One-month DAPT after biodegradable-polymer everolimus-eluting stent implantation in patients at high-bleeding risk: an individual patient data pooled analysis of the SENIOR and POEM trials.

Aims: Dual antiplatelet therapy (DAPT) can be shortened up to 1 month in high-bleeding risk (HBR) patients receiving a contemporary biodegradable-polymer sirolimus-eluting stent. We aimed to summarize the evidence on a similar DAPT regimen after biodegradable-polymer everolimus-eluting stent (EES) implantation in patients at HBR. Methods and results: We pooled the individual participant data from the available trials evaluating this strategy, namely, the SENIOR and the POEM trials. Inclusion criteria were ≥1 biodegradable-polymer EES implantation and ≤1-month duration of DAPT. The primary endpoint was the 1-year composite of cardiovascular death, myocardial infarction, or stroke. Major bleeding was defined as Bleeding Academic Research Consortium (BARC) type 3-5 bleeding. Landmark analyses were performed at 1 month, the time point for intended DAPT interruption. We included 766 participants (age 77.5 ± 8.2 years, women 31.9%), 323 from the SENIOR and 443 from the POEM trial. The primary endpoint occurred in 45 participants (6.0%; 95% confidence interval [CI], 4.3-7.7%) through 1 year of follow-up, with 21 (2.8%; 95% CI, 1.6-3.9%) events during the first month and 24 (3.4%; 95% CI, 2.0-4.7%) thereafter. The incidences of cardiovascular death, myocardial infarction, and stroke were 2.2% (95% CI, 0.36-2.50%), 3.1% (95% CI, 1.8-4.3%), and 1.2% (95% CI, 0.4-2.0%), respectively. BARC type 3-5 bleeding ocuurred in 1.1% (95% CI, 0.3-1.8%) at 1 month and 2.9% (95% CI, 1.6-4.1%) at 1 year. Conclusion: HBR patients receiving biodegradable-polymer EES had few ischemic and bleeding events when given 1 month of DAPT. One-month DAPT after biodegradable-polymer EES implantation seems safe in patients at HBR.

Methuosis Inducer SGI-1027 Cooperates with Everolimus to Promote Apoptosis and Pyroptosis by Triggering Lysosomal Membrane Permeability in Renal Cancer.

The mTOR inhibitor everolimus has been approved as a sequential or second-line therapy for renal cell carcinoma (RCC). However, the development of drug resistance limits its clinical applications. This study aims to address the challenge of everolimus resistance and provide new insights into the treatment of advanced RCC. Here, the cytotoxicity of the DNA methyltransferase 1 (DNMT1) inhibitor SGI-1027 in inducing cell vacuolation and methuosis is discovered and demonstrated for the first time. Additionally, SGI-1027 exerts synergistic effects with everolimus, as their combination suppresses the growth, migration, and invasion of renal cancer cells. Mechanistically, apoptosis and GSDME-dependent pyroptosis triggered by lysosomal membrane permeability (LMP) are observed. The upregulation of GSDME expression and increased lysosomal activity in renal cancer cells provide a therapeutic window for the combination of these two drugs to treat renal cancer. The combination treatment exhibits effective anti-tumor activity and is well tolerated in a subcutaneous tumor model. Overall, this study validates and reveals the specific cytotoxicity property of SGI-1027 and its potent synergistic effect with everolimus, offering new insights into advanced RCC therapy and everolimus-resistance overcoming.

Ten-year follow-up cohort of the everolimus versus azathioprine multinational prospective study focusing on intravascular ultrasound findings.

BACKGROUND: Long-term clinical outcomes of early intravascular ultrasound (IVUS) findings in a prospective cohort of heart transplantation (HTx) patients have not been evaluated. METHODS: This study included patients from 20 centers across Europe and North and South America among the original cohort of the RAD B253 study. Among these patients, 91 had paired IVUS images at baseline and 1-year post-transplant: everolimus 1.5 mg group (n = 25), everolimus 1.5 mg group (n = 33), and azathioprine 3.0 group (n = 33). The primary outcome was a composite of cardiovascular death, retransplantation, myocardial infarction (MI), coronary revascularization, and cardiac allograft vasculopathy (CAV) within a 10-year follow-up period. The secondary outcome was all-cause death, cardiovascular death, retransplantation, MI, coronary revascularization, and CAV. Donor disease was defined as baseline maximal intimal thickness (MIT) >0.66 mm, and rapid progression was defined as a change in MIT > 0.59 mm at 1 year. RESULTS: Donor disease (46 patients) was associated with a higher incidence of the primary outcome (hazard ratio (HR) 4.444, 95% confidence interval [CI] 1.946-10.146, p < 0.001). Rapid progression (44 patients) was associated with a significantly higher incidence of the primary outcome (HR 2.942, 95% CI 1.383-6.260, p = 0.005). Higher-risk features on IVUS (positive both donor disease and rapid progression) were independently associated with poor clinical outcomes (HR 4.800, 95% CI 1.816-12.684, p = 0.002). CONCLUSIONS: An increase in baseline MIT and a change in first-year MIT in IVUS post HTx was associated with poor outcomes up to 10 years. Early IVUS findings can be considered as surrogate endpoints for evaluating long-term outcomes in HTx clinical trials.

