A Real-world Study of Everolimus Plus Aromatase Inhibitor in Hormone Receptor-positive, HER2-negative Advanced Breast Cancer.

BACKGROUND/AIM: Everolimus in combination with exemestane was shown to offer benefit versus exemestane monotherapy in hormone receptor (HR)-positive, HER2-negative advanced breast cancer patients who progressed after aromatase inhibitor (AI) therapy. PATIENTS AND METHODS: The medical records of metastatic breast cancer patients, treated with everolimus, were retrospectively reviewed to generate real life safety and efficacy data. RESULTS: Sixty-eight percent of the patients had received chemotherapy (for early or metastatic disease) and 26% had received chemotherapy for metastatic disease. Among the 25 included patients, the most common adverse events were fatigue, neutropenia, epistaxis, stomatitis, and pneumonitis. Toxicity led to treatment discontinuation in 3 patients (12%). The median progression-free survival (PFS) was 7 months (95%CI=3.5-10.5). With a median follow-up of 73.3 months, the median overall survival was not reached. Twenty-five percent of the patients had received prior therapy with CDK4/6 inhibitors. Median PFS was significantly shorter in this subgroup (p=0.025). There was also a trend towards a longer PFS in patients with grade 3 breast cancer (p=0.085) and in patients receiving everolimus as first-line treatment (p=0.081). Some long responses were noted, with four patients exhibiting a PFS >5 years. CONCLUSION: These real-life data show that everolimus in combination with AI in patients with HER2-negative, HR-positive advanced breast cancer is an effective treatment with an acceptable toxicity profile.

Imaging as an early biomarker to predict sensitivity to everolimus for progressive NF2-related vestibular schwannoma.

PURPOSE: NF2-related schwannomatosis (NF2) is characterized by bilateral vestibular schwannomas (VS) often causing hearing and neurologic deficits, with currently no FDA-approved drug treatment. Pre-clinical studies highlighted the potential of mTORC1 inhibition in delaying schwannoma progression. We conducted a prospective open-label, phase II study of everolimus for progressive VS in NF2 patients and investigated imaging as a potential biomarker predicting effects on growth trajectory. METHODS: The trial enrolled 12 NF2 patients with progressive VS. Participants received oral everolimus daily for 52 weeks. Brain imaging was obtained quarterly. As primary endpoint, radiographic response (RR) was defined as ≥ 20% decrease in target VS volume. Secondary endpoints included other tumors RR, hearing outcomes, drug safety and quality of life (QOL). RESULTS: Eight participants completed the trial and four discontinued the drug early due to significant volumetric VS progression. After 52 weeks of treatment, the median annual VS growth rate decreased from 77.2% at baseline to 29.4%. There was no VS RR and 3 of 8 (37.5%) participants had stable disease. Decreased or unchanged VS volume after 3 months of treatment was predictive of stabilization at 12 months. Seven of eight participants had stable hearing during treatment except one with a decline in word recognition score. Ten of twelve participants reported only minimal changes to their QOL scores. CONCLUSIONS: Volumetric imaging at 3 months can serve as an early biomarker to predict long-term sensitivity to everolimus treatment. Everolimus may represent a safe treatment option to decrease the growth of NF2-related VS in patients who have stable hearing and neurological condition. TRN: NCT01345136 (April 29, 2011).

Drug-Eluting Resorbable Scaffold versus Angioplasty for Infrapopliteal Artery Disease.

BACKGROUND: Among patients with chronic limb-threatening ischemia (CLTI) and infrapopliteal artery disease, angioplasty has been associated with frequent reintervention and adverse limb outcomes from restenosis. The effect of the use of drug-eluting resorbable scaffolds on these outcomes remains unknown. METHODS: In this multicenter, randomized, controlled trial, 261 patients with CLTI and infrapopliteal artery disease were randomly assigned in a 2:1 ratio to receive treatment with an everolimus-eluting resorbable scaffold or angioplasty. The primary efficacy end point was freedom from the following events at 1 year: amputation above the ankle of the target limb, occlusion of the target vessel, clinically driven revascularization of the target lesion, and binary restenosis of the target lesion. The primary safety end point was freedom from major adverse limb events at 6 months and from perioperative death. RESULTS: The primary efficacy end point was observed (i.e., no events occurred) in 135 of 173 patients in the scaffold group and 48 of 88 patients in the angioplasty group (Kaplan-Meier estimate, 74% vs. 44%; absolute difference, 30 percentage points; 95% confidence interval [CI], 15 to 46; one-sided P<0.001 for superiority). The primary safety end point was observed in 165 of 170 patients in the scaffold group and 90 of 90 patients in the angioplasty group (absolute difference, -3 percentage points; 95% CI, -6 to 0; one-sided P<0.001 for noninferiority). Serious adverse events related to the index procedure occurred in 2% of the patients in the scaffold group and 3% of those in the angioplasty group. CONCLUSIONS: Among patients with CLTI due to infrapopliteal artery disease, the use of an everolimus-eluting resorbable scaffold was superior to angioplasty with respect to the primary efficacy end point. (Funded by Abbott; LIFE-BTK ClinicalTrials.gov number, NCT04227899.).

