Use Of Sirolimus Research Articles

1383. Everolimus is Associated with an Increased Risk of Tuberculosis in Solid-Organ Transplant Recipients

BackgroundTuberculosis (TB) is an important post-transplant infection. Everolimus has been documented to reduce the risk of cytomegalovirus infection in transplant recipients, but its impact on other infections is less known. The present study aimed to assess immunosuppressive regimens on TB risk in solid-organ transplant (SOT) recipients via a matched case–control study.MethodsFrom May 2005 to December 2018, SOT recipients with TB were retrospectively identified, and those without TB undergoing transplantation at the same university hospital were selected as controls. Controls and cases were matched by age (±5 years), transplant type and year (±5 years) at a ratio of 4:1. Conditional logistic regression was used to analyze the risk factors of TB.ResultsTB developed in 30 SOT recipients (13 kidney, 7 heart, 6 liver, and 4 lung) after a mean duration of 1,601 days after transplantation, with predominant lung involvement (87%). The diagnosis was made by culture in 70% and pathology in 17%. Rifamycins-based regimens were used in 27 cases, and 4 developed rejection without graft failure. A total of 106 controls were selected. At the time of TB diagnosis, cases were more likely to use everolimus than controls (27% vs. 11%, P < 0.05), but no significant differences were observed in the use of tacrolimus, cyclosporin, sirolimus, prednisolone, or mycophenolate mofetil. The median duration of everolimus use was 585 and 698 days in 8 cases and 12 controls, respectively. Multivariable analysis showed that everolimus use (adjust odds ratio [aOR] 22.3, 95% conference interval [CI] 2.5–203.0) and hemodialysis (aOR 19.6, 95% CI 1.3–287.1) were independently associated with TB.ConclusionTB is more likely to develop in SOT recipients on everolimus and hemodialysis. Further studies to confirm our findings are warranted, and TB risk assessment should be performed for those receiving everolimus and hemodialysis.Disclosures All authors: No reported disclosures.

Sirolimus: efficacy and complications in children with hyperinsulinemic hypoglycemia: A 5-year follow-up study

Introduction Sirolimus, a mammalian target of rapamycin inhibitor, has been used in congenital hyperinsulinism (CHI) unresponsive to diazoxide and octreotide. Reported response to sirolimus is variable, with high incidence of adverse effects. To the best of our knowledge, we report the largest group of CHI patients treated with sirolimus followed for the longest period to date. Methods Retrospective study of CHI patients treated with sirolimus in a tertiary service and review of the 15 publications reporting CHI patients treated with mammalian target of rapamycin inhibitors. Comparison was made between the findings of this study with those previously published. Results Twenty-two CHI patients treated with sirolimus were included in this study. Twenty showed partial response, one showed complete response, and one was unresponsive. Five of the partially/fully responsive patients had compound heterozygous ABCC8 mutations and five had heterozygous ABCC8 mutations. A total of 86.4% (19/22) developed complications, with infection being the most frequent (17/22), of which 11 were of bacterial etiology, followed by persistent diarrhea (3/22) and hyperglycemia (2/22). Seventeen patients stopped sirolimus: 13 from infections; 2 from hyperglycemia; and 2 from alternative treatment (lanreotide) response. Compared with data previously published, our study identified a higher number of partially sirolimus-responsive CHI cases, although the high rate of complications while on this medication limited its potential usefulness. Conclusion Sirolimus candidates must be carefully selected given its frequent and potentially life-threatening side effects. Its use as a short-term, last-resort therapy until normoglycemia is achieved with other agents such as lanreotide could avoid pancreatectomy. Further studies evaluating the use of sirolimus in patients with CHI are required.

A monocentric study of steroid-refractory acute graft-versus-host disease treatment with tacrolimus and mTOR inhibitor.

Acute graft-versus-host disease (aGVHD) remains one of the leading causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. No consensus exists on the best second-line treatment of steroid-refractory acute GVHD (SR-aGVHD). Previously published smaller studies on the use of sirolimus in SR-aGVHD treatment report a response rate of 57 to 86%, with 40% overall survival. The association of tacrolimus and mTOR inhibitor is supported by pre-clinical data and has been used as GVHD prophylaxis. We report 42 patients who received tacrolimus and mTOR inhibitor as a second- or third-line treatment of SR-aGVHD. Thirty-one patients were treated in second-line, with an overall response rate of 48.5% (complete response: 42%). Eleven patients were treated in third-line, with an overall response rate of 27%. Thirty-eight patients had at least one episode of infection, due to bacteria, viruses, fungi and parasites in 61, 42, 12 and two episodes, respectively. For patients treated in second-line, six-month and one-year survival were 61% and 42%, respectively. None of the patients treated in third-line survived. These results were not promising enough to initiate a phase three randomized clinical trial, but tacrolimus and mTOR inhibitor can be discussed among other options for patients with SR-aGVHD.

