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Purpose: To explore the association between carotid artery length and tortuosity, and the occurrence of stroke. Material and Methods: In this retrospective study, IRB approved, 411 consecutive patients (males: 245; median age: 56 ± 12 years, age range: 21-93 years) with anterior circulation ischemic stroke were included. Only patients that underwent CTA within 7 days were considered and stroke caused by cardiac embolism and thoracic aorta embolism were excluded. For each patient, both carotid arteries were considered, and the ICA, CCA-ICA length and tortuosity were calculated. Inter-observer analysis was quantified with the Bland-Altman test. Mann-Whitney test and logistic regression analysis were also calculated to test the association between length and tortuosity with the occurrence of stroke. Results: In the final analysis, 166 patients (males: 72; median age: 54 ± 12 years, age range: 24-89 years) with anterior circulation ischemic stroke that were admitted to our hospital between February 2008 and December 2013 were included. The results showed a good concordance for the length of the vessels with a mean variation of 0.7% and 0.5% for CCA-ICA and ICA length respectively an for the tortuosity with a mean variation of 0.2% and -0.4% for CCA-ICA and ICA respectively. The analysis shows a statistically significant association between the tortuosity index of the ICA and CCA-ICA sides with stroke ( P value = 0.0001 in both cases) and these findings were confirmed also with the logistic regression analysis. Conclusion: Results of this study suggest that tortuosity index is associated with the presence of stroke whereas the length of the carotid arteries does not play a significant role.

Introduction A substantial number of patients with neuroblastoma (NB) have increased excretion of catecholamines and metanephrines. Here, we have investigated the diagnostic role of plasma free metanephrines (PFM), metanephrine (MN), normetanephrine (NMN) and 3-methoxytyramine (3MT) for NB, the most common extra-cranial solid tumour in children. Methods PFM were quantified by using a commercial IVD-CE LC-MS/MS method on a TSQ Quantiva coupled to an Ultimate 3000. The method was further validated on 103 samples from pediatric subjects (54 patients with histologically confirmed NB and 49 age and sex matched controls). Correlations between PFM concentrations with clinical factors were tested. We directly compared MN, NMN, and 3MT concentrations in matched plasma and urine samples of NB patients (n = 29). Results 3MT and NMN showed an excellent diagnostic performance with very high specificity (100% and 95.8%, respectively) and sensitivity (88.2% and 80.4%). ROC curves were obtained (AUC of 0.93 and 0.91 for 3MT and NMN, respectively) and optimal cut-offs that could discriminate between controls and NB patients were defined. A positive correlation between NMN levels in urine and plasma (p = .0017) was found. Discussion The determination of plasma 3MT and NMN should be taken in consideration as a new diagnostic tool for NB. Validation in prospective clinical studies in comparison to urinary catecholamines and metanephrines is warranted.

Neuroblastoma (NB) and malignant cutaneous melanoma (CMM) are neural crest cells (NCC)-derived tumors and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association studies (GWAS). We took a three-staged approach to conduct cross-disease meta-analysis of GWAS for NB and CMM (2101 NB cases and 4202 controls; 12 874 CMM cases and 23 203 controls) to identify shared loci. Findings were replicated in 1403 NB cases and 1403 controls of European ancestry and in 636 NB, 508 CMM cases and 2066 controls of Italian origin. We found a cross-association at locus 1p13.2 (rs2153977, odds ratio = 0.91, P = 5.36 × 10−8). We also detected a suggestive (P < 10−7) NB-CMM cross-association at 2q37.1 with opposite effect on cancer risk. Pathway analysis of 110 NB-CMM risk loci with P < 10−4 demonstrated enrichment of biological processes such as cell migration, cell cycle, metabolism and immune response, which are essential of human NCC development, underlying both tumors. In vitro and in silico analyses indicated that the rs2153977-T protective allele, located in an NB and CMM enhancer, decreased expression of SLC16A1 via long-range loop formation and altered a T-box protein binding site. Upon depletion of SLC16A1, we observed a decrease of cellular proliferation and invasion in both NB and CMM cell lines, suggesting its role as oncogene. This is the largest study to date examining pleiotropy across two NC cell-derived tumors identifying 1p13.2 as common susceptibility locus for NB and CMM risk. We demonstrate that combining genome-wide association studies results across cancers with same origins can identify new loci common to neuroblastoma and melanoma arising from tissues which originate from neural crest cells. Our results also show 1p13.2 confer risk to neuroblastoma and melanoma by regulating SLC16A1.

The genetic aetiology and the molecular mechanisms that characterize high‐risk neuroblastoma are still little understood. The majority of high‐risk neuroblastoma patients do not take advantage of current induction therapy. So far, one of the main reasons liable for cancer therapeutic failure is the acquisition of resistance to cytotoxic anticancer drugs, because of the DNA repair system of tumour cells. PARP1 is one of the main DNA damage sensors involved in the DNA repair system and genomic stability. We observed that high PARP1 mRNA level is associated with unfavourable prognosis in 3 public gene expression NB patients’ datasets and in 20 neuroblastomas analysed by qRT‐PCR. Among 4983 SNPs in PARP1, we selected two potential functional SNPs. We investigated the association of rs907187, in PARP1 promoter, and rs2048426 in non‐coding region with response chemotherapy in 121 Italian patients with high‐risk NB. Results showed that minor G allele of rs907187 associated with induction response of patients (P = .02) and with decrease PARP1 mRNA levels in NB cell line (P = .003). Furthermore, rs907187 was predicted to alter the binding site of E2F1 transcription factor. Specifically, allele G had low binding affinity with E2F1 whose expression positively correlates with PARP1 expression and associated with poor prognosis of patients with NB. By contrast, we did not find genetic association for the SNP rs2048426. These data reveal rs907187 as a novel potential risk variant associated with the failure of induction therapy for high‐risk NB.

Purpose Stage 4S neuroblastoma, a tumor affecting infants, is characterized by the capacity to regress spontaneously and high cure rate. About a third of these infants undergo tumor progression requiring antitumor treatment and 10-15% eventually die. In case of metastatic progression, it may occur either at 4S sites (mainly liver) or sites characterizing stage 4 (mainly bone). Aim of this study was to estimate incidence, presenting features and outcome of infants who progressed to stage 4S or stage 4 sites. Patients Of 280 Italian infants diagnosed with stage 4S neuroblastoma between 1979 and 2013 and registered in the Italian Neuroblastoma Registry, 268 were evaluable for this study, of whom 57 developed metastatic progression. Results Progression to stage 4S sites occurred in 29/268 infants (10.8%) (Group A) and to stage 4 in 28/268 (10.4%) (Group B). No significant difference was observed between the two groups at the time of diagnosis. At the time of progression, Group A infants were younger (7.3 vs 14.4 months, P = .001) and had a shorter interval from diagnosis to progression (3.8 vs 9.6 months, P = .001). Survival after progression was worse for Group B infants (45% vs 69%, P = .058) and was associated with age at diagnosis lower than 2 months (P = .005) and adrenal primary tumor site (P = .008). Survival rates increased for both groups along the study period. Conclusions Infants who progressed to stage 4 did worse, possibly in relation to older age at progression and longer interval between diagnosis and progression. Large prospective studies of these patients may lead to more effective treatments.

This retrospective study evaluated implant survival rate (SR) and marginal bone loss around dental implants placed with ultrasonic implant site preparation. A total of 156 implants were placed in 28 totally and partially edentulous patients. Bone loss was measured on intraoral paralleling digital radiographs taken at the impression phase and after 4 years of loading. As 3 implants (1.92%) failed at the second surgery stage, the SR was 98.08% after 4 years. The mean marginal bone loss was 0.52 ± 0.33 mm (0.51 ± 0.35 mm mesially and 0.53 ± 0.35 mm distally), with comparable values for implants inserted into the maxilla (0.52 ± 0.32 mm) and the mandible (0.52 ± 0.35 mm).

