Safety and efficacy of sirolimus in recurrent intravenous leiomyomatosis, pulmonary benign metastatic leiomyomatosis, and leiomyomatosis peritonealis disseminata: a pilot study.

BACKGROUND: Intravenous leiomyomatosis (IVL), pulmonary benign metastatic leiomyomatosis (PBML), and leiomyomatosis peritonealis disseminata (LPD) are leiomyomas with special growth patterns and high postoperative recurrence rates. We report the safety and efficacy of a pilot study of sirolimus in the treatment of recurrent IVL, PBML, and recurrent LPD. METHODS: This was a pilot study to evaluate the safety and efficacy of sirolimus in the treatment of leiomyomatosis (ClinicalTrials.gov identifier NCT03500367) conducted in China. Patients received oral sirolimus 2 mg once a day for a maximum of 60 months or until disease progression, intolerable toxicity, withdrawal of consent, or investigator decision to stop. The primary end point of this study was the objective response rate. Secondary end points included safety and tolerability, disease control rate, and progression-free survival. RESULTS: A total of 15 patients with leiomyomatosis were included in the study, including five with recurrent IVL, eight with PBML and two with recurrent LPD. The median follow-up time was 15 months (range 6-54 months), nine patients (60%) had treatment-related adverse events (including all levels), and two patients had treatment-related grade 3 or 4 adverse events. The objective response rate was 20.0% (95% CI, 7.1-45.2%), and the disease control rate was 86.7% (95% CI, 62.1-96.3%). Partial response was achieved in three patients. The median response time in the three partial response patients was 33 months (range 29-36 months), and the sustained remission time of these three patients reached 0, 18, and 25 months, respectively. CONCLUSIONS: Sirolimus was safe and effective in the treatment of recurrent IVL, PBML, and recurrent LPD. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03500367. Registered on 18 April 2018.

Long term clinical outcome of sirolimus drug coated balloons in large coronary vessels.

BACKGROUND: Studies evaluating the safety and efficacy of drug coating balloons (DCB) for the treatment of lesions in large coronary vessel are limited. AIMS: Our study aimed to evaluate the performance of a sirolimus DCB in large coronary arteries. METHODS: We analyzed all the procedures included in the EASTBOURNE Registry (NCT03085823) enrolling patients with a clinical indication to percutaneous coronary intervention performed by a sirolimus DCB according to investigator judgment. In the present analysis, a cut-off of 2.75 mm was used to define large coronary arteries. Primary endpoint of the study was clinically driven target lesion revascularization (TLR) at 24 months whereas secondary endpoint included procedural success, myocardial infarction (MI), cardiac death and total mortality. RESULTS: Among the 2123 patients and 2440 lesions enrolled in the EASTBOURNE study between 2016 and 2020, 757 patients/810 lesions fulfilled the criteria for the present analysis. Mean reference vessel diameter was 3.2 ± 0.3 mm with mean lesion length of 22 ± 7 mm. Procedural success was high (96%) and at 2-year follow up the device showed a good efficacy with a TLR rate of 9%. There were 34 deaths (4.5%), 30 MIs (4%) and 8 BARC type 3-5 bleedings (1.1%). In-stent restenosis (629 lesions) and de novo lesions (181) were associated with 11% and 4% rates of TLR at 2 years, respectively (p = 0.003). CONCLUSIONS: Clinical performance of a sirolimus DCB in large coronary artery vessels shows promising signals at 2-year follow up, both in de novo and in-stent restenosis lesions.

Add-on sirolimus for the treatment of mild or moderate systemic lupus erythematosus via T lymphocyte subsets balance.

