Explore the vast range of titles available.

Indolent systemic mastocytosis, including the subvariant of smouldering systemic mastocytosis, is a lifelong condition associated with reduced quality of life. Masitinib inhibits KIT and LYN kinases that are involved in indolent systemic mastocytosis pathogenesis. We aimed to assess safety and efficacy of masitinib versus placebo in severely symptomatic patients who were unresponsive to optimal symptomatic treatments. In this randomised, double-blind, placebo-controlled, phase 3 study, we enrolled adults (aged 18–75 years) with indolent or smouldering systemic mastocytosis, according to WHO classification or documented mastocytosis based on histological criteria, at 50 centres in 15 countries. We excluded patients with cutaneous or non-severe systemic mastocytosis after a protocol amendment. Patients were centrally randomised (1:1) to receive either oral masitinib (6 mg/kg per day over 24 weeks with possible extension) or matched placebo with minimisation according to severe symptoms. The primary endpoint was cumulative response (≥75% improvement from baseline within weeks 8–24) in at least one severe baseline symptom from the following: pruritus score of 9 or more, eight or more flushes per week, Hamilton Rating Scale for Depression of 19 or more, or Fatigue Impact Scale of 75 or more. We assessed treatment effect using repeated measures methodology for rare diseases via the generalised estimating equation model in a modified intention-to-treat population, including all participants assigned to treatment minus those who withdrew due to a non-treatment-related cause. We assessed safety in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00814073. Between Feb 19, 2009, and July 15, 2015, 135 patients were randomly assigned to masitinib (n=71) or placebo (n=64). By 24 weeks, masitinib was associated with a cumulative response of 18·7% in the primary endpoint (122·6 responses of 656·5 possible responses [weighted generalised estimating equation]) compared with 7·4% for placebo (48·9 of 656·5; difference 11·3%; odds ratio 3·6; 95% CI 1·2–10·8; p=0·0076). Frequent severe adverse events (>4% difference from placebo) were diarrhoea (eight [11%] of 70 in the masitinib group vs one [2%] of 63 in the placebo group), rash (four [6%] vs none), and asthenia (four [6%] vs one [2%]). The most frequent serious adverse events were diarrhoea (three patients [4%] vs one [2%]) and urticaria (two [3%] vs none), and no life-threatening toxicities occurred. One patient in the placebo group died (unrelated to study treatment). These study findings indicate that masitinib is an effective and well tolerated agent for the treatment of severely symptomatic indolent or smouldering systemic mastocytosis. AB Science (Paris, France).

Mast cell activation disease comprises disorders characterized by accumulation of genetically altered mast cells and/or abnormal release of these cells' mediators, affecting functions in potentially every organ system, often without causing abnormalities in routine laboratory or radiologic testing. In most cases of mast cell activation disease, diagnosis is possible by relatively non-invasive investigation. Effective therapy often consists simply of antihistamines and mast cell membrane-stabilising compounds supplemented with medications targeted at specific symptoms and complications. Mast cell activation disease is now appreciated to likely be considerably prevalent and thus should be considered routinely in the differential diagnosis of patients with chronic multisystem polymorbidity or patients in whom a definitively diagnosed major illness does not well account for the entirety of the patient's presentation.

This article reviews the diagnostically challenging presentation of mast cell activation disease (MCAD) and current thoughts regarding interactions between microbiota and MCs. A search for all studies on interactions between mast cells, mast cell activation disease, and microbiota published on pubmed.gov and scholar.google.com between 1960 and 2015 was conducted using the search terms mast cell, mastocyte, mastocytosis, mast cell activation, mast cell activation disease, mast cell activation syndrome, microbiome, microbiota. A manual review of the references from identified studies was also conducted. Studies were excluded if they were not accessible electronically or by interlibrary loan. Research increasingly is revealing essential involvement of MCs in normal human biology and in human disease. Via many methods, normal MCs—present sparsely in every tissue—sense their environment and reactively exert influences that, directly and indirectly, locally and remotely, improve health. The dysfunctional MCs of the “iceberg” of MCAD, on the other hand, sense abnormally, react abnormally, activate constitutively, and sometimes (in mastocytosis, the “tip” of the MCAD iceberg) even proliferate neoplastically. MCAD causes chronic multisystem illness generally, but not necessarily, of an inflammatory ± allergic theme and with great variability in behavior among patients and within any patient over time. Furthermore, the range of signals to which MCs respond and react include signals from the body’s microbiota, and regardless of whether an MCAD patient has clonal mastocytosis or the bulk of the iceberg now known as MC activation syndrome (also suspected to be clonal but without significant MC proliferation), dysfunctional MCs interact as dysfunctionally with those microbiota as they interact with other human tissues, potentially leading to many adverse consequences. Interactions between microbiota and MCs are complex at baseline. The potential for both pathology and benefit may be amplified when compositionally variant microbiota interact with aberrant MCs in various types of MCAD. More research is needed to better understand and leverage these interactions.

