Ianus Bifrons: The Two Faces of Metformin.

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?

Impact of Vitamin D Deficiency on Tumor Aggressiveness in Neuroendocrine Neoplasms.

Background: The role of vitamin D (25(OH)D) in the pathogenesis and outcome of several conditions, including autoimmune diseases, diabetes and cancers is largely described in the literature. The aims of this study were to evaluate the prevalence of 25(OH)D deficit in a cohort of patients with neuroendocrine neoplasms (NENs) in comparison to a matched healthy control group and to analyze the possible role of 25(OH)D as a prognostic factor for NENs in terms of biological aggressiveness, tumor progression and survival. Methods: From 2009 to 2023, 172 patients with NENs (99 females; median age, 63 years) were included in the study. Serum 25(OH)D levels were defined as deficient if ≤20 ng/mL. The possible associations between 25(OH)D levels and disease grading, staging, ki67%, overall survival (OS), and progression-free survival (PFS) were considered. Results: NEN patients had significantly lower 25(OH)D levels compared to controls (p < 0.001) regardless of the primary origin. Patients with 25(OH)D < 20 ng/mL had a significantly higher ki67 index (p = 0.02) compared to the ones with 25(OH)D levels above 20 ng/mL. Patients with disease progression were found to have a significantly lower 25(OH)D at baseline (p = 0.02), whereas PFS and OS were not significantly influenced by 25(OH)D. Conclusions: Vitamin D deficiency is highly prevalent among NENs and is associated with higher ki67 and disease progression. Our study highlights the importance of monitoring 25(OH)D levels in patients with NENs, as its deficiency appeared to be linked to the worst biological tumor aggressiveness.

An unusual cause of adrenal insufficiency with elevation of 17-hydroxyprogesterone: case report.

BACKGROUND: We present an intriguing case of primary adrenal lymphoma, with associated primary adrenal insufficiency (PAI), in a patient presenting a transitory partial 21-hydroxylase deficiency during the active phase of the adrenal disease. CASE PRESENTATION: An 85-years old woman was referred because of worsening asthenia, lumbar pain, generalized myalgia and arthralgia. During investigations a computed tomography (CT) scan evidenced two large bilateral adrenal masses, highly suspicious for primary adrenal tumor. The hormonal assessment revealed very low levels of morning plasma cortisol and 24-h urinary cortisol, elevated ACTH levels with low plasma concentration of aldosterone, pointing to the diagnosis of PAI. After diagnosis of PAI our patient started glucocorticoid and mineralcorticoid replacement therapy with clinical benefit. In order to further characterize the adrenal lesions, adrenal biopsy, was performed. The histology revealed a high grade non-Hodgkin lymphoma with an immunophenotype consistent with intermediate aspects between diffuse large B-cell and Burkitt lymphoma, with a high proliferation index (KI-67 > 90%). The patient received chemotherapy with epirubicin, vincristine, cyclophosphamide, and rituximab, associated with methylprednisolone that resulted in a complete clinical and radiological remission within one year. After 2 years from the diagnosis and a total of 6 cycles of rituximab, the patient was in good clinical condition and was taking only the replacement therapy for PAI. The patient initially presented also a slight increase of 17-hydroxyprogesterone (17-OHP) for age that normalize after resolution of lymphoproliferative disease. CONCLUSIONS: In the presence of bilateral adrenal disease and/or in the presence of signs and symptoms of PAI clinicians must exclude the presence of PAL. The evidence of elevated ACTH-stimulated 17-OHP levels also in patients with other adrenal masses, together with the detection of elevated basal 17-OHP levels in our patient make it more plausible, in our view, an effect of the lesion on the "healthy" adrenal tissue residue than a direct secretory activity by the adrenal tumor.

Modulatory activity of testosterone on growth pattern and IGF-1 levels in vanishing testis syndrome: a case report during 15 years of follow-up.