SnoRNA U50A mediates everolimus resistance in breast cancer through mTOR downregulation.

Breast cancer remains the most prevalent cancer in women globally, posing significant challenges in treatment due to the inevitable development of resistance to targeted therapies like everolimus, an mTOR inhibitor. While several mechanisms of resistance have been proposed, the role of snoRNAs in this context remains inadequately explored. Our study unveils a novel connection between snoRNAs and everolimus resistance, focusing on the snoRNA U50A. We discovered that U50A negatively regulates mTOR signaling by transcriptionally downregulating mTOR gene expression, which consequently leads to decreased sensitivity to everolimus treatment. Through RNA sequencing, gene set enrichment analyses, and experimental validations, we established that U50A overexpression in breast cancer cells results in mTOR downregulation and subsequently, everolimus desensitization. Clinical results further supported our findings, showing a higher prevalence of everolimus resistance in tumors with elevated U50A expression. Moreover, our results suggest that U50A's effect on mTOR is mediated through the suppression of the transcription factors c-Myc, with a notable impact on cancer cell viability under everolimus treatment. This study not only highlights the complex role of snoRNAs in cancer drug resistance but also proposes U50A as a potential biomarker for predicting everolimus efficacy in breast cancer treatment.

Efficacy of everolimus plus hormonal treatment after cyclin-dependent kinase inhibitor; real-life experience, A TOG study.

PURPOSE: In advanced breast cancer, endocrine therapy is preferred in the absence of visceral crisis. Cyclin-dependent kinase inhibitors (CDKi) are the gold standards. The selection of subsequent treatments after CDKi treatment is still controversial, and the efficacy of everolimus (EVE) combinations is unknown. In this study, we aimed to investigate the efficacy of EVE after CDKi administration in real-life experiences. METHOD: The study received data from 208 patients from 26 cancer centers. Demographic and histologic features, diagnosis, progression, last visit dates, and toxicities were recorded. This study was a retrospective case series. RESULTS: One hundred and seven patients received palbociclib, while 101 patients received ribociclib as a CDKi. The overall response and disease control rates of EVE combinations were 60% and 88%, respectively. In univariate analysis, the absence of liver metastasis, age > 40 years, better type of response, and immediate treatment after CDKi were related to increased progression-free survival. Liver metastasis and response type were significantly associated with overall survival. In the multivariate analysis, response remained significant in terms of progression-free survival, while response type, liver metastatic disease, and hematologic toxicity were prognostic in terms of overall survival. CONCLUSION: This study provides evidence of the benefits of EVE combinations after CDKi treatment. EVE combinations may be more appropriate for patients with non-liver metastasis, and the first treatment response shows the benefit of treatment. In addition, immediate treatment after CDKi treatment is more beneficial than later lines of treatment.

The role of everolimus in metastatic breast cancer and possibilities of moving forward-a narrative review.

Background and Objective: In hormone-receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer endocrine-based therapies are preferred over chemotherapy. One of the treatment options is the combination of everolimus with exemestane or other endocrine drug in later lines mainly based on progression-free survival (PFS) results of the phase 3 BOLERO-2 trial. Altogether, clinical trials did not prove an overall survival (OS) benefit and considerable side effects hampered its application in the day-by-day practice. In recent years CDK4/6-inhibitors became a first-choice combination partner to the endocrine treatment, everolimus still has a place within the treatment armamentarium. Although everolimus is a targeted drug, there is no accepted predictive biomarker and further patient selection is not possible. However, several directions can be defined how to optimally use everolimus. For update information on everolimus treatment in breast cancer I have performed a literature search. Methods: I used the keywords "breast cancer" and "everolimus" and extended the search in PubMed from 01/01/2014 to 10/02/2023. I considered all phase 3 trials, the phase 1-2 trials with not repetitive information, studies with biomarker results and I also checked review articles to identify potential relevant other clinical trial reports. I also have made a search in clinicaltrials.gov for recently completed and ongoing trials. Key Content and Findings: I summarized the search results in this concise and brief report focusing on main trial results and ongoing research with everolimus. Conclusions: The most promising research directions seem to be further investigations for useable predictive biomarkers, for combinations with other targeted drugs (even in a triple combination) and for the feasibility of pharmacologically guided dosing method.