The low Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet has demonstrated excellent results in terms of symptom control and health-related quality of life (HRQoL) in irritable bowel syndrome (IBS) sufferers, but patients have complained about unsatisfying taste, difficulty in following the diet, and time consumption. To investigate the feasibility of the low FODMAP diet in an Italian (Sardinian) cohort, sixty consecutive eligible outpatients (11 men and 49 women) with IBS were enrolled and followed a low FODMAP diet (gluten allowed, restriction phase of four weeks, reintroduction phase of four weeks). Food habits were assessed using 24-hour dietary recall, Bristol Stool Scale for stool consistency, Visual Analogue Scale for abdominal bloating, VAS (Visual Analogue Scale) for abdominal pain, IBS Severity Scoring System for perceived disease severity, and a 12-item Short Form Survey for HRQoL (psychological component summary + mental component summary) were applied at baseline (T0) and at the end of each phase (T1-four weeks and T2-eight weeks). Statistical analysis was performed by dividing the cohort into diarrhoea-dominant IBS (IBS-D) and other IBS subtypes (selected IBS-others). Comparisons between T1 and T2 vs. T0 and T2 vs. T1 were performed. The low FODMAP diet lowered VASp (VAS pain), VASb (VAS bloating), and IBS SSS (IBS Severity Scoring System), and increased PCS (Physical Component Summary) and MCS (Mental Component Summary) in both subgroups. Bristol Stool Scale (BSS) only improved in the IBS-D subgroup. The dropout mean values for MCS were higher than treated subjects and the percentage of unemployment was lower in the dropouts. According to the dropout features, the low FODMAP diet seems to show greater feasibility for patients with more time to dedicate to the diet (unemployed, homemakers, housewives, or students), more motivation, and more severe clinical features, independent of their place of residence.

Living in an enriched environment (EE) produces a notable impact on several rodent behaviors, including those motivated by drugs of abuse. This picture is somewhat less clear when referring to alcohol-motivated behaviors. With the intent of contributing to this research field with data from one of the few rat lines selectively bred for excessive alcohol consumption, the present study investigated the effect of EE on operant oral alcohol self-administration in Sardinian alcohol-preferring (sP) rats. Starting from Postnatal Day (PND) 21, male sP rats were kept under 3 different housing conditions: impoverished environment (IE; single housing in shoebox-like cages with no environmental enrichment); standard environment (SE; small colony cages with 3 rats and no environmental enrichment); EE (large colony cages with 6 rats and multiple elements of environmental enrichment, including 2 floors, ladders, maze, running wheels, and shelter). From PND 60, rats were exposed to different phases of shaping and training of alcohol self-administration. IE, SE, and EE rats were then compared under (i) fixed ratio (FR) 4 (FR4) schedule of alcohol reinforcement for 20 daily sessions and (ii) progressive ratio (PR) schedule of alcohol reinforcement in a final single session. Acquisition of the lever-responding task (shaping) was slower in EE than IE and SE rats, as the likely consequence of a "devaluation" of the novel stimuli provided by the operant chamber in comparison to those to which EE rats were continuously exposed in their homecage or an alteration, induced by EE, of the rat "emotionality" state when facing the novel environment represented by the operant chamber. Training of alcohol self-administration was slower in EE than IE rats, with SE rats displaying intermediate values. A similar ranking order (IESEEE) was also observed in number of lever-responses for alcohol, amount of self-administered alcohol, and breakpoint for alcohol under FR4 and PR schedules of reinforcement. These data suggest that living in a complex environment reduced the reinforcing and motivational properties of alcohol in sP rats. These results are interpreted in terms of the reinforcing and motivational properties of the main components of EE (i.e., social interactions, physical activities, exploration, novelty) substituting, at least partially, for those of alcohol.

Introduction Chemotherapy prolongs the survival of patients with advanced and metastatic tumors. Since the liver plays an active role in the metabolism of chemotherapy agents, hepatic injury is a common adverse effect. The purpose of this study is to compare a novel quantitative chemical shift encoded magnetic resonance imaging (CSE-MRI) method with conventional T1-weighted In and Out of phase (T1 IOP) MR for evaluating the reproducibility of the methods in an oncologic population exposed to chemotherapy. Materials and methods This retrospective study was approved by the institutional review board with a waiver for informed consent. The study included patients who underwent chemotherapy, no suspected liver iron overload, and underwent upper abdomen MRI. Two radiologists independently draw circular ROIsin the liver parenchyma. The fat fraction was calculated from IOP imaging and measured from IDEAL-IQ fat fraction maps. Two different equations were used to estimate fat with IOP sequences. Intra-class correlation coefficient and repeatability coefficient were estimated to evaluate agreement between two readers on iron level and fat fraction measurement. Results CSE-MRI showed a higher reliability in fat quantification compared with both IOP methods, with a substantially higher inter-reader agreement (0.961 vs 0.372). This has important clinical implications. Conclusion The novel CSE-MRI method described here provides increased reproducibility and confidence in diagnosing hepatic steatosis in a oncologic clinical setting. IDEAL-IQ has been proved to be more reproducible than conventional IOP imaging.

PURPOSE: To investigate the value of second-opinion interpretation of cross-sectional images by subspecialized radiologists to diagnose recurrent pancreatic cancer after surgery. METHODS: The IRB approved and issued a waiver of informed consent for this retrospective study. Initial and second-opinion interpretations of 69 consecutive submitted MRI or CT follow up after pancreatic cancer resection between January 1, 2009 and December 31, 2013 were evaluated by one oncologic imaging radiologist, who was blinded to patient’s clinical details and histopathologic data. The reviewer was asked to classify each interpretation in reference of the diagnosis of PDAC recurrence. It was also recorded if the radiologic interpretation recommended additional imaging studies to confirm recurrence. The diagnosis of recurrence was determined by pathology when available, otherwise by imaging follow up, clinical or laboratory assessments. Cohen’s kappa statistic was used to assess agreement between initial and second-opinion interpretations. The differences between the initial and second-opinion interpretations were examined using McNemar test or Bowker’s test of symmetry. RESULTS: Disagreement on recurrence between the initial report and the second-opinion interpretation was observed in 32% of cases (22/69; k=0.44). Second-opinion interpretations had a higher sensitivity and a higher specificity on recurrence compared to the initial interpretations (0.93 vs 0.75 and 0.90 vs 0.68, respectively), and the difference in specificity was significant (p=0.016). Additional imaging studies were recommended more frequently in the initial interpretation (22% vs 6%, p=0.006). CONCLUSIONS: Our study shows the second-opinion interpretation by subspecialized radiologists improves the detection of pancreatic cancer recurrence after surgical resection.

Rationale and Objectives To determine the impact of second-opinion assessment on cancer staging and patient management in patients with pancreatic ductal adenocarcinoma. Methods and Materials This retrospective study was approved by our institutional review board with a waiver of informed consent. Second-opinion reports between January 1, 2009 and December 31, 2013, alongside outside reports for 65 consecutive cases of biopsy-proven pancreatic adenocarcinomas, were presented in random order to two experienced abdominal surgeons who independently reviewed them blinded to the origin of the report, images of the examinations, and patient identifier. Each surgeon filled in a questionnaire for each report recommending cancer staging and patient management. Recommended patient management and staging were evaluated against reference standards (actual patient management at 6 months following second-opinion assessment, and pathology or other clinical and imaging reference standards at 6 months or longer, respectively) using Cohen kappa. Results Cancer staging differed in 13% (9 of 65) of cases for surgeon 1 and in 18.4% (12 of 65) for surgeon 2. Patient management changed in 38.4% (25 of 65) of cases for surgeon 1 and in 20% (13 of 65) for surgeon 2. When compared to the pathologic staging gold standard, second opinion was correct in 85.7% (six of seven) of the time for both surgeons. Recommended patient management from second-opinion reports showed good agreement with the reference standard (weighted k = 0.6467 [0.4014–0.892] and weighted k = 0.6262 [0.3954–0.857] for surgeon 2). Conclusion Second-opinion review by subspecialized oncologic radiologists can impact patient care, specifically in terms of management decision.

Background and aims Prader–Willi syndrome (PWS) is characterized by a high incidence of altered glucose metabolism (AGM). However, epidemiological data on impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) are still discordant. Methods and results We performed a multicenter study based on 274 PWS patients [144 females, aged 20.3 ± 10.4 yrs (range: 8.1–50.1 years)] evaluating the prevalence for AGM in the entire group, and according to age (children 18 yrs), Body Mass Index (BMI = kg/m2), gender, genotypes (deletion or uniparental disomy for chromosome 15), and GH therapy (GHT) (untreated, previously or currently treated). Altogether, AGM was detected in 67 (24.4%) of patients (0.7% IFG, 10.2% IGT, 13.5% T2DM). The prevalence of AGM was correlated to age (p = 0.001), BMI (p = 0.001) and HOMA-IR (p = 0.001). However, gender, genotype, and GHT did not influence AGM development in univariate analysis. These data were confirmed as positive predictors when inserted in a multivariate analysis model. Conclusion This study is the first report on the prevalence of AGM in a large population of PWS. Overall, PWS subjects show a high prevalence of AGM that appears more common in obese and adult subjects. Our data confirm the main role of obesity on the individual metabolic risk clustering in PWS, and thus reinforce the concept that improvement in weight control remains the most important goal of any PWS treatment program.

