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Blood Apr 2024
Topics: Humans; Bone Marrow; Mast-Cell Sarcoma
PubMed: 38635256
DOI: 10.1182/blood.2023023189 -
EJHaem Apr 2024
PubMed: 38633112
DOI: 10.1002/jha2.893 -
Indian Journal of Dermatology,... Feb 2024
PubMed: 38595013
DOI: 10.25259/IJDVL_712_2023 -
Blood Advances Jun 2024Certain laboratory abnormalities correlate with subvariants of systemic mastocytosis (SM) and are often prognostically relevant. To assess the diagnostic and prognostic...
Certain laboratory abnormalities correlate with subvariants of systemic mastocytosis (SM) and are often prognostically relevant. To assess the diagnostic and prognostic value of individual serum chemistry parameters in SM, 2607 patients enrolled within the European Competence Network on Mastocytosis and 575 patients enrolled within the German Registry on Eosinophils and Mast Cells were analyzed. For screening and diagnosis of SM, tryptase was identified as the most specific serum parameter. For differentiation between indolent and advanced SM (AdvSM), the following serum parameters were most relevant: tryptase, alkaline phosphatase, β2-microglobulin, lactate dehydrogenase (LDH), albumin, vitamin B12, and C-reactive protein (P < .001). With regard to subvariants of AdvSM, an elevated LDH of ≥260 U/L was associated with multilineage expansion (leukocytosis, r = 0.37, P < .001; monocytosis, r = 0.26, P < .001) and the presence of an associated myeloid neoplasm (P < .001), whereas tryptase levels were highest in mast cell leukemia (MCL) vs non-MCL (308μg/L vs 146μg/L, P = .003). Based on multivariable analysis, the hazard-risk weighted assignment of 1 point to LDH (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.1-4.0; P = .018) and 1.5 points each to β2-microglobulin (HR, 2.7; 95% CI, 1.4-5.4; P = .004) and albumin (HR, 3.3; 95% CI, 1.7-6.5; P = .001) delineated a highly predictive 3-tier risk classification system (0 points, 8.1 years vs 1 point, 2.5 years; ≥1.5 points, 1.7 years; P < .001). Moreover, serum chemistry parameters enabled further stratification of patients classified as having an International Prognostic Scoring System for Mastocytosis-AdvSM1/2 risk score (P = .027). In conclusion, serum chemistry profiling is a crucial tool in the clinical practice supporting diagnosis and prognostication of SM and its subvariants.
Topics: Humans; Mastocytosis, Systemic; Prognosis; Registries; Male; Female; Middle Aged; Adult; Aged; Biomarkers; Tryptases
PubMed: 38593217
DOI: 10.1182/bloodadvances.2024012756 -
International Archives of Allergy and... Apr 2024Mast cells are known for their involvement in allergic reactions but also in inflammatory reactions via secretion of numerous pro-inflammatory chemokines, cytokines, and...
INTRODUCTION
Mast cells are known for their involvement in allergic reactions but also in inflammatory reactions via secretion of numerous pro-inflammatory chemokines, cytokines, and enzymes. Drug development has focused on antiproliferative therapy for systemic mastocytosis and not on inhibitors of mast cell activation. The only drug available as a "mast cell blocker" is disodium cromoglycate (cromolyn), but it is poorly absorbed after oral administration, is a weak inhibitor of histamine release from human mast cells, and it develops rapid anaphylaxis. Instead, certain natural flavonoids, especially luteolin, can inhibit mast cell activation.
METHODS
Here, we compared pretreatment (0-120 min) with equimolar concentration (effective dose for 50% inhibition = 100 m
m for inhibition of histamine release by cromolyn) of cromolyn and luteolin on release of mediators from the cultured human LADR mast cell line stimulated either by immunoglobulin E (IgE) and anti-IgE or with IL-33.RESULTS
We show that luteolin is significantly more potent than cromolyn inhibiting release of histamine, tryptase, metalloproteinase-9, and vascular endothelial growth factor. Moreover, while luteolin also significantly inhibited release of IL-1β, IL-6, and IL-8 (CXCL8) and TNF, cromolyn had no effect.
