Use Of Everolimus Research Articles

Everolimus is Safe as a Second-/Third-Line Therapy in Pediatric Autoimmune Hepatitis.

Pretransplant AIH patients aged 0-18 years who received everolimus therapy from 2014 to 2021 were retrospectively identified. All patients underwent regular plasma monitoring of everolimus trough levels to avoid toxicity and assess adherence. Special attention was paid to the clinical and biochemical occurrence of everolimus-related adverse events. We report six difficult-to-treat AIH patients who received everolimus therapy for 8-46 months (median 28 months). No side effects were reported when everolimus plasma trough levels were in the therapeutic range. Liver transaminases improved in 5 of 6 patients at everolimus introduction and significantly decreased at the last follow-up (FU) in our cohort (P < 0.05). None of our patients achieved complete biochemical remission at the last FU and 3 of 6 admitted to have suboptimal adherence to therapy. Our data bring preliminary safety for the use of everolimus as a second-/third-line therapy in pediatric AIH. Although liver transaminases improved in our cohort, prospective studies are needed to determine if everolimus can induce long-term remission.

Efficacy of Combined Use of Everolimus and Second-Generation Pan-EGRF Inhibitors in KRAS Mutant Non-Small Cell Lung Cancer Cell Lines.

Background: EGFR mutations are present in approximately 15–50% of non-small cell lung cancer (NSCLC), which are predictive of anti-EGFR therapies. At variance, NSCLC patients harboring KRAS mutations are resistant to those anti-EGFR approaches. Afatinib and allitinib are second-generation pan-EGFR drugs, yet no predictive biomarkers are known in the NSCLC context. In the present study, we evaluated the efficacy of pan-EGFR inhibitors in a panel of 15 lung cancer cell lines associated with the KRAS mutations phenotype. Methods: KRAS wild-type sensitive NCI-H292 cell line was further transfected with KRAS mutations (p.G12D and p.G12S). The pan-EGFR inhibitors’ activity and biologic effect of KRAS mutations were evaluated by cytotoxicity, MAPK phospho-protein array, colony formation, migration, invasion, and adhesion. In addition, in vivo chicken chorioallantoic membrane assay was performed in KRAS mutant cell lines. The gene expression profile was evaluated by NanoString. Lastly, everolimus and pan-EGFR combinations were performed to determine the combination index. Results: The GI50 score classified two cell lines treated with afatinib and seven treated with allitinib as high-sensitive phenotypes. All KRAS mutant cell lines demonstrated a resistant profile for both therapies (GI50 < 30%). The protein array of KRAS edited cells indicated a significant increase in AKT, CREB, HSP27, JNK, and, importantly, mTOR protein levels compared with KRAS wild-type cells. The colony formation, migration, invasion, adhesion, tumor perimeter, and mesenchymal phenotype were increased in the H292 KRAS mutated cells. Gene expression analysis showed 18 dysregulated genes associated with the focal adhesion-PI3K-Akt-mTOR-signaling correlated in KRAS mutant cell lines. Moreover, mTOR overexpression in KRAS mutant H292 cells was inhibited after everolimus exposure, and sensitivity to afatinib and allitinib was restored. Conclusions: Our results indicate that allitinib was more effective than afatinib in NSCLC cell lines. KRAS mutations increased aggressive behavior through upregulation of the focal adhesion-PI3K-Akt-mTOR-signaling in NSCLC cells. Significantly, everolimus restored sensibility and improved cytotoxicity of EGFR inhibitors in the KRAS mutant NSCLC cell lines.

A Multi-Centric Study Assessing Safety and Efficacy of Everolimus in Adult Chinese Patients With Tuberous Sclerosis Complex Associated Renal Angiomyolipomas.