Background Prader-Willi syndrome (PWS) is a genetic disorder due to loss of expression of paternally transcribed genes of the imprinted region of chromosome 15q11-13. PWS is characterized by peculiar signs and symptoms and many endocrine abnormalities have been described (growth hormone deficiency, hypogonadotropic hypogonadism). The abnormalities of thyroid function are discussed in literature and published data are discordant. The aim of our study was to report the thyroid function in patients with PWS to identify the prevalence of thyroid dysfunction. Methods Thyroid function tests were carried out in 339 patients with PWS, aged from 0.2 to 50 years. A database was created to collect personal data, anthropometric data, thyroid function data and possible replacement therapy with L-thyroxine. Subjects were classified according to thyroid function as: euthyroidism (EuT), congenital hypothyroidism (C-HT), hypothyroidism (HT – high thyroid-stimulating hormone [TSH] and low free thyroxine [fT4]), central hypothyroidism (CE-H – low/normal TSH and low fT4), subclinical hypothyroidism (SH – high TSH and normal fT4), and hyperthyroidism (HyperT – low TSH and high fT4). Results Two hundred and forty-three out of 339 PWS patients were younger than 18 years (71.7%). The prevalence of thyroid dysfunction was 13.6%. Specifically, C-HT was found in four children (1.18%), HT in six patients (1.77%), CE-H in 23 patients (6.78%), SH in 13 patients (3.83%), and HyperT in none. All other subjects were in EuT (86.4%). Conclusions Hypothyroidism is a frequent feature in subjects with PWS. Thyroid function should be regularly investigated in all PWS patients both at the diagnosis and annually during follow-up.

BACKGROUND the available studies on Hurthle cell carcinoma (HCC) in pediatric age are scarce and based on isolated case reports. Aims of the present study were to review the available pediatric literature on HCC (2000-2019), to describe the cohort of children with this cancer histotype, and to estimate its relative prevalence in pediatric age. PROCEDURE We retrospectively reconstructed an HCC course in five patients

Aim Neonatal diabetes is rare, and treatment is challenging. We present aspects on treatment, genetics and incidence. Method This was a prospective cohort study including all cases in our study area in Sweden. We compared with data from the National Diabetes Registry, the Neonatal Quality Register and the National Patient Register. Results In the 19-year study period January 1, 1998 to December 31, 2016, we treated seven infants, five of them boys. Six patients used a subcutaneous insulin pump, and the smallest patient started at a weight of 938 g. Most important was for the pump to deliver minute doses of insulin and the design of cannulas and tubing. All patients could stop insulin treatment at 17-145 days of age. One patient relapsed at age 4.5 years. Four patients used the insulin pump after discharge. A mutation was identified in five patients, and this included all patients born after 30 weeks of gestation. The incidence of neonatal diabetes was 2/1 00 000, higher than previously estimated for Europe. Similar but lower incidences were reported in the registries. Conclusion Insulin pumps were safe in neonatal diabetes. All seven cases were transient. Neonatal diabetes was more common in our area than reported from Europe.

Background The therapeutic strategy for children with cow’s milk allergy (CMA) consists in the elimination of cow’s milk (CM) from their diet. Donkey’s milk (DM) has been reported to be an adequate alternative, mainly to his nutritional similarities with human milk (HM) and excellent palatability. The aim of present prospective study was to evaluate the nutritional impact of DM on the diet of children with CMA in term of children growth. Methods Before the nutritional trial on children and during the study the health and hygiene risks and nutritional and nutraceuticals parameters of DM were monitored. Children with CMA were identified by the execution of in vivo and in vitro tests for CM and subsequent assessment of tolerability of DM with oral food challenge (OFC). Finally, we prescribed DM to a selected group of patients for a period of 6 months during which we monitored the growth of children. A total of 81 children, 70 with IgE mediated cow’s milk protein allergy (IgE-CMPA) and 11 with Food Protein Induced Enterocolitis Syndrome to CM (CM-FPIES), were enrolled. Results Seventy-eight out of 81 patients underwent the OFC with DM and only one patient with IgE-CMPA (1.5 %) reacted. Twenty-two out of 81 patients took part of the nutritional trial. All the 22 patients took and tolerated the DM, moreover DM did not change the normal growth rate of infants. Conclusions In conclusion, DM resulted safe in term of health and hygiene risks and nutritionally adequate: no negative impact on the normal growth rate of children was assessed. Therefore, it may be a suitable alternative for the management of IgE mediated CMA and FPIES, also in the first 6 months of life, if adequately supplemented.

In semi-terrestrial crabs, the production of sounds has been recognized to be related to courtship communication dynamics. The present study aimed to assess if the crab Neohelice granulata (Varunidae) was able to emit acoustic signals and if they played a role in the crab’s behaviour. We also assessed the locomotor behaviours to examine these parameters in different mating contexts of crabs. The study was divided into two different experimental conditions: ‘solitary experiment’ (consisting of three combination layouts with male, unreceptive and receptive females alone) and ‘group experiment’ (consisting of mixed combinations layouts of males, unreceptive, and receptive females). Synchronized acoustic and video monitoring systems were used to record the acoustic signals and locomotor behaviours of alone and grouped specimens. The greatest values of locomotor behavioural parameters were observed in layouts with receptive females alone and with 2 males plus 1 receptive female, probably related to courtship behaviour. N. granulata produced two distinct signals, a multi-pulse rasp signal (highest numbers were recorded in layouts with male alone and with 2 males plus 1 receptive female) and a single rasp signal. These results may suggest that males use the multi-rasp signal to advertise their presence to other males or to attract receptive females. Fil: Filiciotto, Francesco. Consiglio Nazionale Delle Ricerche. Istituto Per L'ambiente Marino Costiero.; Italia Fil: Sal Moyano, María Paz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; Argentina Fil: Hidalgo, Fernando Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; Argentina Fil: de Vincenzi, Giovanni. Consiglio Nazionale Delle Ricerche. Istituto Per L'ambiente Marino Costiero.; Italia Fil: Bazterrica, Maria Cielo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; Argentina Fil: Ceraulo, Maria. Consiglio Nazionale Delle Ricerche. Istituto Per L'ambiente Marino Costiero.; Italia Fil: Corrias, Valentina. Consiglio Nazionale Delle Ricerche. Istituto Per L'ambiente Marino Costiero.; Italia Fil: Quinci, Enza Maria. Consiglio Nazionale Delle Ricerche. Istituto Per L'ambiente Marino Costiero.; Italia Fil: Lorusso, Martin Ignacio. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales; Argentina Fil: Mazzola, Salvatore. Consiglio Nazionale Delle Ricerche. Istituto Per L'ambiente Marino Costiero.; Italia Fil: Buscaino, Giuseppa. Consiglio Nazionale Delle Ricerche. Istituto Per L'ambiente Marino Costiero.; Italia Fil: Gavio, Maria Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; Argentina

To explore the prevalence of Aberrant Salience (AS, an alleged experiential feature of psychosis-proneness) in Italian young people and corroborate the transcultural validity of the Aberrant Salience Inventory (ASI).Young adults attending an Italian university (n = 649) underwent serial evaluations with the ASI together with psychometric proxies for help seeking General Health Questionnaire and attenuated positive and negative symptoms Schizotypal Personality Questionnaire (SPQ). The distribution of ASI scores was explored with latent class analysis (LCA).Reliability of the Italian version of the ASI (I-ASI) was acceptable for all subscales (ordinal alpha.70). Concurrent validity was in the expected direction, with higher correlations with measures of attenuated positive symptoms vs negative symptoms of psychosis (Steigers' z test, P.005 in all comparisons). LCA identified three classes, with 217 (33.4%) participants in the "high aberrant salience" class. Gender and age were not related to class membership. Compared to the baseline class, SPQ scores in the schizotypy range were more likely in the "high aberrant salience" class (OR = 39.1; 95%confidence interval: 5.30-288.1).AS is a relatively common experience among Italian young people. The study also confirmed the validity of field-testing ASI as a tool for the real-world characterization of people with vulnerability to psychosis, such as symptomatic help seekers with clinical high-risk states.