Peptide Receptor Radionuclide Therapy or Everolimus in Metastatic Neuroendocrine Tumors: The SeqEveRIV Study, a National Study from the French Group of Endocrine Tumors and Endocan-RENATEN Network.

Everolimus and peptide receptor radionuclide therapy (PRRT, 177Lu-DOTATATE) are 2 treatments recommended in guidelines for gastroenteropancreatic metastatic neuroendocrine tumors. However, the best treatment sequence remains unknown. Methods: We designed a retrospective multicenter study that included patients from the national prospective database of the Groupe d'Étude des Tumeurs Endocrines who had been treated using everolimus and PRRT between April 2004 and October 2022. The primary aim was to compare the 2 treatments (everolimus and PRRT) in terms of efficacy and safety, and the secondary aim was to evaluate the sequences (PRRT followed by everolimus or everolimus followed by PRRT) based on overall progression-free survival (PFS) (PFS during first treatment + PFS during second treatment) in patients with metastatic neuroendocrine tumors. Results: Both treatments were used for 84 patients. The objective response rate and median PFS were 5 mo (6.0%) and 16.1 mo (95% CI, 11.5-20.7 mo), respectively, under everolimus and 19 mo (22.6%) and 24.5 mo (95% CI, 17.7-31.3 mo), respectively, for PRRT. The safety profile was also better for PRRT. Median overall PFS was 43.2 mo (95% CI, 33.7-52.7 mo) for the everolimus-PRRT sequence and 30.6 mo (95% CI, 17.8-43.4 mo) for the PRRT-everolimus sequence (hazard ratio, 0.69; 95% CI, 0.39-1.24; P = 0.22). Conclusion: PRRT was more effective and less toxic than everolimus. Overall PFS was similar between the 2 sequences, suggesting case-by-case discussion if the patient is eligible for both treatments, but PRRT should be used first when an objective response is needed or in frail populations.

Early Conversion to Everolimus Within 180 Days of Living Donor Liver Transplantation.

BACKGROUND: Early conversion to Everolimus (EVR) post deceased donor liver transplant has been associated with improved renal function but increased rejection. Early EVR conversion has not been evaluated after living donor liver transplant (LDLT). A retrospective cohort study was conducted to compare the rate of rejection and renal function in patients converted to EVR early post-LDLT to patients on calcineurin inhibitors (CNIs). METHODS: This was a single center retrospective cohort study of adult LDLT recipients between January 2012 and July 2019. Patients converted to EVR within 180 days of transplant were compared to patients on CNIs. The primary endpoint was biopsy proven acute rejection (BPAR) at 24 months posttransplant. Key secondary endpoints included eGFR at 24 months, change in eGFR, adverse events, and all-cause mortality. RESULTS: From a total of 173 patients involved in the study: 58 were included in the EVR group and 115 in the CNI group. Median conversion to EVR was 26 days post-LDLT. At 24 months, there was no difference in BPAR (22.7% EVR vs. 19.1% CNI, p = 0.63). Median eGFR at 24 months posttransplant was not significantly different (68.6 [24.8 to 112.4] mL/min EVR vs. 75.9 [35.6-116.2] mL/min CNI, p = 0.103). Change in eGFR from baseline was worse in the EVR group (-13.0 [-39.9 to 13.9] mL/min EVR vs. -5.0 [-31.2 to 21.2] mL/min CNI, p = 0.047). Median change from conversion to 24 months posttransplant (EVR group only) was -3.43 mL/min/1.73 m2 (-21.0 to 9.6). CONCLUSIONS: Early EVR conversion was not associated with increased risk of rejection among LDLT recipients. Renal function was not impacted. EVR may be considered as an alternative after LDLT in patients intolerant of CNIs.

