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Since SARS-CoV-2 outbreak in December 2019, world health-system has been severely impacted with increased hospitalization, Intensive-Care-Unit (ICU) access and high mortality rates, mostly due to severe acute respiratory failure and multi-organ failure. Excessive and uncontrolled release of proinflammatory cytokines (cytokine release/storm syndrome, CRS) have been linked to the development of these events. The recent advancements of immunotherapy for the treatment of hematologic and solid tumors shed light on many of the molecular mechanisms underlying this phenomenon, thus rendering desirable a multidisciplinary approach to improve COVID-19 patients' outcome. Indeed, currently available therapeutic-strategies to overcome CRS, should be urgently evaluated for their capability of reducing COVID-19 mortality. Notably, COVID-19 shares different pathogenic aspects with acute graft-versus-host-disease (aGVHD), hemophagocytic-lymphohistiocytosis (HLH), myelofibrosis, and CAR-T-associated CRS. Specifically, similarly to aGVHD, an induced tissue damage (caused by the virus) leads to increased cytokine release (TNFα and IL-6) which in turn leads to exaggerated dendritic cells, macrophages (like in HLH) and lymphocytes (as in CAR-T) activation, immune-cells migration, and tissue-damage (including late-stage fibrosis, similar to myelofibrosis). Janus Kinase (JAK) signaling represents a molecular hub linking all these events, rendering JAK-inhibitors suitable to limit deleterious effects of an overwhelming inflammatory-response. Accordingly, ruxolitinib is the only selective JAK1 and JAK2-inhibitor approved for the treatment of myelofibrosis and aGVHD. Here, we discuss, from a molecular and hematological point of view, the rationale for targeting JAK signaling in the management of COVID-19 patients and report the clinical results of a patient admitted to ICU among the firsts to be treated with ruxolitinib in Italy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Botta, Indrieri, Garofalo, Biamonte, Bruni, Pasqua, Cesario, Costanzo, Longhini and Mendicino.)

Purpose: Struma ovarii (SO) is a highly specialized ovarian teratoma, consisting of thyroid tissue. Rarely, carcinomas histologically identical to their thyroid counterparts may occur, and are comprehensively defined as malignant struma ovarii (MSO). Their optimal management is controversial, and the molecular profile of the malignant counterpart in the ovary is incompletely known. In this study, the clinicopathological and molecular features of six MSO from different Italian Institutions were analysed, to explore genetic profiles of potential therapeutic interest., Methods: The histopathological features and immunoprofile (according to the known markers Galectin-3, HBME1, cytokeratin 19 and CD56) were reviewed. In addition, all cases underwent genetic analysis with a next-generation sequencing (NGS) hot spot cancer panel detecting mutations in 50 genes involved in cancerogenesis. RET/PTC rearrangements and TERT promoter alterations were also evaluated., Results: Papillary carcinoma in all similar to its thyroid counterpart was found in five of six cases, including classical (two tumors) and follicular variant (three tumors) types. The last case was a poorly differentiated carcinoma. An activating gene mutation, was detected in five of six cases, including two NRAS, two BRAF, and one JAK3 oncogene mutations. No alterations were found in the other panel genes, nor in TERT promoter, or in RET chromosomal regions., Conclusions: MSO is a rare condition. Papillary carcinoma is the predominant malignant type, sharing both histomorphological and molecular features of its thyroid counterpart. Interestingly, the single case of poorly differentiated carcinoma displayed a JAK3 mutation. The presence of such driving mutation could be of potential interest in guiding postoperative treatment.

The proportion of new diagnoses of HIV infection in immigrants residing in Italy raised from 11% in 1992 to 29.7% in 2018. To investigate the HIV clades circulating in this community a retrospective study was performed in 557 HIV-infected immigrants living in 12 Italian cities. Immigrants originated from East-Europe and Central-Asia (11.7%), North Africa and Middle East (7.3%), South and South-East Asia (7.2%), Latin America and the Caribbean (14.4%), and sub-Saharan Africa (59.4%). More than 87% of immigrants were on antiretroviral therapy (ART), although 26.6% of them were viremic. A 22.0% of immigrants had hepatitis (HBV and/or HCV) and/or tuberculosis. HIV phylogenetic analysis on sequences from 192 immigrants showed the presence of clades B (23.4%), G (16.1%), C (10.4%), A1 (9.4%), F1 (5.2%), D (1.6%) and Circulating Recombinant Forms (CRFs) (33.9%). CRF02_AG represented 72.3% of the total CRFs. Clusters between immigrants and Italian natives were also present. Drug resistance mutations to NRTI, NNRTI, and PI drug classes occurred in 29.1% of ART-treated and in 12.9% of ART-naïve individuals. These data highlight the need for tailored public health interventions in immigrants to avoid spreading in Italy of HIV genetic forms and ART-resistant variants, as well as HIV co-morbidities.