RATIONALE AND OBJECTIVES The purpose of this study is to compare image quality, presence and grade of artifacts, signal-to-noise ratio, and apparent diffusion coefficient (ADC) values in pancreatic tissue between high-resolution navigator-triggered (NT) restricted field of view (rFOV) FOCUS single-shot (SS) echo-planar imaging (EPI) diffusion-weighted imaging (DWI) and NT large FOV SS-EPI DWI. MATERIALS AND METHODS Magnetic resonance imaging examinations were performed with GE 3-T systems using a 32-channel body array coil. Seventeen consecutive patients were imaged. A 5-point scale semiquantitative grading system was used to evaluate image quality and general artifacts. Signal-to-noise ratio and ADC were measured in the head, body, and tail of the pancreas. Statistical analysis was performed using Student t test and Wilcoxon signed rank test, with differences considered significant for P value less than 0.05. RESULTS More artifacts were present on large FOV compared with rFOV FOCUS SS-EPI DW images (P < 0.01). Restricted field of view image quality was subjectively better (P < 0.01). No difference in the signal-to-noise ratio was demonstrated between the 2 image datasets. Apparent diffusion coefficient values were significantly lower (P < 0.01) when calculated from rFOV images than large FOV images. CONCLUSIONS Our results demonstrate better image quality and reduced artifacts in rFOV images compared with large FOV DWI. Measurements from ADC maps derived from rFOV DWI show significantly lower ADC values when compared with ADC maps derived from large FOV DWI.

Rationale: Hepatic epithelioid hemangioendothelioma (EHE) is a rare malignant vascular tumor of endothelial origin with a highly variable clinical presentation and natural history. Given its vascular origin, new therapies with inhibitors of vascular endothelial growth factor (VEGF) have been introduced in the treatment of these patients and have shown promising results. Few reports have described the role of 18F-Fluorodeoxyglucose positron emission tomography/contrast-enhanced computed tomography (18F-FDG PET/CT) in the evaluation of this tumor after treatment with anti-angiogenic agents. Our case reports how 18F-FDG PET-CT scan was critical in the assessment of this tumor after treatment with an anti-angiogenic agent, Pazopanib, demonstrating complete metabolic response. Patient concerns: A 30-year-old man with no previous significant medical history presented with pain in the right upper quadrant for over a year. Diagnoses: Multiple hepatic masses were found on abdominal ultrasound. Liver biopsy confirmed the diagnosis of epithelioid hemangioendothelioma. 18F-FDG PET/CT was performed for staging. Multiple FDG-avid hepatic, splenic, and lymph nodes lesions were detected on 18F-FDG PET/CT. A subsequent spleen biopsy confirmed splenic involvement. Immunohistochemistry was positive for CD31, CD34, and ERG, supporting the diagnosis of epithelioid hemangioendothelioma. Interventions: A 1-year cyclophosphamide treatment was provided followed by Pazopanib for 17 months. Outcomes: Six years after the first 18F-FDG PET/CT, 18F-FDG PET/CT performed for restaging demonstrated complete metabolic response to therapy. Follow-up CT demonstrated no interval changes in size of some of the treated lesions. Lesson: 18F-FDG PET/CT is useful for baseline assessment and posttreatment follow-up of this rare cancer.

1 Background: The purpose of this study was to evaluate whether levels of neuroblastoma mRNAs in bone marrow and peripheral blood from stage M infants (≤12 months of age at diagnosis, MYCN amplified) and toddlers (between 12 and 18 months, any MYCN status) predict event‐free survival (EFS). 2 Methods: Bone marrow aspirates and peripheral blood samples from 97 infants/toddlers enrolled in the European High‐Risk Neuroblastoma trial were collected at diagnosis in PAXgene™ blood RNA tubes. Samples were analyzed by reverse transcription quantitative polymerase chain reaction according to standardized procedures. 3 Results: Bone marrow tyrosine hydroxylase (TH) or paired‐like homeobox 2b (PHOX2B) levels in the highest tertile were associated with worse EFS; hazard ratios, adjusted for age and MYCN status, were 1.5 and 1.8 respectively. Expression of both TH and PHOX2B in the highest tertile predicted worse outcome (p = 0.015), and identified 20 (23%) infants/toddlers with 5‐year EFS of 20% (95%CI: 4%–44%). Prognostic significance was maintained after adjusting for over‐fitting bias (p = 0.038), age and MYCN status. In peripheral blood, PHOX2B levels in the highest tertile predicted a two‐fold increased risk of an event (p = 0.032), and identified 23 (34%) infants/toddlers with 5‐year EFS of 29% (95%CI: 12%–48%). Time‐dependent receiver operating characteristic analysis confirmed the prognostic value of combined TH and PHOX2B in bone marrow and of PHOX2B in peripheral blood during the first year of follow‐up. 4 Conclusions: High levels of bone marrow TH and PHOX2B and of peripheral blood PHOX2B at diagnosis allow early identification of a group of high‐risk infant and toddlers with neuroblastoma who may be candidates for alternative treatments. Integration with additional biomarkers, as well as validation in additional international trials is warranted.

BACKGROUND: Due to the lack of specific pediatric studies, no data are available about natural history of endogenous subclinical hyperthyroidism (SH) in childhood. AIMS: (a) To investigate for the first time the natural history of SH [suppressed thyrotropin (TSH) and normal free thyroxine free thyroxine (FT4) levels] when presenting as initial manifestation of Hashimoto's thyroiditis (HT) in childhood (group A); (b) to compare spontaneous evolution of HT-related SH with that observed in age-matched patients with HT-related frank hyperthyroidism (suppressed TSH and elevated FT4 levels), i.e., Hashitoxicosis Htx (group B). RESULTS: In the 11 patients of group A, TSH normalization spontaneously occurred 1-24 months after diagnosis, while in the 10 patients of group B it occurred 3-9 months after diagnosis, with no differences between the 2 groups in terms of time interval from entry to TSH normalization. In group A, this time interval was related to baseline thyroid peroxidase antibodies (r = 0.78, p = 0.04). During follow-up, eight patients of each group remained euthyroid, whereas two became hypothyroid (in both groups) and one developed Graves' disease (in group A). CONCLUSION: (a) HT should be included among the causes of endogenous SH in pediatric age; (b) in children with HT-related SH, spontaneous normalization of TSH levels occurs within the first 24 months after diagnosis, as well as in age-matched patients with Htx; (c) in both these conditions, a further deterioration of thyroid function might re-present in some patients during follow-up; (d) Ht-related SH and Htx might be possibly seen as different biochemical stages along the same continuum.

The role of nonclassical HLA-class Ib molecules HLA-G and HLA-E in the progression of Neuroblastoma (NB), the most common pediatric extracranial solid tumor, has been characterized in the last years. Since BM infiltration by NB cells is an adverse prognostic factor, we have here analyzed for the first time the concentration of soluble (s)HLA-G and HLA-E in bone marrow (BM) plasma samples from NB patients at diagnosis and healthy donors. sHLA-G and sHLA-E are present in BM plasma samples, and their levels were similar between NB patients and controls, thus suggesting that these molecules are physiologically released by resident or stromal BM cell populations. This hypothesis was supported by the finding that sHLA-G and sHLA-E levels did not correlate with BM infiltration and other adverse prognostic factors (MYCNamplification and age at diagnosis). In contrast, BM plasma levels of both molecules were higher in patients with metastatic disease than in patients with localized NB, thus suggesting that concentration of these molecules might be correlated with disease progression. The prognostic role of sHLA-G and sHLA-E concentration in the BM plasma for NB patients will be evaluated in future studies, by analyzing the clinical outcome of the same NB patients at follow-up.

Background: Whether the course of thyroid function in Hashimoto's thyroiditis (HT) differs in children who present with either euthyroidism or subclinical hypothyroidism (SH) has been incompletely investigated. Aim: Using a five-year prospective evaluation of 234 children with HT and no prognostic risk factors, this study investigated whether the evolution of the thyroid status is influenced by the biochemical pattern at initial diagnosis. Results: In the entire series, thyrotropin values significantly increased during follow-up, while free thyroxine values decreased and the proportion of children with a thyroid dysfunction increased from 27.3% to 47.4% (p = 0.0001). An increasing proportion of cases with severe thyroid dysfunction was identified, especially among the 64 patients presenting with SH (group B), but also among the 170 children presenting with euthyroidism (group A) at initial diagnosis. At the end of follow-up, the prevalence of children with overt hypothyroidism was 12.3% in group A compared with 31.2% in group B (p = 0.0007). In the overall population, however, the majority of patients (52.6%) exhibited biochemical euthyroidism at the end of follow-up. Conclusions: Children with HT may develop a deterioration of thyroid status during the first five years of disease. Such a trend may be observed, even in the patients who initially present with a mild biochemical picture (either SH or euthyroidism). A total of 57.1% of initially euthyroid children remain euthyroid, and 40.6% of patients with initial SH normalize thyroid function within five years after HT diagnosis. The patients presenting with SH are more prone to the risk of developing severe thyroid dysfunction over time.

