Mechanistic Target Of Rapamycin Inhibitors Research Articles

Genomic medicine advances for brain tumors.

Cancer genome profiling has revealed important genetic alterations that serve as prognostic indicators and guides for treatment decisions, enabling precision medicine. The shift to molecular diagnosis of brain tumors, as reflected in the 2021 World Health Organization Classification of Tumors of the Central Nervous System, is a crucial role for treatment decision-making. This review discusses the significance and role of cancer genome profiling in precision medicine for malignant brain tumors, particularly gliomas. Furthermore, we explore the progress in cancer genome analysis, focusing on cancer gene panel testing, integration of genomic information in brain tumor classification, and hereditary tumors. Additionally, we discuss the transformative effect of genomic medicine on early detection, risk assessment, and precision medicine strategies. The tumor mutational burden in brain tumors is considered low, but the application of molecular targeted drugs, such as isocitrate dehydrogenase inhibitors, v-raf murine sarcoma viral oncogene homolog B1 inhibitors, fibroblast growth factor receptor inhibitors, neurotrophic tyrosine receptor kinase, mechanistic target of rapamycin inhibitors, and anti-programmed death receptor-1 antibody drugs are promising for glioma treatment. We also discuss the future prospects of molecular targeted drugs.

Liver Transplant for Hepatocellular Carcinoma in Post-Milan Criteria Era: A Long-Term Single-Center Experience.

We investigated the outcomes of liver transplant in patients with hepatocellular carcinoma. Prospectively, recipients of deceased donor liver transplants from 2007 to 2021 at Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran, were enrolled into the study. The Milan criteria were applied for selection of liver transplant candidates diagnosed with hepatocellular carcinoma. Patients with diagnosis of acute liver failure and who underwent secondary liver transplant were excluded. All patients diagnosed with hepatocellular carcinoma were given mechanistic target of rapamycin inhibitor with calcineurin inhibitor minimization 4 weeks after liver transplant. Patients were assigned to the experimental group (with hepatocellular carcinoma; n = 82) or the control group (without hepatocellular carcinoma; n = 1076). We recorded the etiologies of liver cirrhosis in the experimental group, demographic data from all patients, and postoperative complications. Of 1158 total patients, mean age was 44.15 ± 14.71 years (range, 1-73 years) and 712 were male patients (61.5%). In the experimental group (n = 82), there were 76 patients (92.68%) who were within the Milan criteria; others were excluded intraoperatively. All patients were followed for a median of 65.3 ± 40.8 months (range 10-197 months). Patient survival rates in the experimental group and control group at 3 months, 1 year, and 3 years were 89%, 80%, and 78% versus 84%, 81%, and 70%, respectively (P = .742). Hepatocellular carcinoma reoccurred in 6 patients (7.31%) at mean of 16.83 months postoperatively. Liver transplant for patients with hepatocellular carcinoma in the post-Milan criteria era is associated with acceptable outcomes.

BK viral infection: A review of management and treatment.

BK viral infection remains to be a challenging post-transplant infection, which can result in kidney dysfunction. The mainstay approach to BK infection is reduction of immunosuppression. Alterations in immunosuppressive regimen with minimization of calcineurin inhibitors, use of mechanistic target of rapamycin inhibitors, and leflunomide have been attempted with variable outcomes. Over the past few years, investigators have explored potential therapeutic options for BK infection. Fluoroquinolone prophylaxis and treatment was found to have no benefit in kidney transplant recipients. The utility of cidofovir is limited by its nephrotoxicity. Intravenous immunoglobulin is becoming a popular option for treatment and prophylaxis for BK infection, as it increases the neutralizing antibody titers against the most common BK virus serotypes. Virus-specific T cell therapy is an emerging treatment option for BK viremia. In this review, we will explore management and therapeutic options for BK infection and recent evidence available in literature.

Cellular Immunobiology and Molecular Mechanisms in Alloimmunity-Pathways of Immunosuppression.

