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Managing extracranial arteriovenous malformations is challenging. Sirolimus (rapamycin) is increasingly being used when surgery and embolization are not advised. Because of its anti-angiogenic properties here we report all extracranial arteriovenous malformation cases treated with sirolimus in 2 French tertiary centers for vascular anomalies. The outcomes were efficacy (complete, partial, no response) based on arteriovenous malformation volume and necrosis/hemorrhage and side effects. We retrospectively included 10 patients (7 children). The sirolimus dose ranged from 0.6 to 3.5 mg/m2. Median (interquartile range [IQR]) treatment time was 24.5 (4.5; 35) months. Five patients showed no response and 5 showed partial response at a median (IQR) of 3 (1; 5) months followed in 2 cases by therapeutic resistance (i.e., progressive disease after 9 and 24 months of treatment). The most frequent side effect was mouth ulcers. This study shows poor efficacy of sirolimus for treating extracranial arteriovenous malformations.

Background: Alcohol-related liver disease (ALD) is one of the main indications for liver transplantation (LT). For 20 years, tacrolimus (Tac) is the cornerstone immunosuppressive drug used after LT and is very efficient for the prevention of rejection. Nevertheless, the major drawback of long-term use of Tac is the risk for developing dose-dependent adverse effects., Objective: The aim of the present study was to assess the impact of Tac exposure (trough concentrations and concentration/dose (C/D) ratio) during the first year after LT, on short- and long-term complications after LT for ALD., Methods: All patients who underwent a LT for ALD at Lyon Edouard Herriot Hospital from October 1990 to September 2010, and who were treated with Tac for at least one year after LT, were analyzed., Results: The study population consisted in 251 patients, mean age 53.4 ± 7.3 years, and followed during 11.6 ± 4.8 years. Post-LT complications included severe infectious events (44.6%), malignancies (41.4%), arterial hypertension (49.4%) dyslipidemia (44.2%), diabetes (18.7%) and cardiovascular events (15.5%). De novo hypertension, cardiovascular event, CMV infection, non-melanoma skin cancers and HCC recurrence after transplantation were significantly associated with higher Tac trough blood concentration. In addition, Tac fast-metabolizers (defined as C/D < 1.8) had significantly more impaired renal function at 1, 5, and 10 years and more cardiovascular events, PTLD, diabetes and hypertension than slow-metabolizers., Conclusion: Our results strongly support that, in addition to blood trough concentrations, Tac metabolism, as estimated by the simple C/D ratio, could be an efficient parameter in daily practice to identify LT patients at risk to develop long term general complications of Tac., (Copyright © 2019. Published by Elsevier B.V.)

BACKGROUND Potential benefits of once-daily, prolonged-release tacrolimus over the immediate-release formulation include improved adherence to immunosuppressives post transplantation. An observational study was performed to characterize real-world practice surrounding conversion from immediate- to prolonged-release tacrolimus in kidney transplant recipients. MATERIAL AND METHODS We performed a prospective, observational study of renal transplant recipients converted from immediate- to prolonged-release tacrolimus capsules. Conversion took place at the baseline visit, within the first 6 months of transplantation (early conversion group) or between 6 and 12 months of transplantation (late conversion group). Data collection was performed at routine follow-up at 6 and 12 months. Endpoints included conversion ratio from immediate- to prolonged-release tacrolimus, reasons for conversion, additional visits due to conversion, safety, and tolerability. RESULTS The analysis population comprised 591 patients. Baseline characteristics were similar between the 2 groups. The mean conversion ratio of the daily dose of tacrolimus was 0.98±0.17 in the early group and 0.99±0.09 in the late group. Time from conversion (mean ±SD) to first measurement of trough tacrolimus blood concentration was 12.1±11.6 and 27.6±26.7 days in the early and late groups, respectively. The highest number of additional visits required was 6 in the early conversion group, in 3 patients (0.7%), and 3 in the late conversion group, in 2 patients (1.6%). Conversion from immediate- to prolonged-release tacrolimus was associated with a very low rate of graft rejection. CONCLUSIONS Favorable clinical outcomes and safety profiles were observed with conversion from immediate- to prolonged-release tacrolimus over 1 year following renal transplantation, with no marked differences between the early and late conversion groups.

