The Role of Activation of PI3K/AKT/mTOR and RAF/MEK/ERK Pathways in Aggressive Pituitary Adenomas-New Potential Therapeutic Approach-A Systematic Review.

Pituitary tumors (PT) are mostly benign, although occasionally they demonstrate aggressive behavior, invasion of surrounding tissues, rapid growth, resistance to conventional treatments, and multiple recurrences. The pathogenesis of PT is still not fully understood, and the factors responsible for its invasiveness, aggressiveness, and potential for metastasis are unknown. RAF/MEK/ERK and mTOR signaling are significant pathways in the regulation of cell growth, proliferation, and survival, its importance in tumorigenesis has been highlighted. The aim of our review is to determine the role of the activation of PI3K/AKT/mTOR and RAF/MEK/ERK pathways in the pathogenesis of pituitary tumors. Additionally, we evaluate their potential in a new therapeutic approach to provide alternative therapies and improved outcomes for patients with aggressive pituitary tumors that do not respond to standard treatment. We perform a systematic literature search using the PubMed, Embase, and Scopus databases (search date was 2012-2023). Out of the 529 screened studies, 13 met the inclusion criteria, 7 related to the PI3K/AKT/mTOR pathway, and 7 to the RAF/MEK/ERK pathway (one study was used in both analyses). Understanding the specific factors involved in PT tumorigenesis provides opportunities for targeted therapies. We also review the possible new targeted therapies and the use of mTOR inhibitors and TKI in PT management. Although the RAF/MEK/ERK and PI3K/AKT/mTOR pathways play a pivotal role in the complex signaling network along with many interactions, further research is urgently needed to clarify the exact functions and the underlying mechanisms of these signaling pathways in the pathogenesis of pituitary adenomas and their role in its invasiveness and aggressive clinical outcome.

Clinical Implications of mTOR Expression in Papillary Thyroid Cancer-A Systematic Review.

Papillary thyroid cancer (PTC) comprises approximately 80% of all thyroid malignancies. Although several etiological factors, such as age, gender, and irradiation, are already known to be involved in the development of PTC, the genetics of cancerogenesis remain undetermined. The mTOR pathway regulates several cellular processes that are critical for tumorigenesis. Activated mTOR is involved in the development and progression of PTC. Therefore, we performed a systematic review of papers studying the expression of the mTOR gene and protein and its relationship with PTC risk and clinical outcome. A systematic literature search was performed using PubMed, Embase, and Scopus databases (the search date was 2012-2022). Studies investigating the expression of mTOR in the peripheral blood or tissue of patients with PTC were deemed eligible for inclusion. Seven of the 286 screened studies met the inclusion criteria for mTOR gene expression and four for mTOR protein expression. We also analyzed the data on mTOR protein expression in PTC. We analyzed the association of mTOR expression with papillary thyroid cancer clinicopathological features, such as the TNM stage, BRAF V600E mutation, sex distribution, lymph node and distant metastases, and survival prognosis. Understanding specific factors involved in PTC tumorigenesis provides opportunities for targeted therapies. We also reviewed the possible new targeted therapies and the use of mTOR inhibitors in PTC. This topic requires further research with novel techniques to translate the achieved results to clinical application.

Serum Visfatin/NAMPT as a Potential Risk Predictor for Malignancy of Adrenal Tumors.

Adrenocortical carcinomas (ACC) are rare endocrine malignancies, often with a poor prognosis. Visfatin/NAMPT regulates a variety of signaling pathway components, and its overexpression has been found in carcinogenesis. Our study aimed to assess the clinical usefulness of visfatin/NAMPT serum level in discriminating between ACC and benign adrenocortical tumors. Twenty-two patients with ACC and twenty-six patients with benign adrenocortical tumors were recruited. Fasting blood samples were collected from each patient, and visfatin serum levels were measured with the ELISA Kit. Clinical stage, tumor size, Ki67 proliferation index, hormonal secretion pattern, and follow-up were determined in ACC patients. Patients with ACC had significantly higher visfatin serum concentrations (7.81 ± 2.25 vs. 6.08 ± 1.32 ng/mL, p-value = 0.003). The most advanced clinical stage with metastases was associated with significantly elevated visfatin levels (p-value = 0.022). Based on ROC analysis, visfatin serum concentrations higher than 8.05 ng/mL could discriminate ACC with a sensitivity of 50.0% and specificity of 92.3%. Univariate Cox regression indicated that tumor size was significantly related to shorter survival, and the visfatin level was borderline significant in all patients (HR = 1.013, p-value = 0.002, HR = 1.321, p-value = 0.058). In the Kaplan-Meier method, patients with visfatin serum concentrations higher than 6.3 ng/mL presented significantly lower survival probability (p-value = 0.006). Serum visfatin/NAMPT could be a potential risk predictor for the malignancy of adrenal tumors. However, further studies are needed on this subject.

Is eNAMPT/visfatin a potential serum marker of papillary thyroid cancer?

Purpose: The role of nicotinamide phosphoribosyltransferase (NAMPT)/visfatin in a more aggressive course of many malignancies has been proven. Previous studies have noticed the importance of visfatin in thyroid neoplastic tissue, but the diagnostic and prognostic value of its serum concentration has not been investigated so far. Our study aimed to consider whether extracellular NAMPT (eNAMPT) could be a potential serum marker in recurrent papillary thyroid cancer (PTC). Methods: It was a prospective observational study with consecutive enrolment. We recruited 100 patients with PTC after thyroidectomy with postoperative 131I ablation and 100 healthy controls. Also, 50 randomly selected patients underwent laboratory assessment (including eNAMPT serum concentration by ELISA Assay Kit, TSH, free thyroid hormones, TSH-stimulated thyroglobulin Tg, antibodies - TgAbs, TPOAb) and body composition analysis twice: at admission and 6 months after being on suppressive levothyroxine doses. TSH-stimulated Tg of 1 ng/ml was defined as the cutoff value for predicting disease status as complete remission (n = 55) and recurrent or persistent structural disease (n = 45). Results: The visfatin serum concentrations in patients diagnosed with PTC and in healthy subjects were not statistically significantly different (p = 0.9425). The eNAMPT levels were also similar in disease-free patients and the ones with tumour relapse. Besides, ROC curve analysis did not detect eNAMPT as a biomarker of PTC. Conclusion: We have not found visfatin as a potential serum marker of papillary thyroid cancer. Also, eNAMPT has no prognostic value in assessing the risk of disease recurrence or metastasis in PTC management.