The critical role of the Wnt pathway inhibition in sustaining the onset of bone lesions has been demonstrated in a variety of bone diseases and tumors, and it has been associated with cancer aggressiveness. We have previously demonstrated that neuroblastoma cells express Dickkopf 1 (Dkk1), an inhibitor of the canonical Wnt pathway which prevents the differentiation of bone-forming cells. Since Dkk1 is a secreted factor, it could have potential clinical application as tumor marker for detecting bone metastasis and monitoring of disease. In this study, we investigated the diagnostic and prognostic value of Dkk1 plasma levels in 92 children affected by neuroblastoma, including 32 with bone metastases. Fifty-seven children hospitalized for minor surgical problems served as control group. Circulating levels of Dkk1 were higher in healthy children than in normal adults and were comparable to those found in adult patients with aggressive tumors. No significant differences were found between neuroblastoma patients and controls and between patients with and without bone metastases. However, when only patients with metastatic neuroblastoma were considered, the highest Dkk1 levels were detected in patients that poorly responded to induction chemotherapy and in subjects with unamplified MYCN and three or more different metastatic sites. The 'Receiver Operating Characteristic' curve enabled us to identify a threshold value to distinguish patients who were unresponsive to induction treatment. The relationship between Dkk1 and drug resistance was supported by in vitro experiments, since an increased sensitivity to doxorubicin was found in neuroblastoma cells releasing low Dkk1 levels, either constitutively or experimentally following the treatment with specific siRNA. In conclusion, Dkk1 is released by neuroblastoma cells and is able to affect the balance between osteoblastogenesis and osteoclastogenesis, thus favoring the onset of osteolytic metastases. Nevertheless, Dkk1 plasma levels do not allow the detection of bone lesions in neuroblastoma but seem to have a predictive value with regard to the severity and the prognosis of the disease in a subset of patients with metastatic tumor. New knowledge on the biological role of Dkk1 in driving the natural history of neuroblastoma has to be further investigated and could help to establish specific therapeutic strategies able to target key factors of tumor progression.

Background: The development of Graves’ disease (GD) from Hashimoto’s thyroiditis (HT) has sporadically been reported, but no data are available concerning the prevalence of this sequence of events in GD patients. Our aim was to ascertain HT antecedents in the history of GD children in order to assess for the first time the relative frequency of the event sequence leading from HT to GD in a pediatric population. Study Population and Results: In 105/109 patients, no HT antecedents were documented at GD presentation. The remaining 4 patients had previously exhibited a picture of HT with either hypothyroidism or euthyroidism. The interval between HT diagnosis and GD presentation ranged from 1.5 to 2.8 years. Serum thyrotropin receptor antibodies were higher in the patients with no HT antecedents. Conclusions: In at least 3.7% of the children with GD, hyperthyroidism may be preceded by HT presentation with either hypothyroidism or euthyroidism. The clinical course of GD in these patients is not different from the one observed in those with no HT antecedents. Our report confirms the existence of a continuum between HT and GD within the spectrum of autoimmune thyroid diseases.

The aim of this work was to evaluate the capability of lactoferrin- and antitransferrin-modified long circulating liposomes to deliver the hydrophilic peptide senktide, a selective NK3 receptor agonist unable to cross the blood brain barrier, to central nervous system by using an indirect method based on in vivo microdialysis studies to estimate the responsiveness of nucleus accumbens shell dopamine to senktide. To this purpose, senktide was encapsulated in different targeted and not-targeted stealth liposomes prepared using film hydration method. Formulations were characterized in terms of morphology, size distribution, zeta potential, encapsulation efficiency, and antibody presence on the liposome surface. In vivo microdialysis studies were performed injecting intravenously the senktide-loaded liposomes and comparing obtained dopamine levels with those found with the free senktide given intracerebroventricularly. Results showed that all vesicles were spherical, small in size (around 120 nm), homogeneously dispersed, and slightly negatively charged. TEM analysis, using an anti IgG secondary antibody with 10nm gold nanoparticles at its distal end, demonstrated the successful linkage of the antibody on the liposomal surface. Intravenously administered in rats, senktide-loaded targeted stealth liposomes elicited a significant increase of dialysate dopamine in the nucleus accumbens shell, which was comparable to that of the free senktide given intracerebroventricularly when antitransferrin-targeted liposomes were tested. On the contrary, control stealth liposomes did not affect dopamine levels. Senktide brain levels were higher using the antitransferrin-targeted liposomes in comparison with the lactoferrin ones, while the opposite was obtained in the liver tissue where the highest senktide accumulation was always found.

The prognosis of children with metastatic neuroblastoma (NB) > 18 months at diagnosis is dismal. Since the immune status of the tumor microenvironment could play a role in the history of disease, we evaluated the expression ofCD45,CD14,ARG1,CD163,CD4,FOXP3,Perforin-1(PRF1),Granzyme B (GRMB), andIL-10mRNAs in primary tumors at diagnosis from children with metastatic NB and tested whether the transcript levels are significantly associated to event-free and overall survival (EFS and OS, resp.). Children with high expression ofCD14,ARG1andFOXP3mRNA in their primary tumors had significantly better EFS. Elevated expression ofCD14, andFOXP3mRNA was significantly associated to better OS.CD14mRNA expression levels significantly correlated to all markers, with the exception ofCD4. Strong positive correlations were found betweenPRF1andCD163, as well as betweenPFR1andFOXP3. It is worth noting that the combination of high levels ofCD14,FOXP3, andARG1mRNAs identified a small group of patients with excellent EFS and OS, whereas low levels ofCD14were sufficient to identify patients with dismal survival. Thus, the immune status of the primary tumors of high-risk NB patients may influence the natural history of this pediatric cancer.

Pterygium, an ultraviolet radiation (UV)-related disease, is a relatively benign process, but since it displays tumor-like features, it has been proposed to be a neoplastic- like growth disorder. Vitamin D performs a number of functions in addition to calcium homeostasis, as inhibition of cell proliferation, activation of apoptotic pathways, and inhibition of angiogenesis. Since the antitumor actions of vitamin D are mediated primarily through the nuclear vitamin D receptor (VDR), the aim of the present study was to investigate vitamin D status in patients with pterygium and in control subjects, and VDR immunohistochemical expression in samples of pterygium and normal conjunctiva in order to evaluate a possible role of vitamin D pathway in the pathogenesis of the disease. Serum vitamin D concentration was measured among 41 patients with pterygium and 47 volunteers by an automated chemiluminescence immunoassay. Moreover, 23 formalin- fixed and paraffin-embedded pterygium biopsy samples and 24 conjunctiva specimens were treated for the immunohistochemical demonstration of VDR using the streptavidin-biotin alkaline phosphatase method. No differences were observed about vitamin D level between patient with pterygium and control group, but significant differences between VDR immunolocalization in pterygium and normal conjunctiva were observed (P=0.00001). In conjunctiva, the immunoreactivity, localized mainly in cytoplasm of epithelial cells, may probably demonstrate VDR regulation of cell growth, differentiation, and apoptosis, while in pterygium VDR co-localization in the nucleus and cytoplasm of epithelial cells may indicate alternative nuclear pathways by which vitamin D might exert its antiinflammatory and anti-proliferative effects by the regulation of gene expression.

Growth hormone deficiency (GHD) is the most common endocrine late effect observed in childhood cancer survivors (CCS) previously submitted to cranial irradiation. Radiation therapy can also increase the risk of second neoplasms (SNs). Since in previous studies GH replacement therapy was associated with increased incidence of neoplasia, we explored the association between SNs and GH replacement therapy in a cohort of CCS with GHD. Within the clinical cohort of CCS referred to the Transition Unit for Childhood Cancer Survivors of Turin between November 2001 and December 2012, we considered all patients who developed GHD as a consequence of cancer therapies. GHD was always diagnosed in childhood. To evaluate the quality of data, our cohort was linked to the Childhood Cancer Registry of Piedmont. GHD was diagnosed in 49 out of 310 CCS included in our clinical cohort. At least one SN was diagnosed in 14 patients, meningioma and basal cell carcinoma being the most common SNs. The cumulative incidence of SNs was similar in GH-treated and -untreated patients (8 SNs out of 26 GH-treated and 6 out of 23 GH-untreated patients; p = 0.331). Age, sex and paediatric cancer type had no impact on SNs development. In our CCS, GH replacement therapy does not seem to increase the risk of SNs. Anyway, independently from replacement therapy, in these patients we observed an elevated risk of SNs, possibly related to previous radiation therapy, which suggests the need of a close long-term follow-up.

