2026-08-12 | Bone fragility in mastocytosis: Clinical insights from a 5-patient retrospective case series.
ObjectiveThis retrospective case series aimed to describe 36-month skeletal, biochemical, safety, and patient-reported outcomes in five postmenopausal women with mastocytosis treated with denosumab.MethodsA technical expert panel (TEP) retrospectively evaluated five consecutive eligible patients with osteoporosis associated with indolent systemic mastocytosis. All subjects underwent physiatric assessment, DXA assessment, and Mini-Osteoporosis Quality of Life (Mini-OQoL) evaluation using the validated Italian version of the questionnaire. Data collected at baseline (T0), 18 months (T1), and 36 months (T2) following initiation of denosumab 60 mg every 6 months, combined with cholecalciferol and calcium supplementation according to individual requirements, were descriptively analyzed.ResultsOver 36 months, femoral and lumbar spine T-scores showed modest improvement/stabilization. Mean femoral T-score improved from -3.9 ± 0.3 at baseline to -3.5 ± 0.3 at 36 months, while lumbar spine T-score improved from -4.3 ± 0.5 SD to -3.9 ± 0.4. Vitamin D levels normalized during follow-up, and Mini-OQoL scores improved from 54.2 ± 9 to 67.3 ± 6. However, BMD remained within the osteoporotic range and one vertebral fracture was documented at 36 months. No severe adverse events were recorded.ConclusionsIn this case series, denosumab was associated with stabilization or modest improvement of BMD and improvement in patient-reported quality of life over 36 months in women with osteoporosis secondary to indolent systemic mastocytosis. These preliminary observations should be interpreted cautiously because of the small sample size, lack of a comparator, and occurrence of one new vertebral fracture during follow-up. Thus, larger multicenter prospective studies are required.
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2026-08-07 | Anesthetic Management of an Elective Cesarean Section in a Patient With Systemic Mastocytosis and Latex Allergy, Complicated by Incidental Intraoperative Wolff-Parkinson-White Pre-excitation: A Case Report.
Systemic mastocytosis (SM) is a rare clonal mast cell disorder in which physical, pharmacological, or emotional triggers can provoke massive mediator release and life-threatening anaphylactoid reactions. Pregnancy and delivery are recognized as high-risk periods that demand careful multidisciplinary planning. Cardiovascular manifestations of mast cell activation disease are increasingly recognized; however, their interplay with primary conduction abnormalities is poorly characterized, and the available evidence is largely limited to isolated case reports. We describe the elective cesarean delivery of a 40-year-old woman with indolent SM and documented latex allergy, managed within a multidisciplinary framework. After corticosteroid and antihistamine premedication in a latex-free operating room, spinal anesthesia was performed without intrathecal opioids; spinal-induced hypotension was treated with phenylephrine boluses, and postoperative analgesia relied on paracetamol alone, with nonsteroidal anti-inflammatory drugs (NSAIDs) deliberately avoided. Serial serum tryptase concentrations remained within the normal range throughout the perioperative period (baseline 7.9 µg/L; intraoperative 10.1 µg/L; early postoperative 9.3 µg/L), with no value reaching the consensus threshold for significant mast cell activation, supporting the effectiveness and safety of the adopted strategy. Unexpectedly, a new Wolff-Parkinson-White (WPW) pre-excitation pattern appeared intraoperatively in a patient with a normal antepartum tracing. She remained asymptomatic, and the subsequent cardiac workup was unremarkable, with outpatient electrophysiological follow-up arranged. This case highlights the value of a structured, prevention-oriented anesthetic strategy in SM, supports spinal anesthesia with hyperbaric bupivacaine as a reasonable preferred option when not contraindicated, and broadens the spectrum of perioperative electrocardiographic findings that may be observed in this population.
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2026-08-02 | Non-immunoglobulin E-mediated mechanisms of anaphylaxis.
Anaphylaxis attributable to non-immunoglobulin E (IgE)-mediated mechanisms represents an increasingly recognized and clinically challenging subset of severe hypersensitivity reactions. This review synthesizes recent advances in the understanding of IgE-independent pathways, with emphasis on literature published in the last 18 months, and highlights their implications for precision diagnostics and therapeutic targeting. Major IgE-independent mechanisms have attracted substantial recent attention. First, the Mas-related G protein-coupled receptor X2 (MRGPRX2) has been consolidated as a central mediator of IgE-independent drug reactions, with new humanized knock-in mouse models revealing its capacity to amplify both IgE-dependent and IgE-independent systemic anaphylaxis. Second, clonal mast cell disorders-including systemic mastocytosis and monoclonal mast cell activation syndrome-are now recognized as major risk amplifiers for severe and fatal anaphylaxis, particularly following Hymenoptera venom exposure, reinforcing the role of the KIT D816V mutation in lowering the mast cell activation threshold. Third, a comprehensive biomarker meta-analysis confirms that tryptase, platelet-activating factor (PAF), and urinary prostaglandin D2 each contribute differentially to non-IgE reactions, with PAF and PAF-acetylhydrolase emerging as particularly relevant in IgE-independent severity pathways. Non-IgE-mediated anaphylaxis encompasses mechanistically distinct entities that demand tailored diagnostic algorithms. Recognizing MRGPRX2 activation, complement and IgG-dependent pathways, and clonal mast cell disease in the clinical work-up of unexplained or recurrent anaphylaxis is relevant. Emerging biomarkers and therapeutic targets - including MRGPRX2 antagonists - hold promise for transforming the management of this underdiagnosed condition.