Lenvatinib (LEN) is a multikinase inhibitor with antiangiogenic properties recently approved in radioactive iodine-refractory differentiated thyroid cancer, hepatocellular carcinoma, and renal cell carcinoma in combination with everolimus. LEN-treated patients frequently have adverse events (AEs) that generally require such dose modifications, including drug discontinuation. Hypertension, diarrhea, weight loss, proteinuria, fatigue, and palmar-plantar erythrodysesthesia are reported among the most frequent AEs, often leading to discontinuations or dose modifications. This paper reports a case series focusing on the role of the immediate multidisciplinary approach to manage AEs., (© 2019 S. Karger AG, Basel.)

Objective: Primary hyperparathyroidism (PHPT) and thyroid diseases are highly prevalent in the general population, but the putative link between the 2 conditions remains unclear., Methods: A monocentric consecutive series of 434 patients with PHPT was retrospectively evaluated by lab and ultrasonography to look for thyroid abnormalities. Patients were classified in 3 groups: without thyroid abnormalities (group 1, n = 171), with thyroid diseases not previously known (group 2a, n = 69), and thyroid diseases previously known (group 2b, n = 194)., Results: In terms of thyroid disease, no significant difference was found between groups 2a and 2b, except for the significantly larger number of patients with toxic nodular goiter in group 2b. PHPT was more frequently symptomatic in group 2a than in group 2b, despite no differences in serum calcium, creatinine, parathyroid hormone (PTH), or 25-hydroxyvitamin D (25OHD) levels., Conclusion: A total of 60% of PHPT patients had a thyroid disease that was unknown prior to PHPT diagnosis in almost one-third of cases. The newly diagnosed and previously known thyroid diseases were similar, both mostly affecting postmenopausal females., Abbreviations: Ab = antibody; aPHPT = asymptomatic PHPT; 25OHD = 25-hydroxyvitamin D; PHPT = primary hyperparathyroidism; PTH = parathyroid hormone; Tg = thyroglobulin; TPO = thyroperoxidase; TSH = thyroid-stimulating hormone; US = ultrasound.

Aim: The aim of this study was compare the capacity of different irrigation protocols for debris removal from artificial grooves and assess the effectiveness of Easy Clean used in different kinematics by means of micro-CT., Methodology: Fifty acrylic prototyped maxillary incisors were instrumented and included in a muffle. The specimens were longitudinally sectioned, and a longitudinal groove was made on the inner surface of the root canal in one of hemisections, and the dentin debris was inserted into the grooves. The specimens were divided into five groups ( n = 10): G1: Conventional with open-ended needle; G2: Conventional with double side-vented needle; G3: Easy Clean in reciprocating movement; G4: Easy clean in continuous rotation (ECCR); and G5: Passive ultrasonic irrigation (PUI). All specimens were scanned using microcomputed tomography before and after the irrigation technique and calculated the volume (mm 3 ) of dentin debris. The paired t -test and post hoc Tukey test were the statistical tests used, with significance set at 5%., Results: There were no significant difference ( P > 0.05) between PUI and ECCR. ECCR was significantly ( P < 0.05) more effective than the groups of conventional irrigation techniques., Conclusions: PUI and ECCR favored the removal of a larger volume of dentin debris from the groove., Competing Interests: There are no conflicts of interest.

Aim: To evaluate the intratubular antimicrobial activity of several oxidant and chelating agents associated with or without surfactants in experimentally infected root canals, using confocal laser scanning microscopy., Methodology: Twenty-four dentine blocks from bovine incisors were contaminated for 5 days with Enterococcus faecalis (ATCC- 29212). Ten contaminated dentine specimens were irrigated for 5 min with 5.25% NaOCl followed by 17% EDTA for 2 min, and the other 10 with Hypoclean for 5 min followed by Tetraclean NA for 2 min. The remaining four specimens were used as positive and negative controls (two samples each). Then, dentine blocks were stained with Live/Dead BacLight for analysis of the remaining live or dead bacteria using confocal laser scanning microscopy. Comparison between and within groups was performed using the Mann-Whitney test for independent samples and the Wilcoxon signed-rank test, respectively., Results: After exposure to irrigants, the positive control group had a median of 67.41% of viable bacteria (95% CI: 48.15, 78.9), whilst the NaOCl+EDTA group and Hypoclean+Tetraclean NA group had 3.77% (1.28, 15.92) and 0.87% (-0.42, 4.30) of viable bacteria, respectively. These results were significantly different from each other, both overall and distinct by region (cervical and medium third), or depth (superficial and deep layer) (P < 0.01 in all cases)., Conclusions: The use of adjunctive agents reducing the surface tension associated with oxidant and chelating agents improved the antimicrobial activity of irrigating solutions and intratubular decontamination against Enterococcus faecalis, possibly due to better removal of the smear layer and deeper penetration into dentinal tubules., (© 2017 International Endodontic Journal. Published by John Wiley & Sons Ltd.)