Current maintenance immunosuppression commonly comprises a synergistic combination of tacrolimus as calcineurin inhibitor (CNI), mycophenolic acid, and glucocorticoids. Therapy is often individualized by steroid withdrawal or addition of belatacept or inhibitors of the mechanistic target of rapamycin. This review provides a comprehensive overview of their mode of action, focusing on the cellular immune system. The main pharmacological action of CNIs is suppression of the interleukin-2 pathway that leads to inhibition of T cell activation. Mycophenolic acid inhibits the purine pathway and subsequently diminishes T and B cell proliferation but also exerts a variety of effects on almost all immune cells, including inhibition of plasma cell activity. Glucocorticoids exert complex regulation via genomic and nongenomic mechanisms, acting mainly by downregulating proinflammatory cytokine signatures and cell signaling. Belatacept is potent in inhibiting B/T cell interaction, preventing formation of antibodies; however, it lacks the potency of CNIs in preventing T cell-mediated rejections. Mechanistic target of rapamycin inhibitors have strong antiproliferative activity on all cell types interfering with multiple metabolic pathways, partly explaining poor tolerability, whereas their superior effector T cell function might explain their benefits in the case of viral infections. Over the past decades, clinical and experimental studies provided a good overview on the underlying mechanisms of immunosuppressants. However, more data are needed to delineate the interaction between innate and adaptive immunity to better achieve tolerance and control of rejection. A better and more comprehensive understanding of the mechanistic reasons for failure of immunosuppressants, including individual risk/benefit assessments, may permit improved patient stratification.

Xenografts Show Signs of Concentric Hypertrophy and Dynamic Left Ventricular Outflow Tract Obstruction After Orthotopic Pig-to-baboon Heart Transplantation.

Orthotopic cardiac xenotransplantation has seen substantial advancement in the last years and the initiation of a clinical pilot study is close. However, donor organ overgrowth has been a major hurdle for preclinical experiments, resulting in loss of function and the decease of the recipient. A better understanding of the pathogenesis of organ overgrowth after xenotransplantation is necessary before clinical application. Hearts from genetically modified ( GGTA1-KO , hCD46/hTBM transgenic) juvenile pigs were orthotopically transplanted into male baboons. Group I (control, n = 3) received immunosuppression based on costimulation blockade, group II (growth inhibition, n = 9) was additionally treated with mechanistic target of rapamycin inhibitor, antihypertensive medication, and fast corticoid tapering. Thyroid hormones and insulin-like growth factor 1 were measured before transplantation and before euthanasia, left ventricular (LV) growth was assessed by echocardiography, and hemodynamic data were recorded via a wireless implant. Insulin-like growth factor 1 was higher in baboons than in donor piglets but dropped to porcine levels at the end of the experiments in group I. LV mass increase was 10-fold faster in group I than in group II. This increase was caused by nonphysiological LV wall enlargement. Additionally, pressure gradients between LV and the ascending aorta developed, and signs of dynamic left ventricular outflow tract (LVOT) obstruction appeared. After orthotopic xenotransplantation in baboon recipients, untreated porcine hearts showed rapidly progressing concentric hypertrophy with dynamic LVOT obstruction, mimicking hypertrophic obstructive cardiomyopathy in humans. Antihypertensive and antiproliferative drugs reduced growth rate and inhibited LVOT obstruction, thereby preventing loss of function.

Conversion between sirolimus and everolimus in heart transplant recipients.

