This prospective pilot interventional study aimed at studying the efficacy of cannabidiol on pruritus and pain on paediatric patients with recessive dystrophic epidermolysis bullosa. A decrease in average chronic pruritus and pain, pruritus and pain during dressing changes in addition to a significant improvement of quality-of-life scores and sleep were observed. No severe side effects were reported.

Gain-of-function mutations in SCN9A, which encodes the Nav1.7 voltage-gated sodium channel, are known to cause primary erythromelalgia (PEM). This condition is characterized by recurrent episodes of erythema, burning pain, and warmth in the extremities. These genetic insights have spurred the development of Nav1.7 blockers as a promising therapeutic strategy for PEM. However, translating these findings into effective clinical treatments has remained challenging. In this study, we demonstrate that mepyramine, a compound previously shown to alleviate pain in animal models, effectively targets hNav1.7 channels carrying PEM-associated gain-of-function mutations, providing substantial pain relief in PEM patients. Using voltage-clamp recordings in human embryonic kidney (HEK) 293 cells, we demonstrated that mepyramine inhibits hNav1.7 channels carrying three distinct PEM mutations, I848T, L858F, and L1267V, which differentially affect the gating properties of hNav1.7. Importantly, mepyramine’s efficacy was consistent regardless of how these mutations altered channel activation or inactivation properties. To evaluate its clinical potential, we administered a high-dose topical formulation of mepyramine to a group of PEM patients suffering from severe pain that was unresponsive to conventional analgesics, including cases with identified SCN9A mutations. This treatment rapidly and durably reduced burning pain and erythema, providing meaningful relief for patients who had not responded to, or could not tolerate, previous therapies. These results suggest that mepyramine can inhibit PEM-associated Nav1.7 channel mutants and may offer a new therapeutic approach for PEM patients.

Advanced systemic mastocytosis (AdvSM) encompasses heterogeneous mastocytosis subtypes and is associated with poor outcomes. Although midostaurin was the first tyrosine kinase inhibitor to be approved for AdvSM patients, long-lasting responses are limited. The mutation-Adjusted Risk Score (MARS), the International Prognostic Scoring System for mastocytosis (IPSM) and the Global Prognostic Score for Systemic Mastocytosis (GPSM) have been established to characterize the outcomes of patients with overall AdvSM. However, given the outcome's dependency on the AdvSM subtype, prognostic characterization within each subtype is critical. We aimed to study the predictive ability using Harrell's concordance index of prognostic scores according to the AdvSM subtype. We conducted a nationwide retrospective study using the French mastocytosis reference center's registry and included all midostaurin-treated patients with C finding. Overall, 170 patients were identified: 46 aggressive SM (ASM), 11 mast cell leukemia (MCL), and 113 SM with associated hematological neoplasm (SM-AHN). All risk scores improved their discriminative value for overall survival (OS) when combined with the AdvSM subtype. The best predictive value was for adjusted MARS (C-index = 0.689), followed by GPSM (C-index = 0.677) and IPSM (C-index = 0.618). In a multivariable analysis, MARS stratification and the AdvSM subtype were both prognostic for OS. Accordingly, five subgroups of patients with AdvSM and a different median OS were identified: 9.9 months for MCL, 24 months for intermediate/high-risk SM-AHN, 33 months for intermediate/high-risk ASM, 58 months for low-risk SM-AHN and was not reached for low-risk ASM ( p  < 0.001). The AdvSM subtype and the MARS are the most predictive of OS and should prompt specific management.

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.

Pachyonychia congenita (PC) is a rare genodermatosis characterized by focal palmoplantar keratoderma, severe plantar pain and dystrophic nails. Anecdotally, some patients with PC have erythematous soles and episodic burning plantar pain, indicative of secondary erythromelalgia. This study aimed to identify the prevalence and genetic predictors of erythromelalgia in PC.