Beckwith-Wiedemann syndrome (BWS) and hemihyperplasia (HH) are overgrowth conditions with predisposition to hepatoblastoma for which early diagnosis patients undergo cancer screening based on determination of the tumor marker α-fetoprotein (αFP). Repeated blood draws are a burden for patients with consequent compliance issues and poor adherence to surveillance protocol. We sought to analyze feasibility and reliability of αFP dosage using an analytical micromethod based on blood dried on filter paper (DBS).Overall 143 coupled αFP determinations on plasma and DBS collected simultaneously were performed, of which 31 were in patients with hepatoblastoma predisposition syndromes and 112 were in controls. The plasma αFP dosage method was adapted to DBS adsorbed on paper matrix for newborn screening.There was strong correlation between plasmatic and DBS αFP (r2 = 0.999, P0.001). Cohen's k coefficient for correlation was 0.96 for diagnostic cut-off of 10 U/ml (P0.001), commonly employed in clinical practice. The measurements on plasma and DBS were highly overlapping and consistent.The DBS method allowed to dose αFP reliably and consistently for the concentrations commonly employed in clinical settings for the screening of hepatoblastoma, opening new scenarios about conducting cancer screening in overgrowth syndromes.

The impact of bone marrow (BM) GD2-positive cells on survival has been evaluated in 145 Italian children with localised neuroblastoma (NB) evaluated at diagnosis by anti-GD2 immunocytochemistry. Nineteen of these (13.1%) were found to be BM GD2-positive, with the number of positive cells ranging between 1 and 155 out of 1 x 10(6) total cells analysed. Seven/19 (38.8%) GD2-positive vs 12/126 (9.5%) GD2-negative patients relapsed. The 5-year event-free survival (EFS) and overall survival of the GD2-positive patients was significantly worse than that of the GD2-negative ones (62.2 vs 89.9%, P0.001; and 74.9 vs 95.9%, P=0.005, respectively). GD2 positivity was not associated to other known risk factors, and in particular to Myc-N amplification and 1p deletion. Among Myc-N-negative patients, the EFS of those negative for both GD2 and 1p deletion was significantly better than in children positive for either one of these two markers (EFS=96.9 vs 66.0%, P0.001). In conclusion, GD2 positivity may represent a prognostic marker for patients with non-metastatic NB without Myc-N amplification, and its combination with genetic alterations might help identifying patients that require a more careful follow-up.

BACKGROUND It is known that the association with Down syndrome (DS) can affect the phenotypic expression of autoimmune thyroid diseases (AITDs), whilst is unknown whether the clustering of extra-thyroidal autoimmune diseases (ETADs) may also be atypical in DS children. METHODS The aim of this study was to investigate the clustering of ETADs in 832 children with AITDs divided in two groups with or without DS (A and B, respectively) and in four subgroups of patients aged either

OBJECTIVE: To evaluate clinical and biochemical features of 115 children (98 female, mean age 11.3 ± 3.5 years) with Graves disease to identify possible determinants of remission. STUDY DESIGN: We defined as positive outcome the improvement of clinical features and restoration of euthyroidism or induction of hypothyroidism after antithyroid drug (ATD) therapy and as negative outcome hyperthyroidism persistent over 2 years of ATD therapy or relapsed after ATD withdrawal. RESULTS: Thirty-eight children (33%) had remission after 2 years of ATD therapy. The absence of goiter at diagnosis was correlated with a better outcome. Median thyroid-stimulating hormone receptor antibody (TRAb) values at diagnosis were significantly lower in patients with a positive outcome (P = .031). We found a significant relationship between the time required for TRAb normalization and the patient outcome; TRAb normalization within 1 year from time of Graves disease diagnosis was significantly more common among patients with a positive outcome (P < .0001), and the mean time for TRAb normalization was significantly shorter in patients with a positive outcome (1.3 ± 0.8 years) compared with that observed in patients with a negative outcome (2.5 ± 2.7 years, P = .026). CONCLUSIONS: Although no clinical variable investigated is constantly associated with a definite outcome, the absence of goiter at the diagnosis may be associated with a better outcome. The most relevant predictor of Graves disease outcome was serum level; TRAb at time of Graves disease diagnosis less than 2.5 times the upper reference limit, TRAb normalization during ATD, and TRAb normalization timing each may predict positive outcomes. These results may have a role in the empiric clinical management of pediatric patients with Graves disease.

OBJECTIVE: To investigate the correlation between serum thyroid-stimulating hormone (TSH) concentration and nodule nature in pediatric patients with thyroid nodules, with the aim of identifying a marker able to differentiate benign and malignant nodules. STUDY DESIGN: This was a retrospective analysis of serum TSH concentrations in a multicentric case series of 125 pediatric patients with benign and malignant thyroid nodules. RESULTS: Of the 125 patients, 99 had benign thyroid nodules and 26 had differentiated thyroid cancer (24 papillary and 2 follicular). Final diagnosis was based on surgery in 57 cases and on a benign cytology plus clinical follow-up in 68 cases. Serum TSH concentration was significantly higher in patients with thyroid cancer compared with those with benign nodules (3.23 ± 1.59 mU/L vs 1.64 ± 0.99 mU/L; P < .001). Binary logistic regression analysis revealed that serum TSH was the sole predictor of malignancy (P < .001). Dividing the patient cohort into 5 groups based on serum TSH quintiles (TSH cutoffs 0.40, 1.00, 1.50, 1.80, and 2.80 mU/L), we observed that cancer prevalence increased in parallel with serum TSH (P < .001), with respective rates of 0%, 4%, 16%, 32%, and 52% in the 5 quintile groups. CONCLUSION: Because cases with malignant nodules are most likely seen in the upper normal serum TSH range (ie, >2.8 mU/L), serum TSH concentration can serve as a predictor of thyroid cancer in pediatric patients with thyroid nodules and can inform the decision of when to submit patients to further investigation by cytology.

BACKGROUND: Celiac disease (CD) may be associated with other immunologic disorders in adults and children. Previous studies linking CD and autoimmune thyroid disease in children have included very few patients with limited biochemical and immunologic screening tests. The aim of this multicenter study was to establish the prevalence of autoimmune thyroid involvement in a large series of pediatric patients with CD. METHODS: Five hundred seventy-three consecutive pediatric patients were enrolled from clinics in Torino, Bologna, Foggia, Rome (two clinics), Naples, and Bari. Three hundred forty-three patients with CD were studied, 230 girls and 113 boys (median age, 8.5 years). Two hundred fifty-six of the patients with CD (median age, 9 years) had been following a gluten-free diet for 3 months to 16 years; 87 patients were untreated (median age, 6.2 years). The diagnosis of CD was made using the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) criteria. A control group of 230 subjects (median age, 8.3 years) was enrolled. Serum free triiodothyronine, free thyroxine, and thyroid-stimulating hormone (TSH), antithyroperoxidase, antithyroglobulin, anti-TSH receptor antibodies, and thyroid echographic pattern were considered. RESULTS: Autoimmune thyroid disease was found in 90 of 343 (26.2%) patients with CD (62 on a gluten-free diet) and in 20 (10%) of the control subjects (P = 0.001). Fifty-four (15.7%) patients with CD and autoimmune markers had normal thyroid function (euthyroidism) as did 12 (6.0%) of the control subjects; hypothyroidism was observed in 28 (8.1%) patients with CD and in 7 (3.5%) of the control subjects. Hyperthyroidism was diagnosed in four patients with CD and in none of the control subjects with autoimmune markers. An abnormal echographic pattern was seen in 37 patients with CD (16.8%) and only in 1 (1.6%) of the control subjects (P = 0.002). CONCLUSIONS: The high frequency of autoimmune thyroid disease found among patients with CD, even those on a gluten-free diet, may justify a thyroid status assessment at diagnosis and at follow-up evaluation of children with CD.

Prader-Willi syndrome (PWS), the most common genetic cause of obesity, is characterized by elevated morbility and mortality in all ages. In this context, non-obese PWS children showed low frequency of metabolic syndrome (MetS), while a comparable prevalence was observed in obese PWS and obese controls. Aim of this study was to estimate the occurrence of MetS and its components in a large group of PWS adults, according to obesity status.A cross-sectional study was performed in 108 PWS aged 18.0-43.2 years (87 obese and 21 non-obese) and in 85 controls with nonsyndromic obesity matched for age, gender, and BMI with obese PWS. Non-obese PWS showed lower waist circumference, insulin, HOMA-index, triglycerides, diastolic blood pressure, and higher HDL-C than both obese PWS and obese controls (p0.017). Obese PWS showed higher glucose and systolic blood pressure than both non-obese PWS and obese controls (p0.017). MetS was found in 1/21 (4.8%) non-obese PWS, 36/87 (41.4%) obese PWS and 39/85 (45.9%) obese controls. Non-obese PWS showed lower frequency for each MetS component as compared with obese PWS and obese controls. PWS patients with deletion of the chromosome 15q11-13 showed a lower risk for low HDL-C (p0.01) and a trend towards a lower MetS risk (p0.06) compared to subjects without deletion.Our findings suggest the main role that obesity status plays on the individual metabolic risk clustering in PWS adults. Early identification of MetS could be helpful to improve morbidity and prevent mortality in such patients.