Sirolimus and everolimus are mechanistic target of rapamycin inhibitors (mTORi) that may be included in immunosuppression regimens for orthotopic heart transplant (OHT) recipients. mTORi play a role in slowing progression of cardiac allograft vasculopathy; however, they have poor tolerability, sometimes necessitating a change between agents or therapies. The literature surrounding a conversion between mTORi are incongruent, thus this study was designed to assess the concentration/dose ratio for each medication around the time of conversion to provide guidance for a conversion strategy between mTORi. We conducted a retrospective study of adult OHT recipients who were maintained on both sirolimus- and everolimus-based immunosuppression regimens. The primary outcome was the concentration/dose (C/d) ratio of sirolimus to everolimus. Secondary outcomes included changes in hematologic and lipid labs and patient-reported intolerances. The C/d ratio of sirolimus was 4.42, whereas the everolimus ratio was 2.23, resulting in a sirolimus: everolimus ratio of 1.98. Secondarily, after converting between mTORi, 93% of patients who reported intolerance(s) to one agent had a resolution of that intolerance. In our patient population, everolimus appeared better tolerated than sirolimus, with significantly more patients having no reported intolerances and significantly fewer patients experiencing edema. Other lab values were similar between patients receiving sirolimus and everolimus, except for an increased hemoglobin level in those receiving everolimus. The conversion ratio of 1:2 observed in our population suggests OHT recipients may require an increased dose of EVL compared with SRL to maintain the same goal trough levels. A conversion between mTORi appeared to improve tolerability and did not lead to clinically significant worsening of any measured lab value.

Tubular lysosome induction couples animal starvation to healthy aging

Dietary restriction promotes longevity in several species via autophagy activation. However, changes to lysosomes underlying this effect remain unclear. Here using the nematode Caenorhabditis elegans, we show that the induction of autophagic tubular lysosomes (TLs), which occurs upon dietary restriction or mechanistic target of rapamycin inhibition, is a critical event linking reduced food intake to lifespan extension. We find that starvation induces TLs not only in affected individuals but also in well-fed descendants, and the presence of gut TLs in well-fed progeny is predictive of enhanced lifespan. Furthermore, we demonstrate that expression of Drosophila small VCP-interacting protein, a TL activator in flies, artificially induces TLs in well-fed worms and improves C. elegans health in old age. These findings identify TLs as a new class of lysosomes that couples starvation to healthy aging.

Autophagy preserves hematopoietic stem cells by restraining MTORC1-mediated cellular anabolism

ABSTRACT Adult stem cells are long-lived and quiescent with unique metabolic requirements. Macroautophagy/autophagy is a fundamental survival mechanism that allows cells to adapt to metabolic changes by degrading and recycling intracellular components. Here we address why autophagy depletion leads to a drastic loss of the stem cell compartment. Using inducible deletion of autophagy specifically in adult hematopoietic stem cells (HSCs) and in mice chimeric for autophagy-deficient and normal HSCs, we demonstrate that the stem cell loss is cell-intrinsic. Mechanistically, autophagy-deficient HSCs showed higher expression of several amino acid transporters (AAT) when compared to autophagy-competent cells, resulting in increased amino acid (AA) uptake. This was followed by sustained MTOR (mechanistic target of rapamycin) activation, with enlarged cell size, glucose uptake and translation, which is detrimental to the quiescent HSCs. MTOR inhibition by rapamycin treatment in vivo was able to rescue autophagy-deficient HSC loss and bone marrow failure and resulted in better reconstitution after transplantation. Our results suggest that targeting MTOR may improve aged stem cell function, promote reprogramming and stem cell transplantation. List of abbreviations: 5FU: fluoracil; AA: amino acids; AKT/PKB: thymoma viral proto-oncogene 1; ATF4: activating transcription factor 4; BafA: bafilomycin A1; BM: bone marrow; EIF2: eukaryotic initiation factor 2; EIF4EBP1/4EBP1: eukaryotic translation initiation factor 4E binding protein 1; KIT/CD117/c-Kit: KIT proto-oncogene receptor tyrosine kinase; HSCs: hematopoietic stem cells; HSPCs: hematopoietic stem and progenitor cells; Kyn: kynurenine; LSK: lineage− (Lin−), LY6A/Sca-1+, KIT/c-Kit/CD117+; LY6A/Sca-1: lymphocyte antigen 6 family member A; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; MTORC2: MTOR complex 2; OPP: O-propargyl-puromycin; PI3K: phosphoinositide 3-kinase; poly(I:C): polyinosinic:polycytidylic acid; RPS6/S6: ribosomal protein S6; tam: tamoxifen; TCA: tricarboxylic acid; TFEB: transcription factor EB; PTPRC/CD45: Protein Tyrosine Phosphatase Receptor Type C, CD45 antigen.