BACKGROUND: The vanishing testis syndrome (VTS), is a 46, XY disorder of sex development (46, XY DSD) and is characterized by the absence of testis in a 46, XY subject with male genitalia, gonadal dysgenesis and consequent hypergonadotropic hypogonadism. CASE PRESENTATION: A young man affected by VTS has been followed up for more than 15-year in our center. The patient received different testosterone formulations, which modulated his IGF-1 levels and height velocity, depending on different stimulatory effects, mimicking pubertal spurt until achieving a final height in line with his genetic target. Exogenous testosterone, activating GH/IGF-1 system, can directly influence growth pattern. With this particular case report we demonstrate that an accurate monitoring of patients with VTS, as well as a perfect reproduction of testosterone secretion during pubertal spurt, can guarantee a normal growth and development and, consequently, a high level of quality of life in adulthood. CONCLUSION: Testosterone levels act an important role during pubertal spurt in modulating the GH/IGF-1 axis, besides its well-known impact in sexual development. Very little amount of exogenous testosterone can stimulate IGF-1 secretion and provide to growth velocity the drive that characterizes the initial phases of the growth spurt.

Case report: Twice-daily tolvaptan dosing regimen in a challenging case of hyponatremia due to SIAD.

Background: Syndrome of inappropriate antidiuresis (SIAD) is one of the most frequent causes of euvolemic hyponatremia (serum sodium levels < 135 mEq/L) and it represents more than 35% of hyponatremia cases in hospitalized patients. It is characterized by an inappropriate vasopressin (AVP)/antidiuretic hormone (ADH) secretion, which occurs independently from effective serum osmolality or circulating volume, leading to water retention via its action on type 2 vasopressin receptor in the distal renal tubules. Corpus callosum agenesis (CCA) is one of the most common congenital brain defects, which can be associated to alterations in serum sodium levels. This report presents a rare case of chronic hyponatremia associated with SIAD in a woman with CCA, whose correction of serum sodium levels only occurred following twice-daily tolvaptan administration. Case presentation: A 30-year-old female was admitted to our hospital for non-acute hyponatremia with dizziness, headache, distal tremors, and concentration deficits. She had profound hyponatremia (Na 121 mmol/L) with measured plasma hypo-osmolality (259 mOsm/Kg) and urinary osmolality greater than 100 mOsm/Kg (517 mOsm/Kg). She presented clinically as normovolemic. After the exclusion of other causes of normovolemic hyponatremia, such as hypothyroidism and adrenal insufficiency, a diagnosis of SIAD was established. We have ruled out paraneoplastic, inflammatory, and infectious causes, as well as ischemic events. Her medical history showed a CCA and frontal teratoma. We administered tolvaptan initially at a low dosage (15 mg once a day) with persistence of hyponatremia. Therefore, the dosage was first doubled (30 mg once a day) and then increased to 45 mg once a day with an initial improvement in serum sodium levels, although not long-lasting. We therefore tried dividing the 45 mg tolvaptan administration into two doses of 30 mg and 15 mg respectively, using an off-label treatment schedule, thus achieving long-lasting serum sodium levels in the low-normal range associated with a general clinical improvement. Conclusions: This report underlines the importance of the correct diagnosis, management and treatment of SIAD, as well as the need for further studies about the pharmacokinetics and pharmacodynamics of vasopressin receptor antagonists.

Trabecular Bone Score as a Reliable Measure of Lumbar Spine Bone Microarchitecture in Acromegalic Patients.

Although GH and IGF-1 excess has a controversial impact on bone mineral density (BMD), acromegalic patients display variable degrees of bone structure impairment. In this study, we aim to investigate the usefulness of trabecular bone score (TBS), compared to BMD, in identifying acromegalic patients with impaired lumbar spine trabecular microarchitecture. Forty-four acromegalic patients were investigated for disease control, metabolic and gonadal status, bone metabolism parameters, and the presence of vertebral fractures (VFs). Patients and matched healthy controls underwent BMD and TBS examination. Mean TBS values were lower in patients than in controls (p < 0.001), without significant differences in mean lumbar and femoral BMD. TBS values were significantly higher in controlled patients compared to the uncontrolled ones (p = 0.012). No significant differences were found in bone markers with respect to disease control. Mean TBS or lumbar BMD did not significantly differ in patients with or without VFs (prevalence 11.4%). TBS and BMD levels were lower in hypogonadal patients compared to the eugonadal ones (p = 0.030 and p < 0.001, respectively). In conclusion, TBS values are significantly lower in patients than in controls, confirming the presence of impaired lumbar spine trabecular bone in acromegaly. Both uncontrolled disease and hypogonadism contribute to TBS deterioration in acromegaly.

