Experimental Models of Posterior Reversible Encephalopathy Syndrome: A Review From Pathophysiology to Therapeutic Targets.

Posterior reversible encephalopathy syndrome (PRES) is a clinical and radiological entity characterized by nonspecific symptomatology (eg, headache, visual disturbances, encephalopathy, and seizures) and classically cortical and subcortical vasogenic edema predominantly affecting the parietooccipital region. PRES etiologies are usually dichotomized into toxic PRES (eg, antineoplastic drugs, illicit drugs) and clinical condition-associated PRES (eg, acute hypertension, dysimmune disorders). Although the pathophysiology of PRES remains elusive, 2 main pathogenic hypotheses have been suggested: cerebral hyperperfusion due to acute hypertension and cerebral hypoperfusion related to endothelial dysfunction. Research into the pathogenesis of PRES has emerged through the development of animal models in the last decade. The motivation for developing a suitable PRES model is 2-fold: to fill in knowledge gaps of the pathophysiological mechanisms involved, and to open new perspectives for clinical assessment of pharmacological targets to improve therapeutic management of PRES. All current models of PRES have a hypertensive background, on which other triggers (acute hypertension, inflammatory, drug toxicity) have been added to address specific facets of PRES (eg, seizures). The initial model consisted in inducing a reduced uterine perfusion pressure that mimics preeclampsia, a leading cause of PRES. More recently, a model of stroke-prone spontaneously hypertensive rats on high-salt diet, originally developed for hypertensive small vessel disease and vascular cognitive impairment, has been studied in PRES. This review aims to discuss, depending on the research objective, the benefits and limitations of current experimental approaches and thus to define the desirable characteristics for studying the pathophysiology of PRES and developing new therapies.

Indication for a Pneumocystis Prophylaxis Therapy in Patients with Vascular Anomalies Treated with PIK3/AKT/mTOR Pathway Inhibitors: Experts' Opinion and Systematic Review from the Literature.

BACKGROUND: Vascular anomalies (VAs) are increasingly being treated with PI3K/AKT/mTOR pathway inhibitors. These drugs have immunosuppressive properties and thus theoretically overexpose patients to opportunistic infections, especially Pneumocystis jirovecii pneumonia (PJP). PJP prophylaxis use lacks consensus. We aimed to investigate the prevalence of PJP in patients receiving mTOR/PI3K/AKT inhibitors for VAs and determine any indication for pneumocystis prophylaxis in this population. METHODS: The study was conducted in 2 parts: (1) we sent a survey to a panel of international experts of VAs asking about their use of pneumocystis prophylaxis drugs and (2) we performed a systematic review of the literature of all published cases of patients receiving these drugs for VA to estimate the prevalence of PJP in this population. RESULTS: Answers from 68 experts were analyzed: 21 (30.9%) answered they always add PJP prophylaxis when prescribing mTOR inhibitors, 20 (29.4%) case-by-case, and 27 (39.7%) never. For the systematic review, among 3,053 reports screened, 217 were included involving 1,189 patients (1,143 received sirolimus, 38 everolimus, 4 alpelisib, 4 miransertib). Among the 1,189 cases, 2 (0.2%) PJP were reported: one under sirolimus and one under everolimus. Thus, the prevalence of PJP was estimated at 0.88 cases/1,000 patients under sirolimus (95% CI: -0.84 to 2.59) and 26.31 cases/1,000 under everolimus (95% CI: -24.58 to 77.18). Patients with PJP never received prophylaxis drugs. We found no PJP cases under alpelisib and miransertib. PJP prophylaxis was given in 218 (18.3%) cases, more frequently for children (91.3 vs. 77.2% in the non-prophylaxis group, p = 0.012), mostly trimethoprim-sulfamethoxazole (186 patients, 85.3%). CONCLUSION: Our study shows that even if PJP is a rare event, it may occur in patients with VAs treated with an mTOR inhibitor. Although our results cannot allow for revising guidelines, prophylaxis with TMP-SMX might be appropriate for a subgroup of patients with risk factors for PJP.

Thrombotic microangiopathy associated with anticancer and immune system targeting drugs: New insights from real-world data using the WHO pharmacovigilance database.

