Role of contrast-enhanced ultrasound to define prognosis and predict response to biotherapy in pancreatic neuroendocrine tumors.

PURPOSE: The incidence of neuroendocrine tumors (NETs) is progressively increasing. Most cases arise from the digestive system, where ileum, rectum and pancreas represent the commonest site of origin. Liver metastases are frequently detected at diagnosis or during the follow-up. Contrast-enhanced ultrasound (CEUS) is used in patients with pancreatic NETs (P-NETs) and liver metastases from P-NET but its role has not been standardized. The aim of this retrospective study was to investigate CEUS in patients with P-NETs and liver metastases from P-NET both as prognostic factor and predictor of response to therapy with somatostatin analogues (SSAs). METHODS: CEUS was performed at the diagnosis of NET and 3, 6 and 12 months after the beginning of SSAs. CEUS pattern was compared with contrast-enhanced computed tomography (CT) pattern. RESULTS: There was a significant association between CEUS and CT pattern (X 2 = 79.0; p < 0.0001). A significant association was found between CEUS pattern and Ki-67 index (X 2 = 24.6; p < 0.0001). The hypervascular homogeneous CEUS typical pattern was associated with low tumor grading (G1 or G2) (X 2 = 24.0; p < 0.0001). CEUS pattern changed from hypervascular homogeneous in baseline to hypovascular/hypervascular inhomogeneous after SSA therapy, with a significant association between tumor response at CT scan and appearance of hypervascular inhomogeneous pattern at CEUS evaluation (6 months: X 2 = 57.0; p < 0.0001; 12 months: X 2 = 49.8; p < 0.0001). CONCLUSIONS: In patients with P-NET, CEUS pattern correlates with tumor grading, being homogeneous in G1-G2 but not in G3 tumors. After therapy with SSAs, CEUS is predictive of response to SSAs. These findings seem to support a role of CEUS as prognostic and predictive factor of response.

Delineating physiologic defensive reactivity in the domain of self-report: phenotypic and etiologic structure of dispositional fear.

BACKGROUND: Individual differences in fear and fearlessness have been investigated at their extremes in relation to markedly different forms of psychopathology--anxiety disorders and psychopathy, respectively. A documented neural substrate of fear-related traits and disorders is defensive reactivity as reflected in aversive startle potentiation (ASP). METHOD: The current study extended prior work by characterizing, in a sample of adult twins from the community (n = 2511), the phenotypic and etiologic structure of self-report measures of fear and fearlessness known to be associated with ASP. RESULTS: Analyses revealed a hierarchical structure to the trait fear domain, with an overarching, bipolar fear/fearlessness dimension saturating each measure in this domain, and subfactors labeled 'distress,' 'stimulation seeking' and 'sociability' accounting for additional variance in particular measures. The structure of genetic and non-shared environmental associations among the measures closely mirrored the phenotypic structure of the domain. CONCLUSIONS: The findings have implications for proposals to reconceptualize psychopathology in neurobiological terms.

Insulin-like growth factor (IGF)-I and IGF-binding protein-3 serum levels in relapsing-remitting and secondary progressive multiple sclerosis patients.

BACKGROUND: Insulin-like growth factor (IGF)-I has a role in remyelination, and insulin-like growth factor-binding protein-3 (IGFBP-3) might reduce its bioavailability. A role of IGFBP-3 in multiple sclerosis (MS) progression was hypothesized in patients with primary progressive (PP) MS. OBJECTIVE: To evaluate serum levels of IGF-I and IGFBP-3 in patients with relapsing-remitting (RR) and secondary progressive (SP) MS and their correlations with disease activity and progression. METHODS: Sixty-three (41 RR and 22 SP) 'naive' MS patients and 60 age-matched healthy controls were enrolled. Patients were assessed through clinical [Expanded Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), number of relapses] and laboratory investigations. IGF-I and IGFBP-3 were measured by ELISA. RESULTS: Levels of IGF-I and IGFBP-3 were similar in the two MS groups. IGFBP-3 levels were higher in patients with MS than in controls (P < 0.001), with a reduction in IGF-I/BP3 ratio (P < 0.001). Patients showing IGFBP-3 levels higher than 2SD of the normal population had a higher EDSS (mean EDSS 3.7 vs. 2.8, P = 0.021). MSSS was not related to IGF-I or IGFBP-3 serum levels. CONCLUSIONS: Our patients showed high IGFBP-3 serum levels respect to controls and higher serum levels were associated with a higher EDSS, despite of comparable disease duration. Therefore, MS and higher disability seem to be associated with a reduction in bioavailability of IGF-I. MSSS score was not related to IGFBP-3 levels, suggesting that IGFBP-3 might not have the pathogenetic role previously suggested for PP MS, in the mechanism of progression in the SP form of disease.