Nail-patella syndrome (NPS) is a rare genetic disease characterized by dysplastic nails, patella abnormalities, skeletal malformation, and chronic pain. Although chronic pain in NPS is mainly due to bone and musculoskeletal symptoms, it can also result from neurological dysfunction. Conventional analgesics are often insufficient to relieve NPS-associated chronic pain. Cannabinoids, which act on the serotonergic and/or noradrenergic pain systems, may therefore represent valuable non-psychoactive alternatives for managing pain in these patients. The effectiveness and safety of synthetic cannabidiol (CBD) for the management of NPS-associated pain was assessed using real-world data from a pilot cohort of patients with NPS who received a 3-month treatment with oral CBD. The treatment (median dose of 900 mg/day) was associated with a significant reduction in pain intensity (mean score of 7.04 ± 0.24 at initiation versus 4.04 ± 0.38 at 3 months, N = 28, p < 0.0001), which correlated with changes in the peripheral concentration of noradrenaline (r = 0.705, 95% CI [0.44-0.86], p < 0.0001). Health-related quality of life and other NPS-associated symptoms also improved in most patients. CBD treatment was well tolerated and no elevations in liver enzyme levels were reported. Synthetic CBD therefore appears to be a safe and effective treatment option for managing NPS-associated chronic pain.

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.

Background: Mastocytosis and monoclonal mast cell (MC) activation syndrome (MMAS) are heterogeneous conditions characterized by the accumulation of atypical MCs. Despite the recurrent involvement of KIT mutations, the pathophysiologic origin of mastocytosis and MMAS is unclear. Although hereditary a-tryptasemia (HaT, related to TPSAB1 gene duplication) is abnormally frequent in these diseases, it is not known whether the association is coincidental or causal. Objective: We evaluated the prevalence of HaT in all mastocytosis subtypes and MMAS and assessed the pathophysiologic association with HaT. Methods: Clinical data, laboratory data, KIT mutations, TPSAB1 duplication (assessed by droplet digital PCR), and HaT prevalence were retrospectively recorded for all patients with mastocytosis and MMAS registered in the French national referral center database and compared to a control cohort. To increase the power of our analysis for advanced systemic mastocytosis (advSM), we pooled our cohort with literature cases. Results: We included 583 patients (27 with MMAS and 556 with mastocytosis). The prevalence of HaT in mastocytosis was 12.6%, significantly higher than in the general population (5.7%, P = .002) and lower than in MMAS (33.3%, P = .02). HaT+ patients were more likely to have anaphylactic reactions and less likely to have cutaneous lesions than HaT2 patients (43.0% vs 24.4%, P = .006; 57.7% vs 75.6%, respectively, P = .006). In the pooled analysis, the prevalence of HaT was higher in advSM (11.5%) than in control cohorts (5.2%, P = .01). Conclusion: Here we confirm the increase incidence of anaphylaxis in HaT+ mastocytosis patients. The increased prevalence of HaT in all subtypes of systemic mastocytosis (including advSM) is suggestive of pathophysiologic involvement. (J Allergy Clin Immunol 2024;153:349-53.)

Supplementary Methods from E-Cadherin/p120-Catenin and Tetraspanin Co-029 Cooperate for Cell Motility Control in Human Colon Carcinoma

Inflammation can impair intestinal barrier, while increased epithelial permeability can lead to inflammation. In this study, we found that the expression of Tspan8, a tetraspanin expressed specifically in epithelial cells, is downregulated in mouse model of ulcerative disease (UC) but correlated with those of cell–cell junction components, such as claudins and E-cadherin, suggesting that Tspan8 supports intestinal epithelial barrier. Tspan8 removal increases intestinal epithelial permeability and upregulates IFN-γ-Stat1 signaling. We also demonstrated that Tspan8 coalesces with lipid rafts and facilitates IFNγ-R1 localization at or near lipid rafts. As IFN-γ induces its receptor undergoing clathrin- or lipid raft-dependent endocytosis and IFN-γR endocytosis plays an important role in Jak-Stat1 signaling, our analysis on IFN-γR endocytosis revealed that Tspan8 silencing impairs lipid raft-mediated but promotes clathrin-mediated endocytosis of IFN-γR1, leading to increased Stat1 signaling. These changes in IFN-γR1 endocytosis upon Tspan8 silencing correlates with fewer lipid raft component GM1 at the cell surface and more clathrin heavy chain in the cells. Our findings indicate that Tspan8 determines the IFN-γR1 endocytosis route, to restrain Stat1 signaling, stabilize intestine epithelium, and subsequently prevent intestine from inflammation. Our finding also implies that Tspan8 is needed for proper endocytosis through lipid rafts.