BACKGROUND: The worldwide development of immune system targeting/anticancer drugs has revolutionized immuno-oncology, but their implication in thrombotic microangiopathy syndromes (TMA) is increasingly suspected. Using real-world data, the aim of this study was to identify drugs associated with TMA reporting and to describe the evolution of TMA reporting over time with a focus on these drugs. METHODS: A global disproportionality study was performed using the individual case safety reports (ICSRs) extracted from the World Health Organization (WHO) pharmacovigilance database (VigiBase) from its inception (1968) to April 30, 2022. RESULTS: Of the 31,251,040 ICSRs, 6946 cases of suspected drug-induced TMA were included from 55 countries. The outcome was fatal in 18.2% of cases. A total of 72 immune system targeting/anticancer drugs were associated with significant overreporting, including 17 drugs with a potential new safety concern for TMA. Although the rate of TMA reporting per million of ICSRs has remained fairly stable, an absolute increase in reported cases of suspected drug-induced TMA has been observed over the last decade. The pattern of drugs reported in TMA has evolved with a substantial increase in the proportion of cases involving immune system-targeting drugs/anticancer drugs from 47.3% (205/433) in the period 1992-2001 to 80.7% (3819/4730) in the period 2012-2021. CONCLUSION: Several recently marketed immune system targeting/anticancer drugs have been identified as potential new drugs associated with TMA, which will require confirmatory studies. The number of drugs associated with TMA reporting markedly increased within the past 10 years, primarily due to innovative anticancer drugs.

Drug-related hypophosphatemia: Descriptive study and case/non-case analysis of the French national pharmacovigilance database.

Phosphorus is an essential element for all living organisms and is involved in various biological pathways. A severe hypophosphatemia can lead to serious complications (acute heart or respiratory failure, rhabdomyolysis, hemolysis…) and increases mortality in patients at risk. Various drugs are known to induce hypophosphatemia through various mechanisms. The aim of this study was to highlight the main drugs associated with hypophosphatemia and to deduce the underlying mechanisms based on a descriptive analysis and a case/non-case analysis using the cases of drug-induced hypophosphatemia reported to the French Pharmacovigilance Network. A total of 368 cases of hypophosphatemia were included in the study. Patients' mean age was 52±18 years. One hundred and ninety-one cases (52%) were serious including 131 (36%) hospitalizations. The median value of serum phosphorus level was 0.54mmol/L [0.40-0.66] (n=309). Those 368 cases corresponded to 185 different suspected substances among which the most frequent drugs were tenofovir disoproxil (n=175; 48%), ferric carboxymaltose (n=29; 8%), denosumab (n=16; 4%), zoledronic acid (n=14; 4%) and hydrochlorothiazide (n=10; 3%). For these five drugs, a significant disproportionality was found. Tenofovir-disoproxil related hypophosphatemia occurred more than one year after its introduction, and a renal tubulopathy (Fanconi's syndrome) was reported in 44 cases (25%). Hypophosphatemia related to iron carboxymaltose occurred within a median of 20 days after injection and was mostly severe. Mechanism included the fibroblast growth factor 23 which can be measured to confirm drug origin. Concerning anti-osteoporosis treatments, hypophosphatemia could be explained by their mechanism of action (abrupt increase of parathormone induced by hypocalcemia) but the patient history (malignancy condition) was a major bias. For hydrochlorothiazide, hyphosphatemia was often moderate, associated with other electrolytic disturbances and occurred during a long-term treatment. Awareness of healthcare professionals is essential to detect as soon as possible hypophosphatemia and its complications related to these drugs.

Immune checkpoint inhibitor-associated capillary leak syndrome: A systematic review and a worldwide pharmacovigilance study.

BACKGROUND: Although a few case reports have shown that immune checkpoint inhibitors (ICIs) are potential inducers of capillary leak syndrome (CLS), an incidental finding cannot be ruled out. The aim of this study was to describe the clinical characteristics of ICI-induced CLS through a systematic review and to assess a potential safety signal. METHODS: Medline/PubMed, Embase, and Reactions Weekly were screened, and a global disproportionality study was performed using the World Health Organization pharmacovigilance database through January 15, 2023. A signal of disproportionate reporting was defined as a Bayesian information component (IC) with a 95% credibility interval (CrI) lower boundary that exceeds 0. RESULTS: A total of 47 cases of ICI-associated CLS were included, 14 from the systematic review (of 61 screened articles) and 33 from VigiBase (of 34,058,481 reports of adverse drug reactions). The median time to CLS onset from the start of ICI was 12 weeks (interquartile range 8-49, n = 24). A total of 57% (8/14) of patients experienced an immune-related adverse event (irAE) before CLS. A fatal outcome was reported in 23% (7/31) of patients. A significant overreporting of CLS was found with ICIs compared with all other drugs (IC 2.4, 95% CrI from 1.8 to 2.8). CONCLUSION: This study showed a significant signal of disproportionality reporting for ICI-induced CLS, characterized by a long time to onset, and compared with the idiopathic form of the disease with a less abrupt onset and a less consistent hemoconcentration pattern.