Vitamin D status may contribute to serum insulin-like growth factor I concentrations in healthy subjects.

OBJECTIVE: The aim of the study was to evaluate whether vitamin D [25-(OH) D3] status affects serum IGFI concentrations in healthy subjects. DESIGN AND PATIENTS: Two hundred and forty-one consecutive healthy subjects were included in the present study. MEASUREMENTS: Serum IGF-I and 25-(OH) D3 concentrations. RESULTS: As expected, serum IGF-I concentrations progressively decreased with age (r=-0.55, p<0.0001); on the contrary, gender was not related to serum IGF-I levels. A positive relationship was identified between serum 25-(OH) D3 and IGF-I concentrations (r=0.33, p<0.0001); the 25-(OH) D3-dependent changes of serum IGF-I concentrations were observed also when subjects were divided on the basis of vitamin D deficiency; in fact, those with severe 25-(OH) D3 deficiency (<20 ng/ml) had lower (185 ± 83 µg/l) IGF-I values than those with mild-to absent 25-(OH) D3 deficit (225 ± 83 µg/l, p=0.0004). CONCLUSIONS: 25-(OH) D3 status may contribute to determine serum IGF-I levels in healthy population.

Pituitary autoimmunity is associated with hypopituitarism in patients with primary empty sella.

OBJECTIVE: Some evidence suggests that late stage autoimmune hypophysitis (AH) may result in empty sella (ES). Aim of the study was to assess the prevalence of serum pituitary antibodies (PitAb) and their correlation with pituitary function in patients with ES. DESIGN: In this casecontrol study 85 patients with primary ES, 16 patients with ES secondary to head trauma, 214 healthy controls, and 16 AH were enrolled in a tertiary referral center. METHODS: PitAb were assessed in all cases and controls. Endocrine function was assessed by basal hormone measurement and dynamic testing in all ES cases. RESULTS: PitAb prevalence was higher in primary ES (6%) than in healthy subjects (0.5% p=0.003) and lower than in AH patients (50%, p<0.0001). PitAb were not found in patients with secondary ES. Hypopituitarism was found in 49% of primary ES and in 62% of secondary ES (p=0.34). A positive correlation between the presence of PitAb and hypopituitarism was found in primary ES (p=0.02). CONCLUSIONS: The significant association between pituitary autoimmunity and hypopituitarism suggests that ES, in selected cases, could be the final result of AH.

Growth hormone/insulin-like growth factor I axis in neurodegenerative diseases.

Neurodegenerative diseases (ND) are a group of heterogeneous disorders characterized by unknown etiology, subtle onset, and progressive involvement of neuronal systems leading to degeneration and dysfunction. They represent a challenge for basic science and clinical medicine because of increasing prevalence, social cost, complex biochemistry and pathology, and lack of mechanism-based treatments. Endocrine modifications may accompany the progression of ND, due to the intimate connections between central nervous and endocrine systems. Reported data on endocrine changes in different ND have often been non-conclusive or conflicting. GH/IGF-I axis is involved in the regulation of brain growth, development, and metabolism. Dysfunctions in GH/IGF-I axis in most of ND are therefore reviewed. Whether GH deficiency, when present, may act as a contributory factor in the pathogenesis of these diseases, or might represent a consequence of it is presently unknown. A thorough effort in investigating every possible involvement of GH/IGF-I axis is warranted, in the light of future possible therapeutic strategies.

Short- and long-term changes of quality of life in patients with acromegaly: results from a prospective study.

Quality of life (QoL) may be affected in acromegalic patients, although the role of disease activity is still unsettled. The aim of the study was to assess the QoL of acromegalic patients with a specific questionnaire (ACROQOL). ACROQOL was evaluated in a prospective study (at baseline, at 6 and 24 months) in 23 active untreated acromegalic patients. Control of acromegaly was defined by normal age-matched serum IGF-I concentrations. Patient groups were defined as controlled or uncontrolled at 6 months and at 24 months: controlled or uncontrolled during the entire study period (ACRO(CC) or ACRO(NC), respectively) or uncontrolled at 6 months and controlled thereafter (ACRO(C)). At 6 months, ACROQOL scores improved globally (from 54.3+/-21 to 65.1+/-19, p=0.04) as did subdomains and were inversely related to IGF-I variation (r=-0.50, p=0.052). At 24 months, ACROQOL improved globally (from 54.3+/-21 to 65.7+/-18.0, p=0.04) and this was also seen in the appearance subdomains; however, no correlation was revealed between variation of serum IGF-I concentrations and changes in ACROQOL total score (r=0.008, p=0.87). ACROQOL scores did not significantly change in ACRO(NC) (p=0.310) and in ACRO(C) (p=0.583), whereas it improved globally (from 42.1+/-22.1 to 58.8+/-16.04, p=0.021) and in psychological subdomains in ACRO(CC); however, it reflected the improvement occurred within the first 6 months of disease control. In conclusion, successful treatment, which normalizes disease activity, improves QoL in acromegaly in the short term. However, the lack of correlation between the ACROQOL score in the long term might suggest that factors other than serum IGF-I participate in the well-being of acromegalic patients; however, due to the small sample size, our results need to be confirmed in larger studies.

