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Simple Summary: Metformin is one of the most widely used drugs in the world, since its first use in the second part of the 1950s in France (Aron, 1957) and in the United Kingdom (Rona, 1958), and is on the World Health Organization's List of Essential Medicines. Traditionally, metformin is used in diabetes mellitus, mainly in overweight and obese subjects, but also in other conditions of impaired glucose metabolism, such as insulin resistance. In recent years, in vitro and in vivo data on this molecule as an antiproliferative modulator have suggested a series of clinical trials in several tumors that—at the moment—have not confirmed the expected positive results. The aim of this paper is to offer a double vision of this molecule, with a very light side about the metabolic aspects and a darker side concerning its antineoplastic activity, focusing on molecular and subcellular pathways involved in both fields and discussing the contrast between preliminary cellular data and real clinical outcomes in different neoplasms. The ancient Roman god Ianus was a mysterious divinity with two opposite faces, one looking at the past and the other looking to the future. Likewise, metformin is an "old" drug, with one side looking at the metabolic role and the other looking at the anti-proliferative mechanism; therefore, it represents a typical and ideal bridge between diabetes and cancer. Metformin (1,1-dimethylbiguanidine hydrochloride) is a drug that has long been in use for the treatment of type 2 diabetes mellitus, but recently evidence is growing about its potential use in other metabolic conditions and in proliferative-associated diseases. The aim of this paper is to retrace, from a historical perspective, the knowledge of this molecule, shedding light on the subcellular mechanisms of action involved in metabolism as well as cellular and tissue growth. The intra-tumoral pharmacodynamic effects of metformin and its possible role in the management of different neoplasms are evaluated and debated. The etymology of the name Ianus is probably from the Latin term ianua, which means door. How many new doors will this old drug be able to open? [ABSTRACT FROM AUTHOR]

The recent depiction of dopamine receptors (DRs) in tumors that cause Cushing’s syndrome (CS) has renewed the debate about the dopamine control on pituitary-adrenal axis, and opened interesting new perspectives for medical treatment of CS. The new insights arise from the recent accurate characterization of DR subtypes expression within tumors causing CS, the discovery of new mechanisms, such as the dimerization between DRs and other G-protein coupled receptors (CPCRs), including somatostatin receptors (SSTRs), and the recent availability of new agents targeting these receptor subtypes. Corticotropic adenomas express DR subtype 2 (D2R), together with different SSTR subtypes (ssts), in particular sst5. In vitro, activation of D2R inhibits ACTH release in the majority of cultures of corticotropic cells, whereas, in vivo, dopaminergic agents display an inhibitory effect on cortisol levels in a subset of patients with CS. In animal models the receptor profile can be deeply modulated in specific environmental conditions, that may resemble the different clinical phases of CS. The new insights about DRs and receptor-targeting drugs may offer different approaches for medical treatment of CS: combination therapies with different types of compounds, treatment with novel molecules (hybrid compounds) with a wider spectrum of activity, or even pretreatment manipulation of receptor profile. Finally, recent studies showed that D2R is also significantly expressed in ectopic ACTH-secreting tumors and in both normal and tumoral adrenal tissues. Dopamine-agonists may decrease cortisol levels in a number of these patients, strengthening the current (re)emerging interest in DRs as possible targets for medical treatment of CS. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Hormones and neuropeptides may influence the activities of lymphoid organs and cells via endocrine and local autocrine/paracrine pathways. A paradigm of the interactions between the neuroendocrine and immune system is sophisticatedly represented in the thymus. Indeed, receptors for these molecules are heterogeneously expressed in all subsets of thymic cells, and the communications are tuned by feedback circuitries. Herein, we focus on somatostatin (SS), a ubiquitous peptide that regulates several physiological cell processes and acts via five specific receptor (SSR) subtypes (sst1–5). Neuronal and accessory cells, so-called neuroendocrine cells, and immune cells, heterogeneously express SSRs. The functional characterization of SSRs in vivo by nuclear medicine techniques opened a complex scenario on the significance of SS/SSR pathway in immune system and related diseases. Several studies have established that SSR scintigraphy may benefit patients with chronic inflammatory and granulomatous diseases, as well as lymphoproliferative diseases. The results are sufficiently promising to warrant larger studies aimed at defining the exact role of these techniques. The development of SS analogs with antisecretory and antiproliferative effects has radically changed the management of neuroendocrine tumors. Moreover, very important recent findings, emerging from in vitro studies on SSR physiology in immune cells, will certainly expand the potential applications of SS analogs for in vivo diagnostic and therapeutic options. Indeed, the anti-inflammatory and analgesic effects of these drugs remain incompletely understood, but may prove useful in a number of autoimmune diseases. Because SS expression is absent in different immune tissues where SSRs are present, the existence of another ligand was hypothesized. In fact, it has been recently demonstrated that human lymphoid tissues and immune cells may express cortistatin (CST). CST is known to bind SSRs and shares many pharmacological and functional properties with SS. However, CST has also properties distinct from SS, and the higher expression of CST in immune cells supports the hypothesis that CST rather than SS may act as a potential endogenous ligand for SSRs in the human immune system. [ABSTRACT FROM AUTHOR]