OBJECTIVE: The efficacy of sirolimus in treating severe or refractory systemic lupus erythematosus (SLE) has been confirmed by small-scale clinical trials. However, few studies focused on mild or moderate SLE. Therefore, in this study we elucidated clinical efficacy of add-on sirolimus in patients with mild or moderate SLE. METHODS: Data of 17 consecutive patients with SLE were retrospectively collected. SLE Disease Activity Index-2000 (SLEDAI-2K), clinical manifestation, laboratory data and peripheral T lymphocyte subsets with cytokines were collected before and 6 months after sirolimus add-on treatment. T cell subsets were detected by flow cytometry and cytokines were determined by multiplex bead-based flow fluorescent immunoassay simultaneously. Twenty healthy controls matched with age and sex were also included in our study. RESULTS: (1) The numbers of peripheral blood lymphocytes, T cells, T helper (Th) cells, regulatory T (Treg) cells, Th1 cells, Th2 cells and Treg/Th17 ratios in patients with SLE were significantly lower, while the numbers of Th17 cells were evidently higher than those of healthy control (p<0.05). (2) After 6 months of sirolimus add-on treatment, urinary protein, pancytopenia, immunological indicators and SLEDAI-2K in patients with SLE were distinctively improved compared with those before sirolimus treatment (p<0.05). (3) The numbers of peripheral blood lymphocytes, T cells, Th cells, Treg cells, Th2 cells and the ratios of Treg/Th17 in patients with SLE after treatment were clearly higher than those before (p<0.05). (4) The levels of plasma interleukin (IL)-5, IL-6 and IL-10 in patients with SLE decreased notably, conversely the IL-4 levels increased remarkably compared with pretreatment (p<0.05). CONCLUSIONS: (1) Patients with SLE presented imbalanced T cell subsets, especially the decreased ratio of Treg/Th17. (2) Sirolimus add-on treatment ameliorated clinical involvement, serological abnormalities and disease activity without adverse reactions in patients with SLE. (3) The multi-target therapy facilitates the enhanced numbers of Treg cells, Treg/Th17 imbalance and anti-inflammatory cytokines, simultaneously, reducing inflammatory cytokines.

Sirolimus-coated balloon in all-comer population of coronary artery disease patients: the EASTBOURNE DIABETES prospective registry.

BACKGROUND: The outcomes of percutaneous coronary intervention (PCI) in diabetic patients are still suboptimal, and it is unclear if diabetic patients might derive a benefit from the use of drug-coated balloons. AIMS: To evaluate the impact of diabetes mellitus on the outcomes of patients undergoing PCI with sirolimus-coated balloon (SCB) MagicTouch (Concept Medical, India). METHODS: We conducted a subgroup analysis of the prospective, multicenter, investigator-initiated EASTBOURNE registry, evaluating the performance of MagicTouch SCB in patients with and without diabetes. The study primary endpoint was target lesion revascularization (TLR) at 12-month follow-up. Secondary clinical endpoints were major adverse clinical events (MACE), death, myocardial infarction (MI), and BARC 2-5 bleedings. RESULTS: Among 2,083 enrolled patients, a total of 864 suffered from diabetes (41.5%). Patients with diabetes had a numerically higher occurrence of TLR (6.5% vs. 4.7% HR 1.38, 95%CI 0.91-2.08), all-cause death (3.8% vs. 2.6%, HR 1.81, 95%CI 0.95-3.46), and MACE (12.2% vs. 8.9%; HR 1.26 95%CI 0.92-1.74). The incidence of spontaneous MI was significantly higher among diabetic patients (3.4% vs. 1.5%, HR 2.15 95%CI 1.09-4.25); bleeding events did not significantly differ. The overall incidence of TLR was higher among in-stent restenosis (ISR) as compared to de-novo coronary lesions, irrespectively from diabetes status. CONCLUSIONS: In the EASTBOURNE DIABETES registry, diabetic patients treated with the MagicTouch SCB did not have a significant increase in TLR when compared to non-diabetic patients; moreover, diabetic status did not affect the study device performance in terms of TLR, in both de-novo lesions and ISR.

Safety and efficacy of sirolimus in hospitalised patients with COVID-19 pneumonia.