BackgroundEverolimus has been approved in China for adult patients with TSC-AML (tuberous sclerosis associated renal angiomyolipomas) not requiring immediate surgery and has been previously shown to be an effective treatment option for TSC-AML in the Chinese populationMethodsThis is an open label, single arm, multi-center Phase IV post-approval commitment study to further assess the safety and efficacy of everolimus in patients with TSC-AML who do not require immediate surgical intervention. The primary outcome was to evaluate the safety of everolimus while the secondary outcome was to evaluate AML response.ResultsTreatment with everolimus was associated with a clinically meaningful best overall AML response rate of 70% (95% CI: 53.5, 83.4). Of the 38 evaluable patients, 37 (97%) patients experienced a reduction in the sum of volumes of target angiomyolipoma lesions relative to baseline. At Week 12 (n=38), the median percentage change in sum of target AML volume was −56.60%, which further changed by -59.96% at Week 24 (n=38), and by −64.41% at Week 48 (n=22). Throughout the study, renal function remained relatively stable. Patients with TSC associated lymphangiomyomatosis (LAM) (N=13) demonstrated a lower than expected rate of decline in pulmonary function tests (PFTs). Everolimus was generally well tolerated with no significant safety findings in Chinese patients. Most of the adverse events were of grade 1-2, and manageable with appropriate dose adjustments and supportive therapies. There were no treatment discontinuation due to AE and no treatment death was reported.ConclusionsBased on the efficacy and safety data presented in this study, the overall clinical benefit/risk assessment further supports the use of everolimus as a viable treatment option for Chinese patients with TSC-AML.

Tenofovir alafenamide prophylaxis post-liver transplantation: a real-world study in patients with chronic kidney disease.

Tenofovir alafenamide fumarate (TAF) was shown equally efficacious in suppressing hepatitis B virus (HBV) but with less renal toxicity than tenofovir disoproxil fumarate (TDF). The aim of this real-world study was to evaluate renal function in post-liver transplantation (LT) patients that changed TDF with TAF. The TAF group (n=17) included patients who switched to TAF due to low (<60 ml/min/1.73m2) Glomerular Filtration Rate (GFR). The control group included patients that remained on TDF (n=30), although some (n= 14) had chronic kidney disease (CKD) (TDF-CKD group). GFR was assessed using: i) MDRD-6 variable; ii) CKD-EPI formula; iii) radionuclide technique (rGFR). There were no significant differences between the two groups except for the presence of diabetes and follow-up period, which were more common and shorter, respectively, in the TAF group (35% vs. 10%, p=0.03; 13.7 vs. 35.5 months, p<0.001). At the end of follow-up there were no significant changes in renal function between the TAF and the TDF group or TDF-CKD group, although the numerical change in rGFR in the latter comparison was greater in the TAF group (ΔrGFR 3 vs. -2.14 ml/min, p=0.26). The use of everolimus was associated with improvement in renal function (ΔrGFR 2 vs. -7.75 ml/min, p=0.06 [TAF vs. TDF group]; 2 vs. -12 ml/min, p=0.01 [TAF vs. TDF-CKD group]). There were no TAF- related side effects or cases of HBV recurrence. Conversion to TAF in post-LT patients who develop CKD does not lead to improvement of kidney function after a period of one year.

Inhibition of the mToR pathway with everolimus can modulate heat shock genes and ERCC1 gene expression and improves outcomes on serous ovarian cancer in HIPEC in vitro model.

e17541 Background: Worldwide, epithelial ovarian cancer accounts for a significant percentage of malignancies and is the most lethal neoplasm of the gynecological system, mainly due to silent manifestation and late diagnosis. Predominantly, around 70% of newly diagnosed women with epithelial ovarian cancer have the locally advanced or metastatic stage (III/IV). The extensive peritoneal dissemination of epithelial ovarian cancer might occur at the time of primary tumor diagnosis or related to disease relapse after previous treatment. Therefore, understanding the dynamic of peritoneal dissemination is of utmost importance, as peritoneal carcinomatosis is frequently associated with disease morbidity and mortality. Methods: In this study, we cultivated ovarian cancer cells using the OV-90 cell line (high-grade serous) and assessed citoxicity using MTT assay. Initially, the ovarian cancer cells were treated with everolimus 18 nM (37˙C) for 24 hours for both experimental and control groups. Subsequently, two experimental groups were treated with cisplatin in normothermia (Group 1) and hyperthermia (Group 2) (37˙C and 41˙C, respectively) while the control group was treated with phosphate-buffered saline solution 1X at 37˙C (Group 3) and 41˙C (Group 4) for 24 hours. After the first treatment, we re-supplemented each group under the same beforementioned conditions and incubated it for three additional hours. Moreover, the RNA extracts of each sample set were submitted to RT-PCR for the obtention of the qRT-PCR material. Lastly, we compared the expression of the ERCC1 gene and heat shock genes amongst the different intervention groups. Results: There statistical difference concerning cytotoxicity between treatment with everolimus and heated cisplatin versus treatment with everolimus and cisplatin in normothermia. We observed that the ERCC1 and TRAP 1 genes were downregulated in OV-90 cell lines under heated conditions compared to the normothermia group. Conclusions: The use of everolimus in HIPEC in vitro model increases the cytotoxic response and suggest that inhibition of the mTOR pathway modulates the expression of heat shock genes e ERCC1 gene improving outcomes. Nevertheless, there is still a need for studies evaluating the effectiveness of everolimus in preclinical trials under hyperthermic conditions.