Aim: To check the safety and efficacy of boceprevir/telaprevir with peginterferon/ribavirin for hepatitis C virus (HCV) genotype 1 in the real-world settings., Methods: This study was a non-randomized, observational, prospective, multicenter. This study involved 47 centers in Italy. A database was prepared for the homogenous collection of the data, was used by all of the centers for data collection, and was updated continuously. All of the patients enrolled in this study were older than 18 years of age and were diagnosed with chronic infection due to HCV genotype 1. The HCV RNA testing was performed using COBAS-TaqMan2.0 (Roche, LLQ 25 IU/mL)., Results: All consecutively treated patients were included. Forty-seven centers enrolled 834 patients as follows: Male 64%; median age 57 (range 18-78), of whom 18.3% were over 65; mean body mass index 25.6 (range 16-39); genotype 1b (79.4%); diagnosis of cirrhosis (38.2%); and fibrosis F3/4 (71.2%). The following drugs were used: Telaprevir (66.2%) and PEG-IFN-alpha2a (67.6%). Patients were naïve (24.4%), relapsers (30.5%), partial responders (14.8%) and null responders (30.3%). Overall, adverse events (AEs) occurred in 617 patients (73.9%) during the treatment. Anemia was the most frequent AE (52.9% of cases), especially in cirrhotic. The therapy was stopped for 14.6% of the patients because of adverse events or virological failure (15%). Sustained virological response was achieved in 62.7% of the cases, but was 43.8% in cirrhotic patients over 65 years of age., Conclusion: In everyday practice, triple therapy is safe but has moderate efficacy, especially for patients over 65 years of age, with advanced fibrosis, non-responders to peginterferon + ribavirin.

Introduction: A reduction in bone mineral density (BMD) is common in primary hyperparathyroidism (PHPT), above all at cortical sites. Guidelines for the management of asymptomatic PHPT (aPHPT) recommend a BMD evaluation at the lumbar spine, hip, and forearm. Surgery is recommended for patients with a T-score less than or equal to -2.5 at any of these sites. However, a BMD evaluation at the forearm is not routinely performed., Aim: To evaluate the impact of measuring forearm BMD in the clinical management of aPHPT., Subjects and Methods: We retrospectively reviewed a prospective database of 172 patients with aPHPT, selecting the 116 patients in whom a dual x-ray absorptiometry (DXA) scan had been performed at all 3 sites., Results: Seventy-four out of 116 patients had a densitometric diagnosis of osteoporosis (OP) at any site, and the forearm was the only site involved in 13/74 (group A, 17.6% of osteoporotic patients and 11.2% of the whole aPHPT cohort). Patients belonging to group A were significantly older than the other aPHPT patients, whereas no difference was found in biochemical measurements. Six out of 13 patients belonging to group A (5.2% of the whole aPHPT cohort) fulfilled surgical criteria based only on a forearm T-score., Conclusions: DXA at 3 sites revealed OP at the forearm, but not at the other sites, in 11.2% of aPHPT patients. Half of these cases met surgical criteria based on this one factor alone. These patients did not show any clinical (except age) or biochemical differences from the other patients. The implementation of forearm DXA increases the rate of patients with aPHPT meeting surgical criteria.

Introduction: Evidence of crosstalk between bone and insulin metabolism has been identified. In primary hyperparathyroidism (PHPT), scant data exist on this relationship., Aim: To evaluate the relationship between insulin levels or sensitivity and bone mineral density (BMD) in PHPT., Subject and Methods: Two hundred and sixty-seven patients with PHPT without known diabetes mellitus were studied. Fasting blood glucose and insulin levels as well as BMD at lumbar spine, femoral neck and forearm were measured. Insulin sensitivity was assessed using Quantitative Insulin Sensitivity Check Index (QUICKI). The same parameters were measured 2 years (interquartile range 2·8 years) after surgery (PTX) in a subgroup of patients (n = 51)., Results: In univariate analysis, a positive relationship between insulin levels and BMD (R = 0·17, P < 0·03) or T-score (R = 0·20, P < 0·005) was found at femoral neck level. Consequently, a negative relationship between QUICKI and femoral BMD (R = -0·20, P < 0·01) or T-score (R = -0·21, P < 0·004) was found. In multivariate analysis, when femoral BMD was the dependent variable, age (beta = -0·35, P < 0·000004), BMI (beta = 0·39, P < 0·00001), PTH (beta = -0·18, P < 0·05) and QUICKI (R = -0·15, P < 0·05) had an independent effect (R(2) = 0·29). Insulin levels and QUICKI did not change after PTX. No relationship was found between QUICKI or insulin levels at the time of diagnosis and change in BMD at any site at follow-up., Conclusions: Our data show a weak relationship between insulin levels and/or insulin sensitivity and BMD in PHPT. However, the insulin state does not influence change in bone density after PTX in PHPT., (© 2014 John Wiley & Sons Ltd.)