Aim: To evaluate the effectiveness of levothyroxine therapy in benign thyroid nodules in pediatrics. Methods: Data from 78 euthyroid children and adolescents with benign thyroid nodules were retrospectively collected. Subjects were divided into 2 groups: levothyroxine treated (n = 36) and nontreated (n = 42), and the clinical, laboratory and sonographic features of the 2 groups were compared. Nodules were considered benign according to histology, fine-needle aspiration biopsy or by features suggestive for benignity. The groups were followed up for 2.4 ± 1.3 years, and treated patients received a mean dose of levothyroxine of 1.69 ± 0.66 µg/kg/day. Results: Patients in the treated and nontreated groups were comparable for age, sex and follow-up. A reduction in nodule diameter from 2.24 ± 0.94 to 1.86 ± 1.17 cm (p = 0.039) was observed in treated patients, whereas the nodule diameter increased from 1.66 ± 0.86 to 1.78 ± 0.91 cm in nontreated patients (p = 0.024). In the treatment group, 11 patients (30.6%) had a reduction greater than 50% and significantly decreased palpable nodules (p < 0.001). A nonsignificant reduction in reported symptoms was observed, too. The change in nodule size was directly correlated with thyroid-stimulating hormone levels (r = 0.640, p < 0.001) and inversely with levothyroxine dose (r = –0.389, p = 0.009). In nontreated subjects, both palpable nodules and symptoms increased. Conclusion: This study supports levothyroxine treatment effectiveness in shrinking benign nodules.

The aim of the replacement therapy with levothyroxine in congenital hypothyroidism (CH) is to correct hypothyroidism and ensure normal growth and neuropsychological development. Few data are available about the appropriate dose during childhood and early adolescence; therefore, we performed a multicenter observational study in a large population of patients with CH to assess the required levothyroxine dose to obtain euthyroidism. We recruited 216 patients with permanent CH classified into three groups (agenesia, ectopia, and in situ gland) on the basis of the thyroid imaging. The levothyroxine dose was recorded at 6 and 12 months and then yearly until 12 years of age. The daily levothyroxine requirement progressively decreased during the follow-up, irrespective of etiology. It was significantly lower in patients with in situ gland than in patients with athyreosis during the entire study period and with ectopic gland from the age of 1 year. The levothyroxine requirement at 6 months of age was correlated with the requirement at each later time-point. The daily dose was modified less frequently in patients with in situ thyroid (36 %) than in patients with ectopic gland (41.4 %) or with athyreosis (43.6 %). Patients with in situ gland required a lower dose than the other two subgroups. The dose at 6 months seems predictive of the requirement until 12 years of age. Euthyroidism may be achieved in pre-school and in-school patients by 3-4 and 2-3 µg/kg/day (70-90 and 60-80 µg/m(2)/day) of levothyroxine, respectively.

Interleukin (IL)-31A binds to an heterodimer composed of IL-31 receptor A (IL-31RA) and Oncostatin M Receptor (OSMR). The IL-31/IL-31R complex is involved in the pathogenesis of various skin diseases, including cutaneous T-cell lymphoma. No information is available on the relations between the IL-31/IL-31R complex and B-cell lymphoma. Here we have addressed this issue in follicular lymphoma (FL), a prototypic germinal center(GC)-derived B-cell malignancy. IL-31 enhanced primary FL cell proliferation through IL-31R-driven signal transducer and activator of transcription factor 1/3 (STAT1/3), extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt phosphorylation. In contrast, GC B cells did not signal to IL-31 in spite of IL-31R expression. GC B cells expressed predominantly the inhibitory short IL-31RA isoform, whereas FL cells expressed predominantly the long signaling isoform. Moreover, GC B cells lacked expression of other IL-31RA isoforms potentially involved in the signaling pathway. IL-31 protein expression was significantly higher in surface membrane than in cytosol of both FL and GC B cells. IL-31 was detected in plasma membrane microvesicles from both cell types but not released in soluble form in culture supernatants. IL-31 and IL-31RA expression was higher in lymph nodes from FL patients with grade IIIa compared with grade I/II, suggesting a paracrine and/or autocrine role of IL-31/IL-31RA complex in tumor progression through microvesicle shedding.

Background: Studies concerning presentation and evolution over time of Hashimoto’s thyroiditis (HT) in children with Down’s syndrome (DS) are few, are based on limited study populations and do not include control HT groups without DS. The aim of this multicenter study was to shed further light on the relationships between DS and HT in childhood. DESIGN: In this retrospective study we compared thyroid function patterns at HT presentation in 2 groups of children with (group A) or without DS (group B), including 146 and 553 cases, respectively. All group A patients were subsequently re-examined after a median interval of 5.1 years in order to prospectively re-evaluate the evolution over time of thyroid function patterns in DS. Results: In group A, female predominance, age at HT diagnosis and rates of familiarity for thyroid diseases were significantly lower than in group B, whilst the association with non-thyroidal autoimmune diseases was more frequent. The hormonal patterns that were most frequently found in the 2 groups were, respectively, subclinical hypothyroidism (in group A) and euthyroidism (in group B). Thyroid dysfunctions were, overall, more frequent in group A (86.3 vs 45.7%, p

Background: It is known that Hashimoto's thyroiditis (HT) may progress to Graves' disease (GD) and that this phenomenon may be more frequent in the patients with Down syndrome (DS). Aims: To shed light on the relationships between Down syndrome (DS) and metamorphic thyroid autoimmunity. Patients and Methods: We reconstructed the conversion process from HT to GD in 12 DS children. All the data recorded at HT diagnosis and throughout the time interval from entry to GD presentation were retrospectively taken from patients' files, as well as those recorded at GD diagnosis and during the subsequent evolution. From GD diagnosis all patients underwent methimazole treatment, at a dose that was adjusted on the basis of clinical findings and thyroid tests. Results: Time interval between HT and GD was not different in the seven patients who received during that time a L-thyroxine (L-T4) treatment than in those who were not treated. After methimazole onset all patients exhibited a prolonged remission of hyperthyroidism. In 8/12 patients this treatment is still being continued 2-7 years after its initiation. The mean methimazole dosage needed to maintain euthyroidism in these eight patients was 0.12 ± 0.02 mg/kg/day. In the remaining four patients methimazole was withdrawn from 1.9 to 7 years after its initiation and no relapses were recorded 2.0-2.1 years after its withdrawal. These patients developed, 0.1-0.3 years after methimazole withdrawal, a picture of overt hypothyroidism and needed treatment with L-T4, that is now being continued. No patients needed non-pharmacological therapies. Conclusions: 1) DS children might be incline to manifest over time a phenotypic metamorphosis from HT to GD and to subsequently fluctuate from hyperthyroidism to hypothyroidism; 2) in DS GD may have a mild biochemical and clinical course.

PER3 gene polymorphisms have been associated with differences in human sleep-wake phenotypes, and sensitivity to light. The aims of this study were to assess: i) the frequency of allelic variants at two PER3 polymorphic sites (rs57875989 length polymorphism: PER34, PER35; rs228697 SNP: PER3C, PER3G) in relation to sleep-wake timing; ii) the effect of morning light on behavioural/circadian variables in PER34/PER34 and PER35/PER35 homozygotes. 786 Caucasian subjects living in Northern Italy donated buccal DNA and completed diurnal preference, sleep quality/timing and sleepiness/mood questionnaires. 19 PER3 4 /PER3 4 and 11 PER3 5 /PER3 5 homozygotes underwent morning light administration, whilst monitoring sleep-wake patterns and the urinary 6-sulphatoxymelatonin (aMT6s) rhythm. No significant relationship was observed between the length polymorphism and diurnal preference. By contrast, a significant association was observed between the PER3G variant and morningness (OR = 2.10), and between the PER3G-PER34 haplotype and morningness (OR = 2.19), for which a mechanistic hypothesis is suggested. No significant differences were observed in sleep timing/aMT6s rhythms between PER35/PER35 and PER34/PER34 subjects at baseline. After light administration, PER34/PER34 subjects advanced their aMT6s acrophase (p PER3 polymorphic variants/their combinations and both diurnal preference and the response to light.