Oral findings in kidney transplant children and adolescents.

Children and adolescents undergoing kidney transplantation may present oral conditions after the procedure, but a few studies have recently described them. To describe the oral conditions of post-renal transplant children and adolescents. Two calibrated dentists examined all the participants by assessing caries experience, enamel defects, periodontal condition and soft tissue lesions. A total of 120 participants were included in the study, in which 63 (52.5%) were male and 57 (47.5%) were female, with a mean age of 12.78±3.9years. Among the participants, 104 (86.7%) showed at least one oral change directly related to kidney disease. The most frequent oral findings were enamel defect (49/120; 40.8%) and drug-induced gingival overgrowth (DIGO) (20/120; 16.7%). Gingival bleeding was observed on probing in 115 (95.8%) participants, whereas 69 (57.5%) presented dental calculus and 51 (42.5%) had caries experience. Gingival bleeding, enamel defects and DIGO were the most frequent oral findings in kidney transplant children and adolescents. The use of amlodipine and anticonvulsants was associated with DIGO, and there was a positive correlation between oral ulcers and use of everolimus.

A rare drug fever due to everolimus use in a patient with liver transplantation: a case report during the Covid-19 pandemic

Drug-induced fever (DIF) is an uncommon, difficult-to-diagnose complication which is one of the possible causes of fever of unknown origin (FUO). In addition, Covid-19 infection is also a cause of fever in these pandemic days we live. Everolimus (EVR), an inhibitor of the mammalian target of rapamycin (mTOR), is employed as an immunosuppressant in combination with calcineurin inhibitors, following a procedure of organ transplantation, and as a proliferation signal inhibitor coated on a drug-eluting stent and in cancer therapy. EVR has many adverse effects that require follow-up, but fever is not one of the well-known adverse effects thereof. In our literature search, we have found only a single case of fever due to EVR use which had been reported in a patient following a cardiac transplantation in 2004. On the other hand, our case is a patient with a diagnosis of alcohol-induced liver cirrhosis and hepatocellular carcinoma (HCC) who has been subjected to a liver transplantation (LT) has developed fever in the course of our follow-up just after the initiation of EVR treatment at the third month post-transplantation and during the covid-19 pandemic.

Early Use of Everolimus as a Third Immunosuppressive Agent for Intestinal Transplantation: A Report of 2 Cases

In patients with intestinal transplantation (ITx), renal function is easily impaired because of long-term parenteral nutrition and side effects of tacrolimus. Everolimus was used in patients with renal insufficiency in our study. We administered everolimus as a third immunosuppressive agent in addition to tacrolimus and steroids for renal sparing in patients who received ITx. We assessed everolimus levels, complications, and renal function. Two patients received everolimus after ITx. Patient 1 was a 13-year-old boy who underwent ITx for an allied disorder of Hirschsprung's disease. After induction therapy with rabbit antithymocyte globulin, maintenance therapy consisted of tacrolimus and steroids. Everolimus was introduced 3 months after ITx for renal sparing. Seven months later, the patient required partial intestinal graft resection owing to bowel obstruction. Everolimus was suspended for only 2 weeks. Four years after ITx, the trough level of tacrolimus was maintained at 3 to 5 ng/mL. The trough level of everolimus was maintained at 3 to 5 ng/mL. Patient 2 was a 32-year-old man who underwent deceased ITx for short gut syndrome. Induction and maintenance immunosuppression was the same as for patient 1. Everolimus was introduced 1 month after surgery. Two years after ITx, trough levels of tacrolimus and everolimus were the same as in patient 1. No rejection was observed in either patient, and renal function was well maintained. We observed no side effects caused by everolimus. Everolimus could be used safely and effectively after ITx. Early use of everolimus after ITx did not affect wound healing.

