mTOR Inhibitor Use Is Associated With a Favorable Outcome of COVID-19 in Patients of Kidney Transplant: Results of a Retrospective Study.

Introduction: In solid organ transplant recipients, COVID-19 is associated with a poor prognosis because of immunosuppression. Some studies suggest a potential therapeutic role of mammalian Target of Rapamycin (mTOR) inhibitors in SARS-CoV-2 infection. This study aimed to assess the impact of mTOR employment on the evolution and outcome of SARS-CoV-2 infection in solid organ transplant recipients. Methods: We enrolled kidney transplant patients attending the Azienda Ospedaliera Universitaria Federico II in Naples and followed up on these patients from March 2020 to June 2021. We evaluated the risk of acquiring the SARS-CoV-2 infection, the clinical presentation of the disease, and its outcome together with the type of immunosuppressive therapy. Finally, we assessed the impact of mTOR inhibitors on relevant clinical metrics of SARS-CoV-2 infection. Results: We enrolled 371 patients, of whom 56 (15.1%) contracted SARS-CoV-2 infection during the period of the study. There were no differences observed among the different immunosuppressive therapies concerning the risk of acquiring SARS-CoV-2 infection. In contrast, the type of immunosuppressive therapy had a significant impact on the outcome of the disease. In detail, patients who received mTOR inhibitors, as part of their immunosuppressive therapy, compared to other regimens had a lower chance of developing a moderate or severe form of the disease (OR = 0.8, 95, CI: (0.21-0.92), P = 0.041). Conclusion: In kidney transplant patients, the use of mTOR inhibitors as part of an immunosuppressive regimen is associated with a better prognosis in the case of COVID-19.

GH deficiency in cancer survivors in the transition age: diagnosis and therapy.

BACKGROUND: Survival rates among childhood cancer survivors (CCSs) have significantly risen in the last 40 years due to substantial improvements in treatment protocols. However, this improvement has brought with it serious late effects that frequently involve the endocrine system. Of the endocrine disorders, GH deficiency (GHD) is the most common among CCSs as a consequence of a history of cancers, surgery, and/or radiotherapy involving the hypothalamo-pituitary region. METHODS: A comprehensive search of English language articles regardless of age was conducted in the MEDLINE database between December 2018 and October 2019. We selected all studies on GH therapy in CCSs during the transition age regarding the most challenging topics: when to retest; which diagnostic tests and cut-offs to use; when to start GH replacement therapy (GHRT); what GH dose to use; safety; quality of life, compliance and adherence to GHRT; interactions between GH and other hormonal replacement treatments. RESULTS: In the present review, we provide an overview of the current clinical management of challenges in GHD in cancer survivors in the transition age. CONCLUSIONS: Endocrine dysfunction among CCSs has a high prevalence in the transition age and increase with time. Many endocrine disorders, including GHD, are often not diagnosed or under-diagnosed, probably due to the lack of specialized centers for the long-term follow-up. Therefore, it is crucial that transition specialized clinics should be increased in terms of number and specific skills in order to manage endocrine disorders in adolescence, a delicate and complex period of life. A multidisciplinary approach, also including psychological counseling, is essential in the follow-up and management of these patients in order to minimize their disabilities and maximize their quality of life.

The role of mTOR pathway as target for treatment in adrenocortical cancer.

Adrenocortical carcinomas (ACCs) are rare tumors with scant treatment options for which new treatments are required. The mTOR pathway mediates the intracellular signals of several growth factors, including the insulin-like growth factors (IGFs), and therefore represents a potential attractive pathway for the treatment of several malignancies including ACCs. Several mTOR inhibitors, including sirolimus, temsirolimus and everolimus, have been clinically developed. This review summarizes the results of the studies evaluating the expression of the mTOR pathway components in ACCs, the effects of the mTOR inhibitors alone or in combination with other drugs in preclinical models of ACCs and the early experience with the use of these compounds in the clinical setting. The mTOR pathway seems a potential target for treatment of patients with ACC, but further investigation is still required to define the potential role of mTOR inhibitors alone or in combination with other drugs in the treatment of ACC patients.

Vitamin D reverts resistance to the mTOR inhibitor everolimus in hepatocellular carcinoma through the activation of a miR-375/oncogenes circuit.

Primary or acquired resistant mechanisms prevent the employment of individualized therapy with target drugs like the mTOR inhibitor everolimus (EVE) in hepatocellular carcinoma (HCC). The current study evaluated the effect of 1,25(OH)2Vitamin D (VitD) treatment on EVE sensitivity in established models of HCC cell lines resistant to everolimus (EveR). DNA content and colony formation assays, which measure the proliferative index, revealed that VitD pre-treatment re-sensitizes EveR cells to EVE treatment. The evaluation of epithelial and mesenchymal markers by western blot and immunofluorescence showed that VitD restored an epithelial phenotype in EveR cells, in which prolonged EVE treatment induced transition to mesenchymal phenotype. Moreover, VitD treatment prompted hepatic miRNAs regulation, evaluated by liver miRNA finder qPCR array. In particular, miR-375 expression was up-regulated by VitD in EveR cells, in which miR-375 was down-regulated compared to parental cells, with consequent inhibition of oncogenes involved in drug resistance and epithelial-mesenchymal transition (EMT) such as MTDH, YAP-1 and c-MYC. In conclusion, the results of the current study demonstrated that VitD can re-sensitize HCC cells resistant to EVE treatment triggering miR-375 up-regulation and consequently down-regulating several oncogenes responsible of EMT and drug resistance.