BACKGROUND In adult liver transplant patients, the use of prolonged-release tacrolimus may have treatment adherence benefits over the immediate-release formulation. The aim of this study was to characterise real-world practice data on conversion of liver transplant recipients from immediate- to prolonged-release tacrolimus in France. MATERIAL AND METHODS A prospective, observational study (NCT02143479) was conducted in 18 transplant centers in France between June 2014 and March 2016. Liver transplant recipients (n=398) included patients who changed from immediate-release to prolonged-release tacrolimus within the first three months (early conversion group) (n=205) or between three and 12 months after transplantation (late conversion group) (n=184). Clinical data were collected at an initial baseline outpatient visit and six-month and 12-month follow-up visits. Endpoints included the dose conversion ratio from immediate-release to prolonged-release tacrolimus, number of and reasons for additional visits due to conversion, safety, and tolerability. RESULTS Baseline clinical and demographic characteristics were similar between the two cohorts. The mean ±SD ratio of conversion of tacrolimus dose was 1.04±0.28; 1.01±0.28 (early) and 1.08±0.28 (late) (p=0.0247). The mean ±SD time from conversion to the first tacrolimus trough blood concentration was 30.8±42.8 days; 24.8±45.4 days (early) and 37.5±38.7 days (late). Only one patient required an additional visit due to conversion. Reasons for conversion included the physician's preference (56.3%), center practice (38.6%), and the dosing frequency (36.0%). Conversion was associated with a low rate of graft rejection, and no new safety issues were reported. CONCLUSIONS Conversion of liver transplant recipients from immediate-release to prolonged-release tacrolimus within three to 12 months of transplantation was easy to manage and associated with favorable clinical outcomes and safety profiles.

Cryptosporidiosis is a common disease in children and immunodeficient individuals. In 2006, a national network was set up on the surveillance of human cryptosporidiosis in France. Since January 2015, the 41 tertiary care hospitals and the 3 private laboratories of the French National Network on the surveillance of human cryptosporidiosis have been able to declare confirmed cases of cryptosporidiosis online. Between 2015 and 2017, 210 cases of cryptosporidiosis were declared in immunodeficient patients in France; Cryptosporidium parvum and Cryptosporidium hominis represented 66% and 22% of cases, respectively. A peak was observed in autumn. Cryptosporidiosis occurred mainly in a context of solid organ transplantation (SOT) (49%) and of HIV infection (30%). In SOT recipients, cryptosporidiosis appeared more frequently in the first 6 months post transplantation. Regarding cases declared in SOT recipients, mycophenolate mofetil was used in 68%. A mortality rate of 6% was observed. Present results underline the importance of screening for cryptosporidiosis in immunocompromised patients suffering from diarrhea, especially in the course of major cell mediated immunodeficiency or even systematic screening before SOT. Exclusive Cryptosporidium free water feeding could be suggested during major cell mediated immunodeficiency., (Copyright © 2018 Elsevier Inc. All rights reserved.)

BACKGROUND Different pharmaceutical forms of oral tacrolimus allow tailored administration. The granular formulation facilitates accurate dose adjustment of tacrolimus according to patient characteristics, such as weight, or potential concomitant drug interactions. Currently, there are no data describing the use of tacrolimus granules in transplant recipients in France. MATERIAL AND METHODS OPTIMOD was a 6-month prospective, observational multicenter study that aimed to describe patient characteristics and conditions of use of tacrolimus granules. The 25 participating centers enrolled patients at time of tacrolimus granules initiation and were to collect patient and treatment data at initiation and after 6 months of follow-up. All analyses were descriptive. RESULTS Of 61 patients included, 55.7% were children (mainly kidney graft recipients) and 44.3% were adults (mostly lung graft recipients). Overall, 24.6% of patients (all children) initiated tacrolimus granules immediately post-transplant; the remaining 75.4% converted to tacrolimus granules from ciclosporin or immediate-release tacrolimus hard capsules. The main reasons for initiating tacrolimus granules, irrespective of whether first- or second-line therapy, were to offset potential drug-drug interactions in adults by adjusting dose, and to adapt to the particular needs of children as patients. Most patients (78.7%) underwent ≥1 dose modification during follow-up. Eleven rejection episodes occurred during follow-up, of which none led to graft loss. The adverse-event profile of the tacrolimus granules was similar to that of other tacrolimus formulations and 7 treatment-related adverse events were recorded. CONCLUSIONS Results suggest that tacrolimus granules are well tolerated and effective in preventing transplant rejection when administered in routine practice in France.