Proteomic Changes Induced by the Immunosuppressant Everolimus in Human Podocytes.

mTOR inhibitors (mTOR-Is) may induce proteinuria in kidney transplant recipients through podocyte damage. However, the mechanism has only been partially defined. Total cell lysates and supernatants of immortalized human podocytes treated with different doses of everolimus (EVE) (10, 100, 200, and 500 nM) for 24 h were subjected to mass spectrometry-based proteomics. Support vector machine and partial least squares discriminant analysis were used for data analysis. The results were validated in urine samples from 28 kidney transplant recipients receiving EVE as part of their immunosuppressive therapy. We identified more than 7000 differentially expressed proteins involved in several pathways, including kinases, cell cycle regulation, epithelial-mesenchymal transition, and protein synthesis, according to gene ontology. Among these, after statistical analysis, 65 showed an expression level significantly and directly correlated with EVE dosage. Polo-Like Kinase 1 (PLK1) content was increased, whereas osteopontin (SPP1) content was reduced in podocytes and supernatants in a dose-dependent manner and significantly correlated with EVE dose (p < 0.0001, FDR < 5%). Similar results were obtained in the urine of kidney transplant patients. This study analyzed the impact of different doses of mTOR-Is on podocytes, helping to understand not only the biological basis of their therapeutic effects but also the possible mechanisms underlying proteinuria.

Recurrent rejections after liver transplantation for hepatocellular carcinoma with stem cell features in an adult patient.

Patients with hepatoblastoma featuring carcinoma characteristics have better outcomes after liver transplantation, than after chemotherapy and resection. Possibly this should be extrapolated to aggressive subtypes of hepatocellular carcinomas in non-cirrhotic livers, where early liver transplantation might also be indicated. However, the risks associated with liver transplantation and immunosuppressive treatment after liver transplantation are once again demonstrated by this case of a 32-year-old women with a negative personal and familial history of liver diseases. She underwent transplantation (DBD) for a hepatocellular carcinoma with stem cell features (HCC-HS; an aggressive 'hepatoblast subtype' of hepatocellular carcinoma) after chemotherapeutical downstaging techniques failed to sufficiently downstage the tumor. Despite being on conventional immunosuppressive regimens (tacrolimus and mycophenolate mofetil with initial corticosteroids tapered), this patient still developed two severe rejection episodes, one of which necessitated retransplantation (DCD). Both episodes were preceded by alterations in tacrolimus trough levels, either intentionally, when tacrolimus was reduced within a nephroprotective regimen, or unintentionally, when rifampicin, a CYP3A4 inducer, significantly lowered the trough levels. Together, these episodes stress the importance of therapeutic drug monitoring of tacrolimus. Furthermore, the patient experienced an everolimus-linked drug-induced thrombotic microangiopathy, underwent multiple ERCPs for an anastomotic stricture and only one and a half year after the first liver transplantation she already suffers from long-term immunosuppressive-related side effects such as impaired glucose tolerance, hypertension and a potential cardiomyopathy. At present, she is still alive and experienced no recurrence of her primary tumor. Her case underscores the significant challenges in post-liver transplantation care.

A case of repeated stent fracture.

Stent fracture is one of the complications of drug-eluting stent implantation. An 84-year-old man underwent coronary angiography for unstable angina. He had diffuse severe stenosis and calcified plaque in the left anterior descending artery and underwent percutaneous coronary intervention (PCI) in the left anterior descending artery for severe stenosis with chest pain. Thereafter, two subsequent stent fractures occurred, so the patient underwent another PCI to cover them. However, a stent fracture was found again one year later. The patient was asymptomatic and PCI was avoided due to the risk of further stent fracture. When a stent fracture occurs, it is important to provide appropriate treatment according to the anatomical findings of the vessel, symptoms and the presence of ischemia.

Long-term follow-up of the randomized, prospective Scandinavian heart transplant everolimus de novo study with early calcineurin inhibitors avoidance (SCHEDULE) trial.