Pericardial Effusion Associated With Sirolimus Use After Renal Transplantation: A Single-Center Case Series

Pericardial effusion and cardiac tamponade following renal transplantation have been recognized as a potentially serious complications associated with the use of sirolimus for immunosuppression. Our study aims to analyze the development of sirolimus-associated pericardial effusion.Patients who underwent renal transplantation at our institution between 2001 and 2014 were reviewed and the correlation between sirolimus exposure and pericardial effusion was determined. Nineteen out of 792 patients who received a renal transplant over this 14-year period (incidence 2.4%) developed symptomatic pericardial effusion (determined by the need for pericardiocentesis or a pericardial window). All patients had a pre-transplantation cardiac workup, including echocardiogram, which did not reveal the presence of pericardial effusion. Our cohort of patients is mostly male (57.9%) and Caucasian (73.7%), which is consistent with the makeup of transplant recipients at our center. The mean age was 52.42 years at the time of transplantation. The development of symptomatic pericardial effusions occurred at a mean of 5.06 (.5–9.8) years after renal transplant while on sirolimus therapy. Sirolimus levels at diagnosis were 5.19–7.47 ng/mL. No significant pericardial effusion (resulting in tamponade physiology) recurred after therapeutic intervention, including cessation of sirolimus with or without pericardial drainage. This study is the largest single-center report of the possible association between pericardial effusion in renal transplant recipients who received sirolimus. Due to the widespread use of sirolimus in organ transplantation, clinicians must remain vigilant for this potential cardiac complication.

MON-517 Treatment of Gorham-Stout Disease with Combination Sirolimus and Denosumab

Background: Gorham-Stout Disease (GSD), or vanishing bone disease, is a rare condition characterized by lymphatic vessel proliferation associated with progressive, sometimes massive bone resorption. The underlying mechanism of osteolysis in this condition remains unclear; prevailing theories suggest that the disease is driven by lymphovascular growth factors, increased osteoclastic activity, and absence of osteoblast repair. Clinical Case: A 44-year-old Caucasian male was found to have an absent right scapula and multiple right rib fractures on an x-ray performed to evaluate chest discomfort. Notably, 3 years prior, a right shoulder MRI showed normal anatomy. He has no family history of bone disease. Physical exam showed soft tissue swelling in the area of the right scapula and limited range of motion of the right arm to 60 degrees in all directions. Serum calcium, phosphorous, and iPTH were normal. Bone resorption marker C-Telopeptide (CTx) was elevated to 722 pg/mL (93-630 pg/mL) while bone formation marker Procollagen I intact N-terminal (P1NP) was within normal limits. CT and MRI confirmed the absence of the body of his right scapula and identified posterior right rib lesions with overlying fractures. The remnant scapula and rib foci showed abnormally elevated activity on 18F-sodium fluoride (18F-NaF) PET/CT scan. Given his clinical and imaging findings, he was diagnosed with GSD. Treatment included two years of monthly denosumab (120 mg) and sirolimus (trough goal 7-13 mcg/L), followed by zoledronic acid infusion every 2 months for 3 doses to prevent the rebound bone resorption associated with denosumab cessation. After therapy, CTx was suppressed to 70 pg/mL and P1NP to 15 mcg/L (22-87 mcg/L). Serial imaging showed one new posterior right rib lesion noted after 6 months of treatment, but no further bone loss. He noted no pain or new weakness. Adverse events included worsening hypertriglyceridemia due to sirolimus as well as denosumab-induced hypocalcemia and hypophosphatemia. Discussion: There is no consensus on the optimal treatment of GSD. Medical therapy usually includes an antiproliferative agent (usually sirolimus or interferon 2b) and an antiresorptive agent (usually a bisphosphonate). The RANK-ligand inhibitor denosumab, the most potent osteoclast inhibitor, may be a more effective agent in preventing bone resorption in GSD. This case demonstrates the effective use of sirolimus and denosumab in GSD, but further study and careful monitoring for mineral metabolism side effects and rebound are needed.

