included serum tryptase plus urinary N-methyl histamine (N-MH), leukotriene (LT)E4, and 11β-prostaglandin (PG) F2α or 2,3-dinor-11β-PGF2α (BPG)., Results: Most commonly, either a single measured elevation of 1 mediator (48.1%) or elevations of 2 (33.3%) mediators was found at baseline, during symptoms or at both time points. Elevated levels of a single mediator in order of frequency were: BPG > tryptase > LTE4 > N-MH, and for two mediators: BPG + tryptase (n = 16 cases) > BPG + LTE4 (n = 9) > BPG + N-MH (n = 6). Elevations in 3 mediators (n = 8) or 4 mediators (n = 2) were much less frequent. Monoclonal mast cell activation syndrome (n = 6), and systemic and cutaneous mastocytosis (n = 4) were also infrequent. Baseline plus symptom-associated tryptase values were obtained in only 7 patients., Conclusions: This survey suggests that elevations of 1 or 2 mediators are the most common (total 81.4% of cases) findings from initial tests for mast cell activation. Elevated levels of BPG were most commonly found both singly and in combination with other mediators, followed by the finding of elevated levels of tryptase. Baseline plus symptom-associated tryptase levels were measured in only a minority of patients., (© 2019 S. Karger AG, Basel.)

Our current recommendations for diagnosing and treating primary mast cell (MC) activation syndrome make use of the latest studies and consensus guidelines for clinically recognizing systemic anaphylaxis in real time, regardless of whether allergen-triggered or other pathways are involved; our current understanding of the biomarkers secreted by activated MCs that best discriminate this disorder from other conditions; and the therapeutic drugs that might selectively affect those mediators or MCs themselves. Finding familial or somatic mutations of genes that cause MCs to be hyperactivatable would extend our diagnostic tools and potentially indicate new therapeutic interventions, targeting either the mutated gene product or the associated molecular pathway. In conclusion, we trust that the clinical, laboratory, and therapeutic criteria for primary MC activation syndromes described herein will provide clinicians with practical criteria of sufficient sensitivity and specificity to diagnose most cases without overdiagnosing the disorder in patients who likely have other conditions., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Mast cell activation (MCA) accompanies diverse physiologic and pathologic processes and is one of the more frequently encountered conditions in medicine. MCA-related symptoms are usually mild and often transient. In such cases, histamine receptor blockers and other mediator-targeting drugs can usually control MCA. In severe cases, an MCA syndrome (MCAS) may be diagnosed. However, overt MCAS is an unusual condition, and many patients referred because of suspected MCAS are diagnosed with other diseases (autoimmune, neoplastic, or infectious) unrelated to MCA or suffer from MCA-related (eg, allergic) disorders and/or comorbidities without fulfilling criteria of an overt MCAS. These considerations are important as more and more patients are informed that they may have MCA or even MCAS without completing a thorough medical evaluation. In fact, in several instances, symptoms are misinterpreted as MCA/MCAS, and other clinically relevant conditions are not thoroughly pursued. The number of such referrals is increasing. To avoid such unnecessary referrals and to prevent misdiagnoses, we here propose a diagnostic algorithm through which a clinically relevant (systemic) MCA can be suspected and MCAS can subsequently be documented or excluded. In addition, the algorithm proposed should help guide the investigating care providers to consider the 2 principal diagnoses that may underlie MCAS, namely, severe allergy and systemic mastocytosis accompanied by severe MCA. Although validation is required, we anticipate that this algorithm will facilitate the management of patients with suspected MCAS., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Providers caring for patients with mastocytosis are tasked with the decision to consider therapeutic options. This can come with some trepidation because information available in the public domain lists numerous mast cell (MC) activators based on data that do not discriminate between primates, rodents, and MC lines; do not consider dosage; and do not take into account previous exposure and resultant clinical findings. This being said, there is support in the literature for an enhanced MC response in some patients with mastocytosis and in cases in which there is a greater incidence of adverse reactions associated with certain antigens, such as venoms and drugs. Thus this report provides a comprehensive guide for those providers who must decide on therapeutic options in the management of patients with clonal MC disease., (Copyright © 2019. Published by Elsevier Inc.)