Everolimus for Children With Recurrent or Progressive Low-Grade Glioma: Results From the Phase II PNOC001 Trial.

PURPOSE: The PNOC001 phase II single-arm trial sought to estimate progression-free survival (PFS) associated with everolimus therapy for progressive/recurrent pediatric low-grade glioma (pLGG) on the basis of phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway activation as measured by phosphorylated-ribosomal protein S6 and to identify prognostic and predictive biomarkers. PATIENTS AND METHODS: Patients, age 3-21 years, with progressive/recurrent pLGG received everolimus orally, 5 mg/m2 once daily. Frequency of driver gene alterations was compared among independent pLGG cohorts of newly diagnosed and progressive/recurrent patients. PFS at 6 months (primary end point) and median PFS (secondary end point) were estimated for association with everolimus therapy. RESULTS: Between 2012 and 2019, 65 subjects with progressive/recurrent pLGG (median age, 9.6 years; range, 3.0-19.9; 46% female) were enrolled, with a median follow-up of 57.5 months. The 6-month PFS was 67.4% (95% CI, 60.0 to 80.0) and median PFS was 11.1 months (95% CI, 7.6 to 19.8). Hypertriglyceridemia was the most common grade ≥3 adverse event. PI3K/AKT/mTOR pathway activation did not correlate with clinical outcomes (6-month PFS, active 68.4% v nonactive 63.3%; median PFS, active 11.2 months v nonactive 11.1 months; P = .80). Rare/novel KIAA1549::BRAF fusion breakpoints were most frequent in supratentorial midline pilocytic astrocytomas, in patients with progressive/recurrent disease, and correlated with poor clinical outcomes (median PFS, rare/novel KIAA1549::BRAF fusion breakpoints 6.1 months v common KIAA1549::BRAF fusion breakpoints 16.7 months; P < .05). Multivariate analysis confirmed their independent risk factor status for disease progression in PNOC001 and other, independent cohorts. Additionally, rare pathogenic germline variants in homologous recombination genes were identified in 6.8% of PNOC001 patients. CONCLUSION: Everolimus is a well-tolerated therapy for progressive/recurrent pLGGs. Rare/novel KIAA1549::BRAF fusion breakpoints may define biomarkers for progressive disease and should be assessed in future clinical trials.

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

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

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

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

Effectiveness and safety of everolimus treatment in patients with tuberous sclerosis complex in real-world clinical practice.

BACKGROUND: The randomised double-blinded placebo-controlled EXIST-1-3 studies have showed everolimus effective with adverse effects reported as acceptable in treatment of symptoms in patients with tuberous sclerosis complex (TSC), although evidence of outcomes in clinical practice remains limited. This study aimed to investigate, in clinical practice, the effectiveness and safety of everolimus for epilepsy, renal angiomyolipoma (rAML), and subependymal giant cell astrocytoma (SEGA) in patients with TSC. RESULTS: The study included 64 patients with TSC (median age: 19, range 0.9-54 years) receiving everolimus treatment (Norway: n = 35; Denmark: n = 29). Among 45 patients with epilepsy, 14 (31%) were responders experiencing ≥ 50% reduction in seizure frequency in the last 3 months of treatment compared with the last 3 months before treatment. Nineteen (42%) patients changed their anti-seizure medications (ASMs). Responders were more common among patients < 18 years (46%) than among patients ≥ 18 years (14%, p = 0.03). In 29 patients with rAML, everolimus reduced (≥ 30% decrease) and stabilized (< 20% increase, ≤ 30% decrease) longest diameter of rAML in 38% and 59%, respectively, after a mean treatment duration of 37 months. SEGA volume was reduced in three patients by 71%, 43%, and 48% after 39, 34, and 82 months. Adverse effects were reported in 61 of 64 patients (95%) after a median treatment duration of 31 months (range 0-106), with oral ulceration/stomatitis (63%) and upper respiratory tract infections (38%) being the most common. The most common laboratory abnormalities were increased cholesterol (41%), anaemia (30%), and leucopoenia (25%). Grade 3-4 adverse effects were reported in 36% of cases, and life-threatening conditions were reported in two patients. Nine patients discontinued everolimus treatment. CONCLUSIONS: Seizure reduction in this study sample was consistent with results from EXIST, but might be lower than expected, given that changes in concomitant ASMs are part of clinical practice. Seizure reduction was associated with younger age. As with EXIST, everolimus reduced or stabilised rAML size in most patients. SEGA volume was reduced in all three patients. Close follow-up is needed for this group, especially for children and patients who may not be able to report adverse effects.