OBJECTIVE: To investigate a cohort of pediatric patients with thyroid nodules, defining histotype frequency and differences between subjects with hyperthyroidism and euthyroidism and benign and malignant nodules. DESIGN: Retrospective cohort. SETTING: Consecutive cases from 9 Italian pediatric endocrinology centers for the last 10 years. Patients One hundred twenty pediatric patients with thyroid nodules. Intervention Doppler ultrasonography was performed in 71 subjects; scintiscan, in 56; fine-needle aspiration biopsy in 104; and 63 underwent surgery. MAIN OUTCOME MEASURES: The differences in clinical, laboratory, and ultrasonographic data between patients with hyperthyroidism and euthyroidism and malignant and benign nodules were evaluated. RESULTS: One hundred fourteen patients had euthyroidism and 6, hyperthyroidism. The latter had more compressive signs (P=.003), greater nodule diameter (P=.02), intranodular vascularization pattern (P=.01), and increased scintiscan uptake (P

Background: The pediatric literature does not contain any studies comparing the evolution of Hashimoto's thyroiditis (HT)-related subclinical hypothyroidism (SH) with idiopathic SH longitudinally. Aim and design: In the present study, the two-year evolution of HT-related SH in 32 children with no concomitant risk factors (group A) was compared to that observed in 90 age-matched children with idiopathic SH (group B). The aim was to ascertain whether the association with HT could, per se, affect the evolution of thyroid status over time in SH children irrespective of other coexisting factors, such as thyromegaly, association with other autoimmune diseases, and/or concomitant therapies. Results: During the two-year follow-up, the percentage of children whose thyrotropin (TSH) values increased >10mIU/L was significantly higher in group A (p

Aim Gynecomastia is a common finding in male population of all ages. The aim of our study was to present our experience and goals in surgical treatment of gynecomastia. Patients and methods Clinical records of patients affected by gynecomastia referred to our Department of Surgery between September 2008 and January 2015 were analyzed. 50 patients were included in this study. Results Gynecomastia was monolateral in 12 patients (24%) and bilateral in 38 (76%); idiopathic in 41 patients (82%) and secondary in 9 (18%). 39 patients (78%) underwent surgical operation under general anaesthesia, 11 (22%) under local anaesthesia. 3 patients (6%) presented recurrent disease. Webster technique was performed in 28 patients (56%), Davidson technique in 16 patients (32%); in 2 patients (4%) Pitanguy technique was performed and in 4 patients (8%) a mixed surgical technique was performed. Mean surgical time was 80.72±35.14 minutes, median postoperative stay was 1.46±0.88 days. 2 patients (4%) operated using Davidson technique developed a hematoma, 1 patient (2%) operated with the same technique developed hypertrophic scar. Conclusions Several surgical techniques are described for surgical correction of gynecomastia. If performed by skilled general surgeons surgical treatment of gynecomastia is safe and permits to reach satisfactory aesthetic results.

We reviewed data collected during several studies concerning the genetic isolate of Carloforte (Sardinia, Italy) and analyzed new data on Y-chromosome markers. Carloforte is also a language island, where people still speak Tabarchino, an archaic form of Ligurian dialect. Demographic data indicate that, in the early years of its history, the Carloforte population was characterized by a high degree of endogamy and consanguinity rates that started to decrease around 1850, when marriages with Sardinian people began to occur more frequently. Cultural factors, mainly language, account for the high endogamy. Genetic data from classical markers, mtDNA, and Y-chromosome markers confirmed the strong isolation of the Carloforte population, which appears significantly different from the neighboring population of Sardinia. Analysis of mtDNA emphasizes the crucial aspect of sampling strategy—two different samplings of the same population (one based on founder surnames; the other one based on grandparents’ criterion) gave different results. Founder surnames sampling is not affected by recent events, and therefore it better describes the ancestral population, whereas, grandparents’ criterion sampling gives a picture of the present population, shaped by more recent events, such as migration and gene flow. This review further supports the notion that a comprehensive approach, including a detailed knowledge of the history of the population and the collection of different samplings, is essential in anthropology for reconstructing past and recent events that contributed to establishing the present genetic structure of the population. Likewise, it is essential in medical genetics to identify genes involved in complex diseases. An ideal scenario is offered by a genetic isolate with a recent, and well-documented, history, such as Carloforte, that can be a paradigm for this type of investigation.

Little information is available about the kidney's involvement in patients with β-thalassaemia major (TM). In particular, there are no studies reporting the outcome of renal function over time.In this retrospective study, we evaluated the changes in estimated glomerular filtration rate (eGFR) in 81 adult patients with TM followed for 10 years. Only patients who had an eGFR of90 mL/min/1.73 m(2) at presentation were admitted to the study. All patients were regularly followed for at least 10 years.At 10 years, 66 patients showed a mild decline in eGFR that remained, however, within a normal range (from 119.9 to 113.6 mL/min/1.73 m(2), P = 0.636). In the remaining 15 patients (18.5%), eGFR decreased to90 mL/min (from 98.1 to 78.2 mL/min/1.73 m(2); P = 0.004). The repeated-measures models showed that the decline in eGFR over time was significantly higher (P = 0.0068) in patients with baseline phosphaturia1000 mg/24 h (P = 0.0068), while eGFR tended to decline more rapidly in patients with baseline uricuria700 mg/24 h than in those with lower uricuria (P = 0.0783). Univariate Cox's proportional regression models showed that abnormal levels of calcaemia were associated with the risk of kidney damage [hazard ratio (HR) 0.30, 95% confidence interval 0.09-0.97 for calcaemia 8.4-10.2 mg/dL versus HR not estimable for calcaemia8.4 or10.2 mg/dL].In most adults with TM, the eGFR tends to remain within a normal range after 10 years. However, patients with elevated phosphaturia, elevated uricuria and/or abnormal levels of calcaemia show a significant decline in eGFR over time, suggesting that tubular damage acquired in childhood caused by either TM or its treatment may eventually result in abnormal eGFR. Further studies in a larger cohort of TM patients are needed to further elucidate the long-term impact of TM on renal function.

Background: To date, there is no agreement about the frequency or the features of thyroid abnormalities in McCune-Albright syndrome (MAS). The aim of our study was to detect thyroid abnormalities in a cohort of MAS children and adolescents and to give indications for their treatment and follow-up. Methods: In 36 patients, 22 females and 14 males, thyroid function and sonographic features of thyroid were evaluated every 6–12 months. Results: Three males and 1 female had hyperthyroidism: 2 with nodular, 2 with diffuse goiters. They were treated with methimazole (0.2–0.5 mg/kg/day) with good clinical and biochemical responses. The remaining 32 patients were euthyroid, even if 7 displayed sonographic alterations, of whom 5 had nodular goiter with nodules >1 cm, and 2 micronodular goiter. Fine-needle aspiration biopsy was performed in 2 patients with nodules >1 cm, 1 showing hemorrhagic nodule and 1 colloid cystic nodule. Conclusions: Prevalence of thyroid alterations in the studied MAS series was 31%. 64% of 11 patients with thyroid alterations had nodular goiters, with nodules >1 cm. As the onset of thyroid disease ranged from 1 to 20 years, a strict monitoring of thyroid function is recommended every 6 months. Satisfactory treatment can be obtained and maintained with antithyroid drugs.

ObjectiveTo prospectively evaluate the course of subclinical hypothyroidism (SH) in children and adolescents with no underlying diseases and no risk factors, which might interfere with the progression of SH.DesignClinical status, thyroid function, and autoimmunity were prospectively evaluated at entry and after 6, 12, and 24 months in 92 young patients (mean age 8.1±3.0 years) with idiopathic SH.ResultsDuring the study, mean TSH levels showed a trend toward a progressive decrease while FT4 levels remained unchanged. Overall, 38 patients normalized their TSH (group A): 16 patients between 6 and 12 months, and 22 patients between 12 and 24 months. Among the remaining 54 patients, the majority maintained TSH within the baseline values (group B), whereas 11 exhibited a further increase in TSH above 10 mU/l (group C). Baseline TSH and FT4 levels were similar in the patients who normalized TSH, compared with those with persistent hyperthyrotropinemia. Even in the patients of group C, both TSH and FT4 at entry were not different with respect to those of groups A and B. No patients showed any symptoms of hypothyroidism during follow-up and no changes in both height and body mass index were observed throughout the observation period.Conclusions(a) The natural course of TSH values in a pediatric population with idiopathic SH is characterized by a progressive decrease over time; (b) the majority of patients (88%) normalized or maintained unchanged their TSH; and (c) TSH changes were not associated with either FT4 values or clinical status or auxological parameters.