Effect of sirolimus on insulin dynamics in horses.

Sirolimus, a mechanistic target of rapamycin inhibitor, suppresses insulin production in other species and has therapeutic potential for hyperinsulinemia in horses. Determine the pharmacokinetics (PKs) of sirolimus and evaluate its effect on insulin dynamics in healthy and insulin dysregulation (ID) horses. Eight Standardbred geldings. A PK study was performed followed by a placebo-controlled, randomized, crossover study. Blood sirolimus concentrations were measured by liquid chromatography-mass-spectrometry. PK indices were estimated by fitting a 2-compartment model using nonlinear least squares regression. An oral glucose test (OGT) was conducted before and 4, 24, 72, and 144 hours after administration of sirolimus or placebo. Effects of time, treatment and animal on blood glucose and insulin concentrations were analyzed using mixed-effects linear regression. Sirolimus was then administered to 4horses with dexamethasone-induced ID and an OGT was performed at baseline, after ID induction and after 7 days of treatment. Median (range) maximum sirolimus concentration was 277.0 (247.5-316.06) ng/mL at 5 (5-10) min and half-life was 3552 (3248-4767) min. Mean (range) oral bioavailability was 9.5 (6.8-12.4)%. Sirolimus had a significant effect on insulin concentration 24 hours after a single dose: median (interquartile range) insulin at 60 min (5.0 [3.7-7.0] μIU/mL) was 37 (-5 to 54)% less than placebo (8.7 [5.8-13.7] μIU/mL, P=.03); and at 120 min (10.2 [8.4-12.2] μIU/mL) was 28 (-15 to 53)% less than placebo (14.9 [8.4-24.8] μIU/mL, P=.02). There was minimal effect on glucose concentration. Insulin responses decreased toward baseline in ID horses after 7 days of treatment. Sirolimus decreased the insulinemic response to glucose and warrants further investigation.

Mechanistic Target of Rapamycin Inhibition Prevents Coronary Artery Remodeling in a Murine Model of Kawasaki Disease.

Remodeling of the coronary arteries is a common feature in severe cases of Kawasaki disease (KD). This pathology is driven by the dysregulated proliferation of vascular fibroblasts, which can lead to coronary artery aneurysms, stenosis, and myocardial ischemia. We undertook this study to investigate whether inhibiting fibroblast proliferation might be an effective therapeutic strategy to prevent coronary artery remodeling in KD. We used a murine model of KD (induced by the injection of the Candida albicans water-soluble complex [CAWS]) and analyzed patient samples to evaluate potential antifibrotic therapies for KD. We identified the mechanistic target of rapamycin (mTOR) pathway as a potential therapeutic target in KD. The mTOR inhibitor rapamycin potently inhibited cardiac fibroblast proliferation in vitro, and vascular fibroblasts up-regulated mTOR kinase signaling in vivo in the CAWS mouse model of KD. We evaluated the in vivo efficacy of mTOR inhibition and found that the therapeutic administration of rapamycin reduced vascular fibrosis and intimal hyperplasia of the coronary arteries in CAWS-injected mice. Furthermore, the analysis of cardiac tissue from KD fatalities revealed that vascular fibroblasts localizing with inflamed coronary arteries up-regulate mTOR signaling, confirming that the mTOR pathway is active in human KD. Our findings demonstrate that mTOR signaling contributes to coronary artery remodeling in KD, and that targeting this pathway offers a potential therapeutic strategy to prevent or restrict this pathology in high-risk KD patients.

Discovery of small molecule mechanistic target of rapamycin inhibitors as anti-aging and anti-cancer therapeutics.