Mast cell activation syndrome (MCAS) is a condition characterized by recurrent episodes of clinically relevant, systemic, severe reactions to mast cell (MC)-derived mediators released in the context of anaphylaxis or another acute MC-related event. It is important to document MC involvement in these reactions in order to establish the diagnosis MCAS. The most specific and reliable marker of systemic MC activation is an acute and substantial event-related (transient) increase in the serum tryptase level over the individual's baseline value. However, the baseline level of tryptase varies depending on the underlying disease and the genetic background. For example, an estimated 3-5% of healthy individuals exhibit duplications or multiple copies of the TPSAB1 gene encoding for alpha-tryptase, and over 30% of all patients with myeloid neoplasms, including mastocytosis, have elevated basal tryptase levels. Therefore, it is of utmost importance to adjust the event-related diagnostic (MCAS-confirming) increase in tryptase over the individual baseline in a robust approach. To address this challenge, the 20% + 2 formula was proposed by the consensus group in 2012. Since then, this approach has been validated in clinical practice by independent groups and found to be sound. In the current article, we discuss the emerging importance and value of the 20% + 2 formula in clinical practice and its role as a criterion of severe systemic MC activation and MCAS., (© 2019 S. Karger AG, Basel.)

Mastocytosis is a term used to denote a group of rare diseases characterized by an abnormal accumulation of neoplastic mast cells in various tissues and organs. In most patients with systemic mastocytosis, the neoplastic cells carry activating mutations in KIT Progress in mastocytosis research has long been hindered by the lack of suitable in vitro models, such as permanent human mast cell lines. In fact, only a few human mast cell lines are available to date: HMC-1, LAD1/2, LUVA, ROSA and MCPV-1. The HMC-1 and LAD1/2 cell lines were derived from patients with mast cell leukemia. By contrast, the more recently established LUVA, ROSA and MCPV-1 cell lines were derived from CD34 + cells of non-mastocytosis donors. While some of these cell lines (LAD1/2, LUVA, ROSA KIT WT and MCPV-1) do not harbor KIT mutations, HMC-1 and ROSA KIT D816V cells exhibit activating KIT mutations found in mastocytosis and have thus been used to study disease pathogenesis. In addition, these cell lines are increasingly employed to validate new therapeutic targets and to screen for effects of new targeted drugs. Recently, the ROSA KIT D816V subclone has been successfully used to generate a unique in vivo model of advanced mastocytosis by injection into immunocompromised mice. Such a model may allow in vivo validation of data obtained in vitro with targeted drugs directed against mastocytosis. In this review, we discuss the major characteristics of all available human mast cell lines, with particular emphasis on the use of HMC-1 and ROSA KIT D816V cells in preclinical therapeutic research in mastocytosis., (Copyright© 2018 Ferrata Storti Foundation.)

Objective: A growing number of cancer antineoplastic agents can cause life-threatening acute infusion reactions. Because previous studies have not studied these reactions from the perspective of patients, this study was undertaken with that objective in mind., Methods: Patients who had an acute infusion reaction were interviewed based on the Leventhal model. Once saturation of content was achieved, interviews were transcribed and analyzed with qualitative methodology., Results: Twenty-one patients were enrolled. Most were women (n = 15); the median age was 58 years, and paclitaxel was the most common inciting agent. Three themes emerged. First, these reactions are frightening; patients made remarks such as "I was just thinking oh my God, I am dying." Second, prior education about these reactions seemed to mitigate this fear, "Basically everything the nurses told me potentially could happen, like happened. So, I was prepared." Third, when health-care providers were prompt and attentive during the reaction, patients described less fear with future chemotherapy, "So no, I'm really not fearful about going in tomorrow because I know they'll be there and they'll be watching me.", Conclusion: These reactions evoke fear which can be mitigated with education prior to and with prompt responsiveness during the acute infusion reaction.