Sex differences in adverse drug reactions: Are women more impacted?

Pharmacovigilance and pharmacoepidemiology studies regarding the sex difference in adverse drug reactions are numerous, and it is now a challenge to take them into account in order to increase drug safety. Here, we present an overview of this topic through data on epidemiology, mechanisms, and methods used for assessing sex differences in drug safety. Because the literature is extensive, we choose to expose a few examples of studies for cardiovascular drugs, anti-infectious, psychotropics, antidiabetics, anticancer drugs and some specific drugs to illustrate our purpose. Many studies show a higher risk in women for most of drugs involving in sex differences. However, physiological, methodological and subjective points have to be taken into account to interpret these results. Clinical trials must also enroll more women to better evaluate sex differences both in efficacy and pharmacovigilance. Nevertheless, when there is a pharmacological rationale underlying the observed association between sex and drug safety profile, it is now unavoidable to think about its consideration for a personalized prescription.

Incidence and preventability of hospital admissions for adverse drug reactions in France: A prospective observational study (IATROSTAT).

AIMS: In the last French study in 2007, the incidence of hospital admissions (HAs) related to adverse drug reactions (ADRs) was 3.6%. The objective was to assess the current ADR-HA incidence in France and to describe both its characteristics and preventability. METHODS: A prospective multicentre study was conducted among randomly selected French public hospital medical wards (April-July 2018). Patients admitted during a week period were included. ADR-HA cases were collected by the French Regional Pharmacovigilance Centres network. An independent committee validated potential cases and ADR preventability. RESULTS: ADR-HA incidence was 8.5% (95% confidence interval [CI]: 7.6-9.4%), increasing with age (3.3% [95%CI: 1.8-5.5%] ≤16 y vs. 10.6% [95%CI: 9.3-12.0%] ≥65 y). The most common ADRs were haemorrhagic events (8.8%), haematological disorders (6.5%), acute renal failure (6.3%), fluid and electrolyte disorders (6.0%), and falls (5.2%). New drugs were involved: targeted therapies (22.8% of antineoplastics), direct oral anticoagulants (29.6% of antithrombotics) and incretin-based drugs (20.0% of antidiabetics). ADRs were preventable in 16.1% of cases because the drugs involved had not been used in accordance with monographies, package leaflets or other therapeutic guidelines. The main situations of noncompliance addressed either dose or duration of use (27.9%), warning (23.2%), use precaution (18.6%) and inappropriate self-medication or misuse by patients (11.6%). CONCLUSION: In France, ADR-HA incidence dramatically increased over the last decade. A significant proportion was related to new pharmacological classes and considered as preventable. These findings should lead to in-depth thought on preventive actions on at-risk drug classes.

De novo and relapsing necrotizing vasculitis after COVID-19 vaccination.

We describe five cases of severe necrotizing vasculitis following the RNA-based vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including four relapsing anti neutrophil cytoplasmic antibodies (ANCA) vasculitis, 27 days (1-60) after vaccination and one patient with quiescent chronic hepatitis B and de novo polyarteritis nodosa (PAN) 21 days after vaccination. Ten other cases were reported to the French national pharmacovigilance database: six patients with ANCA-associated vasculitis and four patients with PAN (first symptoms 19 days on average after vaccination). Five of these 10 patients developed kidney dysfunction. In conclusion, coronavirus disease 2019 (COVID-19) vaccines can be associated with de novo or recurrent ANCA vasculitis or PAN. Attention should be paid to patients with known ANCA vasculitis or patients with a history of hepatitis B infection.

Incidence and characteristics of intravascular pulmonary migration of etonogestrel implants: A French nationwide study.