Background: Chemical Intolerance (CI) is characterized by intolerances for chemicals, foods, and drugs with multi-system symptoms. As yet, the biomechanism remains unclear. One study reported converging lines of evidence supporting a substantive association between mast cell activation syndrome (MCAS) and CI. The purpose of this study is to (1) confirm a previous report demonstrating that 60% of MCAS patients report CI and (2) examine the parallels between symptoms and intolerances in CI and MCAS. Methods: Five hundred forty-four MCAS patients were assigned a clinical MCAS score using a validated assessment instrument and were assessed for CI using the validated Quick Environmental Exposure Sensitivity Index. Results: Our outcomes confirm the previously published study where the majority of MCAS patients also have CI. There was a clear overlap between various ICD-10 diagnostic categories and CI symptoms, providing further support for a potential shared mechanism. Conclusions: Exposures to pesticides, volatile organic compounds, combustion products, and mold have previously been reported as initiators of CI. However, until recently, little was known about the biological mechanism involved that could explain the multisystem symptoms associated with CI. This paper addresses a newly identified biomechanism for disease, which may underlie a host of “medically unexplained symptoms” triggered by xenobiotics.

For nearly a decade, case reports and series have emerged regarding dysautonomias—particularly postural orthostatic tachycardia syndrome (POTS)—presenting soon after vaccination against human papilloma virus (HPV). We too have observed a number of such cases (all following vaccination with the Gardasil product), and have found several to have detectable mast cell activation syndrome (MCAS) as well as histories suggesting that MCAS was likely present long before vaccination. We detail 11 such cases here, posing a hypothesis that HPV vaccination (at least with the Gardasil product) may have triggered or exacerbated MCAS in teenagers previously not recognized to have it. Only recently recognized, MCAS is being increasingly appreciated as a prevalent and chronic multisystem disorder, often emerging early in life and presenting with inflammatory ± allergic phenomena following from known mast cell (MC) mediator effects. There is rising recognition, too, of associations of MCAS with central and peripheral neuropathic disorders, including autonomic disorders such as POTS. Given the recognized potential for many antigens to trigger a major and permanent escalation of baseline MC misbehavior in a given MCAS patient, we hypothesize that in our patients described herein, vaccination with Gardasil may have caused pre-existing (but not yet clinically recognized) MCAS to worsen to a clinically significantly degree, with the emergence of POTS and other issues. The recognition and management of MCAS prior to vaccinations in general may be a strategy worth investigating for reducing adverse events following HPV vaccinations and perhaps even other types of vaccinations.

Mast cells (MCs) occupy a central role in immunological as well as non-immunological processes as reflected in the variety of the mediators by which MCs influence other cells. Published lists of MC mediators have all shown only subsets—usually quite small—of the full repertoire. The full repertoire of MC mediators released by exocytosis is comprehensively compiled here for the first time. The compilation of the data is essentially based on the largely cytokine-focused database COPE ® , supplemented with data on the expression of substances in human MCs published in several articles, plus extensive research in the PubMed database. Three hundred and ninety substances could be identified as mediators of human MCs which can be secreted into the extracellular space by activation of the MC. This number might still be an underestimate of the actual number of MC mediators since, in principle, all substances produced by MCs can become mediators because of the possibility of their release by diffusion into the extracellular space, mast cell extracellular traps, and intercellular exchange via nanotubules. When human MCs release mediators in inappropriate manners, this may lead to symptoms in any or all organs/tissues. Thus, such MC activation disorders may clinically present with a myriad of potential combinations of symptoms ranging from trivial to disabling or even life-threatening. The present compilation can be consulted by physicians when trying to gain clarity about MC mediators which may be involved in patients with MC disease symptoms refractory to most therapies.