Relationship Between Daily Dose of Everolimus and Treatment Effect in Patients With Luminal HER2-negative Metastatic Breast Cancer.

BACKGROUND/AIM: Everolimus (EVE)-based treatment is an option for hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC), but a predictive marker has not yet been established. The recommended dose of EVE in combination with endocrine therapy is 10 mg/day, but due to adverse effects, patients are frequently forced to reduce the dose. However, the correct maintenance dose to achieve a therapeutic effect is still under debate. Employing real-world data, we examined clinicopathological factors to predict the efficacy of EVE-based treatment, particularly focusing on daily dose intensity (DDI). PATIENTS AND METHODS: Ninety-five patients with MBC who received EVE-based treatment in combination with exemestane during the period from 2014 to 2022 were retrospectively investigated. Doses of EVE were reduced as needed and DDI was calculated with total doses of EVE and the duration of the treatment. RESULTS: Mean time-to-treatment-termination (TTT) was 25.4 weeks. Patients with tumors with a high Ki67 labeling index, low absolute lymphocyte count, and small DDI of EVE had significantly shorter TTT (p=0.006, 0.043, and 0.030, respectively). When patients were categorized based on DDI of EVE, patients with DDI ≤5 mg/day had significantly shorter TTT (p=0.002). There were no correlations between RDI and factors such as age, body weight, and numbers of previous treatments for MBC. CONCLUSION: Maintaining a DDI of at least 5 mg/day seems crucial to achieving a therapeutic effect. Our data might be useful for determining the dosage of EVE in clinical practice.

The everolimus eluting Synergy MegatronTM drug-eluting stent platform: Early outcomes from the European Synergy MegatronTM Implanters' Registry.

BACKGROUND: The Synergy MegatronTM is an everolimus-drug eluting stent that may offer advantages in the treatment of aorto-ostial disease and large proximal vessels. AIMS: To report the short- to medium-term clinical outcomes from the European Synergy MegatronTM Implanters' Registry. METHODS: This registry was an investigator-initiated study conducted at 14 European centers. The primary outcome was target lesion failure (TLF), defined as the composite of cardiovascular death, target vessel myocardial infarction (MI), and target lesion revascularisation. RESULTS: Five hundred seventy-five patients underwent PCI with MegatronTM between 2019 and 2021. Patients were 69 ± 12 years old, 26% had diabetes mellitus, 24% had moderate-severe left ventricular impairment and 59% presented with an acute coronary syndrome. 15% were deemed prohibitively high risk for surgical revascularisation. The target vessel involved the left main stem in 55%, the ostium of the RCA in 13% and was a true bifurcation (Medina 1,1,1) in 50%.  At 1 year, TLF was observed in 40 patients, with 26 (65%) occurring within the first 30 days. The cumulative incidence of TLF was 4.5% at 30 days and 8.6% (95% CI 6.3-11.7) at 1 year. The incidence of stent thrombosis was 0.5% with no late stent thromboses. By multivariate analysis, the strongest independent predictors of TLF were severe left ventricular impairment (HR 3.43, 95% CI: 1.67-6.76, p < 0.001) and a target vessel involving the left main (HR 4.00 95% CI 1.81-10.15 p = 0.001). CONCLUSIONS: Use of the Synergy MegatronTM everolimus eluting stent in a 'real-world' setting shows favorable outcomes at 30 days and 1 year.

Randomized clinical trial of abluminus DES+ sirolimus-eluting stent versus everolimus-eluting DES for percutaneous coronary intervention in patients with diabetes mellitus: An optical coherence tomography study.