Development and chemical characterization of biodegradable polymeric implants containing sirolimus for the treatment of malignant solid tumors.

The use of sirolimus and its analogs has been evaluated in studies aimed at combating several types of cancer; however, because of the limited bioavailability of the drug, the search for new forms of administration is required. Biodegradable polymeric implants containing sirolimus were developed and assessed as an alternative method of drug administration. Implants containing 25 % (w/w) sirolimus were prepared employing the polymer matrices chitosan, polycaprolactone and poly(lactic-co-glycolic acid) (PLGA) in two proportions: PLGA 50:50 and PLGA 75:25. Thermal analysis techniques such as thermogravimetry and differential scanning calorimetry, combined with x-ray diffraction were used to characterize and evaluate the compatibility of the constituents of the formulation. No incompatibilities were found between the components, but drug amorphization was observed in all samples. Implants made from the polymers chitosan and PCL may accelerate the degradation of SRL when these polymers are dissolved in methanol at 50 °C. HPLC analysis showed that the implant prepared with PLGA 75:25 did not present degradation products and maintained its appropriate drug content, even when dissolved in methanol and heated to 50 °C. Therefore, it represents the most suitable biodegradable polymer for use in implants developed for the treatment of malignant solid tumors. However, it is still necessary to further study the drug effects after amorphization of the crystal and also to perform stability and solubility analysis.

SIROLIMUS USE ASSOCIATED WITH LATE-ONSET PERICARDIAL EFFUSION AFTER RENAL TRANSPLANTATION

Pericardial effusion and cardiac tamponade have been recently recognized as potentially serious complications associated with sirolimus use. Our study aims to analyze the risk factors contributing to the development of this complication. This is a single center retrospective study of 585

Combined use of ruxolitinib and sirolimus: increased monitoring of triglycerides required.

Combined use of ruxolitinib and sirolimus: increased monitoring of triglycerides required.

Sirolimus: Efficacy and Complications in Children With Hyperinsulinemic Hypoglycemia: A 5-Year Follow-Up Study.

IntroductionSirolimus, a mammalian target of rapamycin inhibitor, has been used in congenital hyperinsulinism (CHI) unresponsive to diazoxide and octreotide. Reported response to sirolimus is variable, with high incidence of adverse effects. To the best of our knowledge, we report the largest group of CHI patients treated with sirolimus followed for the longest period to date.MethodsRetrospective study of CHI patients treated with sirolimus in a tertiary service and review of the 15 publications reporting CHI patients treated with mammalian target of rapamycin inhibitors. Comparison was made between the findings of this study with those previously published.ResultsTwenty-two CHI patients treated with sirolimus were included in this study. Twenty showed partial response, one showed complete response, and one was unresponsive. Five of the partially/fully responsive patients had compound heterozygous ABCC8 mutations and five had heterozygous ABCC8 mutations. A total of 86.4% (19/22) developed complications, with infection being the most frequent (17/22), of which 11 were of bacterial etiology, followed by persistent diarrhea (3/22) and hyperglycemia (2/22). Seventeen patients stopped sirolimus: 13 from infections; 2 from hyperglycemia; and 2 from alternative treatment (lanreotide) response. Compared with data previously published, our study identified a higher number of partially sirolimus-responsive CHI cases, although the high rate of complications while on this medication limited its potential usefulness.ConclusionSirolimus candidates must be carefully selected given its frequent and potentially life-threatening side effects. Its use as a short-term, last-resort therapy until normoglycemia is achieved with other agents such as lanreotide could avoid pancreatectomy. Further studies evaluating the use of sirolimus in patients with CHI are required.

Clinical Experience of Sirolimus Regarding Efficacy and Safety in Systemic Lupus Erythematosus.