To date, the most studied drug in anti-aging research is the mTOR inhibitor - rapamycin. Despite its almost perfect anti-aging profile, rapamycin exerts one significant limitation - inappropriate physicochemical properties. Therefore, we have decided to utilize virtual high-throughput screening and fragment-based design in search of novel mTOR inhibiting scaffolds with suitable physicochemical parameters. Seven lead compounds were selected from the list of obtained hits that were commercially available (4, 5, and 7) or their synthesis was feasible (1, 2, 3, and 6) and evaluated in vitro and subsequently in vivo. Of all these substances, only compound 3 demonstrated a significant cytotoxic, senolytic, and senomorphic effect on normal and cancerous cells. Further, it has been confirmed that compound 3 is a direct mTORC1 inhibitor. Last but not least, compound 3 was found to exhibit anti-SASP activity concurrently being relatively safe within the test of in vivo tolerability. All these outstanding results highlight compound 3 as a scaffold worthy of further investigation.

Tacrolimus before CTLA4Ig and rapamycin promotes vascularized composite allograft survival in MGH miniature swine

BackgroundWe evaluated the outcome of vertical rectus abdominus myocutaneous flap (VRAM) allotransplantation in a mini-pig model, using a combined co-stimulation blockade (Co-SB) and mechanistic target of rapamycin inhibition (mTORi)-based regimen, with or without preceding calcineurin inhibition (CNI). Materials and methodsVRAM allotransplants were performed between SLA-mismatched MGH miniature swine. Group A (n = 2) was treated continuously with the mTOR inhibitor rapamycin from day −1 in combination with the Co-SB agent cytotoxic T lymphocyte antigen 4-Ig (CTLA4-Ig) from post-operative day (POD) 0. In group B (n = 3), animals received tacrolimus daily from POD 0 to POD 13, followed by rapamycin daily from POD 7 and CTLA4-Ig weekly from POD 7–28. Graft rejection was determined by Banff criteria and host cellular and humoral immunity monitored. ResultsIn group A, allografts developed grade-I acute rejection by POD 2 and POD 7, and reached grade-IV by POD 17 and POD 20, respectively. By contrast, in group B, two allografts demonstrated grade-I rejection on POD 30 and grade-IV on POD 74, while the third exhibited grade-I rejection starting on POD 50, though this animal had to be euthanized on POD 58 due to Pneumocystis jirovecii infection. Time-to-event incidence of grade-I rejection was significantly lower in group A compared to group B. During the first 3 weeks post-transplant, no significant differences in anti-donor immunity were observed between the groups. ConclusionA short course of CNI, followed by combined Co-SB and mTORi significantly delays acute rejection of VRAM allografts in SLA-mismatched miniature swine.

Autophagy-associated immune dysregulation and hyperplasia in a patient with compound heterozygous mutations in ATG9A