BACKGROUND: Diabetic patients are at higher risk of recurrent adverse events following percutaneous coronary intervention (PCI) than the nondiabetics. Despite the introduction of new generation drug-eluting stents, their efficacy in the diabetics is still limited. AIMS: To evaluate the efficacy of the Abluminus DES+ biodegradable polymer sirolimus-eluting stent in reducing neointimal hyperplasia in diabetic patients, compared to a durable polymer everolimus-eluting stent (DP-EES). METHODS: A total of 131 patients with diabetes and coronary artery disease were enrolled in six Italian centers and randomized in a 2:1 fashion to PCI with Abluminus DES+ or DP-EES: 85 were assigned to Abluminus DES+ and 46 to DP-EES. The primary endpoint was optimal coherence tomography (OCT)-derived neointimal volume at 9-12 months. Secondary endpoints included OCT-derived neointimal area, neointimal volume obstruction and adverse clinical events. RESULTS: The primary endpoint, neointimal volume, did not differ between Abluminus DES+ and DP-EES (29.11 ± 18.90 mm3 vs. 25.48 ± 17.04 mm3 , p = 0.40) at 9-12-month follow-up. This finding remained consistent after weighing for the sum of stents lengths (1.14 ± 0.68 mm3 vs. 0.99 ± 0.74 mm3 for Abluminus DES+ and DP-EES, respectively, p = 0.38). Similarly, other OCT-derived and clinical secondary endpoints did not significantly differ between the two groups. Rate of target lesion failure was high in both groups (21.2% for Abluminus DES+ and 19.6% for DP-EES). CONCLUSIONS: This preliminary study failed to demonstrate the superiority of the Abluminus DES+ over the DP-EES in diabetic patients in terms of neointimal proliferation.

Everolimus in combination with vandetanib in children, adolescents, and young adults: a phase I study.

BACKGROUND: Combined use of inhibitors of mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF-2) receptors is a potential strategy to overcome resistance to either class of drugs when used alone. PATIENTS AND METHODS: We designed a phase 1 trial to test the drug combination of a multikinase VEGF receptor 2 inhibitor, vandetanib, and an mTOR inhibitor, everolimus, in a pediatric and young adult patient cohort with advanced cancers. Exceptional responders were probed for tumor mutational profile to explore possible molecular mechanisms of response. RESULTS: Among 21 enrolled patients, clinical benefit was observed in 38% (one patient with partial response and eight patients with stable disease) with a median progression-free survival of 3.3 months. The most common treatment-related adverse event was rash (n = 13). Other treatment-related toxicities included diarrhea, fatigue, hypertension, QT prolongation, hypertriglyceridemia/hypercholesterolemia, transaminitis, thrombocytopenia, and weight loss. None of the patients experienced dose-limiting toxicities. Three exceptional responders were analyzed and were found to harbor genetic alterations including kinase insert domain receptor (KDR) Q472H mutation, EWSR1-CREB3L1, CDKN2A/B loss, and ASPL/ASPSCR1-TFE3 fusion. CONCLUSIONS: The combination of vandetanib and everolimus showed early activity and tolerable toxicity profile in pediatric patients with advanced cancers.

Predictive Factors of BK Virus Development in Kidney Transplant Recipients and the Effect of Low-Dose Tacrolimus Plus Everolimus on Clinical Outcomes.

OBJECTIVES: This study aimed to determine the predictive factors of BK virus viremia/nephropathy in kidney transplant recipients and to evaluate the effects of low-dose tacrolimus plus everolimus. MATERIALS AND METHODS: This study included 3654 kidney transplant recipients. The patients were divided into 2 groups: group 1 were BK virus negative (n = 3525, 96.5%) and group 2 were BK virus positive (n = 129, viremia 3.5%, nephropathy 1%). Predictive factors were determined by receiver operating characteristic curve analysis and logistic regression models.We also divided and analyzed patients with BK virus viremia/nephropathy into 2 groups according to immunosuppressive changes. Group 2a had been switched to low-dose tacrolimus plus everolimus (n = 54, 41.9%), and group 2b had been switched to other immunosuppressive protocols (n = 75, 58.1%). RESULTS: We found that use of anti-T-cell lymphocyte globulin and tacrolimus, deceased donor transplant, and rejection were predictive factors for BK virus viremia/nephropathy. In addition, patients who had low-dose calcineurin inhibitor plus mammalian target of rapamycin inhibitor regimens showed a low rate of BK virus development(only 6.2% of all cases). In Group 2a, both the BK polyomavirus-associated nephropathy rate (n = 23 [42.6%] vs n = 12 [16%] in group 2b; P = .001) and viral load (DNA > 104 copies/mL) (n = 49 [90.7%] vs n = 27 [36%] in group 2b; P = .001) were increased versus group 2b. Graft function, graft survival, viral clearance, and rejection rate were similar between the groups after protocol change. CONCLUSIONS: BK virus viremia/nephropathy rate was lower in patients who received low-dose calcineurin inhibitor plus mammalian target of rapamycin inhibitor protocols; the low-dose tacrolimus plus everolimus switch protocol after BK virus was more effective and safe than other protocols.