Longitudinal monitoring of mRNA levels of regulatory T cell biomarkers by using non-invasive strategies to predict outcome in renal transplantation

BackgroundAcute T-cell mediated rejection (aTCMR) is still an issue in kidney transplantation, for it is associated with chronic rejection, graft loss, and overall worse outcomes. For these reasons, a standard non-invasive molecular tool to detect is desirable to offer a simpler monitoring of kidney transplant recipients (KTRs). The purpose of our study was to examine, in peripheral blood before and after transplantation, the expression patterns of regulatory T cell (Treg)-related genes: the forkhead box P3 (FOXP3) and the two CTLA-4 isoforms (full-length and soluble) to predict acute rejection onset, de novo donor-specific antibodies (DSA) development and renal dysfunction 1 year after transplantation.MethodsWe profiled by using a relative quantification analysis (qRT-PCR) circulating mRNA levels of these biomarkers in peripheral blood of 89 KTRs within the first post-transplant year (at baseline and 15, 60 and 365 days, and when possible at the acute rejection) and compared also the results with 24 healthy controls.ResultsThe three mRNA levels drastically reduced 15 days after transplantation and gradually recovered at 1 year in comparison with baseline, with very low levels at the time of aTCMR for FOXP3 (RQ = 0.445, IQR = 0.086–1.264, p = 0.040), maybe for the pro-apoptotic role of FOXP3 during inflammation. A multivariate Cox regression analysis evidenced a significant relation between aTCMR onset and thymoglobuline induction (HR = 6.749 p = 0.041), everolimus use (HR = 7.017, p = 0.007) and an increased risk from the solCTLA-4 expression at 15 days, mainly considering recipients treated with Mycophelolic acid (HR = 13.94 p = 0.038, 95%CI:1.157–167.87). Besides, solCTLA-4 also predisposed to graft dysfunction (eGFR< 60 mL/min/1.73m2) at 1 year (AOR = 3.683, 95%CI = 1.145–11.845, p = 0.029). On the other hand, pre-transplant solCTLA-4 levels showed a protective association with de novo DSAs development (HR = 0.189, 95%CI = 0.078–0.459, p < 0.001).ConclusionsmRNA levels of Treg-associated genes, mainly for solCTLA-4, in peripheral blood could put forward as candidate non-invasive biomarkers of cellular and humoral alloreactivity in clinical transplantation and might help shape immunosuppression, tailor monitoring and achieve better long-term outcomes of kidney transplantation in the wake of “precision medicine”.

Prevalence of fatty liver disease after liver transplantation and risk factors for recipients and donors

Introduction and objectivesFatty liver disease (FLD) may develop in liver transplant recipients. We investigated the recipient and donor risk factors for FLD development after liver transplantation (LT). MethodsA total of 108 liver transplant recipients (54 men [50.0%]; median age, 52 [20–68] years) treated from 2011–2020 was enrolled. Three recipients died at < 3 months as a result of infection or blood flow impairment, and were excluded from the long-term FLD study. On evaluation of 88 prospective living donors, fatty liver was observed in 21. The prevalence and risk factors for FLD and survival were evaluated. ResultsAfter LT, 28 of 105 recipients (26.7%) developed FLD. FLD was more common in patients with a high body mass index (BMI) and dyslipidemia (both p < 0.01), primary nonalcoholic steatohepatitis (p = 0.02), after living-donor LT (p = 0.03) and everolimus (EVL) use (p = 0.08). Factors predictive of FLD included EVL use and a high BMI (hazard ratios = 3.00 and 1.34; p = 0.05 and p < 0.01, respectively). Sixteen donors lost 6.5 kg (range: 2.0–16.0 kg) of body weight prior to LT. However, there were no cases of primary non-function, which did not affect the FLD prevalence. Development of FLD did not have a negative impact on LT outcome; the 5-year survival rate was 92.6%. ConclusionsRecipient factors were more important than donor factors for FLD onset after LT.

Early Everolimus-Facilitated Reduced Tacrolimus in Liver Transplantation: Results From the Randomized HEPHAISTOS Trial.