New treatment options constitute unmet needs for patients diagnosed with systemic lupus erythematosus (SLE). Inhibition of the mammalian target of rapamycin (mTOR) pathway by sirolimus, a drug approved and in clinical use to prevent transplant rejection, has shown promising effects in lupus animal models as well as in patients with both antiphospholipid syndrome and SLE. Sirolimus inhibits antigen-induced T cell proliferation and increases the number of circulating regulatory T cells. Recently, sirolimus was tested in an open label phase 1/2 trial, including 43 patients with active SLE, resistant or intolerant to conventional medications. The results were encouraging showing a progressive improvement, including mucocutaneous and musculoskeletal manifestations. At our university unit, we have more than 16 years’ experience of sirolimus as treatment for non-renal manifestations of SLE. Herein, we retrospectively evaluated data on tolerance, dosage, affected organ systems, disease activity measures, corticosteroid reduction, concomitant immunosuppressive therapies, and patient-reported outcome measures (PROMs) such as pain intensity, fatigue, well-being and quality-of-life (QoL) in 27 Caucasian patients with mildly active SLE. Musculoskeletal manifestation was the main reason for sirolimus treatment followed by skin involvement and leukocytopenia. Mean time on sirolimus was 47.1 (range 2–140) months. Decreasing global disease activity was observed, as measured by the clinical SLE disease activity index-2000, with a mean reduction of 2.5 points (range -10 to 0) and a corresponding mean reduction of the physician’s global assessment (0–4) of 0.64 (range -2 to 0). The mean daily dose of corticosteroids (prednisolone) was reduced by 3.3 mg (-12.5 to 0). Non-significant trends toward improvements of QoL and pain intensity were found. Serious side-effects were not seen during sirolimus treatment, but early withdrawal due to nausea (n = 4) and non-serious infections (n = 2) appeared. This observational study, including longtime real-life use of sirolimus in SLE, is the largest to date and it essentially confirms the results of the recent phase 1/2 trial. Our data indicate that sirolimus is efficient in patients with musculoskeletal SLE manifestations, particularly arthritis and tendinitis. Further randomized controlled trials evaluating the potential benefits of sirolimus in SLE are warranted, but should aim to enroll patients with shorter disease duration, less accrued damage, and more diverse ethnicities.

Optimizing the clinical utility of sirolimus-based immunosuppression for kidney transplantation.

While calcineurin inhibitors (CNIs) are effective for preventing acute rejection in kidney transplant recipients, long-term use may cause chronic kidney injury and is associated with increased risks of cardiovascular events, cancer, and infection-associated death. Immunosuppression strategies are needed to balance risks of acute and subclinical rejection with long-term benefits of improved kidney function. Sirolimus, an inhibitor of mammalian target of rapamycin, is used for immunosuppression in kidney transplantation. Its clinical utility has evolved, over more than 15years, including de novo sirolimus with and without concomitant CNIs and conversion from CNI-based regimens to sirolimus. Sirolimus-containing regimens are associated with preservation of good renal function, with promising characteristics for improving long-term graft and patient survival, including antiviral and anticancer effects. Based on clinical evidence, use of low-dose sirolimus in a de novo approach with tacrolimus/steroids in the immediate posttransplantation period is appropriate. A feasible alternative is a long term, CNI-free combination with mycophenolate mofetil (following CNI-to-sirolimus conversion at 3-6months). These strategies are appropriate for a broad range of patients with various levels of immunologic risk, including those receiving expanded criteria donor kidneys or at increased risk of delayed graft function, particular challenges in Latin America and other global regions.

The use of sirolimus in patients with recurrent cytomegalovirus infection after kidney transplantation: A retrospective case series analysis.

Cytomegalovirus (CMV) is one of opportunistic infections post solid organ transplant and remains a cause of morbidity and mortality. Mammalian target of rapamycin inhibitors has a theoretical antiviral advantage compared to conventional immunosuppression. The primary outcome was to assess the viremic response and kidney function in a cohort of kidney transplant recipients (KTRs) with difficult to manage CMV infection when converted to sirolimus. We retrospectively analyzed the outcome of substituting sirolimus for mycophenolate mofetil (MMF) or tacrolimus in 18 KTR with difficult to manage, resistant/recurrent CMV viremia unresponsive or intolerant of standard anti-CMV treatment, or immunosuppression reduction. Safety and feasibility of sirolimus conversion were assessed through studying CMV viral loads, creatinine levels, immunosuppression, antiviral therapy, kidney function, and acute rejection episodes before and after starting sirolimus as well as the sirolimus side effects. Data were collected from the hospital filing system. The Wilcoxon matched-pairs signed-rank test and Friedman test were used for statistical analysis. The area under the curve for Log10 CMV viral load (log10 copies/ml) was significantly higher before than after the sirolimus switch (P = 0.0156). The median number of days on antiviral treatment was reduced after conversion to sirolimus [48 days (0-95); vs. 68 days (21-146)]. Acute rejection occurred more commonly before than after starting sirolimus [n =5 (27.7%) vs. n = 2 (11.1%)]. Median serum creatinine before conversion to sirolimus was 175.5 μmol/L (79-243), and showed no deterioration three months and one year after conversion [148 (69-271) and 162.5 (69-287) μmol/L, respectively, P = 0.002]. The use of sirolimus, often alongside tacrolimus and after discontinuation of MMF, is a useful strategy in treating recurrent CMV viremia without provoking rejection.