The epidemiological profile of HCV infection is evolving in Europe, as well as in Italy. We have previously showed genotype distributions and their dynamics in 2,153 HCV RNA positive patients living in Calabria, Southern Italy, over 11 years. In this study, we extend and update this information by evaluating a hospital-based cohort of 945 HCV RNA positive patients attending five hospitals in the Calabria Region from January 2011 to August 2013. We assessed rates of HCV genotypes according to age and gender and the dynamics of HCV genotype distribution over the 3-year period studied. Data showed that genotype 1b is the most prevalent, followed by subtypes 2a/2c and genotype 3. Genotype 4 exhibited an increase between 2011 and 2013. Also, we found a significant decrease in the median age of subjects infected with HCV genotype 3 and 4 during the period studied. Since HCV genotypes are important in epidemiology, pathogenesis and response to antiviral therapy, a continuous epidemiological surveillance is needed.

We present clinical cases, which underline some difficulties in diagnosis and treatment of hepatitis C virus (HCV) infection. Case report #1 shows a patient who avoided clinical follow-up for HCV until the development of hepatocellular carcinoma. In this patient, non-invasive procedures did not allow to make a differential diagnosis between hydatidosis and hepatocellular carcinoma but diagnosis was only made with liver biopsy.

Background: Vitamin D deficiency (VDD) is common in patients with primary hyperparathyroidism (pHPT), and this could affect the clinical expression of the disease. However, few North American or North European studies have addressed this issue, showing vitamin D repletion in only about one-third of the patients., Subjects and Methods: Vitamin D status was evaluated both in an observational study in a series of 206 consecutive patients with pHPT at diagnosis and in a case-control analysis with 113 age- and sex-matched healthy blood donors. Vitamin D status was assessed by measuring plasma 25-hydroxy-vitamin D (25OHD) levels and was defined as VDD or severe VDD if 25OHD was <20 ng/ml (<50 nm) and <10 ng/ml (<25 nm), respectively., Results: No seasonal variability was observed in 25OHD levels. VDD was observed in 75 of 206 patients (36·4%). The VDD was severe in 24 of 75 patients (11·7%). There was no difference in prevalence of VDD between men and women nor between asymptomatic and 'bone and stone' symptomatic patients. 25OHD levels was negatively correlated with parathyroid hormone, ionized calcium, and bone turnover markers, and positively correlated with phosphate. 25OHD levels were also positively correlated with bone mineral density at all sites measured. In the case-control study, the overall prevalence of VDD and severe VDD was higher in patients with pHPT compared with controls (33·6% vs 10·6%, P < 0·0001, and 8·8% vs 1·8%, P = 0·0337, respectively)., Conclusions: Our study shows that VDD occurs in about one-third of patients with pHPT resident in a Southern European area, a lower figure than previously reported. Moreover, VDD is related to a more severe bone disease, and its prevalence is higher in patients with pHPT than in healthy matched subjects., (© 2013 John Wiley & Sons Ltd.)

Aims: Primary hyperparathyroidism (pHPT) is characterized by an increased frequency of glucose tolerance abnormalities associated with insulin resistance. Few studies evaluated the prevalence of metabolic syndrome (MetS) in pHPT and whether there are differences between asymptomatic pHPT patients and symptomatic ones. Thus, we sought to investigate the prevalence of MetS in pHPT patients in comparison to the prevalence of MetS in Italian population., Subjects and Methods: We conducted a retrospective chart review of 294 pHPT patients, of these 154 [age (mean ± SD) 58.7 ± 13.3 yr, body mass index 25.6 ± 4.8 kg/m(2); serum calcium (11.3 ± 1.2 mg/dl) 2.8 ± 0.3 mmol/l; PTH 234.8 ± 224.3 ng/l] met the inclusion criteria. A modified National Cholesterol Educational Program (NCEP)/Adult Treatment Panel III (ATP III) definition of the MetS was used. Prevalence of MetS was compared with that reported for the Italian population (Progetto Cuore Study)., Results: The prevalence of the MetS (34/154, 22.1%) was similar to that reported in the general Italian population. Asymptomatic pHPT patients were older (62.1 ± 12.7 vs 56.4 ± 13.2 yr, p<0.008) and showed higher prevalence of MetS than symptomatic ones (30.2% vs 16.5%, p<0.045). Moreover the prevalence of nephrolitiasis or overt bone disease was not different between patients MetS+pHPT compared to MetS-pHPT, whereas femoral bone mineral density (BMD) was higher in MetS+pHPT (p<0.003). In the logistic regression model age and femoral BMD were independent predictors of MetS., Conclusions: The prevalence of MetS in pHPT is not increased in comparison to the general population, thus, its diagnosis is not an appropriate tool to identify the additional cardiovascular risk related to pHPT. Difference in age affects the increased prevalence of MetS in asymptomatic pHPT patients.