Mast cells leave evidence, a "fingerprint," of their participation in acute and chronic clinical events. That fingerprint is an elevation, either chronic or acute, in levels of their secreted mediators or their metabolites. Of these, only serum tryptase is currently one of the diagnostic criteria for systemic mastocytosis or mast cell activation. Combinations of easily obtained and quantified urinary mast cell mediator metabolite levels correlate well with bone marrow findings of systemic mastocytosis. By inhibiting synthesis of or blockading receptors to the elevated mast cell mediator, relief of clinical symptoms can often be achieved., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To compare echocardiograms and endomyocardial biopsies to diagnose cardiac involvement in hypereosinophilic syndrome., Methods: We examined the agreement between echocardiography and endomyocardial biopsies to detect cardiac involvement in hypereosinophilic syndrome by reviewing cases identified as hypereosinophilia or hypereosinophilic syndrome in Mayo Clinic databases from January 1978 through June 2009. Single-organ cases of eosinophilia such as eosinophilic fasciitis and eosinophilic gastroenteritis were excluded. We recorded echocardiogram and endomyocardial biopsy results including biopsy staining for eosinophil granule major basic protein (if performed). Clinical and laboratory features documented included presenting symptom(s), maximum total eosinophil count, dose of prednisone (if any) and eosinophil count at the time of endomyocardial biopsy, cardiac enzymes, serum tryptase level, electrocardiogram result, the result of testing for the FIP1L1-PDGFRA fusion gene, complications associated with the biopsy procedures and available follow-up information., Results: From a total of 387 patients' records screened 288 met the criteria for hypereosinophilic syndrome and of these 240 had echocardiograms. Among these patients there were 138 normal echocardiograms, 67 had echocardiograms without findings of hypereosinophilic syndrome but with one or more other abnormalities, and 35 had echocardiograms with findings consistent with hypereosinophilic syndrome. Twenty-five patients from this group of 35 patients had both echocardiogram and endomyocardial biopsy. In 15 patients there was agreement between both endomyocardial biopsy and echocardiography as to the presence (n = seven) or absence (n = eight) for findings of cardiac involvement. In 10 of 25 patients test results diverged: 3 patients with positive echocardiographic changes did not have confirmatory findings by endomyocardial biopsy and seven patients with positive biopsy findings had echocardiograms without findings of hypereosinophilic syndrome., Conclusions: Echocardiograms and endomyocardial biopsies agree for presence or absence of cardiac involvement 60% of the time. Endomyocardial biopsy detected cardiac involvement in 7 patients in whom the echocardiogram was negative for findings of hypereosinophilic syndrome.

Objective/hypothesis: Eosinophilic otitis media (EOM) is a variant of chronic otitis media that is characterized by the development of thick mucoid middle ear effusion, adult onset bronchial asthma, sinonasal polyposis, and aspirin sensitivity. EOM is typically refractory to corticosteroid therapy and surgical intervention. Pegylated interferon (PEG-IFN) has effectively treated hypereosinophilic syndrome in clinical trials; however, the efficacy of this medication for EOM treatment remains undefined., Study Design: Retrospective, case series, tertiary academic center., Methods: A retrospective chart review was performed on EOM patients from 2008-2014. A total of 32 patients met the clinical criteria for EOM according to established diagnostic guidelines. Outcomes of all patients with severe, refractory EOM who initiated PEG-IFN therapy are reported., Results: Eight patients were treated with pegylated interferon-α 2a or 2b for refractory EOM. Half of the patients had significant side effects with interferon treatment. Three of these were able to continue at a reduced dosage without side effect reoccurrence, and one patient stopped the medication permanently. Four of eight (50%) patients had a complete clinical response with total resolution of otorrhea and normalization of middle ear mucosa, and were able to discontinue corticosteroid treatment. Two patients attempted to stop PEG-IFN therapy after prolonged symptom remission and had recurrent otorrhea. Both patients had symptom resolution after PEG-IFN reinitiation., Conclusions: These data demonstrate that pegylated interferon-α 2a and 2b therapy may benefit patients with severe, refractory EOM. Further larger studies with long-term follow-up are required to validate these early but promising results., Level of Evidence: 4. Laryngoscope, 127:1208-1216, 2017., (© 2016 The American Laryngological, Rhinological and Otological Society, Inc.)

The development and utilization of monoclonal antibodies (mAbs) have been of great interest in all fields of medicine. A substantial increase in the production and development of mAbs has occurred because these biologic agents are proving to be effective and less toxic given their targeted mechanism of action. However, data are limited on coadministration of two or more mAbs. With the increasing availability of mAbs and the comorbidities of some patients, assessment is needed of the ability to safely use multiple mAbs for an individual patient. Although the efficacy of coadministered mAbs may be inferred from their specific targets, we could find no literature reporting such a finding. Herein, we report our experience using two different classes of mAbs to treat hypereosinophilic syndrome and ulcerative colitis in a single patient.