Everolimus‐facilitated reduced‐exposure tacrolimus (EVR + rTAC) at 30 days after liver transplantation (LT) has shown advantages in renal preservation. This study evaluated the effects of early initiation of EVR + rTAC in de novo LT recipients (LTRs). In HEPHAISTOS (NCT01551212, EudraCT 2011‐003118‐17), a 12‐month, multicenter, controlled study, LTRs were randomly assigned at 7 to 21 days after LT to receive EVR + rTAC or standard‐exposure tacrolimus (sTAC) with steroids. The primary objective was to demonstrate superior renal function (assessed by estimated glomerular filtration rate [eGFR]) with EVR + rTAC versus sTAC at month 12 in the full analysis set (FAS). Other assessments at month 12 included the evaluation of renal function in compliance set and on‐treatment (OT) patients, efficacy (composite endpoint of graft loss, death, or treated biopsy‐proven acute rejection [tBPAR] and individual components) in FAS, and safety. In total, 333 patients (EVR + rTAC, 169; sTAC, 164) were included in the FAS. A high proportion of patients was nonadherent in maintaining tacrolimus trough levels (EVR + rTAC, 36.1%; sTAC, 34.7%). At month 12, the adjusted least square mean eGFR was numerically higher with EVR + rTAC versus sTAC (76.2 versus 72.1 mL/minute/1.73 m2, difference: 4.1 mL/minute/1.73 m2; P = 0.097). A significant difference of 8.3 mL/minute/1.73 m2 (P = 0.03) favoring EVR + rTAC was noted in the compliance set. Incidence of composite efficacy endpoint (7.7% versus 7.9%) and tBPAR (7.1% versus 5.5%) at month 12 as well as incidence of treatment‐emergent adverse events (AEs) and serious AEs were comparable between groups. A lower proportion of patients discontinued EVR + rTAC than sTAC treatment (27.2% versus 34.1%). Early use of everolimus in combination with rTAC showed comparable efficacy, safety, and well‐preserved renal function versus sTAC therapy at month 12. Of note, renal function was significantly enhanced in the compliance set.

Edema Associated With Everolimus de Novo

The appearance of edema limits the use of everolimus de novo together with tacrolimus and steroids in kidney transplantation. We aimed to investigate the frequency and characteristics of patients with edema and compare them according to the type of immunosuppression. We studied 150 kidney transplant recipients between 2015 and 2017 based on receiving everolimus de novo (group A) or mycophenolic acid derivatives (group B). We analyzed 50 patients in group A and 100 in group B. Follow-up was 26.2 ± 10 months. Fifty-six patients presented edema (37.3%): 54% in group A and 29% in group B (P=.003). Edema was mild in 74% of patients in group A and 57.1% in group B. The probability of edema was 10.1%, 22.4%, and 41% at 3, 6, and 12 months, respectively, in group A vs 10.1%, 20.3%, and 25.4% in group B (P=.006). Patients were treated mostly with diuretics (14.3% in group A vs 27.6% in group B) and discontinuation of calcium channel blockers (46.4% in group A vs 48.3% in group B). Improvement was 70.4% in group A vs 60.7% in group B; patient worsening was 0% in group A vs 10.7% in group B; and there was no change in 29.6% in group A vs 28.6% in group B. We did not find differences in patient or graft survival in those who presented edema, regardless of the treatment group. The use of everolimus and standard doses of tacrolimus caused edema in 54% of patients, with no impact on renal function or survival compared with mycophenolic acid derivatives. The edema was mostly of low intensity and improved in most patients.

Time-to-onset of diabetes with everolimus use: analysis of a spontaneous reporting system database.

The incidence of hyperglycemia and diabetes induced by everolimus has been shown in previous studies. Our study analyzed diabetes time-to-onset profiles after everolimus use in patients who underwent transplantation and patients with cancer. Using data from April 2007 to December 2018 in the Japanese Adverse Drug Event Report database, the reports with everolimus were classified according to its use as an immunosuppressant or anticancer drug. The median (25%-75%) days of diabetes time-to-onset in patients who underwent transplantation and patients with cancer were 172 (56-315) and 32 (18.5-57), respectively. There were no significant variations among patients with breast cancer, neuroendocrine tumor, and renal cell carcinoma. By conducting a Weibull shape parameter test, the lower limits of the 95% confidence intervals of the shape parameter β values for the indications of the cancer types were >1, indicating the wear out failure type profile, whereas those for transplantation data indicated a random failure type profile. The diabetes time-to-onset profiles after everolimus use differed between usage as an anticancer drug and immunosuppressant and there were no significant variations among the type of cancer. It was suggested that the incidence of diabetes should be monitored for 1-2 months in patients with cancer, whereas continuous monitoring is needed in patients who undergo transplantation.