Phase II study of everolimus and temozolomide as first-line treatment in metastatic high-grade gastroenteropancreatic neuroendocrine neoplasms.

BACKGROUND: The optimal treatment for metastatic high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms when Ki-67 ≤55% is unknown. A prospective multi-centre phase 2 study was performed to evaluate the efficacy and safety of everolimus and temozolomide as first-line treatment for these patients. METHODS: Patients received everolimus 10 mg daily continuously and temozolomide 150 mg/m2 for 7 days every 2 weeks. Endpoints included response, survival, safety and quality of life (QoL). Histopathological re-evaluation according to the 2019 WHO classification was performed. RESULTS: For 37 eligible patients, the primary endpoint with 65% disease control rate (DCR) at 6 months (m) was reached. The response rate was 30%, the median progression-free survival (PFS) 10.2 months and the median overall survival (OS) 26.4 months. Considering 26 NET G3 patients, 6 months DCR was 77% vs. 22% among nine NEC patients (p = 0.006). PFS was superior for NET G3 vs. NEC (12.6 months vs. 3.4 months, Log-rank-test: p = 0.133, Breslow-test: p < 0.001). OS was significantly better for NET G3 (31.4 months vs. 7.8 months, p = 0.003). Grade 3 and 4 toxicities were reported in 43% and 38%. QoL remained stable during treatment. CONCLUSION: Everolimus and temozolomide may be a treatment option for selected GEP-NET G3 patients including careful monitoring. Toxicity did not compromise QoL. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NTC02248012).

Adverse Events of Everolimus in Patients with Tuberous Sclerosis Complex Treated for Renal Angiomyolipoma/Subependymal Giant Cell Astrocytoma.

Background: Although regarded as a potentially efficient approach to address tuberous sclerosis complex (TSC)-associated complications, the adverse event profile of everolimus has not yet been fully elucidated. The present study aimed to clarify the adverse event spectrum in patients with TSC who are using everolimus for common indications, in comparison to those who do not use everolimus. Materials and Methods: We recruited patients with TSC who were followed up annually at TSC integrated clinics or referred for medical assistance. Medical reviews and laboratory investigations were performed at baseline and annually by clinical physicians. The adverse events were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Events. Results: Common adverse events in everolimus users included hypercholesterolemia (55%), gingivostomatitis (50%), proteinuria (50%), and hyperglycemia (40%). Compared with everolimus nonusers, the occurrence of gingivostomatitis and proteinuria was significantly higher in everolimus users (gingivostomatitis, p=0.02; proteinuria, p=0.02). Among the everolimus users, 12 patients had level I CTCAE, and five had level II CTCAE. None of the everolimus users presented with CTCAE level III or higher. Conclusion: Patients with TSC who are everolimus users had a higher tendency to develop gingivostomatitis and proteinuria compared to nonusers. However, no differences were observed in the occurrence of other adverse events between everolimus users and nonusers.

Everolimus-Eluting Stents or Bypass Surgery for Multivessel Disease in Diabetics: The BEST Extended Follow-Up Study.