Acute myelogenous leukemia (AML) carrying t(8;21)(q22;q22) or inv(16)/t(16;16)(p13;q22) is classified as core binding factor (CBF)-AML and accounts for approximately 15% of AML. c-KIT mutation can be detected in 17%∼46% of CBF-AML and is associated with poor prognosis. c-KIT mutation is a crucial hit and cooperates with AML1-ETO resulting from t(8;21)(q22;q22) to cause overt AML. Tyrosine kinase inhibitors (TKI) targeting c-KIT, such as imatinib, has been used successfully to treat c-KIT driven gastrointestinal stromal tumors. However, the effect of TKI on c-KIT-driven leukemia, including CBF-AML and systemic mastocytosis (SM), has not been satisfactory. BPR1J373 is a 5-phenylthiazol-2-ylamine-pyriminide derivative targeting multiple tyrosine kinases. It was shown to inhibit cell proliferation and induce apoptosis in AML cells with constitutively activated c-KIT via inhibiting c-KIT phosphorylation and its downstream signals. The compound induced apoptosis by the mitochondrial intrinsic pathway through upregulation of proapoptotic proteins Bax and Bak and caspase 8 and 9 activation in c-KIT mutant Kasumi-1 cells. Furthermore, it induced cell-cycle arrest via targeting aurora kinase B in c-KIT wild-type KG-1 cells. The antitumor response of BPR1J373 was also shown in subcutaneously grafted SCID mice. BPR1J373 was shown to effectively suppress c-KIT phosphorylation of D816V mutation by treating c-KIT-null COS-1 cells transfected with c-KIT D816V mutant plasmid. In conclusion, BPR1J373 inhibits cell proliferation of c-KIT-driven AML cells via induction of apoptosis and cell-cycle arrest. It is also effective for multiple drug-resistant c-KIT D816V mutation. BPR1J373 deserves further development for clinical use in c-KIT-driven myeloid leukemia. Mol Cancer Ther; 15(10); 2323-33. ©2016 AACR., (©2016 American Association for Cancer Research.)

Objectives: Systemic mastocytosis (SM) is a disorder characterized by the excessive accumulation of clonally derived mast cells in various tissues. When triggered, mast cells release large amounts of histamine, prostaglandins and leukotrienes. Leukotriene E4 (LTE4) is the primary stable metabolite of total cysteinyl leukotrienes. We hypothesized that secretion of LTE4 would be increased in SM and could be used alone or in combination with current urinary biomarkers to optimize screening for SM., Design and Methods: LTE4 was measured by liquid chromatography followed by tandem mass spectrometry (LC-MS/MS). Analytical assay validation was performed using residual urine specimens. LTE4 results were normalized to urine creatinine for clinical use. Reference interval was established using a healthy volunteer cohort. Clinical sensitivity and specificity for SM detection were determined by measuring urinary biomarkers (LTE4, N-methyl histamine [NMH] and 11β-prostaglandin F2α [BPG]) in a cohort of 409 patients referred to allergy specialists, 66 (16%) of which were diagnosed with SM., Results: Urinary LTE4 measurement was accurate, precise and linear across a range of 31-3020pg/mL. The 95th percentile of the reference interval population was <104pg/mg creatinine. Median urine LTE4 concentrations were significantly higher among patients with SM (97pg/mg cr. vs. 50pg/mg cr.; p<0.01). Elevated urinary LTE4 was 48% sensitive and 84% specific for SM. Clinical sensitivity was 53% for BPG (>1000ng/mL) and 71% for NMH (>200ng/mL). Incorporating all three urinary metabolites improved the SM diagnostic sensitivity to 97%, with minimal change in specificity., Conclusions: We have developed a sensitive and precise LC-MS/MS assay for quantitation of LTE4 in urine. Incorporating LTE4 into a panel including BPG and NMH provides a much-needed screening tool for a complicated disease with non-specific symptoms and invasive confirmatory testing., (Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