BACKGROUND: Early substitution of calcineurin inhibitor (CNI) with mammalian target of rapamycin inhibitors has been shown to improve kidney function and reduce intimal hyperplasia in heart transplant (HTx) recipients but data on long-term outcome of such a regime are still sparse. METHODS: In the SCHEDULE trial, 115 de novo HTx recipients were randomized to (1) everolimus with reduced exposure of CNI followed by CNI withdrawal at week 7-11 post-transplant or (2) standard-exposure with CNI. Both groups received mycophenolate mofetil and corticosteroids. Herein we report on the 10-12-year long-term follow-up of the study. RESULTS: A total of 78 patients attended the follow-up visit at a median time of 11 years post-transplant. In the everolimus intention to treat (ITT) group 87.5% (35/40 patients) still received everolimus and in the CNI ITT group 86.8% (33/38) still received CNI. Estimated glomerular filtration rate (eGFR) (least square mean (95% CI)) at the 10-12 years visit was 82.7 (74.2-91.1) ml/min/1.73 m2 and 61.0 (52.3-69.7) ml/min/1.73 m2 in the everolimus and CNI group, respectively (p < 0.001). Graft function measured by ejection fraction, ECG, NT-proBNP and drug safety were comparable between groups. During the study period there was a total of 28 deaths, but there was no difference in survival between the everolimus and the CNI group (aHR 0.61 (95% CI 0.29-1.30) p = 0.20). For the composite endpoint of death, re-transplantation, myocardial infarction, PCI, dialysis, kidney transplantation or cancer no between group differences were found (aHR 1.0 (95% CI 0.57-1.77) p = 0.99). CONCLUSIONS: De novo HTx patients randomized to everolimus and low dose CNI followed by CNI free therapy sustained significantly better long-term kidney function than patients randomized to standard therapy. The graft function at 10-12 years was similar in both groups and there was no difference in survival.

Unconventional mechanism of action and resistance to rapalogs in renal cancer.

mTORC1 is aberrantly activated in renal cell carcinoma (RCC) and is targeted by rapalogs. As for other targeted therapies, rapalogs clinical utility is limited by the development of resistance. Resistance often results from target mutation, but mTOR mutations are rarely found in RCC. As in humans, prolonged rapalog treatment of RCC tumorgrafts (TGs) led to resistance. Unexpectedly, explants from resistant tumors became sensitive both in culture and in subsequent transplants in mice. Notably, resistance developed despite persistent mTORC1 inhibition in tumor cells. In contrast, mTORC1 became reactivated in the tumor microenvironment (TME). To test the role of the TME, we engineered immunocompromised recipient mice with a resistance mTOR mutation (S2035T). Interestingly, TGs became resistant to rapalogs in mTORS2035T mice. Resistance occurred despite mTORC1 inhibition in tumor cells and could be induced by coculturing tumor cells with mutant fibroblasts. Thus, enforced mTORC1 activation in the TME is sufficient to confer resistance to rapalogs. These studies highlight the importance of mTORC1 inhibition in nontumor cells for rapalog antitumor activity and provide an explanation for the lack of mTOR resistance mutations in RCC patients.

Drug to genome to drug: a computational large-scale chemogenomics screening for novel drug candidates against sporotrichosis.

Sporotrichosis is recognized as the predominant subcutaneous mycosis in South America, attributed to pathogenic species within the Sporothrix genus. Notably, in Brazil, Sporothrix brasiliensis emerges as the principal species, exhibiting significant sapronotic, zoonotic and enzootic epidemic potential. Consequently, the discovery of novel therapeutic agents for the treatment of sporotrichosis is imperative. The present study is dedicated to the repositioning of pharmaceuticals for sporotrichosis therapy. To achieve this goal, we designed a pipeline with the following steps: (a) compilation and preparation of Sporothrix genome data; (b) identification of orthologous proteins among the species; (c) identification of homologous proteins in publicly available drug-target databases; (d) selection of Sporothrix essential targets using validated genes from Saccharomyces cerevisiae; (e) molecular modeling studies; and (f) experimental validation of selected candidates. Based on this approach, we were able to prioritize eight drugs for in vitro experimental validation. Among the evaluated compounds, everolimus and bifonazole demonstrated minimum inhibitory concentration (MIC) values of 0.5 µg/mL and 4.0 µg/mL, respectively. Subsequently, molecular docking studies suggest that bifonazole and everolimus may target specific proteins within S. brasiliensis- namely, sterol 14-α-demethylase and serine/threonine-protein kinase TOR, respectively. These findings shed light on the potential binding affinities and binding modes of bifonazole and everolimus with their probable targets, providing a preliminary understanding of the antifungal mechanism of action of these compounds. In conclusion, our research advances the understanding of the therapeutic potential of bifonazole and everolimus, supporting their further investigation as antifungal agents for sporotrichosis in prospective hit-to-lead and preclinical investigations.