Prevalence of diabetic striatopathy and predictive role of glycated hemoglobin level.

BACKGROUND: Diabetic striatopathy is defined as a state of hyperglycemia associated with chorea/ballism, striatal hyperdensity at CT, or hyperintensity at T1-weighted MRI. It is considered a rare complication of uncontrolled diabetes but prevalence data are scarce. OBJECTIVES: Characterize diabetic striatopathy prevalence in the population afferent to the largest teaching hospital in Genova (Liguria, Italy) and investigate the role of glycated hemoglobin level in predicting the risk. METHODS: Data were retrospectively obtained from general population undergoing blood sampling for glycated hemoglobin and resulting with HbA1c values ≥ 8%, from January 2014 to June 2017. Brain neuroimaging of those who underwent at least a brain CT or MRI was examined in search of findings compatible with diabetic striatopathy and clinical information was collected. Logistic regression was used to predict the risk of diabetic striatopathy based on age and HbA1c values. RESULTS: Subjects with uncontrolled diabetes were 4603. Brain neuroimaging was available in 1806 subjects and three patients with diabetic striatopathy were identified, all of them reporting choreic movements. The prevalence of hemichorea due to diabetic striatopathy was therefore 3 cases out of 1806 (0.16%) in our population. Hepatic and hypoxic encephalopathies were the conditions most frequently mimicking diabetic striatopathy. Odds ratio of diabetic striatopathy and HbA1c level was significantly correlated (p = 0.0009). CONCLUSIONS: To the best of our knowledge, this study is the first to evaluate the prevalence of diabetic striatopathy in Italy. High HbA1c values may have a role in predicting diabetic striatopathy.

Low-grade inflammation, CoVID-19, and obesity: clinical aspect and molecular insights in childhood and adulthood.

The new 2019 coronavirus 19 disease (CoVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious threat to health systems. As a global health problem, this pandemic poses a huge threat to people and is responsible for significant morbidity and mortality worldwide. On the other hand, obesity has also reached epidemic proportions and poses another challenge to the healthcare system. There is increasing evidence of a strong association between obesity and CoVID-19 disease, but the mechanisms underlying the link between the two remain unclear and the role of obesity also remains to be elucidated. In particular obesity-related low-grade inflammation has been hypothesized as the Achille's heel that could predispose subjects with obesity to a more severe CoVID-19 compared to subjects with normal weight. Hence, we summarized recent evidence on the role of low-grade inflammation in clinical aspects of CoVID-19 in subjects with obesity in both childhood and adulthood. Further, we provide molecular insights to explain this link.

Effects of magnesium supplementation on post-thyroidectomy hypocalcemia: a prospective single-center study.

BACKGROUND: Severe and/or symptomatic hypocalcemia due to hypoparathyroidism is the main contraindication for discharge in patients who have undergone thyroid surgery. Hypomagnesemia may contribute to the onset of hypoparathyroidism and is frequently observed after thyroid surgery in hypocalcemic patients. The impact of prophylactic and postoperative Magnesium supplementation on postoperative hypocalcemia and hypomagnesemia was prospectively evaluated by comparing patients undergoing prophylactic supplementation to a control group of patients who had only received Magnesium after evidence of postoperative hypoMg. METHODS: One hundred and twenty patients who underwent a total thyroidectomy participated in the study. Seventy-three patients were included in the study group, 47 in the control group. Prior to surgery, patients in the study group were given Magnesium orally for 5 days; postoperatively, Calcium and Magnesium was administered to all patients who displayed hypocalcemia and hypomagnesemia. RESULTS: Postoperative biochemical hypocalcemia (serum Calcium<8.5 mg/dL, regardless of its clinical severity) was found in 60 patients (50%) on D1 and in 58 patients (48.4%) on D2. Among hypocalcemic patients, hypomagnesemia was recorded in 29 at D1 (48%), and in 46 at D2 (79%). A significant positive correlation was found between Magnesium, Calcium, and parathyroid hormone in the first two postoperative days, while a significant inverse correlation occurred for these same parameters and length of hospital stay (p<0.001). One hundred and five patients (87.5%) were discharged as expected on the second postoperative day (Study group = 65, Control group = 40, p = 0.724), whereas 15 patients (12.5%) required prolonged hospitalization (Study group = 8, Control group = 7, p = 0.721). The Study group only showed significantly higher Magnesium levels on the first postoperative day (p=0.03). CONCLUSIONS: Although Magnesium and Calcium levels showed the same trend after thyroidectomy, neither Magnesium prophylaxis nor Magnesium treatment influenced the clinical course of postoperative hypocalcemia.