OBJECTIVE(S): To describe the features of etonogestrel implant (Nexplanon and Implanon) migration into the pulmonary vasculature and to estimate its incidence in France. STUDY DESIGN: We retrospectively reviewed French cases of implant migration into the pulmonary vasculature reported up to 2018. Patient clinical data were collected. The annual incidence of migration was estimated from the number of cases reported and number of implants sold. RESULTS: Twenty-seven cases of migration into the pulmonary vasculature were identified. In 19 cases (70%) it was stated that this was into the pulmonary artery (nine into the left branch, four into the right branch and six unspecified) and in the other eight cases (30%) it was it not specified whether this was into the pulmonary artery or one of its branches. The migration was discovered following a request for implant removal in 59% of cases, following respiratory complaints in 24%, and because the implant was no longer palpable in 17%. In the 24 cases for which information on removal (or not) was available, the implant was removed in 15 (60% by an endovascular procedure and 40% by invasive surgery); in the remainder it was left in situ. The incidence of migration into the pulmonary vasculature was 1.23 per 100,000 implants sold [95% CI 0.25-3.58] in 2014, increasing to 3.17 per 100,000 implants sold [1.37-6.24] in 2017. In 2016, the French National Agency for Medicines and Health Products Safety (ANSM) had recommended performing a systematic search for non-palpable implants, including at thorax level. CONCLUSIONS: The incidence of migration into the pulmonary vasculature is low. Nonetheless, because the consequences are potentially serious, in December 2019 the ANSM made recommendations to reduce this risk.

Rituximab-induced serum sickness is more frequent in autoimmune diseases as compared to hematological malignancies: A French nationwide study.

INTRODUCTION: Rituximab induced serum sickness (RISS) is a rare delayed hypersensitivity reaction. The aim of this study was to describe the epidemiological and clinical characteristics of the RISS cases reported in France. METHOD: Serum sickness cases involving rituximab were identified from the French PharmacoVigilance Database from 1998 to 2016. RESULTS: We analyzed 37 cases of RISS. Rituximab was prescribed for an autoimmune disease in 78% of cases. Serum sickness occurred mainly after the first injection (54%) with a median time to onset of 12 days. The most frequent manifestations were rheumatologic symptoms (92%), fever (87%), and skin lesions (78%). The incidence was significantly higher when rituximab was used for autoimmune diseases than for a hematological malignancies. Taking into account the existence of a Systemic Lupus Erythematosus (SLE) as the indication of rituximab or as a comorbidity, the incidence of RISS in patients with SLE was even higher. DISCUSSION: We report on the largest series of RISS studied to date and confirm that this reaction preferentially occurs in patients with autoimmune disease, especially SLE. This may be due to B-cell lysis, leading to the release of intracellular antigens into the serum and subsequent antigen-antibody complex formation, especially in patients with elevated autoantibody production. This could also explain why RISS often occurred after a single injection. CONCLUSION: Patients generally recovered from RISS rapidly without obvious benefit from corticosteroid therapy. The risk of recurrence should prompt clinicians to question the use of rituximab after an episode of RISS.

Clinical practice guidelines for contraception by the French National College of Gynecologists and Obstetricians (CNGOF).

The French College of Obstetrics and Gynecology (CNGOF) has released its first comprehensive recommendations for clinical practices in contraception, to provide physicians with an updated synthesis of the available data as a basis for their practice. The organizing committee and the working group adopted the objective methodological principles defined by the French Authority for Health (HAS) and selected 12 themes relevant to medical professionals' clinical practices concerning contraception. The available literature was screened through December 2017 and served as the basis of 12 texts, reviewed by experts and physicians from public and private practices, with experience in this field. These texts enabled us to develop evidence based, graded recommendations. Male and female sterilization, as well as the use of hormonal treatments not authorized for contraception ("off-label") were excluded from the scope of our review. Specific practical recommendations are provided for the management of contraception prescription, patient information concerning effectiveness, risks, and benefits of the different methods, patient follow-up, intrauterine contraception, emergency contraception, local and natural methods, contraception in teenagers, in women after 40, for women at high thromboembolism or cardiovascular risk, and for those at of primary cancer or relapse. The short- and mid-term future of contraception depends mainly on improving the use of currently available methods. This includes reinforced information for users and increased access to contraception for women, regardless of their social and clinical contexts. The objective of these guidelines is to aid in enabling this improvement.

Pregnancy outcomes in women exposed to cancer chemotherapy.