ABSTRACT Autophagy involving core machinery proteins such as ATG9A is part of a cytoprotective process whose dysregulation is associated with carcinogenesis, neurodegeneration and autoimmunity, but few examples exist of monogenic diseases to further insights into human disease. In the present studies, we report a patient with novel compound heterozygous mutations in ATG9A after patient and parental DNA were subjected to whole exome sequencing. The patient developed hyperplastic proliferations of T and B cells in lung and brain and exhibited defects in lymphocyte memory cell populations after developing an infection with Epstein-Barr virus (EBV). Peripheral blood leukocytes from the patient exhibited defects in autophagic activity and EBV-transformed cells redemonstrated this defect which was also associated with defective NFKB (nuclear factor kappa B) signaling and accumulation of the pro-proliferative protein MYC (MYC proto-oncogene, bHLH transcription factor) and anti-apoptotic protein BCL2 (BCL2 apoptosis regulator), leading to increased proliferative capacity. Defects were corrected after transformation with plasmids expressing ATG9A and after treatment of cells as well as the patient with the MTOR (mechanistic target of rapamycin kinase) inhibitor, autophagy-inducing immunosuppressant rapamycin. These results point to a novel role of ATG9A and autophagy in human cellular signaling associated with hyperplasia and lymphocyte biology and provide an example how genetic studies may suggest effective specific therapeutic interventions. Abbreviations BCL2: BCL2 apoptosis regulator; BCL10: BCL10 immune signaling adaptor; CARD11: caspase recruitment domain family member 11; CBM: CARD11-BCL10-MALT1; CR2: complement C3d receptor 2; EBNA: Epstein Barr nuclear antigen; EBV: Epstein-Barr virus; FCGR3A; Fc gamma receptor IIIa; GLILD: granulomatous-lymphocytic interstitial lung disease; HV: healthy volunteer; IKBKB/IKB kinase: inhibitor of nuclear factor kappa B kinase subunit beta; IL2RA: interleukin 2 receptor subunit alpha; MALT1: MALT1 paracaspase; MS4A1: membrane spanning 4-domain A1; MTOR: mechanistic target of rapamycin kinase; MYC: MYC proto-oncogene, bHLH: transcription factor; NCAM1: neural cell adhesion molecule 1; NFKB: nuclear factor kappa B; NIAID: National Institute of Allergy and Infectious Diseases; NK: natural killer; PTPRC: protein tyrosine phosphatase receptor type C; SELL: selectin L; PBMCs: peripheral blood mononuclear cells; TR: T cell receptor; Tregs: regulatory T cells; WT: wild-type

Hepatic Epstein-Barr Virus-Associated Smooth Muscle Tumor in a Heart and Liver Transplant Recipient

ABSTRACTEpstein-Barr virus (EBV)-associated smooth muscle tumors (SMT) have been described in immunosuppressed states, including in post-transplant patients. Here, we discuss a heart-liver transplant recipient who was found to have multifocal hepatic EBV-SMT. His immunosuppression was initially transitioned from tacrolimus to sirolimus because of the proposed benefits of the mechanistic target of rapamycin inhibitors on EBV-SMT. Unfortunately, he suffered acute rejection of his liver allograft while on sirolimus therapy, which ultimately led to consideration of retransplantation.

MTOR-mediated interaction between the oocyte and granulosa cells regulates the development and function of both compartments in mice†.

Coordinated development of the germline and the somatic compartments within a follicle is an essential prerequisite for creating a functionally normal oocyte. Bi-directional communication between the oocyte and the granulosa cells enables the frequent interchange of metabolites and signals that support the development and functions of both compartments. Mechanistic target of rapamycin (MTOR), a conserved serine/threonine kinase and a widely recognized integrator of signals and pathways key for cellular metabolism, proliferation, and differentiation, is emerging as a major player that regulates many facets of oocyte and follicle development. Here, we summarized our recent observations on the role of oocyte- and granulosa cell-expressed MTOR in the control of the oocyte's and granulosa cell's own development, as well as the development of one another, and provided new data that further strengthen the role of cumulus cell-expressed MTOR in synchronizing oocyte and follicle development. Inhibition of MTOR induced oocyte meiotic resumption in cultured large antral follicles, as well as cumulus expansion and the expression of cumulus expansion-related transcripts in cumulus-oocyte complexes in vitro. In vivo, the activity of MTOR in cumulus cells was diminished remarkably by 4h after hCG administration. These results thus suggest that activation of MTOR in cumulus cells contributes to the maintenance of oocyte meiotic arrest before the LH surge. Based on the observations made by us here and previously, we propose that MTOR is an essential mediator of the bi-directional communication between the oocyte and granulosa cells that regulates the development and function of both compartments.

A mechanistic target of rapamycin inhibitor, everolimus safely ameliorated lupus nephritis in a patient complicated with tuberous sclerosis.