BACKGROUND: There is a critical need to develop novel therapies for COVID-19. METHODS: We conducted a phase 2, multicentre, placebo-controlled, double-blind, randomised trial; hospitalised patients with hypoxemic respiratory failure due to COVID-19 and at least one poor prognostic biomarker, were given sirolimus (6 mg on Day 1 followed by 2 mg daily for 14 days or hospital discharge, whichever happens first) or placebo, in a 2:1 randomization scheme favouring sirolimus. Primary outcome was the proportion of patients alive and free from advanced respiratory support measures at Day 28. RESULTS: Between April 2020 and April 2021, 32 patients underwent randomization and 28 received either sirolimus (n = 18) or placebo (n = 10). Mean age was 57 years and 75 % of the subjects were men. Twenty-two subjects had at least one co-existing condition (Diabetes, hypertension, obesity, CHF, or asthma/COPD) associated with worse prognosis. Mean FiO2 requirement was 0.35. There was no difference in the proportion of patients who were alive and free from advanced respiratory support measures in the sirolimus group (n = 15, 83 %) compared with the placebo group (n = 8, 80 %). Although patients in the sirolimus group demonstrated faster improvement in oxygenation and spent less time in the hospital, these differences were not statistically significant. There was no between-group difference in the rate of change in serum biomarkers such as LDH, ferritin, d-dimer or lymphocyte count. There was a decreased risk of thromboembolic complications in patients on sirolimus compared with placebo. CONCLUSIONS: Larger studies are warranted to evaluate the role sirolimus in COVID-19 infection.

Efficacy and safety of mTOR inhibition in cutaneous sarcoidosis: a single-centre trial.

BACKGROUND: Sarcoidosis is an inflammatory condition that can affect various organs and tissues, causing the formation of granulomas and subsequent functional impairment. The origin of sarcoidosis remains unknown and there are few treatment options. Mechanistic target of rapamycin (mTOR) activation is commonly seen in granulomas of patients across different tissues and has been shown to induce sarcoidosis-like granulomas in a mouse model. This study aimed to examine the efficacy and safety of the mTOR inhibitor sirolimus as a treatment for cutaneous sarcoidosis. METHODS: We did a single-centre, randomised study treating patients with persistent and glucocorticoid-refractory cutaneous sarcoidosis with sirolimus at the Vienna General Hospital, Medical University of Vienna (Vienna, Austria). We recruited participants who had persistent, active, and histologically proven cutaneous sarcoidosis. We used an n-of-1 crossover design in a placebo-controlled, double-blind topical treatment period and a subsequent single-arm systemic treatment phase for 4 months in the same participants. Participants initially received either 0·1% topical sirolimus in Vaseline or placebo (Vaseline alone), twice daily. After a washout period, all participants were subsequently administered a 6 mg loading dose followed by 2 mg sirolimus solution orally once daily, aiming to achieve serum concentrations of 6 ng/mL. The primary endpoint was change in the Cutaneous Sarcoidosis Activity and Morphology Index (CSAMI) after topical or systemic treatment. All participants were included in the safety analyses, and patients having completed the respective treatment period (topical treatment or systemic treatment) were included in the primary analyses. Adverse events were assessed at each study visit by clinicians and were categorised according to their correlation with the study drug, severity, seriousness, and expectedness. This study is registered with EudraCT (2017-004930-27) and is now closed. FINDINGS: 16 participants with persistent cutaneous sarcoidosis were enrolled in the study between Sept 3, 2019, and June 15, 2021. Six (37%) of 16 participants were men, ten (63%) were women, and 15 (94%) were White. The median age of participants was 54 years (IQR 48-58). 14 participants were randomly assigned in the topical phase and 2 entered the systemic treatment phase directly. Daily topical treatment did not improve cutaneous lesions (effect estimate -1·213 [95% CI -2·505 to 0·079], p=0·066). Systemic treatment targeting trough serum concentrations of 6 ng/mL resulted in clinical and histological improvement of skin lesions in seven (70%) of ten participants (median -7·0 [95% CI -16·5 to -3·0], p=0·018). Various morphologies of cutaneous sarcoidosis, including papular, nodular, plaque, scar, and tattoo-associated sarcoidosis, responded to systemic sirolimus therapy with a long-lasting effect for more than 1 year after treatment had been stopped. There were no serious adverse events and no deaths. INTERPRETATION: Short-term treatment with systemic sirolimus might be an effective and safe treatment option for patients with persistent glucocorticoid-refractory sarcoidosis with a long-lasting disease-modulating effect. The effect of sirolimus in granulomatous inflammation should be investigated further in large, multi-centre, randomised clinical trials. FUNDING: Vienna Science and Technology Fund, Austrian Science Fund.