Predictors of De Novo Nonalcoholic Fatty Liver Disease After Liver Transplantation and Associated Fibrosis.

Nonalcoholic fatty liver disease (NAFLD) can occur de novo in patients undergoing liver transplantation (LT) for indications other than NAFLD, and it has been increasingly recognized as a complication in the post-LT setting. This study aims to better characterize de novo NAFLD after LT by identifying risk factors for its development, describing incidence and extent of fibrosis, assessing the diagnostic utility of noninvasive serum fibrosis algorithms, and comparing survival to those without NAFLD. This was a retrospective single-center analysis of de novo NAFLD in a post-LT cohort. Those whose primary indication for LT was nonalcoholic steatohepatitis (NASH) were excluded. Risk factors were analyzed by univariate and multivariate analyses. De novo NAFLD and fibrosis were assessed on posttransplant liver biopsies, and noninvasive fibrosis scores were calculated from concomitant blood tests. After applying the exclusion criteria, 430 for-cause post-LT biopsies were evaluated; 33.3% (n = 143) had evidence of de novo steatosis and/or NASH at a median of 3.0 years after transplant. On multivariate analysis, body mass index (BMI; odds ratio [OR], 1.12; P < 0.001), diabetes mellitus (OR, 3.01; P = 0.002), hepatitis C virus (OR, 4.61; P < 0.001), weight gain (OR, 1.03; P = 0.007), and sirolimus use (OR, 3.11; P = 0.02) were predictive of de novo NAFLD after LT. Significant fibrosis (≥F2) was present in almost 40% of the cohort. Noninvasive serum fibrosis scores were not useful diagnostic tests. There was no significant difference in the short-term or longterm survival of patients who developed de novo NAFLD. In conclusion, diabetes, BMI, weight gain after LT, and sirolimus-based immunosuppression, in keeping with insulin resistance, were the only modifiable factors associated with development of de novo NAFLD. A significant proportion of patients with de novo NAFLD had fibrosis and given the limited utility of noninvasive serum fibrosis algorithms, alternative noninvasive tools are required to screen for fibrosis in this population. There was no significant difference in the short-term or longterm survival of patients who developed de novo NAFLD.

Pediatric dermatology-Critical approach to the new treatments.

The field of pediatric dermatology treatment has been rich in new developments. Several recent therapeutic advances in pediatric dermatology have been made. This review will focus on critical approach to the new treatments for several entities encountered in pediatric dermatology. The use of biologics and small molecules in children with atopic dermatitis and psoriasis, exciting advances in the use of propranolol and other beta-blockers for the treatment of infantile hemangiomas, the use of sirolimus for vascular anomalies will be discussed.

Post-Transplant Cyclophosphamide and Sirolimus in Matched Related and Unrelated Allogeneic Transplant with a Treosulfan-Based Conditioning