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multisystem condition destined to become pandemic in the coming decades. This study aimed at evaluating the economic impact of MASLD in the Italian population from the Italian National Healthcare Service (NHS) perspective., Methods: The economic impact of the MASLD was assessed by developing a calculation model in Microsoft Excel ® from the Italian NHS perspective, considering healthcare resources and direct costs. The target population was based on the prevalence data. Through a literature search, complications of MASLD were identified, including MASH, with relative risk of evolution into CC, DCC, HCC, T2DM, cardiovascular diseases, in particular AMI and stroke, CKD, and CRC. The differential impact between complication development in the population with MASLD and the same sample size population without-MASLD was evaluated. Differential risk data, mortality rates, and event unit costs were drawn from the published international literature. Frequency and cost data were applied to the total target population, the total annual costs and mortality data, referring to the two arms, were then calculated, and the differential value was obtained., Results: Based on an estimated 11,546,370 MASLD target population, an annual illness impact of €12,251,631,822 was calculated, corresponding to a difference of €7,731,674,054 compared with the same sample size without MASLD. Moreover, the MASLD population is expected to experience 13,438 additional deaths annually., Conclusion: The growing epidemiological impact of MASLD and its complications represent a huge economic burden for healthcare services worldwide. An integrated approach, including changes in lifestyle behaviors, will be the first step. Specific drugs for MASLD are not yet available; however, studies are underway, and combined pharmaceutical therapies may be an inevitable choice to achieve adequate control of MASLD and its complications., Competing Interests: The authors declare that they have no conflicts of interest in this work., (© 2024 Torre et al.)

Here we describe the case of a 41-year-old woman with a history of Cushing disease who had previously undergone unsuccessful neurosurgery, followed by stereotactic radiosurgery. More than 4 years after this treatment, she presented severe visual impairment, which started in the left eye and was documented by neuro-ophthalmic evaluation. Radiological assessment by contrast-enhanced magnetic resonance (MR) imaging initially suggested the diagnosis of glioma of the optic nerve and the patient started corticosteroid treatment (first with prednisone, 80 mg/day, followed by dexamethasone, 8 mg/day). Despite the therapy, vision in the left eye rapidly worsened until light was no longer perceptible; similar symptoms and signs also developed in the right eye, evolving to complete temporal hemianopsia. The clinical evidence was confirmed by the rapid progression of the MR picture, which showed homogeneous enhancement of the chiasm and optic nerves. On the basis of these findings, the original diagnosis of glioma was excluded, and radiation-induced optic neuropathy was diagnosed. As corticosteroids had proved inefficacious, hyperbaric oxygen (HBO) therapy was promptly instituted and vision steadily started to improve. This improvement was documented and confirmed by the progressive recovery of the visual field in the right eye and the changes in the sequential follow-up MR scanning. Optic neuropathy is an infrequent but dramatic complication of radiation therapy. Symptoms develop, on average, 12 months after treatment, and the onset may be acute and characterized by the progressive loss of vision in one or both eyes. HBO has already been used to treat this complication, but its efficacy is still controversial. Here, in addition to describing this particular case, which presented a significantly delayed radiation injury of the optic pathways, we provide a brief literature review and discuss some important points.