Background: Post-transplant diabetes mellitus (PTDM) is a major complication of immunosuppressive therapy, with many risk factors reported in adults with renal transplantation. The objective of this study was to investigate potential non-genetic and genetic risk factors of PTDM in children with renal transplantation treated with tacrolimus., Methods: A national database was screened for patients developing PTDM within 4 years following tacrolimus introduction. PTDM was defined as glucose disorder requiring anti-diabetic treatment. PTDM patients were matched to "non-PTDM" control transplanted children according to age, gender, and duration of post-transplant follow-up. Patients were genotyped for six selected genetic variants in POR*28 (rs1057868), PPARa (rs4253728), CYP3A5 (rs776746), VDR (rs2228570 and rs731236), and ABCB1 (rs1045642) genes, implicated in glucose homeostasis and tacrolimus disposition., Results: Among the 98 children with renal transplantation enrolled in this multicentre study, 18 developed PTDM. None of the clinical and biological parameters was significant between PTDM and control patients. Homozygous carriers of POR*28 or wild-type ABCB1 (rs1045642) gene variants were more frequent in PTDM than in control patients with differences close to significance (p = 0.114 and p = 0.066 respectively). A genetic score based on these variants demonstrated that POR*28/*28 and ABCB1 CC or CT genotype carriers were at a significantly higher risk of developing PTDM after renal transplantation., Conclusion: Identification of PTDM risk factors should allow clinicians to allocate the best immunosuppressant for each patient with renal transplantation, and improve care for patients who are at a higher risk.

Background: New-onset diabetes mellitus (NODM)-a common complication of kidney transplantation-is associated with increases in graft loss, morbidity and mortality., Methods: This is a purely observational study of 527 patients taking a calcineurin inhibitor (CNI), based on data collected at a single routine visit 6-24 months after kidney transplantation. Diabetes was defined according to ADA/WHO guidelines., Results: The mean age of the patients was 47.2 years and 61.1% were men; 49.5% were receiving cyclosporine microemulsion (CsA-ME) and 50.5% tacrolimus (Tac). NODM developed in 7.0% after a median interval of 1.6 months. In CsA-ME-treated patients, the unadjusted cumulative risks of NODM were 5.5% and 8.4% at 1- and 2-year post-transplantation, while in Tac-treated patients, the risks were respectively 17.4% and 21%. Four independent risk factors (RFs) were identified by multivariate analysis: maximum lifetime body mass index>25 [odds ratio (OR)=5.1], pre-transplantation impaired fasting glucose (OR=4.7), hepatitis C status (OR=4.7) and Tac vs CsA-ME treatment (OR=3.0)., Conclusions: NODM is associated with certain RFs present prior to kidney transplantation, and with treatment with Tac as opposed to CsA-ME.

(1) Symptomatic treatment of atopic dermatitis is initially based on simple measures and moisturising creams. Topical corticosteroids are reserved for treatment of inflammatory exacerbations. (2) After topical tacrolimus, marketing authorisation has been granted in France for a second topical immunosuppressant, pimecrolimus, as a short-term symptomatic treatment for atopic dermatitis in children from the age of two years, and intermittently for long-term prevention of new exacerbations. (3) Short-term treatment with pimecrolimus has been tested in three trials in children with mild to moderate dermatitis (against the excipient), in one adult trial against the excipient, and in one dose-finding study in adults that included a group treated with topical corticosteroids. (4) Longer term treatment periods of 6 to 12 months have been tested in two trials versus excipient in children, and two adult trials, one versus moderately active topical corticosteroids. (5) These trials show that pimecrolimus works better than the excipient, but not nearly as well as moderately active topical corticosteroids. Pimecrolimus has not been compared with topical corticosteroids in children, the age group most vulnerable to atopic dermatitis. (6) The commonest adverse effects observed in clinical trials were local and included a burning sensation at the site of application and skin infections. Systemic adverse effects (mainly infections) were most marked in infants. Long-term risks, especially the risk of skin cancer, have not been assessed. (7) In practice, the reference treatment for exacerbations of atopic dermatitis is a topical corticosteroid; in children, it seems best to begin with a weak preparation. There is no reason to use pimecrolimus, which is less active than topical corticosteroids and whose potential long-term adverse effects, especially in children, are unknown.