Mast cell activation syndrome is thought to be a common, yet under-recognized, chronic multi-system disorder caused by inappropriate mast cell activation. Gastrointestinal symptoms are frequently reported by these patients and are often mistaken by physicians as functional gastrointestinal disorders. This syndrome can be diagnosed by the medical history and measurable biomarkers. Gastroenterologists manage diseases associated with active inflammatory cells including neutrophils, lymphocytes, macrophages, and eosinophils. The mast cell has only recently been recognized as a major player in our specialty. Gastrointestinal disorders from mast cell mediators often present with apparent irritable bowel syndrome, dyspepsia, chronic or cyclical nausea, and heartburn. Individuals with mast cell activation syndrome experience significant delays in diagnosis. The gastrointestinal symptoms are often refractory to symptom-targeted prescription medications. Beyond avoiding triggers, the best therapy is directed at modulating mast cell activation and the effects of the mediators. Many of these therapies are simple over-the-counter medications. In this article, we review mast cell function and dysfunction and the gastrointestinal symptoms, comorbid conditions, diagnosis, and management of mast cell activation syndrome. Gastroenterologists who become aware of this syndrome can dramatically improve the quality of life for their patients who previously have been labeled with a functional gastrointestinal disorder.

Background:  It has been shown repeatedly that mast cells can promote or prevent cancer development and growth. If development and/or progression of a solid cancer is substantially influenced by mast cell activity, the frequencies of occurrence of solid cancers in patients with primary mast cells disorders would be expected to differ from the corresponding prevalence data in the general population. In fact, a recent study demonstrated that patients with systemic mastocytosis (i.e., a rare neoplastic variant of the primary mast cell activation disease) have increased risk for solid cancers, in particular melanoma and non-melanoma skin cancers. The aim of the present study is to examine whether the risk of solid cancer is increased in systemic mast cell activation syndrome (MCAS), the common systemic variant of mast cell activation disease. Methods: In the present descriptive study, we have analysed a large (n=828) patient group with MCAS, consisting of cohorts from Germany and the USA, for occurrence of solid forms of cancer and compared the frequencies of the different cancers with corresponding prevalence data for German and U.S. general populations. Results: Sixty-eight of the 828 MCAS patients (46 female, 22 male) had developed a solid tumor before the diagnosis of MCAS was made. Comparison of the frequencies of the malignancies in the MCAS patients with their prevalence in the general population revealed a significantly increased prevalence for melanoma and cancers of the breast, cervix uteri, ovary, lung, and thyroid in MCAS patients. Conclusions: Our data support the view that mast cells may promote development of certain malignant tumors. These findings indicate a need for increased surveillance of certain types of cancer in MCAS patients irrespective of its individual clinical presentation.

Study Objectives: Sleep disturbance is common in long-COVID (LC). Restless legs syndrome (RLS) is characterized by sleep disturbance and has been reported after viral infections. Therefore, we evaluated RLS symptoms cross-sectionally in individuals with LC at both current and pre–coronavirus disease 2019 (pre-COVID-19) time points. Methods: Adults on LC-focused Facebook pages were recruited for an online assessment of symptoms before COVID-19 infection and during their present LC state in a cross-sectional manner. The LC group documented baseline symptoms retrospectively. Questions were included about the presence/severity of RLS symptoms and assessments of fatigue, quality of life, and sleep apnea. A control group was recruited and included individuals ≥ 18 years of age who never had overt symptoms of COVID-19. Pregnancy was an exclusion criterion for both groups. Results: There were 136 participants with LC (89.7% females, age 46.9 ± 12.9 years) and 136 controls (65.4% females, age 49.2 ± 15.5). RLS prevalence in females with LC was 5.7% pre-COVID-19 and 14.8% post-COVID-19 ( P < .01) vs 6.7% in control females. Severity of RLS was moderate in both groups. Logistic regression predicting post-COVID-19 RLS among females with LC failed to find significant effects of hospitalization, sleep apnea, neuropathic pain severity, or use of antihistamines and antidepressants. Conclusions: The baseline prevalence of RLS in females with LC was similar to the general population group as well as to patients in epidemiological studies. The prevalence significantly increased in the LC state. Postinfectious immunological mechanisms may be at play in the production for RLS symptoms. Citation: Weinstock LB, Brook JB, Walters AS, Goris A, Afrin LB, Molderings GJ. Restless legs syndrome is associated with long-COVID in women. J Clin Sleep Med . 2022;18(5):1413–1418.