PURPOSE: There is little data on the effects of cancer chemotherapy in pregnant women. The objective of this study was to describe pregnancy outcomes of women exposed to cancer chemotherapy, recorded in the French Terappel database. METHODS: We performed a descriptive, prospective study of the pregnancies of women exposed to cancer chemotherapy recorded in Terappel between June 1984 and December 2016. Terappel is a French database that has recorded questions of health professionals and/or individuals at the Regional Pharmacovigilance Centres about drugs and pregnancy. For each question, pregnancies are monitored and the outcome is recorded in the database. RESULTS: In total, 75 questions about "anti-cancer drugs and pregnancy" received by 16 Regional Pharmacovigilance Centres between 1997 and 2016 were recorded in Terappel. Breast cancer accounted for 62.7% of the cases, followed by leukaemia (13.3%) and lymphoma (9.3%). Cyclophosphamide is the leading anti-cancer drug with 40.0% of exposed pregnant women, followed by 5-fluorouracil (34.7%), epirubicin (32.0%), tamoxifen (26.7%), and doxorubicin (16.0%). Among the 75 pregnancies, we observed 55 births with 57 children (73.3%) (two cases of twins), nine medical terminations of pregnancy (12.0%), six voluntary terminations of pregnancy (8.0%), three intrauterine foetal deaths (4.0%), and two miscarriages (2.7%). We found a malformation rate of 7.8%. Sixteen of 57 (28.1%) newborns developed one or more neonatal pathologies. CONCLUSION: Pregnancy of women taking anti-cancer drugs resulted in birth in 73% of cases. Nevertheless, pregnant women exposed to cancer chemotherapy remains at risk of malformations and neonatal conditions related to prematurity and drugs.

Glycemic dysregulation in a patient with type 2 diabetes treated with 5-azacitidine: a case report.

BACKGROUND: Diabetes and myelodysplastic syndrome are two conditions that may coexist in a single patient, since both diseases are prevalent in the elderly. The pathophysiology of myelodysplastic syndrome involves recurrent genetic mutations, especially in genes controlling epigenetic regulation. Although the pathophysiology of diabetes is not well understood, several studies suggest a role of epigenetics in type 2 diabetes. CASE PRESENTATION: We report here for the first time the case of a 75-year-old Caucasian man who was treated for both diabetes and acute myeloid leukemia secondary to myelodysplastic syndrome, with a temporal association between glycemic dysregulation and the intake of 5-azacitidine. In fact, 2-3 days after starting each 7-day cycle of 5-azacitidine, he reported higher blood glucose levels, requiring an increased dose of self-administered insulin. CONCLUSION: This observation could help to understand the pathophysiology of these two conditions and could encourage physicians to monitor blood glucose levels in patients under hypomethylating agent with a history of diabetes.

Treatment of voluminous and complicated superficial slow-flow vascular malformations with sirolimus (PERFORMUS): protocol for a multicenter phase 2 trial with a randomized observational-phase design.

BACKGROUND: Slow-flow superficial vascular malformations (VMs) are rare congenital anomalies that can be responsible for pain and functional impairment. Currently, we have no guidelines for their management, which can involve physical bandages, sclerotherapy, surgery, anti-inflammatory or anti-coagulation drugs or no treatment. The natural history is progressive and worsening. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that acts as a master switch in cell proliferation, apoptosis, metabolism and angio/lymphangiogenesis. Sirolimus directly inhibits the mTOR pathway, thereby inhibiting cell proliferation and angio/lymphangiogenesis. Case reports and series have reported successful use of sirolimus in children with different types of vascular anomalies, with heterogeneous outcomes. OBJECTIVE: The objective of this trial is to evaluate the efficacy and safety of sirolimus in children with complicated superficial slow-flow VMs. METHODS/DESIGN: This French multicenter randomized observational-phase, phase 2 trial aims to include 50 pediatric patients 6 to 18 years old who have slow-flow (lymphatic, venous or lymphatico-venous) voluminous complicated superficial VM. Patients will be followed up for 12 months. All patients will start with an observational period (no treatment). Then at a time randomly selected between month 4 and month 8, they will switch to the experimental period (switch time), when they will receive sirolimus until month 12. Each child will undergo MRI 3 times: at baseline, at the switch time, and at month 12. For both periods (observational and treatment), we will calculate the relative change in volume of the VM divided by the study period duration. This relative change weighted by the study period duration will constitute the primary endpoint. VM will be measured by MRI images, which will be centralized and interpreted by the same radiologist who will be blinded to the study period. Hence, each patient will be his/her own control. Secondary outcomes will include assessment of safety and efficacy by viewing standardized digital photographs and according to the physician, the patient or proxy; impact on quality of life; and evolution of biological makers (coagulation factors, vascular endothelial growth factor, tissue factor). DISCUSSION: The main benefit of the study will be to resolve uncertainty concerning the efficacy of sirolimus in reducing the volume of VMs and limiting related complications and the safety of the drug in children with slow-flow VMs. This trial design is interesting in these rare conditions because all included patients will have the opportunity to receive the drug and the physician can maintain it after the end of the protocol if is found efficient (which would not be the case in a classical cross-over study). TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02509468 , first received: 28 July 2015. EU Clinical Trials Register EudraCT Number: 2015-001096-43.