Down-regulation of ABCB1 in Everolimus-resistant Renal Cell Carcinoma Cells.

BACKGROUND/AIM: Everolimus-resistant Caki/EV and 786/EV cells have been established from human derived renal cell carcinoma cells, Caki-2 and 786-O, respectively. These cells exhibit resistance to everolimus and to other mTOR inhibitors and erlotinib. However, the sensitivity of these resistant cells to classical and cytotoxic anticancer drugs remain unclear. The aim of the study was to examine sensitivity of Caki/EV and 786/EV cells to classical and cytotoxic anticancer drugs. MATERIALS AND METHODS: Sensitivity to classical and cytotoxic anticancer drugs in Caki/EV and 786/EV cells was evaluated using the WST-1 (tetrazolium salts) colorimetric assay and was compared to those of the corresponding parental cells. The mRNA expression levels were measured using SYBR® green based quantitative reverse transcription-polymerase chain reaction. RESULTS: Sensitivity to vinblastine, vincristine, paclitaxel, doxorubicin, etoposide, SN-38 (active metabolite of irinotecan), 5-fluorouracil, cisplatin, and carboplatin varied in the resistant cells. Sensitivity to carboplatin and SN-38 was comparable between resistant cells and their parental cells, whereas sensitivity to vinca alkaloids, etoposide, 5-fluorouracil, and cisplatin decreased in the resistant cells. However, sensitivity to paclitaxel and doxorubicin was remarkably enhanced in both resistant cells compared to that of parental cells, this could be partially explained by down-regulation of ABCB1 mRNA expression. CONCLUSION: The everolimus-resistant Caki/EV and 786/EV cells showed cross-resistance to classical and cytotoxic anticancer drugs. However, Caki/EV and 786/EV cells exhibited a remarkable increase in sensitivity to paclitaxel and doxorubicin, and ABCB1 mRNA was down-regulated in response to long-term exposure to everolimus.

Quantitative SSTR-PET/CT: a potential tool for predicting everolimus response in neuroendoctine tumour patients.

BACKGROUND: This study aimed to assess 68Ga-DOTA-TATE (-TOC) PET/CT quantitative parameters in monitoring and predicting everolimus response in neuroendocrine tumor (NET) patients with hepatic metastases (NELM). PATIENTS AND METHODS: This retrospective analysis included 29 patients with 62 target lesions undergoing everolimus treatment and pre-therapy, and follow-up 68Ga-DOTA-TATE (-TOC) PET/CT scans. Response evaluation utilized progression-free survival (PFS) categorized as responders (R; PFS > 6 months) and non-responders (NR; PFS ≤ 6 months). Lesion size and density, along with maximum and median standardize uptake value (SUV) in target lesions, liver, and spleen were assessed. Tumor-to-spleen (T/S) and tumor-to-liver (T/L) ratios were calculated, including the tumor-to-spleen (T/S) ratio and tumor-to-liver (T/L) ratio (using SUVmax/SUVmax, SUVmax/SUVmean, and SUVmean/SUVmean). RESULTS: PET/CT scans were acquired 19 days (interquartile range [IQR] 69 days) pre-treatment and 127 days (IQR 74 days) post-starting everolimus. The overall median PFS was 264 days (95% CI: 134-394 days). R exhibited significant decreases in Tmax/Lmax and Tmean/Lmax ratios compared to NR (p = 0.01). In univariate Cox regression, Tmean/Lmax ratio was the sole prognostic parameter associated with PFS (HR 0.5, 95% CI 0.28-0.92, p = 0.03). Percentage changes in T/L and T/S ratios were significant predictors of PFS, with the highest area under curve (AUC) for the percentage change of Tmean/Lmax (AUC = 0.73). An optimal threshold of < 2.5% identified patients with longer PFS (p = 0.003). No other imaging or clinical parameters were predictive of PFS. CONCLUSIONS: This study highlights the potential of quantitative SSTR-PET/CT in predicting and monitoring everolimus response in NET patients. Liver metastasis-to-liver parenchyma ratios outperformed size-based criteria, and Tmean/Lmax ratio may serve as a prognostic marker for PFS, warranting larger cohort investigation.

mTOR inhibitors after lung transplantation: a real-life experience.