A 26-year-old woman with tuberous sclerosis complex (TSC) received outpatient treatment for the complication of systemic lupus erythematosus (SLE) at our hospital. She visited our hospital with a chief complaint of pitting oedema in bilateral lower legs for 3 days. The urinalysis showed massive proteinuria with a lot of white blood cell casts. The blood tests revealed hypoalbuminaemia, hypercholesterolaemia, hypocomplementaemia, and elevated anti-double-stranded DNA antibody titre. Renal biopsy was not performed because of multiple renal angiomyolipomas, which was one of the features of TSC. She was diagnosed with a nephrotic state due to lupus nephritis. Although she had a standard therapy with high-dose corticosteroid and mycophenolate mofetil and tacrolimus, complete remission had not been achieved leading to a steroid-dependent nephrotic syndrome. During the follow-up, the angiomyolipomas became larger and had a risk of rupture at the age of 29 years. Everolimus, a mechanistic target of rapamycin (mTOR) inhibitor, was started for the treatment of angiomyolipomas, and mycophenolate mofetil and tacrolimus were terminated instead. The activity of lupus nephritis was surprisingly ameliorated, and the amount of corticosteroid successfully tapered. Everolimus has been continued for 6 years without severe side effects. Accumulating evidence suggests that the activated mTOR pathway plays a key role in the pathogenesis of SLE. We reported the long-term efficacy and safety of everolimus for refractory SLE in a patient with TSC for the first time. This case suggests that everolimus can be a promising option for the treatment of lupus nephritis.

Efficacy and Safety of Topical Mechanistic Target of Rapamycin Inhibitors for Facial Angiofibromas in Patients with Tuberous Sclerosis Complex: A Systematic Review and Network Meta-Analysis.

Previous studies have suggested that the topical mechanistic target of rapamycin (mTOR) inhibitors may be effective in treating facial angiofibromas in patients with tuberous sclerosis complex (TSC). Various concentrations of topical sirolimus for TSC have been tested, but their comparative efficacy and safety remained unclear. To assess the effects of topical mTOR inhibitors in treating facial angiofibromas, we conducted a systematic review and network meta-analysis (NMA) and searched MEDLINE, Embase, and Cochrane Library for relevant randomized controlled trials on 14 February 2022. The Cochrane Collaboration tool was used to assess the risk of bias of included trials. Our outcomes were clinical improvement and severe adverse events leading to withdrawal. We included three trials on 261 TSC patients with facial angiofibromas. The NMA found when compared with placebo, facial angiofibromas significantly improved following the application of various concentrations of topical sirolimus (risk ratio being 3.87, 2.70, 4.43, and 3.34 for 0.05%, 0.1%, 0.2%, and 1%, respectively). When compared with placebo, all concentrations of topical sirolimus did not differ in severe adverse events leading to withdrawal. The ranking analysis suggested topical sirolimus 0.2% as the most effective drug. In conclusion, topical sirolimus 0.05–1% are effective and safe in treating facial angiofibromas in patients with TSC, with topical sirolimus 0.2% being the most effective.

Genitourinary Cancers Following Kidney Transplant: Our 20 Years of Experience With Mechanistic Target of Rapamycin Inhibitors.