GH Replacement in the Elderly: Is It Worth It?

Growth hormone (GH), once the age of linear growth is completed, continues to play a fundamental role for the human body. In adulthood, GH contributes to regulate muscle, cardiovascular and bone metabolism. The same happens in old age, although there is less data on the effect of GH in the elderly. Regardless the age of onset, a reduced quality of life (QoL), an increased cardiovascular risk and an accelerated age-related decline in physical strength have been demonstrated in the elderly with GH deficiency (EGHD). In adults with GH deficiency (AGHD), recent studies suggest a role of GH replacement therapy (GHrt) in improving lean/fat mass ratio, blood pressure, lipid profile, bone metabolism and QoL. Despite these recent studies, there is still a lack of randomized controlled trials proving these positive effects in EGHD. Moreover, the lack of a long-term positive outcome on mortality, and the cost of GHrt could often impact on treatment decision-making and lead to postpone or avoid the prescription. The aim of this mini-review is to summarize the available data on GHrt in EGHD, in order to highlight its weaknesses and strengths and to provide directions to clinicians that will help in the management of this specific set of patients.

"Present and future of immunotherapy in Neuroendocrine Tumors".

Immunotherapy, so promising in many neoplasms, still does not have a precise role in the treatment of neuroendocrine neoplasms (NENs). In this article, we provide an overview on the current knowledge about immunotherapy with immune checkpoint inhibitors (ICIs) applied to NENs, evaluating future perspectives in this setting of tumors.Evidence so far available for ICIs in gastroenteropancreatic (GEP)-NENs is definitively not as robust as for other tumors such as Small Cell Lung Cancer or Merkel Cell Carcinoma. In fact, with regard to the well-differentiated forms of NENs (NETs), the results obtained nowadays have been disappointing. However, the near future, might reserve interesting results for ICIs in GEP-NEN from a total of nine different ICI drugs, used throughout 19 randomised controlled trials. Such numbers highlight the growing attention gathering around NENs and ICIs, in response to the need of stronger evidences supporting such therapy.For the future, the most important aspect will be to study strategies that can make NETs more susceptible to response to ICI and, thus, enhance the effectiveness of these treatments. Therefore, the combination of conventional therapy, target therapy and immunotherapy deserve attention and warrant to be explored. A sequential chemotherapy, possibly inducing an increase in tumor mutational burden and tested before immunotherapy, could be a hypothesis deserving more consideration. A radiation treatment that increases tumor-infiltrating lymphocytes, could be another approach to explore before ICIs in NENs. Equally essential will be the identification of biomarkers useful for selecting patients potentially responsive to this type of treatment.

ESE audit on management of Adult Growth Hormone Deficiency in clinical practice.

Guidelines recommend adults with pituitary disease in whom GH therapy is contemplated, to be tested for GH deficiency (AGHD); however, clinical practice is not uniform. AIMS: 1) To record current practice of AGHD management throughout Europe and benchmark it against guidelines; 2) To evaluate educational status of healthcare professionals about AGHD. DESIGN: On-line survey in endocrine centres throughout Europe. PATIENTS AND METHODS: Endocrinologists voluntarily completed an electronic questionnaire regarding AGHD patients diagnosed or treated in 2017-2018. RESULTS: Twenty-eight centres from 17 European countries participated, including 2139 AGHD patients, 28% of childhood-onset GHD. Aetiology was most frequently non-functioning pituitary adenoma (26%), craniopharyngioma (13%) and genetic/congenital mid-line malformations (13%). Diagnosis of GHD was confirmed by a stimulation test in 52% (GHRH+arginine, 45%; insulin-tolerance, 42%, glucagon, 6%; GHRH alone and clonidine tests, 7%); in the remaining, ≥3 pituitary deficiencies and low serum IGF-I were diagnostic. Initial GH dose was lower in older patients, but only women <26 years were prescribed a higher dose than men; dose titration was based on normal serum IGF-I, tolerance and side-effects. In one country, AGHD treatment was not approved. Full public reimbursement was not available in four countries and only in childhood-onset GHD in another. AGHD awareness was low among non-endocrine professionals and healthcare administrators. Postgraduate AGHD curriculum training deserves being improved. CONCLUSION: Despite guideline recommendations, GH replacement in AGHD is still not available or reimbursed in all European countries. Knowledge among professionals and health administrators needs improvement to optimize care of adults with GHD.