Sirolimus for the treatment of patients with refractory connective tissue disease-related thrombocytopenia: a pilot study.

OBJECTIVE: CTD-related immune thrombocytopenia (CTD-ITP) represents an unmet medical need because the drugs that are available are only partly effective and have considerable side-effects. The aim of this study was to assess the efficacy and safety of sirolimus in refractory CTD-ITP patients. METHODS: We did a single-arm, open-label, pilot study of sirolimus in patients with CTD-ITP unresponsive to, or intolerant of, conventional medications. Patients received oral sirolimus for 6 months at a starting dose of 0.5-1 mg per day, with dose adjusted according to tolerance and to maintain a therapeutic range of 6-15 ng/ml. The primary efficacy end point was changes in platelet count, and overall response assessed according to the ITP International Working Group Criteria. Safety outcomes included tolerance as assessed by the occurrence of common side-effects. RESULTS: Between November 2020 and February 2022, 12 consecutively hospitalized patients with refractory CTD-ITP were enrolled and prospectively followed. Of these, six patients (50%) achieved complete response, two (16.7%) achieved partial response, and four (33.3%) were no response under therapy. Three of four patients with primary Sjögren's syndrome and two of three patients with systemic lupus erythematosus achieved overall response. One of two patients with overlapping Sjögren's syndrome and systemic lupus erythematosus achieved complete response at 6 months. No severe drug-related toxicities were observed. CONCLUSION: Our results do support sirolimus as an alternative regimen for refractory CTD-ITP patients, including systemic lupus erythematosus and primary SS.

An updated meta-analysis of effectiveness and safety of mTOR inhibitors in the management of tuberous sclerosis complex patients.

PURPOSE: Tuberculous sclerosis complex (TSC) is an autosomal dominant multi-system disease. In TSC patients, the inhibition of mTOR pathway is weakened, which leads to the uncontrolled proliferation of normal resting cells. Therefore, mTOR inhibitors have many therapeutic potentials in the treatment of TSC. However, there is no consensus on the safety and efficacy of mTOR inhibitors so far. This article aimed to present new evidence for the efficacy and safety of mTOR inhibitors in the treatment of TSC by evaluating published clinical trials. METHODS: A systemic search of online databases, such as Cochrane Library, Embase, PubMed, and the US National Institutes of Health Clinical Trials Registry, was conducted. The researchers selected studies that met the following entry criteria: randomized, double-blinded or single-blinded, placebo-controlled, parallel-group studies with active and control arms receiving rapamycin or everolimus and matched placebo, respectively. The meta-analysis included seven studies. Tumor response or epilepsy seizure frequency response rates were considered efficacy outcomes. RESULTS: In seven studies involving 877 patients, using of mTOR inhibitors therapy showed an improvement in both tumor response and seizure frequency outcomes in TSC. In combination of AML (angiomyolipomas), SEGA (subependymal giant cell astrocytoma), epilepsy, and facial angiofibroma subjects, the RR is 3.01 (95% CI 2.03 to 4.45, p = 0.000) with observed heterogeneity (I-squared = 55.4%). The main side effect of mTOR inhibitors was stomatitis. CONCLUSION: The updated meta-analysis suggests that the use of mTOR inhibitors is an effective therapy for patients with TSC.

A Head-to-head Comparison of De Novo Sirolimus or Everolimus Plus Reduced-dose Tacrolimus in Kidney Transplant Recipients: A Prospective and Randomized Trial.