COMPLETE PURGING OF EWING SARCOMA FROM HUMAN OVARIAN CORTEX TISSUE FRAGMENTS BY INHIBITING THE mTOR PATHWAY WITH EVEROLIMUS

To assess the use of Everolimus for the ex vivo purging of Ewing sarcoma metastases from human ovarian cortex before autotransplantation by inhibiting the mTOR pathway, without compromising ovarian tissue integrity.

From clinical trials to clinical practice: the use of everolimus and exemestane in the treatment of hormone receptor-positive metastatic breast cancer: real-world data

Everolimus combined with exemestane can modulate endocrine resistance. The combination showed significant improvement in progression-free survival (PFS) in phase III clinical trials for hormone receptor positive metastatic breast cancer patients. It also showed serious adverse events. We evaluate the efficacy and prevalence of serious adverse events in a real-world setting. We retrospectively examined 91 breast cancer patients; all were previously treated with chemotherapy and fulvestrant (84% and 59%, respectively). After a 13-month median follow-up, 29% had a partial response, and 32% had stable disease. The PFS was 7.8 months. Due to adverse events, 19% of patients stopped the treatment, while 31% required a dose reduction. Despite enrolling heavier-pretreated patients, our real-world outcome for the efficacy and safety of the exemestane and everolimus match those of the clinical trials. Such results should assure clinicians and lead to wider adoption of this oral, chemotherapy-sparing regimen.

Efficacy, Retention and Tolerability of Everolimus in Patients with Tuberous Sclerosis Complex: A Survey-Based Study on Patients' Perspectives.

BackgroundThe approval of everolimus (EVE) for the treatment of angiomyolipoma (2013), subependymal giant cell astrocytoma (2013) and drug-refractory epilepsy (2017) in patients with tuberous sclerosis complex (TSC) represents the first disease-modifying treatment option available for this rare and complex genetic disorder.ObjectiveThe objective of this study was to analyse the use, efficacy, tolerability and treatment retention of EVE in patients with TSC in Germany from the patient’s perspective.MethodsA structured cross-age survey was conducted at 26 specialised TSC centres in Germany and by the German TSC patient advocacy group between February and July 2019, enrolling children, adolescents and adult patients with TSC.ResultsOf 365 participants, 36.7% (n = 134) reported the current or past intake of EVE, including 31.5% (n = 115) who were taking EVE at study entry. The mean EVE dosage was 6.1 ± 2.9 mg/m2 (median: 5.6 mg/m2, range 2.0–15.1 mg/m2) in children and adolescents and 4 ± 2.1 mg/m2 (median: 3.7 mg/m2, range 0.8–10.1 mg/m2) in adult patients. An early diagnosis of TSC, the presence of angiomyolipoma, drug-refractory epilepsy, neuropsychiatric manifestations, subependymal giant cell astrocytoma, cardiac rhabdomyoma and overall multi-organ involvement were associated with the use of EVE as a disease-modifying treatment. The reported efficacy was 64.0% for angiomyolipoma (75% in adult patients), 66.2% for drug-refractory epilepsy, and 54.4% for subependymal giant cell astrocytoma. The overall retention rate for EVE was 85.8%. The retention rates after 12 months of EVE therapy were higher among adults (93.7%) than among children and adolescents (88.7%; 90.5% vs 77.4% after 24 months; 87.3% vs 77.4% after 36 months). Tolerability was acceptable, with 70.9% of patients overall reporting adverse events, including stomatitis (47.0%), acne-like rash (7.7%), increased susceptibility to common infections and lymphoedema (each 6.0%), which were the most frequently reported symptoms. With a total score of 41.7 compared with 36.8 among patients not taking EVE, patients currently being treated with EVE showed an increased Liverpool Adverse Event Profile. Noticeable deviations in the sub-items ‘tiredness’, ‘skin problems’ and ‘mouth/gum problems’, which are likely related to EVE-typical adverse effects, were more frequently reported among patients taking EVE.ConclusionsFrom the patients’ perspective, EVE is an effective and relatively well-tolerated disease-modifying treatment option for children, adolescents and adults with TSC, associated with a high long-term retention rate that can be individually considered for each patient. Everolimus therapy should ideally be supervised by a centre experienced in the use of mechanistic target of rapamycin inhibitors, and adverse effects should be monitored on a regular basis.