We investigated patients with genitourinary cancer after kidney transplant and the effects of immunosuppression reduction and switching to mechanistic target of rapamycin inhibitors. We retrospectively evaluated kidney transplant recipients seen at our center between January 2000 and January 2020. Patients with <1 year of follow-up were excluded. Of 827 patients, genitourinary cancer was detected in 11 (1.3%): prostate cancer in 5 patients (45%), renal cell carcinoma in native kidney in 3 (27%), renal cell carcinoma in allograft kidney in 2 (18%), and transitional cell carcinoma of the bladder in 1 (9%). All patients had surgery. Two patients had bone metastasis due to prostate cancer at diagnosis. Two patients had allograft nephrectomy due to de novo renal cell carcinoma. Mean follow-up and age were 97 ± 45 months (range, 26-189) and 50 ± 10.2 years (19% female). After cancer diagnosis, excluding the 2 patients with allograft nephrectomy, immunosuppression was changed in 8 patients (88.8%) (1 patient received the same treatment before and after cancer diagnosis). Six patients received double-drug and 3 received triple-drug protocols. Of 9 patients, 2 were already using mechanistic target of rapamycin inhibitors before cancer diagnosis and 7 were switched: 4 to double-based and 3 to triple-based regimens. Six were switched from tacrolimus. With new treatments, patients showed no progressive kidney failure or rejection (38 ± 40 mo average follow-up). At last follow-up, mean glomerular filtration rate was 62.8 ± 34 mL/min/1.72 m2, which was similar to rate at cancer diagnosis (58.9 ± 24 mL/ min/1.72 m2; P = .78). During follow-up, no patients developed local recurrence of primary tumor or new metastasis, and none showed adverse effects after switch to mechanistic target of rapamycin inhibitors. Three patients died of malignancy-unrelated reasons (ileus, urinary sepsis, heart failure). Mechanistic target of rapamycin inhibitor-based drugs can be an important maintenance immunosuppressive treatment option for kidney transplant recipients with genitourinary cancers.

Immunosuppression, Compliance, and Tolerance After Orthotopic Liver Transplantation: State of the Art.

Orthotopic liver transplantation is the treatment of choice for several otherwise irreversible forms of acute and chronic liver diseases. Early implemented immunosuppressant regimens have had disappointing results with high rejection rates. However, new drugs have reduced the daily immunosuppression requirements, thereby improving graft and patient survival as well as kidney function. Liver rejection is a T-cell-driven immune response and is the active target of immunosuppressive agents. Immunosuppressants can be divided into pharmacological or biological drugs: the gold standard is the calcineurin inhibitors, steroids, mycophenolate mofetil, and mechanistic target of rapamycin inhibitors. Compliance with these agents is essential, although they can increase the risk of infections and neoplastic diseases. In some patients, graft tolerance can be achieved. Graft tolerance is defined as the absence of acute and chronic rejection in a graft, with normal function and histology in an immunosuppression-free, fully immunocompetent host, usually as the final result of a successful attempt at immunosuppression withdrawal. The occurrence of immunosuppressive-related complications has led to new protocols aimed at protecting renal function and preventing de novo cancer and dysmetabolic syndrome. The backbone of immunosuppression remains calcineurin inhibitors in association with other drugs, mainly over the short-term period. To avoid rejection and the side effects on renal dysfunction, de novo cancer, and cardiovascular syndrome, optimal long-term immunosuppressive therapy should be tailored in liver transplant recipients.

Treatment of Aggressive Retinal Astrocytic Hamartoma with Oral Mechanistic Target of Rapamycin Inhibition

To describe the clinical course and outcomes of aggressive retinal astrocytic hamartoma (RAH) treated with oral mechanistic target of rapamycin inhibitors (mTORis). A retrospective clinical case series. Five patients with genetically confirmed tuberous sclerosis complex and visually significant RAH due to tumor growth or exudation. In this retrospective clinical case series, a review of electronic medical records was performed to determine baseline and follow-up ophthalmic examination characteristics, along with ancillary imaging findings, in patients receiving off-label treatment with either oral sirolimus or everolimus for symptomatic RAH. Visual acuity, change in tumor size, degree of exudation, and adverse effects of the mTORis were evaluated. The 5 patients in this series ranged in age from 8 months to 54 years. Four were treated with sirolimus, and 1 received everolimus. In all the cases, the tumor height was stable or decreased after the treatment (median follow-up duration, 39 months; range, 11-73 months). Exudation improved after the treatment in all the cases. In an 8-month-old infant, frequent upper respiratory tract infections prompted the cessation of treatment. In 1 patient, the mTORi was temporarily withheld because of elevated liver enzyme levels. No other significant adverse effects were noted. Sirolimus and everolimus should be considered in the management of vision-threatening RAH, particularly in the setting of exudative and rapidly growing tumors. Four of the 5 patients in this series tolerated the oral mTORi and continued with the therapy. There were no serious complications.