Syndrome of inappropriate antidiuresis/hyponatremia in COVID-19.

Hyponatremia is the most frequent electrolyte alteration among hospitalized patients and it has been reported in 20-40% of patients with SARS-CoV-2 (COVID-19) infection. Multiple causes of hyponatremia have been hypothesized in these patients. The syndrome of inappropriate antidiuresis (SIAD) has been considered one of the main reasons leading to hyponatremia in this condition. SIAD can be secondary to cytokines release, in particular IL-6. Positive pressure ventilation can be another cause of hyponatremia due to SIAD. Other possible etiologies of hyponatremia in COVID-19 patients can be related to secondary hypocortisolism, nausea, vomiting, heart and kidney damage. Similar to many other clinical conditions, there is strong evidence that hyponatremia is associated with a worse prognosis also in patients with COVID-19 infection. In particular, hyponatremia has been identified as an independent risk of ICU transfer, need of non-invasive ventilation and death. Hyponatremia in COVID-19 patients is in principle acute and symptomatic and should be treated as such, according to the published guidelines. Therefore, patients should be initially treated with i.v. hypertonic saline (3% NaCl) infusion and serum [Na+] should be frequently monitored, in order to remain within a safe rate of correction. There is evidence showing that serum [Na+] correction is associated with a better outcome in different pathologies, including COVID-19 infection.

Effects of Reduced Extracellular Sodium Concentrations on Cisplatin Treatment in Human Tumor Cells: The Role of Autophagy.

Hyponatremia is the prevalent electrolyte imbalance in cancer patients, and it is associated with a worse outcome. Notably, emerging clinical evidence suggests that hyponatremia adversely influences the response to anticancer treatments. Therefore, this study aims to investigate how reduced extracellular [Na+] affects the responsiveness of different cancer cell lines (from human colon adenocarcinoma, neuroblastoma, and small cell lung cancer) to cisplatin and the underlying potential mechanisms. Cisplatin dose-response curves revealed higher IC50 in low [Na+] than normal [Na+]. Accordingly, cisplatin treatment was less effective in counteracting the proliferation and migration of tumor cells when cultured in low [Na+], as demonstrated by colony formation and invasion assays. In addition, the expression analysis of proteins involved in autophagosome-lysosome formation and the visualization of lysosomal areas by electron microscopy revealed that one of the main mechanisms involved in chemoresistance to cisplatin is the promotion of autophagy. In conclusion, our data first demonstrate that the antitumoral effect of cisplatin is markedly reduced in low [Na+] and that autophagy is an important mechanism of drug escape. This study indicates the role of hyponatremia in cisplatin chemoresistance and reinforces the recommendation to correct this electrolyte alteration in cancer patients.

The Vasopressin Receptor Antagonist Tolvaptan Counteracts Tumor Growth in a Murine Xenograft Model of Small Cell Lung Cancer.

We have previously demonstrated that the vasopressin type 2 receptor (AVPR2) antagonist tolvaptan reduces cell proliferation and invasion and triggers apoptosis in different human cancer cell lines. To study this effect in vivo, a xenograft model of small cell lung cancer was developed in Fox1nu/nu nude mice through the subcutaneous inoculation of H69 cells, which express AVPR2. One group of mice (n = 5) was treated with tolvaptan for 60 days, whereas one group (n = 5) served as the control. A reduced growth was observed in the tolvaptan group in which the mean tumor volume was significantly smaller on day 60 compared to the control group. In the latter group, a significantly lower survival was observed. The analysis of excised tumors revealed that tolvaptan effectively inhibited the cAMP/PKA and PI3K/AKT signaling pathways. The expression of the proliferative marker proliferating cell nuclear antigen (PCNA) was significantly lower in tumors excised from tolvaptan-treated mice, whereas the expression levels of the apoptotic marker caspase-3 were higher than those in control animals. Furthermore, tumor vascularization was significantly lower in the tolvaptan group. Overall, these findings suggest that tolvaptan counteracts tumor progression in vivo and, if confirmed, might indicate a possible role of this molecule as an adjuvant in anticancer strategies.

The Yin and Yang Effect of the Apelinergic System in Oxidative Stress.