Emerging drugs for the treatment of acromegaly.

INTRODUCTION: Acromegaly is a disease characterized by elevated growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels. Surgery is the only curative treatment, while medical therapies are administered life-long. To date, almost 30% of patients treated with the currently available medical therapies do not achieve biochemical control. AREAS COVERED: This review focuses on new drugs in development for acromegaly. In detail, we provide an overview of the new molecules designed to improve disease control rate (such as novel somotostatin receptor ligands and antisense oligonucleotides), as well as the new formulations of existing medications aiming to improve patients' compliance (e.g. oral or long-acting subcutaneous octreotide). EXPERT OPINION: The constant progresses in the medical treatment of acromegaly could lead to an individualized therapy based on tumor, as well as patient's characteristics. Besides disease control, patient's need represents a major target of medical treatment in chronic diseases such as acromegaly, in order to improve compliance to therapy and patients' quality of life.

Octreotide-Resistant Acromegaly: Challenges and Solutions.

Acromegaly is a rare and severe disease caused by an increased and autonomous secretion of growth hormone (GH), thus resulting in high circulating levels of insulin-like growth factor 1 (IGF-1). Comorbidities and mortality rate are closely related to the disease duration. However, in most cases achieving biochemical control means reducing or even normalizing mortality and restoring normal life expectancy. Current treatment for acromegaly includes neurosurgery, radiotherapy and medical therapy. Transsphenoidal surgery often represents the recommended first-line treatment. First-generation somatostatin receptor ligands (SRLs) are the drug of choice in patients with persistent disease after surgery and are suggested as first-line treatment for those ineligible for surgery. However, only about half of patients treated with octreotide (or lanreotide) achieve biochemical control. Other available drugs approved for clinical use are the second-generation SRL pasireotide, the dopamine agonist cabergoline, and the GH-receptor antagonist pegvisomant. In the present paper, we revised the current literature about the management of acromegaly, aiming to highlight the most relevant and recent therapeutic strategies proposed for patients resistant to first-line medical therapy. Furthermore, we discussed the potential molecular mechanisms involved in the variable response to first-generation SRLs. Due to the availability of different medical therapies, the choice for the most appropriate drug can be currently based also on the peculiar clinical characteristics of each patient.

Dipeptidyl peptidase-4 inhibitors do not alter GH/IGF-I axis in adult diabetic patients.

PURPOSE: Incretin-based therapies have been introduced in clinical practice for type 2 diabetes mellitus (T2DM) treatment in the last few years. Current available medications of this class include glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors. In addition to GLP-1, DPP-4 is able to inactivate many others peptides as hypothalamic growth hormone-releasing hormone (GHRH). The aim of this exploratory study was to evaluate, on adult diabetic patients, the impact of therapy with incretins, particularly DPP-4 inhibitors on GH/IGF-I axis. METHODS: 60 patients with T2DM were included in the study and they were divided into three groups (age and sex comparable) on the basis of their hypoglycemic drugs in the last 4 months: group 1 (17 patients, exenatide or liraglutide + metformin), group 2 (18 patients, sitagliptin or vildagliptin + metformin), group 3 (25 patients, metformin). Anthropometric data, glycemia, glycosylated hemoglobin (HbA1c), IGF-I and acid-labile subunit (ALS) were collected in all patients. RESULTS: Weight, waist circumference and BMI of group 1 were significantly higher (P < 0.05) compared to the other groups. Fasting plasma glucose and HbA1c of the group 1 were similar compared to those of group 3 (P ns) and higher compared to those of group 2 (P < 0.05). IGF-I absolute values, IGF-I SDS were not significantly different in the three groups. CONCLUSIONS: Our data evidence that DPP-4 inhibition does not influence significantly GH/IGF-I system, confirming what was observed in animal models. Further studies are needed to better characterize the properties of these molecules on endocrine system.