The SINERGIE (South Italian Network for Rational Guidelines and International Epidemiology) project is intended to set up a collaborative network comprising virologists, clinicians and public health officials dealing with patients affected by HCV disease in the Calabria Region. A prospective observational data-base of HCV infection will be developed and used for studies on HCV natural history, response to treatment, pharmaco-economics, disease complications, and HCV epidemiology (including phylogenetic analysis). With this approach, we aim at improving the identification and care of patients, focusing on upcoming research questions. The final objective is to assist in improving care delivery and inform Public Health Authorities on how to optimize resource allocation in this area.

Osteocalcin (OC) has been proposed as a regulator of insulin sensitivity in both humans and other animals. Primary hyperparathyroidism (PHPT) is characterized by high OC levels and insulin resistance. The aim of this study was to evaluate whether in PHPT the link between OC levels and blood markers of insulin resistance was maintained. In a consecutive series of 219 adult PHPT patients, serum OC as well as fasting insulin and glucose levels were measured. Insulin sensitivity was estimated by homeostatic model assessment (HOMA2-S%). The same parameters were evaluated in a subgroup of 45 patients after parathyroidectomy (PTX). PHPT patients were characterized by markedly high OC levels. After subdividing them according to glucose tolerance, it was found that OC was similar in subjects with normal glucose tolerance (NGT) and impaired glucose tolerance (IGT), while diabetic subjects had lower serum OC than those with NGT (P < 0.02) or IGT (P < 0.04). OC was negatively associated with fasting glucose and positively associated with HOMA2-S%. OC independently predicted HOMA2-S% in a multivariate analysis. In the subgroup of surgically cured PHPT patients, OC levels significantly decreased after PTX, while HOMA2-S% did not change. Our findings indicate that in PHPT there is a positive relationship between OC and glucose metabolism, OC being one of the predictors of insulin sensitivity. However, data in surgically cured patients, showing OC normalization in spite of unchanged HOMA2-S%, suggest that OC does not likely play a major role in affecting insulin sensitivity in PHPT.

The kidney is one of the classical target organs of PTH action. Symptomatic primary hyperparathyroidism (PHPT) is nowadays less frequent but mostly occurs with renal symptoms, in particular kidney stones. Nephrocalcinosis and polyuria, the latter closely related to the severity of hypercalcemia, are uncommon. Parathyroidectomy leads to a marked and long-lasting improvement of nephrolithiasis, whereas it has a limited effect on nephrocalcinosis. Kidney failure is one of the long-term complications of PHPT and is associated with a more severe clinical expression of the disease and a higher risk of morbidity and mortality. Current guidelines on the management of asymptomatic PHPT, the most common presentation of PHPT today, recommend surgical treatment if renal function is decreased. However, in this particular clinical setting it is unclear whether PHPT is really associated with a more rapid decline of renal function or whether successful parathyroidectomy could protect renal function.

Background: The impairment of renal function can affect the clinical presentation of primary hyperparathyroidism (PHPT), increasing cardiovascular morbidity, fracture rate, and the risk of mortality., Aim: The aim of the study was to assess the differences in bone status in a series of consecutive patients affected by PHPT without overt renal failure at diagnosis grouped according to creatinine clearance (Ccr)., Methods: A total of 161 consecutive patients with PHPT were studied. They were divided into two groups based on Ccr. Group A had Ccr 70 ml/min or less (n = 49), and group B had Ccr greater than 70 ml/min (n = 112). PTH, total and ionized serum calcium; urinary calcium and phosphate; serum 25-hydroxyvitamin D3; serum and urinary bone markers; lumbar, forearm, and femoral bone mineral density (BMD) were evaluated., Results: Patients in group A were older than those in group B (P < 0.0001). PTH levels did not differ in the two groups, whereas both urinary calcium and phosphorus were lower in group A than group B (P < 0.01). Lower BMD was evident in group A at lumbar spine (P < 0.002), forearm (P < 0.0001), and femur (P < 0.01). In asymptomatic PHPT, those with Ccr 70 ml/min or less had lower forearm BMD than patients with higher Ccr (P < 0.00001). When adjusting for age and body mass index in PHPT, BMD at each site persisted being lower (P < 0.05) in group A than group B. In all PHPT subjects, Ccr (beta = 0.29, P < 0.0005), age (beta = -0.27, P < 0.00001), and PTH levels (beta = -0.27, P < 0.0005) were all independently associated with forearm BMD., Conclusions: In PHPT a slight decrease in renal function is associated with more severe BMD decrease, independent of age, body mass index, and PTH levels. This association is also present in asymptomatic PHPT and strengthens the National Institutes of Health recommendations for surgery in patients with mild PHPT.