Apelin is an endogenous ligand for the G protein-coupled receptor APJ and has multiple biological activities in human tissues and organs, including the heart, blood vessels, adipose tissue, central nervous system, lungs, kidneys, and liver. This article reviews the crucial role of apelin in regulating oxidative stress-related processes by promoting prooxidant or antioxidant mechanisms. Following the binding of APJ to different active apelin isoforms and the interaction with several G proteins according to cell types, the apelin/APJ system is able to modulate different intracellular signaling pathways and biological functions, such as vascular tone, platelet aggregation and leukocytes adhesion, myocardial activity, ischemia/reperfusion injury, insulin resistance, inflammation, and cell proliferation and invasion. As a consequence of these multifaceted properties, the role of the apelinergic axis in the pathogenesis of degenerative and proliferative conditions (e.g., Alzheimer's and Parkinson's diseases, osteoporosis, and cancer) is currently investigated. In this view, the dual effect of the apelin/APJ system in the regulation of oxidative stress needs to be more extensively clarified, in order to identify new potential strategies and tools able to selectively modulate this axis according to the tissue-specific profile.

Hyponatremia Promotes Cancer Growth in a Murine Xenograft Model of Neuroblastoma.

In cancer patients, hyponatremia is detected in about 40% of cases at hospital admission and has been associated to a worse outcome. We have previously observed that cancer cells from different tissues show a significantly increased proliferation rate and invasion potential, when cultured in low extracellular [Na+]. We have recently developed an animal model of hyponatremia using Foxn1nu/nu mice. The aim of the present study was to compare tumor growth and invasivity of the neuroblastoma cell line SK-N-AS in hyponatremic vs. normonatremic mice. Animals were subcutaneously implanted with luciferase-expressing SK-N-AS cells. When masses reached about 100 mm3, hyponatremia was induced in a subgroup of animals via desmopressin infusion. Tumor masses were significantly greater in hyponatremic mice, starting from day 14 and until the day of sacrifice (day 28). Immunohistochemical analysis showed a more intense vascularization and higher levels of expression of the proliferating cell nuclear antigen, chromogranin A and heme oxigenase-1 gene in hyponatremic mice. Finally, metalloproteases were also more abundantly expressed in hyponatremic animals compared to control ones. To our knowledge, this is the first demonstration in an experimental animal model that hyponatremia is associated to increased cancer growth by activating molecular mechanisms that promote proliferation, angiogenesis and invasivity.

Immunotherapy in Underrepresented Populations of Patients with Cancer: Do We Have Enough Evidence at Present? A Focus on Patients with Major Viral Infections and Autoimmune Disorders.

The safety and activity of immune checkpoint inhibitors have been characterized in interventional and observational studies. However, only small studies have specifically investigated these agents in patients who are excluded or underrepresented in clinical trials, frequently referred to as "special populations" or "underrepresented populations." These include older adults, those with dysregulated immune activation, patients with a compromised immune function, and those carrying major viral infections, lymphoproliferative diseases, and major organ dysfunctions. Therefore, there remains substantial uncertainty regarding the use of immune checkpoint inhibitors in these specific settings. The Network of Italian Supportive Care in Oncology has carried out a multidisciplinary project, with the contribution of oncologists and other specialists, to retrieve the existing evidence on the use of immunotherapy in patients with solid and hematological cancers with the final aim to provide an expert guidance. The results of this effort are presented in this article, which is focused on patients with major viral infections or those with immune dysregulation/autoimmune diseases, and could be useful to guide decisions in clinical practice and to design prospective clinical trials focusing on the use of immunotherapy in these populations. IMPLICATIONS FOR PRACTICE: Substantial uncertainty remains regarding the use of immune checkpoint inhibitors in "underrepresented" patients, such as older adults, those with dysregulated immune activation, and patients with a compromised immune function, major viral infections, lymphoproliferative diseases or major organ dysfunctions. The Network of Italian Supportive Care in Oncology has carried out a multidisciplinary project to retrieve the existing evidence on the use of immunotherapy in underrepresented patients with cancer in order provide an expert guidance. The results of this effort, with a focus on patients with major viral infections or those with immune dysregulation/autoimmune diseases, are presented in this article and could be useful to guide decisions both in clinical practice and to design clinical trials.

Hyponatremia, falls and bone fractures: A systematic review and meta-analysis.

