Perioperative Management of Pheochromocytomas and Sympathetic Paragangliomas

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors arising from chromaffin cells of the adrenal medulla or extra-adrenal paraganglia, respectively. PPGLs have the highest degree of heritability among endocrine tumors. Currently, ~40% of PPGL individuals have a genetic germline and there exist at least 12 different genetic syndromes related to these tumors. Metastatic PPGLs are defined by the presence of distant metastases at sites where chromaffin cells are physiologically absent. Approximately 10% of pheochromocytomas and ~40% of sympathetic paragangliomas are linked to metastases explaining why complete surgical resection is the first-choice treatment for all PPGL patients. The surgical approach is a high-risk procedure requiring perioperative management by a specialized multidisciplinary team in centers with broad expertise. In this review, we summarize and discuss the most relevant aspects of perioperative management in patients with pheochromocytomas and sympathetic paragangliomas.

Targeting Aggressive Pituitary Adenomas at the Molecular Level—A Review

Pituitary adenomas (PAs) are mostly benign endocrine tumors that can be treated by resection or medication. However, up to 10% of PAs show an aggressive behavior with invasion of adjacent tissue, rapid proliferation, or recurrence. Here, we provide an overview of target structures in aggressive PAs and summarize current clinical trials including, but not limited to, PAs. Mainly, drug targets in PAs are based on general features of tumor cells such as immune checkpoints, so that programmed cell death 1 (ligand 1) (PD-1/PD-L1) targeting may bear potential to cure aggressive PAs. In addition, epidermal growth factor receptor (EGFR), mammalian target of rapamycin (mTOR), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and their downstream pathways are triggered in PAs, thereby modulating tumor cell proliferation, migration and/or tumor angiogenesis. Temozolomide (TMZ) can be an effective treatment of aggressive PAs. Combination of TMZ with 5-Fluorouracil (5-FU) or with radiotherapy could strengthen the therapeutic effects as compared to TMZ alone. Dopamine agonists (DAs) are the first line treatment for prolactinomas. Dopamine receptors are also expressed in other subtypes of PAs which renders Das potentially suitable to treat other subtypes of PAs. Furthermore, targeting the invasive behavior of PAs could improve therapy. In this regard, human matrix metalloproteinase (MMP) family members and estrogens receptors (ERs) are highly expressed in aggressive PAs, and numerous studies demonstrated the role of these proteins to modulate invasiveness of PAs. This leaves a number of treatment options for aggressive PAs as reviewed here.

An Overview of Pancreatic Neuroendocrine Tumors

Pancreatic neuroendocrine tumors are a group of endocrine tumors that constitute 7% of all pancreatic neoplasms. They can be benign or malignant. Their presentation can vary from slow growing, non infiltrative, indolent masses to rapidly progressing, highly aggressive, metastasizing tumors. In the past, there was paucity of scientific data available about the diagnosis and treatment strategy of these neoplasms but in recent years, ongoing research has inferred much data regarding classification, prognostic stratification and therapy of pancreatic neuroendocrine tumors. In this chapter we will discuss epidemiology, clinical presentation and classification, diagnosis and management of these tumors. We will also deliberate about the latest developments in treatment of pancreatic neuroendocrine tumors with focus on recent studies done on this topic.

An Update on Silent Corticotroph Adenomas: Diagnosis, Mechanisms, Clinical Features, and Management

With the introduction of 2017 World Health Organization (WHO) classification of endocrine tumors, T-PIT can serve as a complementary tool for identification of silent corticotroph adenomas (SCAs) in some cases if the tumor is not classifiable by pituitary hormone expression in pathological tissue samples. An increase of the proportion of SCAs among the non-functioning pituitary adenomas (NFPAs) has been witnessed under the new rule with the detection of T-PIT-positive ACTH-negative SCAs. Studies of molecular mechanisms related to SCA pathogenesis will provide new directions for the diagnosis and management of SCAs. A precise pathological diagnosis can help clinicians better identify SCAs. Understanding clinical features in the context of the pathophysiology of SCAs is critical for optimal management. It could provide information on appropriate follow-up time and aid in early recognition and treatment of potentially aggressive forms. Management approaches include surgical, radiation, and/or medical therapies.

Integrated or Independent Actions of Metformin in Target Tissues Underlying Its Current Use and New Possible Applications in the Endocrine and Metabolic Disorder Area

Metformin is considered the first-choice drug for type 2 diabetes treatment. Actually, pleiotropic effects of metformin have been recognized, and there is evidence that this drug may have a favorable impact on health beyond its glucose-lowering activity. In summary, despite its long history, metformin is still an attractive research opportunity in the field of endocrine and metabolic diseases, age-related diseases, and cancer. To this end, its mode of action in distinct cell types is still in dispute. The aim of this work was to review the current knowledge and recent findings on the molecular mechanisms underlying the pharmacological effects of metformin in the field of metabolic and endocrine pathologies, including some endocrine tumors. Metformin is believed to act through multiple pathways that can be interconnected or work independently. Moreover, metformin effects on target tissues may be either direct or indirect, which means secondary to the actions on other tissues and consequent alterations at systemic level. Finally, as to the direct actions of metformin at cellular level, the intracellular milieu cooperates to cause differential responses to the drug between distinct cell types, despite the primary molecular targets may be the same within cells. Cellular bioenergetics can be regarded as the primary target of metformin action. Metformin can perturb the cytosolic and mitochondrial NAD/NADH ratio and the ATP/AMP ratio within cells, thus affecting enzymatic activities and metabolic and signaling pathways which depend on redox- and energy balance. In this context, the possible link between pyruvate metabolism and metformin actions is extensively discussed.

Phosphate Metabolism and Pathophysiology in Parathyroid Disorders and Endocrine Tumors

The advent of new insights into phosphate metabolism must urge the endocrinologist to rethink the pathophysiology of widespread disorders, such as primary hyperparathyroidism, and also of rarer endocrine metabolic bone diseases, such as hypoparathyroidism and tumor-induced hypophosphatemia. These rare diseases of mineral metabolism have been and will be a precious source of new information about phosphate and other minerals in the coming years. The parathyroid glands, the kidneys, and the intestine are the main organs affecting phosphate levels in the blood and urine. Parathyroid disorders, renal tubule defects, or phosphatonin-producing tumors might be unveiled from alterations of such a simple and inexpensive mineral as serum phosphate. This review will present all these disorders from a ‘phosphate perspective’.