Infections are major complications and constitute the second most common cause of mortality and a main cause of morbidity in patients with thalassaemia, a group of genetic disorders of haemoglobin synthesis characterised by a disturbance of globin chain production. Thalassaemias are among the most common genetic disorders in the world. Predisposing factors for infections in thalassaemic patients include severe anaemia, iron overload, splenectomy, and a range of immune abnormalities. Major causative organisms of bacterial infections in thalassaemic patients are Klebsiella spp in Asia and Yersinia enterocolitica in western countries. Transfusion-associated viral infections (especially hepatitis C) can lead to liver cirrhosis and hepatocellular carcinoma. A unique and challenging infection detected in Asian patients is pythiosis, caused by a fungus-like organism, the mortality rate of which is very high. Because the prognosis for thalassaemia has much improved, with many patients surviving to the fifth decade of life in developed countries, it is mandatory to reduce mortality by recognising and presumptively treating infections in these patients as quickly as possible.

Rapid intraoperative parathyroid hormone (RIOPTH) monitoring predicts complete removal of all hypersecreting tissue by means of a significant parathyroid hormone (PTH) decrease. In this study we have tried to provide an explanation for some unexpected results of RIOPTH monitoring observed during a series of 125 conventional parathyroidectomies for primary hyperthyroidism, discussing the possible consequences on the surgical strategy. Three main groups can be recognized: (1) spikes: a PTH increase 10 minutes after removal of the diseased gland was observed in three patients; (2) false-negative results: six patients showed an inadequate PTH decreases at 10 minutes, three of them resulting in cure at 20 minutes (all six patients were cured at follow-up); (3) false-positive results: five patients with multiglandular disease showed a PTH decrease to a cure level despite excision of one adenoma only (in two of these patients a 20-minute sample showed a PTH increase soon after manipulation of the second adenoma). We concluded that the spike, almost certainly a consequence of manipulating the adenoma, when detected should be considered the "true" baseline value. False-negative results are to some extent related to undetected spikes. The assay used for RIOPTH determination and PTH half-life variability may also play a role. A false-negative result usually prolongs the surgical time. False-positive results are usually related to a double adenoma, one functionally prevailing over the other. Because in our experience manipulation of the second adenoma brought a PTH increase detected with RIOPTH monitoring, we believe that the second adenoma should be excised.

Symptomatic hypoglycemia is described in children with severe GH deficiency (GHD), but is rare in adults with GHD. We describe the case of a 62- yr-old man, referred for recurrent hypoglycemic events. He reported a previous head trauma at the age of 20 yr and a diagnosis of reactive hypoglycemia at the age of 50 yr. In the last months, during a period of job-related stress, the hypoglycemic episodes became more frequent and severe (glucose <2.2 mmol/l), finally requiring hospitalization. On admission, the patient was in good general health, with normal renal and hepatic function. During hospitalization, no hypoglycemic episodes were recorded, also during a 72-h fasting test. Biochemical data and abdominal computed tomography (CT) excluded insulinoma. A tumor-induced hypoglycemia was ruled out. The 4-h oral glucose tolerance test (OGTT) showed an impaired glucose tolerance with a tendency toward asymptomatic hypoglycemia. Hormonal study disclosed low levels of GH (0.2 ng/ml) and IGF-I (51 ng/ml); the response of GH to GHRH plus arginine confirmed a severe GHD (GH peak 2.7 ng/ml). Other pituitary and counterregulation hormones were within the normal range and magnetic resonance imaging (MRI) of the pituitary gland was normal. Replacement therapy with a low dose of rhGH induced an increase of IGF-I up to low-normal values, accompanied by lasting regression of hypoglycemic events. In conclusion, hypoglycemia was the main clinical symptom of isolated adult onset GHD, in the present case. The possible pathogenesis of isolated adult onset GHD and the association of GHD with conditions predisposing to hypoglycemia are considered and discussed.