OBJECTIVE: To perform a meta-analysis based on published studies that compared falls and bone fractures between patients with and without hyponatremia. CONTEXT: There is evidence suggesting that hyponatremia is associated with an increased risk of falls and bone fractures. DESIGN: An extensive Medline, Embase and Cochrane search was performed to retrieve all studies published up to, 30 April 2017, using the following words: "hyponatremia" or "hyponatraemia" AND "falls" and "bone fractures." A meta-analysis was performed including all studies comparing falls and bone fractures in subjects with or without hyponatremia. PATIENTS AND RESULTS: Of 216 retrieved articles, 15 studies satisfied inclusion criteria encompassing a total of 51 879 patients, of whom 2329 were hyponatremic. Across all studies, hyponatremia was associated with a significantly increased risk of falls (MH-OR = 2.14[1.71; 2.67]. This result was confirmed when only hospitalized patients were considered (MH-OR = 2.44 [1.97; 3.02]). A meta-regression analysis showed that the hyponatremia-related risk of falls was higher in those studies considering a lower serum [Na+ ] cut-off to define hyponatremia. Interestingly, the estimated risk of falls related to hyponatremia was already significantly higher when a serum [Na+ ] cut-off of 135 mmol/L was considered (MH-OR = 1.26[1.23;1.29]). The presence of hyponatremia was also associated with a higher risk of fractures, particularly hip fractures (MH-OR = 2.00[1.43;2.81]). CONCLUSIONS: This study confirms that hyponatremia is associated with an increased risk of falls and bone fractures. The clinical, social and economic relevance of such association is strengthened by the increased incidence of hyponatremia in older people.

A case of malignant insulinoma responsive to somatostatin analogs treatment.

BACKGROUND: Insulinoma is a rare tumour representing 1-2% of all pancreatic neoplasms and it is malignant in only 10% of cases. Locoregional invasion or metastases define malignancy, whereas the dimension (> 2 cm), CK19 status, the tumor staging and grading (Ki67 > 2%), and the age of onset (> 50 years) can be considered elements of suspect. CASE PRESENTATION: We describe the case of a 68-year-old man presenting symptoms compatible with hypoglycemia. The symptoms regressed with food intake. These episodes initially occurred during physical activity, later also during fasting. The fasting test was performed and the laboratory results showed endogenous hyperinsulinemia compatible with insulinoma. The patient appeared responsive to somatostatin analogs and so he was treated with short acting octreotide, obtaining a good control of glycemia. Imaging investigations showed the presence of a lesion of the uncinate pancreatic process of about 4 cm with a high sst2 receptor density. The patient underwent exploratory laparotomy and duodenocephalopancreasectomy after one month. The definitive histological examination revealed an insulinoma (T3N1MO, AGCC VII G1) with a low replicative index (Ki67: 2%). CONCLUSIONS: This report describes a case of malignant insulinoma responsive to octreotide analogs administered pre-operatively in order to try to prevent hypoglycemia. The response to octreotide analogs is not predictable and should be initially assessed under strict clinical surveillance.

A systematic review of known interventions for the treatment of chronic nonhypovolaemic hypotonic hyponatraemia and a meta-analysis of the vaptans.

International and national guidelines on the treatment of chronic nonhypovolaemic hypotonic hyponatraemia differ; therefore, we have undertaken this systematic review and meta-analysis to investigate the efficacy and safety of interventions for the treatment of chronic nonhypovolaemic hypotonic hyponatraemia. Following registration of the review protocol with PROSPERO, systematic literature searches were conducted to identify randomized and quasi-randomized controlled trials assessing any degree of fluid restriction or any drug treatment with the aim of increasing serum sodium concentration in patients with chronic nonhypovolaemic hypotonic hyponatraemia. Where appropriate, outcome data were synthesized in a meta-analysis. A total of 45 716 bibliographic records were identified from the searches and 18 trials (assessing conivaptan, lixivaptan, tolvaptan and satavaptan) met the eligibility criteria. Results suggest that all four vasopressin receptor agonists ("vaptans") significantly improve serum sodium concentration. Lixivaptan, satavaptan and tolvaptan were associated with greater rates of response versus placebo. There was no evidence of a difference between each of the vaptans compared with placebo for mortality, discontinuation and rates of hypernatraemia. No RCT evidence of treatments other than the vaptans for hyponatraemia such as oral urea, salt tablets, mannitol, loop diuretics demeclocycline or lithium was identified. Vaptans demonstrated superiority over placebo for outcomes relating to serum sodium correction. Few trials documented the potential benefit of vaptans on change in health-related quality of life as a result of treatment. There was also a lack of high-quality RCT evidence on the comparative efficacy of the vaptans and other treatment strategies for the treatment of chronic nonhypovolaemic hypotonic hyponatraemia.