Early use of everolimus improved renal function after adult deceased donor liver transplantation

Tacrolimus (TAC) is a main therapy for liver transplantation (LT) patients, but it has side effects such as chronic nephrotoxicity that progressively aggravate renal function. The purpose of this study was to retrospectively compare the renal function between a TAC group and a combination of everolimus and reduced TAC (EVR-TAC) group after deceased donor liver transplantation (DDLT). The study comprised 131 patients who underwent DDLT between January 2013 and April 2018 at our institution. They received TAC or EVR-TAC after DDLT. EVR was introduced between one and six months after DDLT. Thirty-six of 131 patients (27.5%) received EVR-TAC. The incidence of chronic kidney disease (CKD) (eGFR <60 mL/1.73 m2) in the EVR-TAC group was higher than in the TAC group (25% vs. 8.4%; p = 0.019). Increasing serum creatinine (n = 23, 63.9%) was the most common cause for adding EVR to treatment of the post-transplant patients. There were no statistical differences in acute rejection and CKD between the two groups. The TAC trough level was significantly lower in the EVR-TAC group than in the TAC group, and the renal function of the EVR-TAC group was worse than that of the TAC group until one year after DDLT. However, the renal function of the EVR-TAC group improved and became similar to that of TAC group at 3 years post-transplant. The present study suggests that EVR should be introduced as soon as possible after DDLT to reduce exposure to high doses of TAC to improve the renal function.

Everolimus Shows Synergistic Anti-Myeloma Effects with Bortezomib Via the AKT/mTOR Pathway

Introduction: Multiple myeloma (MM) is characterized by the proliferation of malignant plasma cells and a subsequent overabundance of monoclonal paraprotein (M protein). Everolimus ,as an oral mammalian target of rapamycin (mTOR) inhibitor, plays an important role in multiple myeloma. In the phase I trial explored the use of everolimus in relapsed and/or refractory multiple myeloma patients ,the median time to progression was 90 days (range, 13 to 278 days),and no dose-limiting toxicity was observed at daily dose of 10 mg. At the same time, the observed responses are promising in some testing combination strategies. The pre-clinical activity of pan-histone deacetylase inhibitor LBH589 in combination with everolimus caused potent G0/G1 arrest and induced pronounced apoptosis, the combination led to down regulation of pStat3, cyclins, CDKs and XIAP and up regulation of pro-apoptotic Bcl-2 family proteins. Everolimus enhances the cytotoxicity of bendamustine in multiple myeloma cells through a network of pro-apoptotic and cell-cycle-progression regulatory proteins.Down regulation of vascular endothelial cell growth factor and everolimus synergistic antitumor activity in multiple myeloma cells. Furthermore, In a phase I study of everolimus in combination with lenalidomide in relapsed or refractory multiple myeloma patients, the overall response rate was 65% and median progression-free survival was 5.5 months. Bortezomib was the first therapeutic proteasome inhibitor to be tested in humans with MM. However, the combination of bortezomib and everolimus for the treatment of MM is still less reported.Methods: To evaluate the in vitro and in vivo anti-tumor activity of the combination of everolimus with bortezomib.CCK-8 was used to explore the proliferation of MM cells. Flow cytometry was used to determine the effect on apoptosis of cells.Western blot and Immunohistochemical staining was used to determine the epression of proteins.Results: In our study, the experimental results demonstrated that everolimus combined with bortezomib suppressed cell proliferation. Treatment with 20 nM everolimus in combination with 10 nM bortezomib for 72h achieved the lowest cell survival rate in both U266 and LP-1 MM cell lines. The combination of everolimus and bortezomib was synergistic in both cell lines indicated by combination index (CI) values of <0.8.Flow cytometry was used to determine the effect on apoptosis of bortezomib in combination with everolimus. everolimus alone and bortezomib alone induced approximately 22.5% and 17.2% apoptosis, combination treatment induced28.8% apoptosis in U266 cells, and the results were 15.6%,10.0% and 16.7% in LP-1 cells. Western blot was used to explore the mechanisms. The expression of AKT1, mTOR, p70S6K1, 4EBP1 and NF-kB was significantly down regulated while the expression of Caspase-3was significantly up regulated in combination group than other alone group. Furthermore, Synergistic antitumor effect of everolimus and bortezomib was observed in the animal model carrying the myeloma xenograft on the 25th day after tumor implantation . The results of immunohistochemical staining further demonstrated that the expression of AKT1, mTOR, p70S6K1, 4EBP1 and NF-kB was significantly down regulated and the expression of Caspase-3 was significantly up regulated in combination group.Conclusion:Our results shows synergistic antitumor effects of the combination therapy of bortezomib and everolimus induced myeloma cell apoptosis in vitro and in vivo xenograft mouse model ,which mainly through the inhibition of the AKT/mTOR pathway. Our results provided provide a rationale application for the combinatorial treatment of MM with proteasome inhibitor agents and mTOR inhibitors in future clinical practice. DisclosuresNo relevant conflicts of interest to declare.