We examined whether tamoxifen citrate at 20mg/day for 1 year had a beneficial effect on laboratory findings, bone marrow mastocytosis, common clinical symptoms, or quality-of-life assessment for 5 women and 2 men with indolent systemic mastocytosis. Tamoxifen was well tolerated. We found significant reductions in the platelet count, serum alkaline phosphatase, and 24-h urinary excretion of N-methylhistamine and significant increases in serum lactate dehydrogenase and (excluding 2 patients taking aspirin) in 24-h urinary excretion of 11β-prostaglandin F2α. Overall, no change occurred in percent involvement of bone marrow by mastocytosis. Symptom scores were mild and did not change during the treatment. The 36-Item Short Form Health Survey scores for quality of life physical and mental components showed no marked changes. Tamoxifen, an older, nonhematotoxic medication, has limited activity in systemic mastocytosis at the dosage used in this study., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Mast cell (MC) disease has long been thought to be just the rare disease of mastocytosis (in various forms, principally cutaneous and systemic), with aberrant MC mediator release at symptomatic levels due to neoplastic MC proliferation. Recent discoveries now show a new view is in order, with mastocytosis capping a metaphorical iceberg now called "MC activation disease" (MCAD, i.e. disease principally manifesting inappropriate MC activation), with the bulk of the iceberg being the recently recognized "MC activation syndrome" (MCAS), featuring inappropriate MC activation to symptomatic levels with little to no inappropriate MC proliferation. Given increasing appreciation of a great menagerie of mutations in MC regulatory elements in mastocytosis and MCAS, the great heterogeneity of MCAD's clinical presentation is unsurprising. Most MCAD patients present with decades of chronic multisystem polymorbidity generally of an inflammatory ± allergic theme. Preliminary epidemiologic investigation suggests MCAD, while often misrecognized, may be substantially prevalent, making it increasingly important that practitioners of all stripes learn how to recognize its more common forms such as MCAS. We review the diagnostically challenging presentation of MCAD (with an emphasis on MCAS) and current thoughts regarding its biology, epidemiology, natural history, diagnostic evaluation, and treatment.

Cutaneous lesions in patients with mastocytosis are highly heterogeneous and encompass localized and disseminated forms. Although a classification and criteria for cutaneous mastocytosis (CM) have been proposed, there remains a need to better define subforms of cutaneous manifestations in patients with mastocytosis. To address this unmet need, an international task force involving experts from different organizations (including the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology) met several times between 2010 and 2014 to discuss the classification and criteria for diagnosis of cutaneous manifestations in patients with mastocytosis. This article provides the major outcomes of these meetings and a proposal for a revised definition and criteria. In particular, we recommend that the typical maculopapular cutaneous lesions (urticaria pigmentosa) should be subdivided into 2 variants, namely a monomorphic variant with small maculopapular lesions, which is typically seen in adult patients, and a polymorphic variant with larger lesions of variable size and shape, which is typically seen in pediatric patients. Clinical observations suggest that the monomorphic variant, if it develops in children, often persists into adulthood, whereas the polymorphic variant may resolve around puberty. This delineation might have important prognostic implications, and its implementation in diagnostic algorithms and future mastocytosis classifications is recommended. Refinements are also suggested for the diagnostic criteria of CM, removal of telangiectasia macularis eruptiva perstans from the current classification of CM, and removal of the adjunct solitary from the term solitary mastocytoma., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Certain hematologic malignancies are associated with hypereosinophilia or tissue eosinophilia. It is unclear if patients with hypereosinophilia are more likely to develop one of these malignancies., Objective: This study sought to quantify the specific hematologic malignancies that developed in patients with preexisting hypereosinophilia., Methods: Adult patients with eosinophilia associated with the development of hematologic malignancy were identified by a retrospective review of the Mayo Clinic patient database between 2000 and 2013., Results: Of 2642 patients identified with eosinophilia, hypereosinophilia, or hypereosinophilic syndrome, 25 (aged 28.8 to 86.1 years; 13 male; 12 female) had a diagnosis of either lymphoma or leukemia. The majority of these patients had non-Hodgkin lymphoma (17 of 25). T-cell-derived lymphomas were more common (12 of 17) than B-cell-derived lymphomas (4 of 17). In patients with leukemia (8 of 25), chronic lymphocytic leukemia (4 of 8) was most common, followed by chronic eosinophilic leukemia (3 of 8). Approximately 5.1% of patients with hypereosinophilia developed a hematologic malignancy. On average, the malignancy developed 30.0 ± 42.7 months after the onset of hypereosinophilia., Conclusions: The development of hematologic malignancies in this referral population with eosinophilia was rare (0.2%), but more common in those with hypereosinophilia (5.1%). Non-Hodgkin's lymphomas, particularly T-cell-derived malignancies, were most commonly diagnosed. Patients with preexisting hypereosinophilia were diagnosed with hematologic conditions that were rarer within the general population., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)