Clinical aspects and therapeutic outcome in thyrotropin-secreting pituitary adenomas: a single center experience.

BACKGROUND AND AIM: The management of pituitary adenomas secreting TSH has evolved considerably over the last decades.We report the clinical features, management, and outcome of a large monocentric series. MATERIAL AND METHODS: A monocentric retrospective cohort of 26 patients admitted to our Department of Endocrinology between 1983 and 2007, followed for a period up to 204 months. The diagnosis of TSH-secreting adenoma was based on clinical and biochemical findings of central hyperthyroidism. Evaluation of basal and dynamic pituitary function, magnetic resonance imaging or computerized tomography scan were performed in all patients. Twenty-two patients, of whom 15 pre-treated by somatostatin analogs (SSA), underwent trans-sphenoidal surgery and were regularly re-evaluated. RESULTS: The number of cases increased over the years. Age at diagnosis, micro- to macroadenoma ratio, and mean estimated latency between first symptoms and diagnosis did not appreciably change over time. Latency was significantly shorter in macroadenomas. Following surgery, 55% of patients obtained remission (success rate of 40 and 67% in macro- and microadenomas, respectively). SSA pre-treatment led to an apparent although not statistically- significant increase in success rate in micro- but not in macroadenomas. CONCLUSIONS: In a monocentric group of 26 TSH-secreting adenomas the high ratio between micro- and macroadenomas remained stable over time with a significantly shorter diagnosis latency in macroadenomas. A more precocious recognition of the tumors and possibly the use of presurgical SSA allowed a high remission rate. A varied combination of neurosurgery, SSA, radiotherapy, and thyroid ablation led to the control of the disease in all the patients studied.

Acceptance and commitment therapy as an adjunct to the MOVE! programme: a randomized controlled trial.

OBJECTIVE: The current study tested the efficacy of an acceptance and commitment therapy (ACT) group intervention for disinhibited eating behaviour as an adjunct to the Veterans Affairs MOVE!© weight management programme. METHODS: Veterans (N = 88) with overweight or obesity who completed the MOVE! weight management programme and self-identified as having problems with 'stress-related eating' were randomized to four 2-h weekly ACT sessions or a continued behavioural weight-loss (BWL) intervention. Assessments were completed at baseline, post-treatment and 3- and 6-month follow-up on outcomes of interest including measures of disinhibited eating patterns, obesity-related quality of life, weight-related experiential avoidance and weight. RESULTS: The BWL group exhibited significantly greater reductions in binge eating behaviour at post-treatment compared with the ACT group. Significant improvements in other outcomes were found with minimal differences between groups. In both groups, decreases in weight-related experiential avoidance were related to improvements in binge eating behaviour. CONCLUSIONS: Taken together, the continued BWL intervention resulted in larger improvements in binge eating behaviour than the ACT intervention. The two groups showed similar improvements in other disinhibited eating outcomes. Future studies are encouraged to determine if more integrated or longer duration of ACT treatment may maximize eating outcomes in MOVE.Trial Registration Number: This trial was registered with ClinicalTrials.gov database (NCT01757847).

Dopamine D2 receptor gene polymorphisms and response to cabergoline therapy in patients with prolactin-secreting pituitary adenomas.

Dopamine-agonist cabergoline (CB) reduces prolactin (PRL) secretion and tumor size in 80% of patients with prolactin-secreting adenomas (PRL-omas) by binding type 2 dopamine receptor (DRD2). The mechanisms responsible for resistance to CB remain largely unknown. To assess the association of DRD2 with sensitivity to CB, TaqI-A1/A2, TaqI-B1/B2, HphI-G/T and NcoI-C/T genotypes were determined in a cross-sectional retrospective study, including 203 patients with PRL-oma. DRD2 alleles frequencies did not differ between patients and 212 healthy subjects. Conversely, NcoI-T allele frequency was higher in resistant rather than responsive patients, considering both PRL normalization (56.6 vs 45.3%, P=0.038) and tumor shrinkage (70.4 vs 41.4%, P=0.006). Finally, [TaqI A1-/TaqI B1-/HphI T-/NcoI T-] haplotype was found in 34.5% of patients normalizing PRL with < or =3 mg/week of CB vs 11.3% of resistants (P=0.021). In conclusion, resistance to CB was associated with DRD2 NcoI-T+ allele, consistent with evidence suggesting that this variant may lead to reduction and instability of DRD2 mRNA or protein.