Mastocytosis patients often experience a number of symptoms, including mastocytosis-associated pain that is difficult to manage due to resistance to usual antalgic treatments and/or the patient’s poor tolerance. Mastocytosis patients display significantly higher levels of indoleamine-2,3-dioxygenase-1 (IDO1) activity, leading to hyperactivation of the N-methyl-D-aspartate receptor. As cannabidiol (CBD) is known to inhibit IDO1′s enzymatic activity, we hypothesized that pharmaceutical-grade CBD is an effective treatment for mastocytosis-associated pain. Patients with non-advanced mastocytosis and refractory pain were eligible for inclusion in this observational pilot study. CBD was initiated at 50 mg/day and increased to a maximum of 900 mg/day. Pain was scored on a 0-to-10 numerical rating scale (NRS). A total of 44 patients were included over a 2-year period. The median dose of CBD prescribed was 300 mg/day (range: 50–900 mg/day). Elevated liver enzymes were observed in one patient. The mean ± standard deviation NRS pain score decreased significantly from 7.27 ± 1.35 before treatment to 3.78 ± 1.99 after 3 months of treatment (p < 0.0001). Fifteen patients (34%) were able to discontinue all their previous antalgic medications. CBD treatment might be a safe, effective treatment for mastocytosis-associated pain and its use requires confirmation in a randomized, controlled trial.

Supplementary Movie 2 from E-Cadherin/p120-Catenin and Tetraspanin Co-029 Cooperate for Cell Motility Control in Human Colon Carcinoma

BACKGROUND:Medical child abuse (MCA; or Munchausen syndrome by proxy) is a severe form of adult and medical maltreatment of children. Currently, few data on MCA in adolescents exist. OBJECTIVE:To describe the clinical characteristics and medical history of children and adolescents aged 10 to 18 years with suspected or confirmed MCA in the pediatric hospital setting. METHODS:We included patients aged 10 to 18 years who were seen in five tertiary care hospitals in the Paris area and identified by physician recall such as suspected MCA between 2015 and 2021. RESULTS:We included 29 adolescents; the mean (SD) age was 12.9 (10.8-15.0) years at suspected diagnosis. Medical wandering was common, with a mean of 23 (12.8-33.2) alleged symptoms and 33 (9.2-56.8) specialized consultations in a mean of six different hospitals. The mean number of emergency visits was 11.8 (0-25.9) and radiologic exams 24.3 (5-43.6). Overall, 62 % (18/29) of the adolescents had an underlying organic pathology. The impact of MCA on quality of life was major, with a high rate of school dropout (96 %). The mean delay to the suspected diagnosis was 5.8 (2.6-9) years, and even when recognized, it was rarely the subject of a social or judiciary report (only 42 % of adolescents). In total, 50 % of the adolescents subsequently exhibited Munchausen syndrome. CONCLUSION:Adolescent MCA is poorly known among the medical profession. Increasing awareness, education and knowledge of risk factors could contribute to better care.

Supplementary Movie Legends 1-6 from E-Cadherin/p120-Catenin and Tetraspanin Co-029 Cooperate for Cell Motility Control in Human Colon Carcinoma

Tspan8 is a member of the tetraspanins family of cell surface molecules. The ability of tetraspanins to organize membrane microdomains with other membrane molecules and interfere with their function suggests that they could act as surface integrators of external or internal signals. Among the first identified tetraspanins, Tspan8 promotes tumor progression and metastasis, presumably by stimulating angiogenesis and cell motility. In patients, its expression on digestive tract tumors seems to be associated with a bad prognosis. We showed previously that Tspan8 associates with E-cadherin and EGFR and modulates their effects on cell motility. Using Mass spectrometry and western blot, we found a new partner, the endothelin converting enzyme ECE1, and showed that Tspan8 amplifies its activity of conversion of the endothelin-1 precursor bigET1 to endothelin. This was observed by transduction of the colon carcinoma cell line Isreco1, which does not express Tspan8, and on ileum tissue fragments of tspan8ko mice versus wild type mice. Given these results, Tspan8 appears to be a modulator of the endothelin axis, which could possibly be targeted in case of over-activity of endothelins in biological processes of tissues expressing Tspan8.