BACKGROUND: Mammalian target of rapamycin inhibitors (mTORi), sirolimus (SRL) and everolimus (EVR), have distinct pharmacokinetic/pharmacodynamics properties. There are no studies comparing the efficacy and safety of de novo use of SRL versus EVR in combination with reduced-dose calcineurin inhibitor. METHODS: This single-center prospective, randomized study included first kidney transplant recipients receiving a single 3 mg/kg antithymocyte globulin dose, tacrolimus, and prednisone, without cytomegalovirus (CMV) pharmacological prophylaxis. Patients were randomized into 3 groups: SRL, EVR, or mycophenolate sodium (MPS). Doses of SRL and EVR were adjusted to maintain whole blood concentrations between 4 and 8 ng/mL. The primary endpoint was the 12-mo incidence of the first CMV infection/disease. RESULTS: There were 266 patients (SRL, n = 86; EVR, n = 90; MPS, n = 90). The incidence of the first CMV event was lower in the mTORi versus MPS groups (10.5% versus 7.8% versus 43.3%, P < 0.0001). There were no differences in the incidence of BK polyomavirus viremia (8.2% versus 10.1% versus 15.1%, P = 0.360). There were no differences in survival-free from treatment failure (87.8% versus 88.8% versus 93.3%, P = 0.421) and incidence of donor-specific antibodies. At 12 mo, there were no differences in kidney function (75 ± 23 versus 78 ± 24 versus 77 ± 24 mL/min/1.73 m 2 , P = 0.736), proteinuria, and histology in protocol biopsies. Treatment discontinuation was higher among patients receiving SRL or EVR (18.6% versus 15.6% versus 6.7%, P = 0.054). CONCLUSIONS: De novo use of SRL or EVR, targeting similar therapeutic blood concentrations, shows comparable efficacy and safety. The reduced incidence of CMV infection/disease and distinct safety profile of mTORi versus mycophenolate were confirmed in this study.

Delayed ulceration following combination pulse dye laser and topical sirolimus treatment for port wine birthmarks: A case series.

Port wine birthmarks (PWB) are capillary vascular malformations within the papillary and reticular dermis, most commonly occurring on the head and neck and may darken and thicken with age. Pulsed dye laser (PDL) is the gold standard of treatment for PWB as it selectively targets involved vessels. Sirolimus is a macrolide antibiotic that selectively inhibits mammalian target of rapamycin, thereby suppressing the angiogenesis pathways that can be activated by PDL. Sirolimus and PDL may be used together to treat PWB. We present a case series describing three cases of delayed ulceration and systemic sirolimus absorption following combination therapy, highlighting a potential complication and patient safety concern.

Prevalence and clinical characteristics of oral lesions in heart transplant patients induced by sirolimus and everolimus: a systematic review and meta-analysis on a global scale.

OBJECTIVE: Sirolimus (SRL) and everolimus (EVL) are increasingly included in immunosuppressive protocols after heart transplantation. They present some side effects, including the appearance of painful lesions in the oral cavity. Therefore, this systematic review aimed to verify the global prevalence and clinical characteristics of oral lesions induced by SRL and EVL in heart transplant patients. STUDY DESIGN: A systematic review was performed using 5 main electronic databases (Medline/PubMed, SCOPUS, EMBASE, Web of Science, and LILACS), in addition to the gray literature. Studies were independently assessed by 2 reviewers based on established eligibility criteria. The risk of bias was assessed using the Joanna Briggs Institute appraisal tools, and the certainty of evidence was evaluated through GRADE assessment. RESULTS: Seventeen studies (860 patients) were included in the qualitative analysis. Of these, 11 studies were pooled in a meta-analysis of prevalence. The worldwide prevalence of oral lesions induced by SRL and EVL in heart transplant patients was 10.0%, and most lesions were described as ulcers >1.0 cm, related to significant pain. CONCLUSIONS: Oral lesions induced by SRL and/or EVL, although not very prevalent, have a relevant impact on patient's lives and the continuity of treatment.

The effect of gender on clinical outcomes following routine revascularizations with polymer-free sirolimus-eluting stents.