Nivolumab in routine practice for older patients with advanced or metastatic non-small cell lung cancer.

BACKGROUND: Nivolumab is approved worldwide as second-line treatment for metastatic non-small cell lung cancer (NSCLC). Despite the fact that most of these cancers are being diagnosed in the older patients, few of the patients were included in pivotal trials. We aimed to describe efficacy and safety in a "real-world" older population. PATIENTS AND METHODS: We retrospectively collected data from older patients (≥70 years old) with advanced or metastatic NSCLC treated with Nivolumab in our institution. We analyzed safety (CTCAE v4.0 criteria), efficacy (clinical benefit rate, progression-free survival, and overall survival), and correlated these features to geriatric parameters and PD-L1 expression. Along with this cohort, we assessed safety at a national level by retrieving all cases of Nivolumab (prescribed for NSCLC) induced adverse events analyzed by the French pharmacovigilance network during the inclusion period. RESULTS: From July 2015 to September 2016, 30 patients were enrolled with a median age of 75.2. Clinical benefit rate was 30.6%. Median progression-free survival and overall survival were 3.3 and 7.1 months, respectively. Fifteen patients (50%) presented an immune-related adverse event (IrAE) of any grade, including four high grade IrAEs. Two hundred and eighty IrAEs had been notified to the French pharmacovigilance network including 91 (35.2%) concerning older patients. Frequency and pattern of IrAEs were similar for older patients and younger subjects. CONCLUSIONS: Even though frequency and patterns of IrAEs are different from pivotal studies, these results don't seem specific to older patients. Further prospective investigations are needed to better characterize and predict the impact of Nivolumab on older patients with NSCLC.

Interstitial Nephritis Secondary to Vedolizumab Treatment in Crohn Disease and Safe Rechallenge Using Steroids: A Case Report.

Vedolizumab is a gut-selective humanized monoclonal antibody that binds selectively to the α4 ß7 integrin and acts as a lymphocyte-homing antagonist. It is indicated in ulcerative colitis and Crohn disease. We report a case of acute interstitial nephritis following vedolizumab infusion in a 55-year-old white woman treated for severe Crohn disease resistant to several therapies. Other kidney disease causes were ruled out. Glucocorticoids were administrated, leading to full renal recovery. In the absence of other therapeutic options, vedolizumab was re-administered along with transient corticosteroids; this treatment was well tolerated. Fewer than 10 cases of immunoallergic acute interstitial nephritis following treatment with monoclonal antibody have previously been reported in the literature. The pathophysiology of delayed-type hypersensitivity secondary to monoclonal antibody therapeutics is discussed in this case report.

Efficacy and Safety of Mammalian Target of Rapamycin Inhibitors in Vascular Anomalies: A Systematic Review.

Mammalian target of rapamycin (mTOR) inhibitors are a promising new treatment in vascular anomalies, but no published randomized controlled trials are available. The aim of this systematic review of all reported cases was to assess the efficacy and safety of mTOR inhibitors in all vascular anomalies, except cancers, in children and adults. In November 2014 MEDLINE, CENTRAL, LILACS and EMBASE were searched for studies of mTOR inhibitors in any vascular condition, except for malignant lesions, in humans. Fourteen publications and 9 posters, with data on 25 and 59 patients, respectively, all < 18 years old were included. Of these patients, 35.7% (n = 30) had vascular tumours, and 64.3% (n = 54) had malformations. Sirolimus was the most frequent mTOR inhibitor used (98.8%, n = 83). It was efficient in all cases, at a median time of 2 weeks (95% confidence interval 1-10 weeks). Sirolimus was well tolerated, the main side-effect being mouth sores, which led to treatment withdrawal in one case. The dosage of sirolimus was heterogeneous, the most common being 1.6 mg/m2/day.