Hyponatraemia alters the biophysical properties of neuronal cells independently of osmolarity: a study on Ni(2+) -sensitive current involvement.

What is the central question of this study? Hyponatraemia, an electrolyte disorder encountered in hospitalized patients, can cause neurological symptoms usually attributed to a reduction in plasma osmolarity. Here, we investigated whether low [Na(+) ] per se can cause neuronal changes independent of osmolarity, focusing on involvement of the Na(+) -Ca(2+) exchanger. What is the main finding and its importance? We show that hyponatraemia per se causes alterations of neuronal properties. The novel finding of Na(+) -Ca(2+) exchanger involvement helps us to elucidate the volume regulation following hyponatraemia. This might have relevance in a translational perspective because Na(+) -Ca(2+) exchanger could be a target for novel therapies. Hyponatraemia is the most frequent electrolyte disorder encountered in hospitalized patients, and it can cause a wide variety of neurological symptoms. Most of the negative effects of this condition on neuronal cells are attributed to cell swelling because of the reduction of plasma osmolarity, although in hyponatraemia different membrane proteins are supposed to be involved in the conservation of neuronal volume. We have recently reported detrimental effects of hyponatraemia on two different neuronal cell lines, SK-N-AS and SH-SY5Y, independent of osmotic alterations. In this study we investigated, in the same cell lines, whether hyponatraemic conditions per se can cause electrophysiological alterations and whether these effects vary over time. Accordingly, we carried out experiments in low-sodium medium in either hyposmotic [Osm(-)] or isosmotic [Osm(+)] conditions, for a short (24 h) or long time (7 days). Using a patch pipette in voltage-clamp conditions, we recorded possible modifications of cell capacitance (Cm ) and membrane conductance (Gm ). Our results indicate that in both Osm(-) and Osm(+) medium, Cm and Gm show a similar increase, but such effects are dependent on the time in culture in different ways. Notably, regarding the possible mechanisms involved in the maintenance of Cm , Gm and Gm /Cm in Osm(+) conditions, we observed a greater contribution of the Na(+) -Ca(2+) exchanger compared with Osm(-) and control conditions. Overall, these novel electrophysiological results help us to understand the mechanisms of volume regulation after ionic perturbation. Our results might also have relevance in a translational perspective because the Na(+) -Ca(2+) exchanger can be considered a target for planning novel therapies.

Current treatment practice and outcomes. Report of the hyponatremia registry.

Current management practices for hyponatremia (HN) are incompletely understood. The HN Registry has recorded diagnostic measures, utilization, efficacy, and outcomes of therapy for eu- or hypervolemic HN. To better understand current practices, we analyzed data from 3087 adjudicated adult patients in the registry with serum sodium concentration of 130 mEq/l or less from 225 sites in the United States and European Union. Common initial monotherapy treatments were fluid restriction (35%), administration of isotonic (15%) or hypertonic saline (2%), and tolvaptan (5%); 17% received no active agent. Median (interquartile range) mEq/l serum sodium increases during the first day were as follows: no treatment, 1.0 (0.0-4.0); fluid restriction, 2.0 (0.0-4.0); isotonic saline, 3.0 (0.0-5.0); hypertonic saline, 5.0 (1.0-9.0); and tolvaptan, 4.0 (2.0-9.0). Adjusting for initial serum sodium concentration with logistic regression, the relative likelihoods for correction by 5 mEq/l or more (referent, fluid restriction) were 1.60 for hypertonic saline and 2.55 for tolvaptan. At discharge, serum sodium concentration was under 135 mEq/l in 78% of patients and 130 mEq/l or less in 49%. Overly rapid correction occurred in 7.9%. Thus, initial HN treatment often uses maneuvers of limited efficacy. Despite an association with poor outcomes and availability of effective therapy, most patients with HN are discharged from hospital still hyponatremic. Studies to assess short- and long-term benefits of correction of HN with effective therapies are needed.

Erectile Dysfunction is Common among Men with Acromegaly and is Associated with Morbidities Related to the Disease.