Everolimus therapy and side‑effects: A systematic review and meta‑analysis.

Recent studies have focused on identifying novel targeted agents in order to reduce the undesired side‑effects of conventional chemotherapeutic agents on normal cells. However, even targeted therapies may exert certain negative effects on healthy tissues. The present systematic review was performed in order to evaluate the type and the incidence of side‑effects in patients treated with everolimus. The PubMed and Scopus databases were searched using the following free words and MESH terms: 'everolimus' AND 'side‑effects' OR 'toxicities' OR 'adverse events'. A total of 912 potentially relevant studies that were screened based on the title and abstracts were identified. A total of 731were excluded as they did not fulfil the inclusion criteria. Of the 181remaining studies included, the adverse events reported were obtained. The primary adverse events reported were stomatitis, leukopenia, anorexia, anaemia and fatigue. The majority of the patients reported adverse events limited to grade1or2. On the whole, the data presented herein confirm the findings of previous studies on the relative safety of everolimus, a targeted therapeutic agent, which differs from that of conventional chemotherapy, and highlight the potential adverse events associated with the therapeutic use of everolimus.

Donor-Specific Antibodies Against Donor Human Leukocyte Antigen are Associated with Graft Inflammation but Not with Fibrosis Long-Term After Liver Transplantation: An Analysis of Protocol Biopsies.

BackgroundDonor-specific antibodies (DSA) against donor human leukocyte antigen after liver transplantation, which are associated with histological changes, have been widely studied with respect to their sustained impact on transplant function. However, their long-term impact after liver transplantation remains unclear.MethodsWe performed a cross-sectional analysis from June 2016 to July 2017 that included all patients who presented themselves for scheduled follow-up after receiving a liver transplantation between September 1989 and December 2016. In addition to a liver protocol biopsy, patients were screened for human leukocyte antigen antibodies (HLAab) and donor-specific antibodies. Subsequently, the association between human leukocyte antigen antibodies, donor-specific antibodies, histologic and clinical features, and immunosuppression was analyzed.ResultsAnalysis for human leukocyte antigen antibodies and donor-specific antibodies against donor human leukocyte antigen was performed for 291 and 271 patients. A significant association between higher inflammation grades and the presence of human leukocyte antigen antibodies and donor-specific antibodies was detected, while fibrosis stages remained unaffected. These results were confirmed by multivariate logistic regression for inflammation showing a significant increase for presence of human leukocyte antigen antibodies and donor-specific antibodies (OR: 4.43; 95% CI: 1.67–12.6; p=0.0035). Furthermore, the use of everolimus in combination with tacrolimus was significantly associated with the status of negative human leukocyte antigen antibodies and donor-specific antibodies. Viral etiology for liver disease, hepatocellular carcinoma (HCC) and higher steatosis grades of the graft were significantly associated with a lower rate of human leukocyte antigen antibodies. The impact of human leukocyte antigen antibodies and donor-specific antibodies against donor human leukocyte antigen was associated with higher levels of laboratory parameters, such as transaminases and bilirubin.ConclusionDonor-specific antibodies against donor human leukocyte antigen are associated with histological and biochemical graft inflammation after liver transplantation, while fibrosis seems to be unaffected. Future studies should validate these findings for longer observation periods and specific subgroups.