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Figure 1 Radiological response to JAK1/JAK2 blockade with ruxolitininb. (A) Chest CT scan before the initiation of ruxolitinib. (B) Chest CT scan 12 months after the initiation of ruxolitinib. Figure 2 T helper immunophenotyping. (A) Gating strategy in the patient's peripheral blood mononuclear cells (PBMCs) for T helper immunophenotyping. (B) Representative fluorescence activated cell sorting (FACS) plots are presented. The horizontal bars represent the mean+/-SD. Frequencies of T helper subsets within the CD4 + memory compartment in controls and P. Subsets were defined as follows: Th1 (CXCR5 − CXCR3 + CCR4 − CCR6 −), Th2 (CXCR5 − CXCR3 − CCR4 + CCR6 −), Th17 (CXCR5 − CXCR3 − CCR4 + CCR6 +) and Tfh (CXCR5 +).

SummaryLevamisole-induced vasculitis is a well-characterised antineutrophil cytoplasm antibodies (ANCA)-positive vasculitis in cocaine abuser patients. However, due to the short half-life of levamisole in serum and urine, the causal role of levamisole is not established. Here we report the detection of both levamisole and cocaine in hair samples of a patient who presented with an ANCA-positive vasculitis. The higher concentration of levamisole in proximal sample of the hair confirms that the patient abused of cocaine added with levamisole in the days preceding the development of skin lesions. Although a direct causative role has not been established, our report strongly suggests that levamisole may have triggered vasculitis in this case. BACKGROUND

Aims:The diagnosis of mastocytosis in skin biopsies can be challenging -particularly in cases with very few mast cells. More diagnostic criteria are needed. Methods and results: We analyzed 103 skin biopsies from patients with mastocytosis and compared them with biopsies from inflammatory skin lesions and normal skin. Using CD117 immunostaining, we determined the mast cell distribution pattern, the percentage of mast cells in the inflammatory infiltrate, and the mast cell count per mm². We found that a sheet-like or subepidermal distribution of mast cells was specific for mastocytosis. The most significant feature was the percentage of mast cells and not the mast cell count. We found that a mast cell percentage above 40% was fully specific in both adults and children but lacked sensitivity, especially in adults. In children, all cases with a percentage below 40% harbored a number of mast cells above 90 per mm², allowing a straightforward diagnosis. In adults, the diagnosis was more challenging and cases with less than 40% of mast cells could be diagnosed on account of a number of mast cells above 40 per mm², with 88.5% sensitivity and 95.2% specificity. Additional signs might be useful in difficult cases. However, CD25 immunostaining was not useful. Conclusions: We confirmed that the criteria currently applied in the bone marrow were not appropriate for the skin. Accordingly, we developed an algorithm for the diagnosis of mastocytosis in skin biopsies with a high level of interrater reproducibility (mean kappa 0.8).

Mastocytosis is a rare disease due to the abnormal accumulation of mast cells in various tissues. Its clinical presentation is heterogeneous depending on mast cell infiltration and mediators release. In some cases, it is associated with hematological malignancies. Prognosis varies from very good with a life expectancy similar to the general population in indolent forms of the disease to a survival time of just a few months in mast cell leukemia. Although in most cases a somatic KIT D816V mutation is found in tumor mast cells, the physiopathology of the disease is not yet fully understood. Additional germline and somatic mutations may explain this heterogeneity. Treatments aim at blocking effect of mast cell mediators, reducing mast cell activation and tumor burden. New drugs mainly directed against the tyrosine kinase activity of KIT have dramatically changed the quality of life and prognosis of mast cell diseases. Present and future therapeutic strategies are discussed in this review.

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Mastocytosis is a heterogeneous disease characterized by an abnormal accumulation of mast cells (MCs) in one or several organs. Although a somatic KIT D816V mutation is detected in ~85% of patients, attempts to demonstrate its oncogenic effect alone have repeatedly failed, suggesting that additional pathways are involved in MC transformation. From three children presenting with both Greig cephalopolysyndactyly syndrome (GCPS, MIM#175700) and congenital mastocytosis, we demonstrated the involvement of the hedgehog (Hh) pathway in mastocytosis. GCPS is an extremely rare syndrome resulting from haploinsufficiency of GLI3, the major repressor of Hh family members. From these familial cases of mastocytosis, we demonstrate that the Hh pathway is barely active in normal primary MCs and overactive in neoplastic MCs. We show that GLI3 and KIT mutations have a synergistic, tumorigenic effect on the onset of mastocytosis in a GCPS mouse model. Finally, we show that Hh inhibitors suppress neoplastic MC proliferation in vitro and extend the survival time of aggressive systemic mastocytosis (ASM) mice. This work revealed, for the first time, the involvement of Hh signaling in the pathophysiology of mastocytosis and demonstrated the cooperative effects of the KIT and Hh oncogenic pathways in ASM, leading to the identification of new promising therapeutic targets.