Introduction: Mastocytosis is a spectrum of diseases characterized by the accumulation of atypical mast cells (MC) in tissues. The most frequent form in adult patients is systemic mastocytosis (SM) including indolent SM, bone marrow mastocytosis, smoldering SM and advanced SM (adv-SM). Adv-SM encompasses aggressive SM (ASM), MC leukemia (MCL), SM associated with hematological neoplasms (SM-AHN) and is associated with a poor outcome. Prior the use of tyrosine kinase inhibitors (TKIs), therapeutic options were limited in adv-SM patients. The first TKI developed for adv-SM with KIT D816V mutation was midostaurin, which greatly improved outcomes for patients. However, most patients are primary refractory or relapse early (<12 months) after midostaurin onset. To identify high risk adv-SM patients, a prognostic score the so-called Mutation-Adjusted Risk Score (MARS) have been developed. However, given the heterogeneity of outcomes according to subtype of adv-SM, the identification of high-risk patients within each subtype is critical to optimize therapy. To address this question, we investigated predictive value on outcome of MARS score risk in midostaurin treated Adv-SM patients in a larger group of patients, according to each subtype of adv-SM. Methods: We conducted a nationwide retrospective study of all patients with Adv-SM patients included in the French national mastocytosis reference center registry (CEREMAST). Main inclusion criteria were: (i) adults patients treated with midostaurin in France since 2009 (ii) diagnosis of adv-SM according to WHO 2016 classification (iii) presence of C findings. Patients that have received combination therapy (i.e. azacytidine) or with chronic type of MCL without C finding or lymphoid neoplasm AHN or AML prior midostaurin onset were excluded. Response to midostaurin was assessed according to Valent criteria and MARS score was used to stratify patients into 3 risk groups (high risk, intermediate and low). Results: Overall, 170 patients treated with midostaurin were identified, including 46 ASM patients, 11 MCL patients and 113 SM-AHN patients. Among SM-AHN patients, chronic myelomonocytic leukemia was the most frequent neoplasm (52%). Response to midostaurin was significantly different regarding subtype of adv-SM (73% in ASM vs 27% in MCL vs 50% in SM-AHN, p=0.006). With a median follow-up of 19 months since midostaurin start, median overall survival (OS) was 69, 9.9 and 32 months (p=0.0013) and time to treatment failure (TTF) was 30, and 3.6 and 9 months in ASM, MCL and SM-AHN (p<0.0001), respectively. MARS risk group distribution was heterogeneous between ASM, MCL and SM-AHN (p=0.026). In MARS low risk group, median OS was not reached (NR) and 58 months in ASM and SM-AHN respectively (p=0.034, Figure 1). Median OS for both low risk ASM and low risk SM-AHN were significantly different compared with intermediate/high-risk (int/high-risk) groups (NR vs 33 months for ASM, p=0.003 and 58 months vs 24 months, p=0.017). Int/high-risk SM-AHN was the only group with a median OS not significantly different compared with MCL (24 months vs 9 months p=0.266) Median TTF was 60 months for low risk ASM, 26 months for low risk SM-AHN and only 6.7 months for high/int-risk ASM, 8.4 months for high/int-risk SM-AHN and 3.6 months for MCL. For the 19 patients who underwent hematopoietic stem cell transplantation (HSCT), median OS was 88 months but did not reach statistical significance compared to non-transplanted patients (47 months, p=0.15). In multivariate analysis, MARS and WHO mastocytosis subtype were the only variables independently associated with OS ( figure 2). MARS and midostaurin response were not predictive for both AHN progression and AML transformation in SM-AHN, which occurred in 31% and, 22% of patients respectively. In contrast, presence of portal hypertension/ascites (68% vs 29%, p<0.001) and abnormal karyotype (40 vs 11%, p=0.007) were predictive of AML transformation. Conclusions: We report herein the largest cohort of adv-SM patients treated with midostaurin. We identified portal hypertension/ascites and karyotype abnormalities as risk factors predictive of AML evolution. Subtype of adv-SM are heterogeneous and, together with MARS, are predictive for both OS and TTF. According to these variables, 5 sub-groups of adv-SM have been identified with different outcomes prompting for specific management.