Abstract Introduction: Post transplant cyclophosphamide (PT-Cy) has recently emerged as a very promising pharmacological strategy to overcome human leukocyte antigen (HLA) barriers in the setting of haploidentical hematopoietic cell transplant (HCT). We recently reported a promising preliminary experience on the use of PT-Cy and sirolimus as graft-versus-host disease (GVHD) prophylaxis in matched allo-HSCT (Greco R et al, Blood 2016). Herein we describe long-term outcomes of matched allogeneic HSCT, using treosulfan-based conditioning, and GVHD prophylaxis with PT-Cy and sirolimus. Methods: In our center, we collected 104 adult patients (pts) receiving matched HSCT for high-risk hematological malignancies, mainly acute myeloid leukemia (n=43). Donor was matched related (MRD) for 45 pts, 10/10 matched unrelated (MUD) for 39 pts and 9/10 MUD for 20 pts. Median age was 48 years (range 19-78). At HSCT, 51% of patients were not in complete remission (CR), 39% were in CR1 and 11% in subsequent CR. Graft source was mainly PBSCs (95%). All pts received a conditioning regimen based on treosulfan and fludarabine; 89% received an intensified conditioning with the addition of melphalan. All pts received PT-Cy (50 mg/kg/day) on days 3 and 4. Sirolimus was given from day 5, and withdrawn 3 months after HSCT. Mycophenolate mofetil (MMF) was added from day 5 to day 30, only in MUD. All patients were treated according to current institutional programs upon written informed consent for transplant procedures. Results: Median follow up was over 16 months (range 3-51). Median CD34+ and CD3+ cell doses were 5.6x10^6/Kg (range, 1.5-10.9) and 2.0x10^8/Kg (range, 0.2-8.0), respectively. All the recipients of allo-HSCT experienced a sustained donor cell engraftment. The cumulative incidence of grades II-IV and III-IV acute GVHD at 100 days was 21% and 9%, respectively. The cumulative incidence of chronic GVHD was 25% at 2 years; we observed severe chronic GVHD only in 4% of pts. The cumulative incidences of relapse and non-relapse mortality (NRM) were 33% and 8% at 2 years, respectively. Two-year overall survival (OS) was 67% and progression free survival (PFS) 59%. The composite end point of GVHD-free/relapse-free survival (GRFS) was 52% at 2 years, in which events include grade 3-4 acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death. There was a longer OS, 2-year OS was 77% (p = 0.05), and a trend towards higher PFS and GRFS, 63% (p=0.07) and 58% (p=0.06) respectively, for pts with CR status at HSCT. We did not found a significant effect of HLA-matching (9/10 versus 10/10) or donor type (related versus unrelated) on major transplant outcomes (NRM, PFS, GRFS, relapse, acute and chronic GvHD). Conclusion: These outcomes confirmed that matched allogeneic HSCT using treosulfan-based chemotherapy, PT-Cy and sirolimus, is associated with low NRM and acceptable severe GVHD, providing relevant long-term survival in high-risk diseases. A randomized trial comparing this strategy with other kind of in-vivo T-cell depletion (i.e. ATG) is warranted. Disclosures Vago: Moderna TX: Research Funding; GENDX: Research Funding.

Clinical Outcomes One Year and Beyond After Combination Sirolimus-Eluting Endothelial Progenitor Cell Capture Stenting During Primary Percutaneous Coronary Intervention in ST-Segment Elevation Myocardial Infarction.

Primary percutaneous coronary intervention (PCI) during acute ST-segment elevation myocardial infarction (STEMI) represents a thrombotic milieu and is associated with delayed healing after stenting. The pro-healing combination sirolimus eluting endothelial progenitor cell (EPC) capture stents encourage early endothelialization after stenting and may be beneficial in the STEMI population. We aim to evaluate the clinical outcomes one year and beyond for patients with STEMI who received the combination sirolimus eluting EPC capture stents during primary PCI. All STEMI patients implanted with combination sirolimus eluting EPC capture stents during primary PCI from November 2013 to December 2016 were enrolled. The primary outcome was target lesion failure (TLF) at in-hospital, one-month, one-year and beyond one year. A total of 260 consecutive STEMI patients (283 lesions) were implanted with 313 combination sirolimus eluting EPC capture stents during primary PCI. Mean age was 56.1 ± 11.2 years and 88.8% were male. One in ten patients (10.9%) had cardiogenic shock on presentation, 7.3% needed mechanical ventilation and 7.7% had intra-aortic balloon pump inserted. A total of 97.9% of lesions achieve final TIMI 3 flow. Device success was seen in all patients. At extended follow up period (median 23.4 months), the clinical outcomes were TLF 8.8%, major adverse cardiovascular events 10.8%, cardiac mortality 4.2%, target vessel myocardial infarction 3.4%, target lesion revascularization 3.8%, and definite stent thrombosis 1.9%. This study demonstrated acceptable clinical outcomes for an all-comers STEMI patients undergoing primary PCI with the use of combination sirolimus eluting EPC cell capture stents.

Impact of single nucleotide polymorphisms on P450 oxidoreductase and peroxisome proliferator-activated receptor alpha on tacrolimus pharmacokinetics in renal transplant recipients.