CONCLUSION
These findings support the use of luteolin, especially in liposomal form to increase oral absorption, may be a useful alternative to cromolyn.
PubMed: 38588651
DOI: 10.1159/000537752 -
American Journal of Hematology Jun 2024Systemic mastocytosis (SM) corresponds to a rare and heterogeneous spectrum of diseases characterized by the accumulation of atypical mast cells (MCs). Advanced...
Systemic mastocytosis (SM) corresponds to a rare and heterogeneous spectrum of diseases characterized by the accumulation of atypical mast cells (MCs). Advanced mastocytosis (Adv-SM) is associated with poor survival; in contrast, patients with non-advanced SM (non-Adv-SM) usually have a normal life expectancy but may experience poor quality of life. Despite recent therapeutic progress including tyrosine kinase inhibitors, new treatment options are needed for refractory and/or intolerant patients with both severely symptomatic and Adv-SM. In vitro, the mTOR pathway is activated in MCs from patients bearing the KIT D816V mutation. Furthermore, rapamycin induces the apoptosis of KIT D816V MCs selectively. In this nationwide study, we report the outcomes of patients diagnosed with SM and treated with a mammalian target of rapamycin inhibitor (imTOR) within the French National Reference Center for mastocytosis (CEREMAST). All patients registered were relapsing, treatment-refractory, or ineligible for other cytoreductive therapy. Non-Adv-SM patients received imTOR as a monotherapy (rapamycin/everolimus), and Adv-SM patients received imTOR as a monotherapy or in combination with cytarabine. The objective response rate (ORR) in non-Adv-SM was 60% (partial response in 40% and major response in 20%), including reductions in skin involvement, mediator release symptoms, and serum tryptase. In the Adv-SM group, the ORR was 20% (including one major response and one partial response, both in patients with a KIT D816V mutation), which enabled a successful bridge to allogeneic stem cell transplantation in one patient. Our results suggest that imTOR treatment has potential benefits in patients with SM harboring a KIT D816V mutation.
Topics: Humans; Mastocytosis, Systemic; Pilot Projects; Female; Male; Middle Aged; Adult; France; Aged; Sirolimus; MTOR Inhibitors; Proto-Oncogene Proteins c-kit; Everolimus; Treatment Outcome; TOR Serine-Threonine Kinases; Aged, 80 and over
PubMed: 38581211
DOI: 10.1002/ajh.27323 -
The Journal of Allergy and Clinical... Mar 2024Anaphylaxis is a common feature of patients with mastocytosis, particularly with Hymenoptera venoms. Hence, it is hypothesized that patients with mastocytosis may have...
BACKGROUND
Anaphylaxis is a common feature of patients with mastocytosis, particularly with Hymenoptera venoms. Hence, it is hypothesized that patients with mastocytosis may have an increased susceptibility to developing drug-induced anaphylaxis (DIA). Patients and medical practitioners are therefore concerned when there is a need to use various drugs. However, this issue has not been systematically investigated.
OBJECTIVE
To investigate the prevalence and clinical characteristics of anaphylaxis to various types of drugs among patients with mastocytosis.
METHODS
A retrospective study was conducted among 470 consecutive patients (18 years and older) with confirmed clonal mast cell diseases recruited from 2 independent mastocytosis reference centers. All patients underwent a comprehensive, individualized allergy workup with evaluation of the (self)reported drug hypersensitivity.
RESULTS
The overall prevalence of DIA was 6.3%, accounting for one-third of the confirmed drug hypersensitivity reactions. Nonsteroidal anti-inflammatory drugs were the most common elicitors of DIA (56%), followed by perioperative agents (23%) and antibiotics (13%). Anaphylactic reactions were severe in most cases, with 43% of patients experiencing hypotensive syncope. All drug-related hypersensitivity reactions occurred before mastocytosis was diagnosed.