Current perspectives on the impact of clinical disease and biochemical control on comorbidities and quality of life in acromegaly.

Acromegaly is a rare chronic, systemic disorder caused by excessive growth hormone (GH) secretion from a somatotroph pituitary adenoma. GH hypersecretion leads to overproduction of insulin-like growth factor-1 (IGF-1), which contributes to the somatic overgrowth, physical disfigurement, onset of multiple systemic comorbidities, reduced quality of life (QoL) and premature mortality of uncontrolled patients. Somatostatin receptor ligands, dopamine agonists and a GH receptor antagonist are currently available for medical therapy of acromegaly. The main aim of treatment is biochemical normalisation, defined as age-normalised serum IGF-1 values and random GH levels <1.0 µg/L. However, there is an increasing evidence suggesting that achieving biochemical control does not always decrease the burden of disease-related comorbidities and/or improve patients' QoL. This lack of correlation between biochemical and clinical control can be due to both disease duration (late diagnosis) or to the peculiarity of a given comorbidity. Herein we conducted ad hoc literature searches in order to find the most recent and relevant reports on biochemical and clinical disease control during medical treatment of acromegaly. Particularly, we analyse and describe the relationship between biochemical, as well as clinical disease control in patients with acromegaly receiving medical therapy, with a focus on comorbidities and QoL. In conclusion, we found that current literature data seem to indicate that clinical disease control (besides biochemical control), encompassing clinical signs and symptoms, comorbidities and QoL, emerge as a primary focus of acromegaly patient management.

Cell specific interaction of pasireotide: review of preclinical studies in somatotroph and corticotroph pituitary cells.

BACKGROUND: Pasireotide is a second-generation somatostatin (SRIF) receptor ligand (SRL), approved for medical treatment of acromegaly and Cushing's disease (CD). The molecule is a stable cyclohexapeptide synthetized based on SRIF structure. Differently from first-generation SRLs (e.g. octreotide), preferentially binding somatostatin receptor (SST) subtype 2 (SST2), pasireotide has high affinity for multiple SSTs (SST5 > SST2 > SST3 > SST1). Interestingly, early preclinical studies demonstrated that pasireotide shows distinct functional properties compared to SRIF and first-generation SRLs when binding SSTs. METHODS: We aimed to highlight the differential receptor-targeted action of pasireotide in the treatment of somatotroph and corticotroph adenomas, throughout the critical revision of preclinical studies carried out on acromegaly and CD models. RESULTS: Different authors demonstrated that the antisecretory effect of pasireotide in somatotroph adenoma cell cultures is comparable to that of the SST2-preferential agonist octreotide. Some reports even show a direct correlation between SST2 mRNA expression and GH reduction after pasireotide treatment, thus laying for a predominant role of SST2 in driving pasireotide efficacy in somatotropinomas in vitro. On the other hand, the inhibitory effect of pasireotide on ACTH secretion in corticotropinoma cells seems to be mainly mediated by SST5. Indeed, most reports show a higher potency and efficacy of pasireotide compared to SST2 preferential agonists, while functional studies confirm the pivotal role of SST5 targeting in corticotroph cells. CONCLUSIONS: The analysis of preclinical studies carried out in somatotroph and corticoph adenomas points out that pasireotide shows a cell-specific activity, exerting its biological effects via different SSTs in the different adenoma histotypes.

One-year GH replacement therapy reduces early cardiac target organ damage (TOD) in adult GHD patients.

Hypopituitarism reduces life expectancy and increases the risk of cardiovascular and cerebrovascular diseases, as well as death. Abnormalities in the cardiovascular system may be independently related to GH deficiency (GHD). The aim of this study was to prospectively investigate coronary flow reserve and diastolic function in GHD adult patients at diagnosis and after 1 year of GH replacement therapy. As control group, an age- and sex-matched population was chosen. All patients and controls were non-smokers, non-diabetic, and normotensive, with no history of vascular disease. 14 patients with adult-onset GHD and 17 controls represent the two study groups. Anthropometric data, blood pressure, lipid profile, glycosylated hemoglobin (HbA1c) and IGF-I plasma levels, coronary flow reserve (CFR), and LV diastolic function (evaluated by E/A) were collected in all subjects before and after 12 months of GH replacement therapy. Compared with controls, systolic and diastolic blood pressure and LDL cholesterol levels were significantly higher at baseline and return, comparable to controls after 1 year of GH replacement (GHRT). GHD patients showed a blunted CFR at baseline (P < 0.001) and a significant improvement after GHRT, returning to values comparable with those recorded in the control group. In addition, after therapy a significant (P < 0.001) improvement in E/A was recorded. One year of GH therapy improves CFR and E/A in the patient population analyzed, thereby encouraging the early start of GHRT.