The P450 oxidoreductase (POR) and peroxisome proliferator-activated receptor alpha (PPARA) genes are associated with the activity of cytochrome P450 enzymes in vivo. We aimed to investigate the impact of single nucleotide polymorphisms (SNPs) in the POR and PPARA genes on the pharmacokinetics of tacrolimus (TAC) in renal transplant recipients. A total of 220 recipients were assessed and 105 recipients were included for final quantitative analysis. Blood samples were collected and DNA was extracted. Targeting sequencing based on next-generation sequencing was applied to detect the SNPs in the POR and PPARA genes. In addition, a systematic review and meta-analysis was performed to comprehensively evaluate the influence of POR and PPARA mutations on the TAC concentrations. A total of 81 SNPs were obtained. Three SNPs (POR*28, Chr7:75619677 and Chr7:75614288) were found to be significantly associated with the TAC pharmacokinetics at 3 months, 6 months, and more than 12 months. No significant association was observed in the combined effect analysis of CYP3A4*1G and CYP3A5*3 with three significant SNPs in the POR gene. Age, post-transplant duration, and the use of sirolimus were identified as the most important factors that influenced the TAC concentrations. A meta-analysis of four studies results and our cohort indicated that compared with recipients carrying the CT or TT genotypes, recipients carrying the CC genotypes of POR*28 showed significantly higher TAC concentrations. Our study suggested the positive influence of mutations in the POR gene on TAC exposure at 3 months after kidney transplantation.

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

BackgroundSlow-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.ObjectiveThe objective of this trial is to evaluate the efficacy and safety of sirolimus in children with complicated superficial slow-flow VMs.Methods/designThis 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).DiscussionThe 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 registrationClinicalTrials.gov Identifier: NCT02509468, first received: 28 July 2015.EU Clinical Trials Register EudraCT Number: 2015-001096-43.

Comparative Study of Pediatric Coronary Allograft Vasculopathy Between Single Centers in North America and United Kingdom

BackgroundCoronary allograft vasculopathy (CAV) is the leading cause of death after pediatric heart transplantation from 1 year postoperation. Anecdotal evidence suggests a difference in the severity of disease between UK and North America. We performed a comparative study using intravascular ultrasound (IVUS). MethodsConsecutive IVUS procedures from a single year were included from each center. Using standardized techniques, measurement of the vessel area, lumen area, and maximal intimamedial thickening (IMT) were performed with calculation of intimal index (II) for each slice. Mean II, mean IMT, and absolute maximum IMT were calculated along the left coronary artery for each patient. Transplant demographics and treatment details were included in the analysis. ResultsOne hundred four patients were included between the 2 centers. Interobserver variability for IVUS analysis was excellent. Patients were aged mean 14.2 (SD 3.3) years at the time of the study and 9.2 (SD 6.0) years earlier post-transplant procedure. UK patients were older, at transplant for a shorter time, and demonstrated more severe CAV. Multiple regression analysis demonstrated the detrimental effect of donor age and time from transplant on CAV severity and benefits of sirolimus use. ConclusionsThe data show more severe CAV in the UK cohort despite significantly shorter time post-transplant. Donor age and time post-transplant were associated with more severe CAV and sirolimus use was associated with a reduction in IMT. This study demonstrates a marked difference in the prevalence of CAV in children between UK and North America. The causes are likely to be multifactorial; however, younger donors and recipients have significantly less disease.

Treatment of Lymphatic Malformations with the mTOR Inhibitor Sirolimus: A Systematic Review.

Extensive lymphatic malformations are low-flow vascular malformations that can cause devastating complications. Treatment of these malformations is challenging. This systematic review presents current use of sirolimus in patients with extensive lymphatic malformations. MEDLINE and Google scholar search was conducted for studies on sirolimus treatment of lymphatic malformations up to July 2017. Search items included "lymphatic malformation," "lymphangioma," "cystic hygroma," "vascular malformation," "low-flow malformation," "sirolimus," "rapamycin," and "mTOR inhibitor." Twenty studies, including 71 patients receiving sirolimus, were included into this review. Forty-five patients had lymphatic malformations, eight patients venolymphatic malformations, and 19 patients capillary-lymphatico-venous malformations. Sirolimus led to a partial remission of disease in 60 patients, three patients had a progressive disease, and the outcome of eight patients was not reported. Dosing, target trough level, and duration of treatment differed between the studies. Common adverse effects were hyperlipidemia and neutropenia. Available literature indicated that sirolimus therapy might be effective for lymphatic malformations. However, further randomized controlled studies are required to analyze the efficacy and long-term adverse events and to clarify the potential role for sirolimus in the management of lymphatic malformations.