Insulinoma is characterized by spontaneous fasting hypoglycemia. Diagnosis relies on inappropriately increased insulin levels (>6 microU/ml), high insulin/glucose ratio (IGR >0.3), raised proinsulin values (>5 pMol/l). A 74-yr-old man was referred to us for episodes of symptomatic hypoglycemia without hyperinsulinemia and imaging [abdominal computed tomography (CT) and magnetic resonance scans] negative for neuroendocrine tumor (NET). During hospitalization severe hypoglycemic crises persisted requiring continuous glucose iv infusion. Insulin values (immunofluorimetric method) were not inappropriately increased, accordingly IGR was normal but C-peptide was in the upper-normal range. Proinsulin levels measured with specific radioimmunoassay were remarkably high. Octreoscan study was negative whereas endoscopic ultrasound disclosed a 10 mm lesion in the body of the pancreas, confirmed by rapid spiral CT scanning with dynamic images. Increased proinsulin levels allowed diagnosis of a secreting NET. After removal of the lesion, the patient experienced hyperglycemia. Histology confirmed a benign NET positively staining for insulin. In conclusion, proinsulin assay is of particular help when immunoreactive insulin, measured by specific new immunometric assays (immunoenzymometric and immunofluorimetric assays), is normal. These methods have good precision and specificity (no cross reactivity with intact or Des 31,32 proinsulin), but rare insulinomas secreting most, or all, of their insulin-like activity as proinsulins would go undetected if insulin levels alone were measured.

Aims: To evaluate the frequency of impaired glucose tolerance (IGT)and undiagnosed diabetes mellitus together with the indices of insulin resistance (IR) in primary hyperparathyroidism (pHPT)., Methods: Out of 105 consecutive pHPT patients (F/M 78/27, asymptomatic/symptomatic 68/37, age (mean +/- s.d.) 60.7 +/- 12.7 years,body mass index 25.2 +/- 3.8 kg/m2, ionized calcium (iCa) 1.49 +/- 0.16 mmol/l,parathormone 200.4 +/- 233.9 pg/ml),59 without known diabetes mellitus and controls (n = 60) underwent an oral glucose tolerance test (OGTT, 75 g os). As indices of IR, homeostasis model assessment (HOMAIR)or OGTT data (insulin sensitivity index composite (ISI comp)) were evaluated., Results: In pHPT the prevalence of IGT (mean, 95% confidence intervals (CI), 40.7%, 27.8-53.6) was higher than in controls (25.0%, 13.7-36.3, P < 0.03). Similarly,the prevalence of undiagnosed diabetes mellitus was higher in pHPT(15.3%, 5.8-24.7) than in controls (5.0%, 0-10.7, P < 0.05). Moreover,the prevalence of IGT and undiagnosed diabetes was higher in pHPT than that previously reported in the general population of Northern Italy(8.5% and 3.2%, respectively). The indices showed that insulin resistance was higher in pHPT than in controls: HOMAIR (median, 95% CI,2.6, 2.5-3.9 vs. 1.7, 1.6-2.5, respectively; P < 0.003); ISI comp (3.5, 3.4-4.6 vs. 5.1, 4.9-7.2, respectively; P < 0.002)., Conclusions: Our data in a large and modern day pHPT series, with a preponderance of asymptomatic patients, confirm increased insulin resistance and pre-valence of IGT and undiagnosed diabetes.