INTRODUCTION: The prevalence of erectile dysfunction (ED) and its correlates in men with acromegaly has never been investigated. AIM: The aim of this study was to evaluate sexual function in men with acromegaly. METHODS: Multicenter-based, retrospective analysis of a nonselected series of 57 acromegalic subjects (mean age: 52.7 ± 14.2 years) was performed. Acromegalic subjects reporting ED (n = 24) were compared with matched ED patients without acromegaly or pituitary disease (controls), selected from a cohort of more than 4,000 subjects enrolled in the Florence Sexual Medicine and Andrology Unit. MAIN OUTCOME MEASURES: Patients were interviewed using Structured Interview on Erectile Dysfunction (SIEDY) structured interview, a 13-item tool for the assessment of ED-related morbidities. Several clinical and biochemical parameters were taken. Penile color Doppler ultrasound (PCDU) was performed in a subgroup of 37 acromegalic subjects. RESULTS: ED was reported by 42.1% of acromegalic subjects. After adjusting for age and testosterone, acromegalic subjects with ED had a higher prevalence of hypertension and more often reported an impairment of sleep-related erections and a longer smoking habit. Accordingly, acromegaly-associated ED was characterized by a higher organic component and worse PCDU parameters. No relationship between ED and testosterone levels or other acromegaly-related parameters was found. However, acromegalic subjects with severe ED reported a longer disease duration. In a case-control analysis, comparing acromegalic subjects with ED-matched controls free from acromegaly (1:5 ratio), acromegalic men had a worse ED problem and a higher organic component of ED, as derived from SIEDY score. In line with these data, acromegalic patients with ED had a higher prevalence of major adverse cardiovascular events history at enrollment and lower PCDU parameters. CONCLUSIONS: Subjects with complicated acromegaly are at an increased risk of developing ED, especially those with cardiovascular morbidities. Our data suggest including a sexual function evaluation in routine acromegaly follow-up.

Copeptin (CTproAVP), a new tool for understanding the role of vasopressin in pathophysiology.

Arginine vasopressin (AVP) plays a key role in many physiologic and pathologic processes. The most important stimulus for AVP release is a change in plasma osmolality. AVP is also involved in the response and adaptation to stress. Reliable measurement of AVP is hindered by several factors. Over 90% of AVP is tightly bound to platelets, and its estimation is influenced by the number of platelets, incomplete removal of platelets or pre-analytical processing steps. Copeptin (CTproAVP), a 39-aminoacid glycopeptide, is a C-terminal part of the precursor pre-provasopressin (pre-proAVP). Activation of the AVP system stimulates CTproAVP secretion into the circulation from the posterior pituitary gland in equimolar amounts with AVP. Therefore CTproAVP directly reflects AVP concentration and can be used as a surrogate biomarker of AVP secretion. In many studies CTproAVP represents AVP levels and its behavior represents changes in plasma osmolality, stress and various disease states, and shows some of the various physiologic and pathophysiologic conditions associated with increased or decreased AVP. Increased CTproAVP concentration is described in several studies as a strong predictor of mortality in patients with chronic heart failure and acute heart failure. Autosomal polycystic kidney disease (ADPKD) patients have both central and nephrogenic defects in osmoregulation and CTproAVP balance. A possibility raised by these clinical observations is that CTproAVP may serve to identify patients who could benefit from an intervention aimed at countering AVP.

A case of osmotic demyelination syndrome occurred after the correction of severe hyponatraemia in hyperemesis gravidarum.

BACKGROUND: Osmotic demyelination syndrome (ODS) may be observed as a result of a rapid change in serum osmolarity, such as that induced by an overly rapid correction of serum sodium levels in hyponatraemic patients. CASE PRESENTATION: We describe the case of a 21-year-old woman who was hospitalized at week 10 of gestation because of severe hyperemesis. At admission the patient appeared restless and confused and severe hyponatraemia (serum sodium 107 mmol/L) and hypokalemia (serum potassium 1.1 mmol/L) were detected. Active and simultaneous correction of these imbalances led to an overly rapid increase of serum sodium levels (17 mmol/L in the first 24 hours). Isotonic saline solution was stopped and replaced by 5% dextrose solution infusion. However, the neurological alterations worsened and the radiological features were consistent with the diagnosis of extra-pontine ODS. Steroids were administered intravenously with progressive improvement of biochemical and clinical abnormalities. At the time of discharge, 20 days later, the patient was able to walk and eat autonomously with only minimal external support. CONCLUSIONS: This report illustrates an unusual case of ODS, occurred after an excessive rate of correction of hyponatraemia obtained with isotonic saline infusion. Hypokaliemia and its active correction very likely played a crucial role in facilitating the onset of ODS. This interesting aspect will be explained in detail in the article. A more cautious and thoughtful correction of electrolyte alterations, would have probably prevented the onset of ODS in this patient. Physicians should be aware of the possibly fatal consequences that an exceedingly rapid change of serum osmolarity may have and should strictly follow the known safety measures in order to prevent it to occur.