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2026-07-08 | Systemic Mastocytosis: Molecular Pathophysiology, WHO Diagnostic Framework, and KIT-Directed Targeted Therapies
Background: Systemic mastocytosis (SM) is a clonal mast cell (MC) neoplasm driven by somatically acquired activating mutations in the KIT receptor tyrosine kinase (CD117), resulting in pathological accumulation of morphologically atypical MCs in extracutaneous organs. The KIT D816V substitution is detectable in over 95% of cases by high-sensitivity next-generation sequencing (NGS) or allele-specific PCR. This gain-of-function variant confers ligand-independent receptor autophosphorylation, leading to constitutive activation of downstream signaling cascades that promote MC progenitor survival, clonal expansion, and resistance to apoptosis. Co-occurring somatic mutations in TET2, SRSF2, ASXL1, CBL, and RUNX1, increasingly identified in the context of clonal hematopoiesis of indeterminate potential, are associated with more aggressive phenotypes and independently confer adverse prognostic impact. Results: The 2022 WHO classification delineates indolent forms from advanced-phase SM, aggressive SM, SM with an associated hematologic neoplasm (SM-AHN), and MC leukemia, which produce progressive end-organ damage through both neoplastic tissue infiltration and uncontrolled mediator release. Formal diagnosis requires integration of histological criteria (multifocal bone marrow MC aggregates of ≥15 cells), immunophenotypic aberrancies (CD25, CD2, and/or CD30 coexpression on MCs by flow cytometry or immunohistochemistry), biochemical markers (baseline serum tryptase ≥ 20 ng/mL), and molecular confirmation of KIT D816V or equivalent pathogenic KIT mutation. The development of type I KIT inhibitors with selectivity for the D816V-mutant conformation has fundamentally restructured the therapeutic field of advanced SM. Conclusions: This review provides a thorough synthesis of SM pathobiology, WHO-defined diagnostic and classification criteria, validated prognostic tools, and the developing landscape of KIT-directed and combination therapies, with direct translational relevance for specialist practitioners managing this heterogeneous myeloid neoplasm.
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2026-06-27 | Mast cell proteases and their significance in physiology, pathology, and therapeutic approaches.
Mast cells (MCs) are versatile, multifunctional immune cells with broad roles in physiological homeostasis and pathogenic processes. MCs are found in most tissues, including skin, lungs, intestines, and peritoneum, and they vary in numbers, types, and biological functions. MCs are implicated in host defense against various pathogens, including bacteria, viruses, and fungi. Additionally, MCs are crucial in protecting against toxins, including those present in venoms from multiple species, such as honeybees, snakes, scorpions, and lizards. Although MCs play an essential role in host defense, they are mostly known for their detrimental actions in allergic reactions, such as asthma, food allergy, anaphylaxis, mastocytosis, and various inflammatory skin conditions. Under such conditions, MCs are activated (via IgE-mediated or other mechanisms) and release a range of potent proinflammatory mediators, including tumor necrosis factor α. In addition to cytokines, they are major producers of histamine and various proteases, including chymase, tryptase, and carboxypeptidase A3. As a result, these mediators contribute to the pathological manifestations associated with inflammatory conditions and other disorders. This review focuses mainly on the biological role of MCs and their proteases, with a focus on chymase and tryptase, as well as their inhibitors as candidate therapies for MC-driven diseases. SIGNIFICANCE STATEMENT: Mast cells (MCs) and their proteases are central regulators of tissue homeostasis, barrier defense, and inflammation across multiple organs, but are also associated with numerous diseases. Ongoing research has shown that the function of MCs is highly dependent on their tissue location, where the local tissue environment shapes their phenotype, protease expression, and, consequently, their biological functions. However, further investigation is required to more precisely understand the physiological conditions governing the transition of MCs from maintaining tissue homeostasis to acquiring pathogenic functions, particularly with respect to their protease-dependent activities. By profiling MC heterogeneity using multiomics approaches to map protease-driven signaling networks, it will be possible to gain deeper insight into their functional roles and establish a conceptual framework to guide the development of next-generation, mechanism-based therapeutics that selectively modulate MC activity in human diseases.
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