Bone turnover and mineral density in adult thalassemic patients: relationships with growth hormone secretory status and circulating somatomedins.

Previous evidence supports a role for growth hormone (GH)-insulin-like growth factor (IGF)-I deficiency in the pathophysiology of osteopenia/osteoporosis in adult thalassemia. Moreover, serum IGF-II has never been studied in this clinical condition. Thus, we elected to study the GH secretory status and the levels of circulating somatomedins, correlating these parameters with bone mineral density (BMD) and biochemical markers of bone turnover. A hundred and thirty-nine normal weight adult thalassemic patients (72 men and 67 women) were studied. Lumbar and femoral neck BMD were measured in 106/139 patients. Sixty-eight patients underwent growth hormone releasing hormone plus arginine testing. Measurement of baseline IGF-I and IGF-II was performed in all patients, while osteocalcin, C-terminal telopeptide of type I collagen (CTx), and urinary cross-linked N-telopeptides of type I collagen (NTx) were assayed in 95 of them. Femoral and lumbar osteoporosis/Z score below the expected range for age were documented in 61.3 and in 56.6 % of patients, respectively. Severe GH deficiency (GHD) was demonstrated in 27.9 % of cases, whereas IGF-I SDS was low in 86.3 %. No thalassemic patients displayed circulating levels of IGF-II below the reference range. GH peaks were positively correlated with femoral, but not lumbar, Z score. No correlations were found between GH peaks and osteocalcin, CTx and NTx. GH peaks were positively correlated with IGF-I values, which in their turn displayed a positive correlation with osteocalcin, CTx, and NTx. No correlations emerged between IGF-I values and either femoral or lumbar Z scores. No correlations were found between IGF-II and any of the following parameters: GH peaks, osteocalcin, CTx, NTx, femoral Z score, and lumbar Z score. Our study, besides providing for the first time evidence of a normal IGF-II production in thalassemia, contributes to a better understanding of the involvement of the somatotropin-somatomedin axis in the pathophysiology of bone demineralization in this disease. In particular, the contribution of GHD to femoral osteoporosis appears to be likely mediated by locally produced rather than circulating IGF-I.

Twenty years of gastroenteropancreatic neuroendocrine tumors: is reclassification worthwhile and feasible?

Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) are rare neoplasms with heterogeneous clinical behavior and potential long-term survival. In 2006/2007, the European Neuroendocrine Tumors Society introduced an important parameter, grade (based on mitoses and Ki-67 proliferation rate), which became part of the latest 2010-WHO classification. Since this is an important tool in the choice of therapeutic algorithm of patients with NETs, our aim was to audit whether retrospective reclassification is possible and feasible and correlate pathological findings with survival. From the histopathology archive, 338 GEP-NETs (1994-2014) were identified, of which 250 were diagnosed pre-2010 and 80 of these have needed, up till now, classification (morphology and grade-mitotic count/Ki-67). Morphology was well differentiated (WD) in 74 cases while only 6 cases were poorly differentiated (PD). Grade was reclassified: G1-45 cases (56 %); G2-28 cases (35 %); G3-7 cases (9 %). Overall survival (OS) in WD NETs was strikingly better compared to PD neoplasms. Differences in OS between grade were statistically significant (p < 0.0001) and, in particular, grade identified a subgroup of patients with WD lesions but with less favorable clinical behavior (OS at 5 years: G1-89 %; G2-48 %; G3-0 %; G1 vs G2 p = 0.03). Feasibility analysis quantified time for reclassification to be between 45 and 64 min/case. Our series confirms the importance of grade in prognostic stratification and underlines that reclassification is feasible, and may prove worthwhile in patient management, especially in view of the potential long survival of patients with NETs and risk of use of inappropriate therapies.