CONCLUSIONS
The prevalence of DIA in mastocytosis tends to be higher than in the general population, but is overall low. However, its severity is more pronounced. Our results suggest that patients with mastocytosis with a previous reaction to drugs should undergo a thorough allergy workup. Well-tolerated drugs can be further used without specific precautions.
PubMed: 38556047
DOI: 10.1016/j.jaip.2024.03.040 -
Liver International : Official Journal... Jul 2024Systemic mastocytosis (SM) is characterized by the accumulation of atypical mast cells (MCs) in organs. Liver histology of SM has been marginally described and accurate...
BACKGROUND AND AIMS
Systemic mastocytosis (SM) is characterized by the accumulation of atypical mast cells (MCs) in organs. Liver histology of SM has been marginally described and accurate histological classification is critical, given the consequences of aggressive SM diagnosis. We aimed to describe the histological features associated with liver SM using updated tools.
METHODS
Using the database of the French Reference Centre for Mastocytosis, we retrospectively identified patients with a liver biopsy (LB) and a diagnosis of SM. All LB procedures were performed according to the local physician in charge and centrally reviewed by an expert pathologist.
RESULTS
A total of 28 patients were included: 6 had indolent SM, 9 had aggressive SM, and 13 had SM with an associated hematologic neoplasm. Twenty-five (89%) patients presented hepatomegaly, and 19 (68%) had portal hypertension. The LB frequently showed slight sinusoid dilatation (82%). Fibrosis was observed in 3/6 indolent SM and in almost all advanced SM cases (21/22), but none of them showed cirrhosis. A high MC burden (>50 MCs/high-power field) was correlated with elevated blood alkaline phosphatase levels (p = .030). The presence of portal hypertension was associated with a higher mean fibrosis grade (1.6 vs. 0.8 in its absence; p = .026). In advanced SM, the presence of nodular regenerative hyperplasia (NRH) was associated with decreased overall survival (9.5 vs. 46.3 months, p = .002).
CONCLUSIONS
MC infiltration induced polymorphic hepatic lesions and the degree of fibrosis is associated with portal hypertension. NRH identifies a poor prognosis subgroup of patients with advanced SM. Assessing liver histology can aid in SM prognostic evaluation.
Topics: Humans; Mastocytosis, Systemic; Retrospective Studies; Female; Liver; Male; Middle Aged; Adult; Biopsy; Hepatomegaly; Aged; Hypertension, Portal; France; Liver Cirrhosis; Mast Cells; Alkaline Phosphatase; Prognosis
PubMed: 38554045
DOI: 10.1111/liv.15913 -
Indian Dermatology Online Journal 2024
PubMed: 38550813
DOI: 10.4103/idoj.idoj_242_23 -
NPJ Genomic Medicine Mar 2024Familial gastrointestinal stromal tumors (GIST) are rare. We present a kindred with multiple family members affected with multifocal GIST who underwent whole genome...
Familial gastrointestinal stromal tumors (GIST) are rare. We present a kindred with multiple family members affected with multifocal GIST who underwent whole genome sequencing of the germline and tumor. Affected individuals with GIST harbored a germline variant found within exon 13 of the KIT gene (c.1965T>G; p.Asn655Lys, p.N655K) and a variant in the MSR1 gene (c.877 C > T; p.Arg293*, pR293X). Multifocal GISTs in the proband and her mother were treated with preoperative imatinib, which resulted in severe intolerance. The clinical features of multifocal GIST, cutaneous mastocytosis, allergies, and gut motility disorders seen in the affected individuals may represent manifestations of the multifunctional roles of KIT in interstitial cells of Cajal or mast cells and/or may be suggestive of additional molecular pathways which can contribute to tumorigenesis.
PubMed: 38538628
DOI: 10.1038/s41525-024-00405-z