BACKGROUND: Gender-specific outcomes after percutaneous coronary interventions were studied by a number of research groups with different endpoints and cohorts of different ethnic extractions. The purpose of this report is to use propensity score matching to determine gender-specific differences in clinical outcomes after percutaneous coronary interventions with polymer-free sirolimus-coated stents. MATERIALS AND METHODS: The basis for this post hoc analysis was two large all-comers studies with prospectively enrolled patients from Europe and Asia. Data were pooled and analyzed in terms of clinical outcomes to assess the impact of gender in patients with stable coronary artery disease and acute coronary syndrome. The primary endpoint was the accumulated target-lesion revascularization rate whereas secondary endpoints consisted of the event rates for major adverse cardiac events (MACE), myocardial infarction, bleeding events and death from all causes. The purpose of these post hoc analyses was to detect potential differences in clinical outcomes between females and males in unselected and propensity-score-matched cohorts. RESULTS: Overall, in the unmatched cohorts, accumulated target-lesion revascularization rates did not differ between both genders (2.7% vs. 2.0%; P = 0.101), however, accumulated MACE rates were higher in females than in males (5.2% vs. 3.9%; P = 0.020). After propensity-score-matching, primarily adjusting for age, hypertension and diabetes, our data revealed similar accumulated MACE in women and men (5.5% vs. 5.2%; P = 0.749). In the unmatched STEMI subgroup, all-cause mortality was significantly higher in females driven by older age ( P < 0.001). CONCLUSION: In the propensity-score-matched real-world cohorts, female gender was not a predictor for increased rates of accumulated MACE. In the unmatched STEMI subgroup, all-cause mortality was significantly higher in females due to older age. Age seems to be the determining factor for increased clinical event rates and not gender.

In-Hospital and 1-Year Clinical Results from the French Registry Using Polymer-Free Sirolimus-Eluting Stents in Acute Coronary Syndrome and Stable Coronary Artery Disease.

Objectives: The aim of this postmarket clinical study was to assess the safety and efficacy of the latest generation polymer-free sirolimus-eluting stents (PF-SES) in an all-comers population comparing outcomes in stable coronary artery disease (CAD) versus acute coronary syndrome (ACS) in France. Background: The efficacy and safety of the first-generation PF-SES have already been demonstrated by randomized controlled trials and "all-comers" observational studies. Methods: For this all-comers observational, prospective, multicenter study, 1456 patients were recruited in 22 French centers. The primary endpoint was target lesion revascularization (TLR) rate at 12 months and secondary endpoints included major adverse cardiac events (MACE) and bleeding. Results: 895 patients had stable CAD and 561 had ACS. At 12 months, 2% of patients had a TLR, with similar rates between stable CAD and ACS (1.9% vs 2.2%, p = 0.7). The overall MACE rate was 5.2% with an expected higher rate in patients with ACS as compared to those with stable CAD (7.3% vs 3.9%, p = 0.007). The overall bleeding event rate was 4.5%, with similar rates in stable CAD as compared to ACS patients (3.8% vs 5.6%, p = 0.3). Dual antiplatelet therapy (DAPT) interruptions prior to the recommended duration occurred in 41.7% of patients with no increase in MACE rates as compared to patients who did not prematurely interrupt DAPT (3.9% vs 6.1%, p = 0.073). Conclusions: The latest generation PF-SES is associated with low clinical event rates in these all-comers patients. There was a high rate of prematurely terminated DAPT, without any effect on MACE at 12 months. This trial is registered with NCT03809715.

Rapamycin extenuates experimental colitis by modulating the gut microbiota.