Objective: The desmopressin test is generally regarded as an alternative to the CRH test but it is unclear whether desmopressin is as effective as CRH in the differential diagnosis of ACTH-dependent Cushing's syndrome. However, a precise assessment of the operating characteristics of the desmopressin test in comparison with the CRH test has not been reported. The aim of the present study was to make a comparative evaluation of desmopressin and CRH tests in a consecutive cohort of patients with ACTH-dependent Cushing's syndrome and in a group of healthy subjects., Design and Subjects: We studied 34 patients with Cushing's disease (CD) and nine patients with ectopic ACTH syndrome (EAS). The control group included 30 healthy subjects. Estimates of sensitivity and specificity were determined for a value of ACTH percent increment (Delta%) > 35% and for a Delta % > 50%, following either desmopressin or CRH, to differentiate CD from EAS. The sensitivity and specificity of a composite rule requiring an ACTH net increment (Delta) > 4.5 pmol/l at both values of Delta % was also calculated. When evaluating cortisol responses, the criteria were Delta % > 20% and Delta > 193 nmol/l. Moreover, to allow comparison of individual end points of the desmopressin and CRH tests at multiple levels of Delta % or Delta either for ACTH or cortisol without the bias of predetermined criteria, univariate curves of the receiver operating characteristics (ROC) were constructed by plotting the sensitivity against 1 - specificity at each level., Results: In the patients with CD, the frequency of ACTH response was of 90% after both tests while the figures for cortisol were 73% after CRH and 77% after desmopressin, respectively. In the 15 patients who underwent both tests the magnitude of ACTH and cortisol responses induced by the 2 stimuli were fully comparable. In the patients with EAS a (false) positive ACTH response was found in 2/9 cases (22%) after the CRH test and in 2/5 patients (40%) after the desmopressin test. In the healthy subjects the CRH test was performed in 25 cases and the desmopressin test in 15 cases. The frequency of ACTH response was 52% following CRH and 13% following desmopressin. In the 10 healthy subjects who underwent both tests the ACTH response was significantly greater after CRH than desmopressin. The area under the ROC curve for the ACTH Delta % was significantly different than that occurring by chance following CRH but not desmopressin. The point on the ROC curve closest to 1 corresponded to an ACTH Delta % of 47% (sensitivity 87% and specificity 89%). However, a criterion of 100 % specificity would require an increase in the threshold for the ACTH Delta % to 259%. ROC analysis validated also the use of the ACTH Delta as a method to assess the response to CRH, but not after desmopressin. However, the diagnostic performance of this parameter was reduced in comparison to that of the ACTH Delta %, since the best cut-off for the Delta (6.2 pmol/l) had inferior specificity (79%). The operating characteristics of CRH and desmopressin were worse when considering cortisol responses., Conclusions: The present data suggest that the CRH test is more reliable than the desmopressin test in determining the aetiology of Cushing's syndrome. The desmopressin test resulted in a high frequency of false positive results in patients with ectopic ACTH secondary to carcinoid tumours. This finding may be due to the capability of these tumours to express the V3 vasopressin receptor through which desmopressin acts. However, the clinical endocrinologist may be confronted with some disturbing cases which are misdiagnosed because it is almost impossible to set a diagnostic criterion providing complete specificity in the differentiation of (occult) ectopic Cushing's syndrome using either CRH or desmopressin tests.

Objective: The association between primary hyperparathyroidism (PHPT) and increased mortality mainly from cardiovascular disease is still debated. The increased mortality previously reported in PHPT was not confirmed in a recent population based study. A high prevalence of left ventricular (LV) hypertrophy was, however, reported in this disease. Although arterial hypertension is regarded as the principal factor, the pathogenesis of LV hypertrophy in PHPT is complex and not completely defined, moreover the effects of successful parathyroidectomy (PTX) are not fully elucidated. The aims of this study were: to ascertain the prevalence of LV hypertrophy in a series of patients with PHPT in comparison to a control population, to seek for relationship between biochemical markers of disease, blood pressure (BP) levels and LV measurements and to evaluate the effects of successful PTX on LV hypertrophy during short-term follow-up., Subjects and Design: Forty-three patients affected by active PHPT (16 males and 27 females, mean age 60.2 +/- 12.7 years) and 43 controls age- and sex-matched with the same prevalence of arterial hypertension were studied in a case-control analysis. Each subject underwent a M- and 2D mode echocardiographic evaluation and repeated BP measurement. In 21 PHPT submitted to surgery the echocardiographic measurement was repeated 6 months after successful PTX., Measurements: Serum concentrations of parathyroid hormone (PTH), total-(Ca) and ionized calcium (iCa), phosphate, creatinine, total alkaline phosphatase (TALP) were measured in patients with PHPT at diagnosis and six months after PTX in the subgroup operated on; BP values were measured in three different occasion; mono and 2D echocardiographic evaluation was performed in control subjects and patients with PHPT either before and after PTX., Results: LV hypertrophy, measured by LV mass index (LVMI), was present in 28/43 PHPT patients (65.1%) and in 15/43 (34.8%) controls, P < 0.05; among hypertensive subjects, 21/21 (100%) PHPT patients and 13/21 (61.9%) controls P < 0.05 were hypertrophic while among normotensive subjects, these figures were 7/22 (31.8%) for PHPT patients and 2/22 (9%) for controls, P = 0.67. At multiple regression analysis in a model including biochemical parameters and BP values, serum PTH levels were associated with LVMI values as the strongest predicting variable (0.46, P < 0.02). Six months after PTX, LVMI decreased (137.8 +/- 37.3 vs 113.0 +/- 28.5, P < 0.05) without changes in mean BP values and ratio of hypertensive patients., Conclusion: The present data confirm the high prevalence of LV hypertrophy in primary hyperparathyroidism also in a group of patients with an asymptomatic clinical presentation. The correlation between PTH values and left ventricular mass index suggests an action of the hormone in the pathogenesis of LV hypertrophy confirmed also by the decrease of left ventricular mass index after the reduction of PTH levels. The reversal of left ventricular mass index after parathyroidectomy could affect mortality in primary hyperparathyroidism. An echocardiographic study could be suggested in the clinical work-up of primary hyperparathyroidism in order to evaluate heart involvement and the response to successful parathyroidectomy.