Background: The mammalian target of rapamycin (mTOR) inhibitors in combination with calcineurin inhibitors (CNIs), antimetabolites and corticosteroids for immunosuppression after lung transplantation (TPL) have gained importance in patients with chronic kidney disease (CKD). The goal of this study was to characterize lung transplant recipients (LTR) treated with mTOR inhibitors, with a special focus on kidney function. Methods: LTR transplanted at the University Hospital Zurich between December 1992 and April 2022 were analyzed. Demographics, estimated glomerular filtration rate (eGFR) before and after mTOR initiation, TPL circumstances, immunosuppressive regimens, and allograft function were recorded. We used linear regression to calculate the Mitch curves and a linear mixed-effects model to compare the eGFR. Results: Of all LTR, 70/593 (12%) received mTOR inhibitors. Intolerance or adverse events of antimetabolites were the most common indications for mTOR inhibitor introduction. Discontinuation in 34/70 (49%) was often related to planned or urgent surgery to prevent impaired wound healing. The majority of patients had a preserved baseline eGFR at mTOR inhibitor introduction with CKD Kidney Disease Improving Global Outcomes (KDIGO) stage G1 or 2. The mean annual eGFR decline changed significantly from -16.19 mL/min/1.73 m2/year [95% confidence interval (CI): -22.27 to -10.11] 12 months before to -6.16 mL/min/1.73 m2/year (95% CI: -13.37 to 1.05) 12 months after mTOR initiation (P=0.009) showing better outcomes with earlier mTOR inhibitor initiation after lung TPL. Conclusions: This retrospective study suggests stabilization of kidney function after mTOR inhibitor initiation in LTR documented by a slower eGFR decline after mTOR inhibitor introduction with better outcomes early after lung TPL. Intolerance or adverse events of antimetabolites are important indications for the introduction of mTOR inhibitors. A relatively high discontinuation rate (49%) can be explained by planned discontinuation of mTOR inhibitors prior to surgery to avoid impaired wound healing.

The Cytoprotective and Cytotoxic Functions of Autophagy in Response to mTOR Inhibitors.

The inhibitors of mammalian target of rapapmycin (mTOR), everolimus, temsirolimus and rapamycin, have a wide range of clinical utility; however, as is inevitably the case with other chemotherapeutic agents, resistance development constrains their effectiveness. One putative mechanism of resistance is the promotion of autophagy, which is a direct consequence of the inhibition of the mTOR signaling pathway. Autophagy is primarily considered to be a cytoprotective survival mechanism, whereby cytoplasmic components are recycled to generate energy and metabolic intermediates. The autophagy induced by everolimus and temsirolimus appears to play a largely protective function, whereas a cytotoxic function appears to predominate in the case of rapamycin. In this review we provide an overview of the autophagy induced in response to mTOR inhibitors in different tumor models in an effort to determine whether autophagy targeting could be of clinical utility as adjuvant therapy in association with mTOR inhibition.

Temporal Trends in the Outcomes of Percutaneous Coronary Intervention With Zotarolimus Eluting Stents Versus Everolimus Eluting Stents: A Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Long-term follow-up results of various trials comparing Zotarolimus eluting stents (ZES) with Everolimus eluting stents (EES) have been published recently. Additionally, over the last decade, there have been new trials comparing the ZES with various commercially available EES. We aim to conduct an updated meta-analysis in light of new evidence from randomized controlled trials (RCTs) to provide comprehensive evidence regarding the temporal trends in the clinical outcomes. METHODS: A comprehensive literature search was conducted across PubMed, Cochrane, and Embase. RCTs comparing ZES with EES for short (<2 years), intermediate (2-3 years), and long-term follow-ups (3-5 years) were included. Relative risk was used to pool the dichotomous outcomes using the random effects model employing the inverse variance method. All statistical analysis was conducted using Revman 5.4. RESULTS: A total of 18 studies reporting data at different follow-ups for nine trials (n = 14319) were included. At short-term follow-up (<2 years), there were no significant differences between the two types of stents (all-cause death, cardiac death, Major adverse cardiovascular events (MACE), target vessel myocardial infarction, definite or probable stent thrombosis or safety outcomes (target vessel revascularization, target lesion revascularization, target vessel failure, target lesion failure). At intermediate follow-up (2-3 years), EES was superior to ZES for reducing target lesion revascularization (RR = 1.28, 95% CI = 1.05-1.58, p < 0.05). At long-term follow-up (3-5 years), there were no significant differences between the two groups for any of the pooled outcomes (p > 0.05). CONCLUSION: ZES and EES have similar safety and efficacy at short, intermediate, and long-term follow-ups.