BACKGROUND AND AIM: Autophagy and gut microbiota correlates closely with the inflammatory bowel disease. Herein, we aimed to study the roles of rapamycin on the gut microbiota in inflammatory bowel disease. METHODS: Acute colitis was induced with dextran sodium sulfate (DSS) and 2,4,6-trinitrobenzenesulfonic acid solution in mice. Mice were administered with rapamycin or hydroxychloroquine. Weight loss, disease activity index scores, histopathological score, serum inflammatory cytokines, intestinal permeability, and colonic autophagy-related proteins were detected. Cecal content was also preserved in liquid nitrogen and subsequently analyzed following the 16S DNA sequencing. The antibiotic cocktail-induced microbiome depletion was performed to further investigate the relationship between autophagy activation and gut microbiota. RESULTS: Compared with the control group, the colonic autophagy-related proteins of P62, mTOR, and p-mTOR increased significantly, while the levels of LC3B and ATG16L1 decreased (all P < 0.05) in the model group. After rapamycin intervention, the colonic pathology of mice improved, while the disease activity index score decreased substantially; the colon length increased, and the expression of IL-6 and TNF-α decreased. Following hydroxychloroquine treatment, some indicators suggested aggravation of colitis. Principal coordinates analysis showed that the DSS group was located on a separate branch from the rapamycin group but was closer to the hydroxychloroquine group. Compared with the DSS group, the rapamycin group was associated with higher abundances of f_Lactobacillaceae (P = 0.0151), f_Deferribacteraceae (P = 0.0290), g_Lactobacillus (P = 0.0151), g_Mucispirillum (P = 0.0137), s_Lactobacillus_reuteri (P = 0.0028), and s_Clostridium_sp_Culture_Jar-13 (P = 0.0082) and a lower abundance of s_Bacteroides_sartorii (P = 0.0180). Linear discriminant analysis effect size showed that rapamycin increased the abundances of Lactobacillus-reuteri, Prevotellaceae, Paraprevotella, Christensenella and Streptococcus and decreased those of Peptostreptococcaceae and Romboutsia Bacteroides-sartorii. Besides, the improvement effect of autophagy activation on colitis disappears following gut microbiome depletion. CONCLUSION: The therapeutic effects of rapamycin on extenuating experimental colitis may be related to the gut microbiota.

Preliminary results of the European multicentric phase III trial regarding sirolimus in slow-flow vascular malformations.

BACKGROUNDSlow-flow vascular malformations frequently harbor activating mutations in the PI3K/AKT/mTOR cascade. Phase II trials pinpointed sirolimus effectiveness as a drug therapy. Efficacy and safety of sirolimus thus need to be evaluated in large prospective phase III trials.METHODSThe Vascular Anomaly-Sirolimus-Europe (VASE) trial, initiated in 2016, is a large multicentric prospective phase III trial (EudraCT 2015-001703-32), which evaluates efficacy and safety of sirolimus for 2 years in pediatric and adult patients with symptomatic slow-flow vascular malformations. In this interim analysis, we studied all patients enrolled up to October 2021 who received sirolimus for 12 or more months or who prematurely stopped the treatment.RESULTSThirty-one pediatric and 101 adult patients were included in this analysis; 107 completed 12 or more months of sirolimus, including 61 who were treated for the whole 2-year period. Sirolimus resulted in a clinical improvement in 85% of patients. The efficacy appeared within the first month for the majority of them. Grade 3-4 adverse events were observed in 24 (18%) patients; all resolved after treatment interruption/arrest. Sirolimus increased feasibility of surgery or sclerotherapy in 20 (15%) patients initially deemed unsuitable for intervention. Among the 61 patients who completed the 2-year treatment, 33 (54%) reported a recurrence of symptoms after a median follow-up of 13 months after sirolimus arrest. While there was no difference in efficacy, clinical improvement was faster but subsided more rapidly in PIK3CA-mutated (n = 24) compared with TIE2-mutated (n = 19) patients.CONCLUSIONSirolimus has a high efficacy and good tolerance in treatment of slow-flow vascular malformations in children and adults.TRIAL REGISTRATIONClinicalTrials.gov NCT02638389 and EudraCT 2015-001703-32.FUNDINGThe Fonds de la Recherche Scientifique (FNRS grants T.0247.19, P.C005.22, T.0146.16, and P.C013.20), the Fund Generet managed by the King Baudouin Foundation (grant 2018-J1810250-211305), the Walloon Region through the FRFS-WELBIO strategic research programme (WELBIO-CR-2019C-06), the MSCA-ITN network V.A. Cure no. 814316, the Leducq Foundation Networks of Excellence Program grant "ReVAMP" (LFCR grant 21CVD03), the European Union's Horizon 2020 research and innovation programme under grant agreement no. 874708 (Theralymph), the Swiss National Science Foundation under the Sinergia project no. CRSII5_193694, and a Pierre M. fellowship.