BACKGROUND: Diabetes mellitus is associated with more complex coronary artery diseases. Coronary artery bypass grafting (CABG) is a preferred revascularization strategy over percutaneous coronary intervention (PCI) in diabetics with multivessel coronary artery disease (MVD). OBJECTIVES: This study sought to examine the different prognostic effects of revascularization strategies according to the diabetes status from the randomized BEST (Randomized Comparison of Coronary Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients With Multivessel Coronary Artery Disease) trial. METHODS: Patients (n = 880) with MVD were randomly assigned to undergo PCI with an everolimus-eluting stent vs CABG stratified by diabetics (n = 363) and nondiabetics (n = 517). The primary endpoint was the composite of death, myocardial infarction, or target vessel revascularization during a median follow-up of 11.8 years (IQR: 10.6-12.5 years). RESULTS: In diabetics, the primary endpoint rate was significantly higher in the PCI group than in the CABG group (43% and 32%; HR: 1.53; 95% CI: 1.12-2.08; P = 0.008). However, in nondiabetics, no significant difference was found between the groups (PCI group, 29%; CABG group, 29%; HR: 0.97; 95% CI: 0.67-1.39; P = 0.86; Pinteraction= 0.009). Irrespective of the presence of diabetes, no significant between-group differences were found in the rate of a safety composite of death, myocardial infarction, or stroke and mortality rate. However, the rate of any repeat revascularization was significantly higher in the PCI group than in the CABG group. CONCLUSIONS: In diabetics with MVD, CABG was associated with better clinical outcomes than PCI. However, the mortality rate was similar between PCI and CABG irrespective of diabetes status during an extended follow-up. (Ten-Year Outcomes of Randomized Comparison of Coronary Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients With Multivessel Coronary Artery Disease [BEST Extended], NCT05125367; Randomized Comparison of Coronary Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients With Multivessel Coronary Artery Disease [BEST], NCT00997828).

Use of everolimus following kidney transplantation during pregnancy: A case report and systematic review.

OBJECTIVE: There is limited safety data on the use of everolimus during pregnancy. In this study, we present the maternal and neonatal outcomes of everolimus used throughout the course of pregnancy and conducted a systematic review of reports of everolimus use after organ transplantation during pregnancy. CASE REPORT: A woman with type 1 diabetes who underwent kidney transplantation was treated with tacrolimus, everolimus, and prednisolone. Two years later, she became pregnant. At 27 weeks of gestation, an emergent cesarean delivery was performed owing to severe preeclampsia and fetal distress. No congenital malformation was noted in the baby at a corrected age of 4 months, and the maternal renal function remained stable. CONCLUSION: Our systematic review did not identify evidence of teratogenicity in babies exposed to everolimus as an immunosuppressant after transplantation. To better assess the risk of exposure to everolimus during pregnancy, all cases of new pregnancies occurring in transplant recipients receiving treatment with mammalian target of rapamycin inhibitor inhibitors should be reported.

Tremor Induced by Cyclosporine, Tacrolimus, Sirolimus, or Everolimus: A Review of the Literature.

Calcineurin inhibitors such as cyclosporine and tacrolimus are immunosuppressant drugs that are known to induce tremors. Non-calcineurin inhibitors such as sirolimus and everolimus have also reportedly been accompanied by tremors, albeit less likely. However, the prevalence rates reported in the literature are notably wide, and the risk profiles for these drug-induced tremors are less understood. We searched PubMed to extract data on the risk of tremors with these drugs when prescribed for various transplant and non-transplant indications. We ascertained whether the risk of drug-induced tremor is influenced by the underlying diagnosis, dosing formulations, drug concentrations, and blood monitoring. We extracted data on treatment strategies and outcomes for tremors. Articles were primarily screened based on English language publications, abstracts, and studies with n ≥ 5, which included case series, retrospective studies, case-controlled studies, and prospective studies. We found 81 eligible studies comprising 33 cyclosporine, 43 tacrolimus, 6 sirolimus, and 1 everolimus that discussed tremor as an adverse event. In the pooled analysis of studies with n > 100, the incidence of tremor was 17% with cyclosporine, 21.5% with tacrolimus, and 7.8% with sirolimus and everolimus together. Regarding the underlying diagnosis, tremor was more frequently reported in kidney transplant (cyclosporine 28%, tacrolimus 30.1%) and bone marrow transplant (cyclosporine 40%, tacrolimus 41.9%) patients compared with liver transplant (cyclosporine 9%, tacrolimus 11.5%) and nontransplant indications (cyclosporine 21.5%, tacrolimus 11.3%). Most studies did not report whether the risk of tremors correlated with drug concentrations in the blood. The prevalence of tremors when using the twice-daily formulation of tacrolimus was nearly the same as the once-daily formulation (17% vs 18%). Data on individual-level risk factors for tremors were lacking. Except for three studies that found some benefit to maintaining magnesium levels, there were minimal data on treatments and outcomes. A large body of data supports a substantive and wide prevalence of tremor resulting from tacrolimus use followed by cyclosporine, especially in patients receiving a kidney transplant. However, there is little reporting on the patient-related risk factors for tremor, risk relationship with drug concentrations, treatment strategies, and outcomes.