Altered expression of 3-betahydroxysterol delta-24-reductase/selective Alzheimer's disease indicator-1 gene in Huntington's disease models.

INTRODUCTION: 3-betahydroxysterol delta-24-reductase (DHCR24), also called selective Alzheimer's disease indicator-1, is a crucial enzyme in cholesterol biosynthesis with neuroprotective properties that is downregulated in brain areas affected by Alzheimer's disease. AIM: In the present study, we investigated modifications of DHCR24 expression in models of Huntington's disease (HD), a neurodegenerative disorder caused by a polyglutamine expansion in huntingtin (Htt) protein that induces degeneration of cerebral cortex and striatum as well as lateral hypothalamic abnormality. METHODS: Basal expression of DHCR24 and its modulation after oxidative stress were evaluated in rat striatal precursors cells (ST14A) transfected with wild-type (Htt) or mutant Htt (mHtt) and in brain tissue of an HD mouse model (R6/2). RESULTS: The results showed that DHCR24 transcript levels were decreased in ST14A cells expressing mHtt and in the brain of symptomatic R6/2 mice, but were significantly increased in ST14A cells overexpressing wild-type Htt. In addition, we demonstrated that, in the striatal precursors, the decrease of DHCR24 expression in response to oxidative stress was modified according to the presence of Htt or of its mutant form. Preliminary results indicated a modification of DHCR24 expression in post-mortem brain samples of HD patients. CONCLUSIONS: In conclusion, these results support the hypothesis of a possible role of DHCR24 in HD.

Human striatum remodelling after neurotransplantation in Huntington's disease.

BACKGROUND: Restoration of functions in Huntington's disease (HD) by neurotransplantation stems from the formation of a striatum-like structure capable of establishing host connections as a result of grafted striatal neuroblast maturation. For the first time, we demonstrated some developmental steps accomplished by progenitor cells in the brain of an HD patient and analysed the molecular asset of the human primordium. CASE REPORT: Surgery involved bilateral (two sessions) stereotactic, caudate-putaminal transplantation of whole ganglionic eminence fragments from single legally aborted fetuses. MRI showed that the tissue deposits of the left hemisphere grew and joined to constitute a single tissue mass that remodelled basal ganglia anatomy and remained stable in size over time. No evidence of graft growth was observed contralaterally. PET demonstrated increased striatal and stable cortical metabolism. Unified Huntington's Disease Rating Scale assessments demonstrated improvement of motor performances, which faded over the 36-month follow-up. Cognitive performance tended to decrease at a lower rate than before transplantation. CONCLUSION: The striatal primordium grew into the host brain and this process was associated with metabolic change and some clinical benefit. The study suggests the plasticity and reparative potential of un-manipulated primordium in an era where promising cell-based therapies are still in their infancy.

A pharmacoeconomic analysis from Italian guidelines for the management of prolactinomas.

Background: Prolactinoma, the most common pituitary adenoma, is usually treated with dopamine agonist (DA) therapy like cabergoline. Surgery is second-line therapy, and radiotherapy is used if surgical treatment fails or in relapsing macroprolactinoma. Objective: This study aimed to provide economic evidence for the management of prolactinoma in Italy, using a cost-of-illness and cost-utility analysis that considered various treatment options, including cabergoline, bromocriptine, temozolomide, radiation therapy, and surgical strategies. Methods: The researchers conducted a systematic literature review for each research question on scientific databases and surveyed a panel of experts for each therapeutic procedure's specific drivers that contributed to its total cost. Results: The average cost of the first year of treatment was €2,558.91 and €3,287.40 for subjects with microprolactinoma and macroprolactinoma, respectively. Follow-up costs from the second to the fifth year after initial treatment were €798.13 and €1,084.59 per year in both groups. Cabergoline had an adequate cost-utility profile, with an incremental cost-effectiveness ratio (ICER) of €3,201.15 compared to bromocriptine, based on a willingness-to-pay of €40,000 per quality-adjusted life year (QALY) in the reference economy. Endoscopic surgery was more cost-effective than cabergoline, with an ICER of €44,846.64. Considering a willingness-to-pay of €40,000/QALY, the baseline findings show cabergoline to have high cost utility and endoscopic surgery just a tad above that. Conclusions: Due to the favorable cost-utility profile and safety of surgical treatment, pituitary surgery should be considered more frequently as the initial therapeutic approach. This management choice could lead to better outcomes and an appropriate allocation of healthcare resources.

Hyponatremia and Cancer: From Bedside to Benchside.

Hyponatremia is the most common electrolyte disorder encountered in hospitalized patients. This applies also to cancer patients. Multiple causes can lead to hyponatremia, but most frequently this electrolyte disorder is due to the syndrome of inappropriate antidiuresis. In cancer patients, this syndrome is mostly secondary to ectopic secretion of arginine vasopressin by tumoral cells. In addition, several chemotherapeutic drugs induce the release of arginine vasopressin by the hypothalamus. There is evidence that hyponatremia is associated to a more negative outcome in several pathologies, including cancer. Many studies have demonstrated that in different cancer types, both progression-free survival and overall survival are negatively affected by hyponatremia, whereas the correction of serum [Na+] has a positive effect on patient outcome. In vitro studies have shown that cells grown in low [Na+] have a greater proliferation rate and motility, due to a dysregulation in intracellular signalling pathways. Noteworthy, vasopressin receptors antagonists, which were approved more than a decade ago for the treatment of euvolemic and hypervolemic hyponatremia, have shown unexpected antiproliferative effects. Because of this property, vaptans were also approved for the treatment of polycystic kidney disease. In vitro evidence indicated that this family of drugs effectively counteracts proliferation and invasivity of cancer cells, thus possibly opening a new scenario among the pharmacological strategies to treat cancer.

Treatment Guidelines for Hyponatremia: Stay the Course.

International guidelines designed to minimize the risk of complications that can occur when correcting severe hyponatremia have been widely accepted for a decade. On the basis of the results of a recent large retrospective study of patients hospitalized with hyponatremia, it has been suggested that hyponatremia guidelines have gone too far in limiting the rate of rise of the serum sodium concentration; the need for therapeutic caution and frequent monitoring of the serum sodium concentration has been questioned. These assertions are reminiscent of a controversy that began many years ago. After reviewing the history of that controversy, the evidence supporting the guidelines, and the validity of data challenging them, we conclude that current safeguards should not be abandoned. To do so would be akin to discarding your umbrella because you remained dry in a rainstorm. The authors of this review, who represent 20 medical centers in nine countries, have all contributed significantly to the literature on the subject. We urge clinicians to continue to treat severe hyponatremia cautiously and to wait for better evidence before adopting less stringent therapeutic limits.

Italian Guidelines for the Management of Prolactinomas.

INTRODUCTION: This guideline (GL) is aimed at providing a reference for the management of prolactin (PRL)-secreting pituitary adenoma in adults. However, pregnancy is not considered. METHODS: This GL has been developed following the methods described in the Manual of the Italian National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinologi (AME) has identified potentially relevant outcomes, which have then been rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" have been considered in the systematic review of evidence and only those classified as "critical" have been considered in the formulation of recommendations. RESULTS: The present GL provides recommendations regarding the role of pharmacological and neurosurgical treatment in the management of prolactinomas. We recommend cabergoline (Cab) vs. bromocriptine (Br) as the firstchoice pharmacological treatment to be employed at the minimal effective dose capable of achieving the regression of the clinical picture. We suggest that medication and surgery are offered as suitable alternative first-line treatments to patients with non-invasive PRL-secreting adenoma, regardless of size. We suggest Br as an alternative drug in patients who are intolerant to Cab and are not candidates for surgery. We recommend pituitary tumor resection in patients 1) without any significant neuro-ophthalmologic improvement within two weeks from the start of Cab, 2) who are resistant or do not tolerate Cab or other dopamine-agonist drugs (DA), 3) who escape from previous efficacy of DA, and 4) who are unwilling to undergo a chronic DA treatment. We recommend that patients with progressive disease notwithstanding previous tumor resection and ongoing DA should be managed by a multidisciplinary team with specific expertise in pituitary diseases using a multimodal approach that includes repeated surgery, radiotherapy, DA, and possibly, the use of temozolomide. CONCLUSION: The present GL is directed to endocrinologists, neurosurgeons, and gynecologists working in hospitals, in territorial services or private practice, and to general practitioners and patients.