Pathophysiology and Management of Glycemic Alterations before and after Surgery for Pheochromocytoma and Paraganglioma.

Glycemic alterations are frequent in patients with pheochromocytoma and paraganglioma (PPGL), but the real incidence of secondary diabetes mellitus (DM) is uncertain, because prospective multicenter studies on this topic are lacking in the literature. The main pathophysiological mechanisms of glucose homeostasis alterations in PPGL, related to catecholamine hypersecretion, are impaired insulin and glucagon-like peptide type 1 (GLP-1) secretion and increased insulin resistance. Moreover, it has been reported that different pathways leading to glucose intolerance may be related to the secretory phenotype of the chromaffin tumor. Predictive factors for the development of glucose intolerance in PPGL patients are a higher age at diagnosis, the need for a higher number of anti-hypertensive drugs, and the presence of secreting neoplasms. Tumor resection is strongly related to the resolution of DM in PPGL patients, with a significant improvement of glycemic control in most cases. We can hypothesize a different personalized therapeutic approach based on the secretory phenotype. The adrenergic phenotype is more closely related to reduced insulin secretion, so insulin therapy may be required. On the other hand, the noradrenergic phenotype mainly acts by increasing insulin resistance and, therefore, insulin-sensitizing antidiabetic agents can find a greater application. Regarding GLP-1 receptor agonists, the data suggest a possible promising therapeutic effect, based on the assumption that GLP-1 secretion is impaired in patients with PPGL. The principal predictors of remission of glycemic alterations after surgery for PPGL are a lower preoperative body mass index (BMI), a larger tumor, higher preoperative catecholamine levels, and a shorter duration of the disease (under three years). Otherwise, after resection of PPGL, hypoglycemia can occur as the result of an excessive rebound of preoperative hyperinsulinemia. It is a rare, but potentially severe complication reported in a lot of case reports and a few small retrospective studies. Higher 24-h urinary metanephrine levels, longer operative times and larger tumors are predictive factors for hypoglycemia in this setting. In conclusion, alterations of carbohydrate metabolism are clinically relevant manifestations of PPGL before and after surgery, but there is the need to conduct multicenter prospective studies to obtain an adequate sample size, and to allow the creation of shared strategies for the clinical management of these potentially severe manifestations of PPGL.

End-of-Life in Oncologic Patients' Dream Content.

Both non-rapid eye movements and rapid eye movements sleep facilitate the strengthening of newly encoded memory traces, and dream content reflects this process. Numerous studies evaluated the impact of diseases on dream content, with particular reference to cancer, and reported the presence of issues related to death, negative emotions, pain and illness. This study investigates death and illness experiences in 13 consecutive patients with sarcoma compared to paired controls, early after diagnosis, evaluating dream contents, fear of death, mood and anxiety, distress, and severity of disease perception (perceived and communicated). Ten patients and 10 controls completed the study. Dream contents were significantly different between patients and normative data (DreamSat) and patients and controls (higher presence of negative emotions, low familiar settings and characters and no success involving the dreamer). Illness and death were present in 57% of patients' dreams (0% among controls), but no differences emerged between patients and controls in regard to anxiety and depression, distress and fear of death, even if the severity of illness was correctly perceived. The appearance of emotional elements in dreams and the absence of conscious verbalization of distress and/or depressive or anxious symptoms by patients could be ascribed to the time required for mnestic elaboration (construction/elaboration phase) during sleep.

HLA DRB1*0415: a new possible genetic susceptibility factor for Hirata's disease.

CONTEXT: Hirata's disease (HD) is a rare autoimmune cause of hypoglycemia. Patients suffering from this condition have a genetic predisposition, determined by HLA DR4, with some differences in the worldwide population. In Caucasians HLA DRB1*0403 is the most frequent susceptibility background on which some drugs play as triggers. CASE DESCRIPTION: We reported the case of a woman with several hypoglycemic episodes, characterized by high insulin and c-peptide levels. Biochemical and morphological exams excluded a neuroendocrine tumor. HD was diagnosed according to insulin autoantibodies positivity and patient's history, particularly about drugs taken. The HLA analysis revealed DRB1*0415 allele. CONCLUSIONS: We found a potential new predisposing factor for HD, HLA DRB1*0415 allele, never described before as genetic background to insulin autoimmune syndrome in Caucasians.

Progression of pituitary tumours: impact of GH secretory status and long-term GH replacement therapy.

BACKGROUND: Most patients treated for hypothalamic-pituitary tumours develop GH deficiency. Long-term GH replacement treatment in adults with a previous history of hypothalamic-pituitary tumour could represent a concern about increasing the risk of tumour enlargement or recurrence. PURPOSE: To assess the progression risk of hypothalamic-pituitary tumours according to the GH secretory status (normal GH secretion, non-treated and treated GH deficiency). and determine the predictors of neoplasm recurrence. METHODS: We retrospectively reviewed 309 patients with tumours of the hypothalamic-pituitary region (294 subjects underwent neurosurgery while 81 radiotherapy) who were followed for 9.9 ± 8.3 years. RESULTS: Out of 309 patients, 200 were affected by severe GH deficiency; 90 of these underwent GH therapy. The tumour progression rate did not differ among GH-sufficient, not-treated and treated GH-deficient patients (16.5%, 16.4%. and 10.0%, respectively). In a multivariate analysis, previous radiotherapy (HR 0.12, CI 0.03-0.52, p < 0.005) and residual tumour (HR 8.20, CI 2.38-28.29, p < 0.001) were independent predictors of recurrence. After controlling for multiple covariates, the tumour recurrence risk in GH-sufficient and GH-treated patients was similar to that observed in not-treated GH-deficient patients. CONCLUSIONS: With limitations of retrospective analysis, GH therapy is not associated with an increased progression rate of tumours of the hypotalamic-pituitary region during long follow-up, thus supporting the long-term safety of GH treatment. The only predictors of tumour recurrence appear to be the presence of residual disease and the lack of radiotherapy.

Familial multinodular goiter and Sertoli-Leydig cell tumors associated with a large intragenic in-frame DICER1 deletion.

OBJECTIVE: Familial multinodular goiter (MNG), with or without ovarian Sertoli-Leydig cell tumor (SLCT), has been linked to DICER1 syndrome. We aimed to search for the presence of a germline DICER1 mutation in a large family with a remarkable history of MNG and SLCT, and to further explore the relevance of the identified mutation. DESIGN AND METHODS: Sanger sequencing, Fluidigm Access Array and multiplex ligation-dependent probe amplification (MLPA) techniques were used to screen for DICER1 mutations in germline DNA from 16 family members. Where available, tumor DNA was also studied. mRNA and protein extracted from carriers' lymphocytes were used to characterize the expression of the mutant DICER1. RESULTS: Nine of 16 tested individuals carried a germline, in-frame DICER1 deletion (c.4207-41_5364+1034del), which resulted in the loss of exons 23 and 24 from the cDNA. The mutant transcript does not undergo nonsense-mediated decay and the protein is devoid of specific metal ion-binding amino acids (p.E1705 and p.D1709) in the RNase IIIb domain. In addition, characteristic somatic 'second hit' mutations in this region were found on the other allele in tumors. CONCLUSIONS: Patients with DICER1 syndrome usually present a combination of a typically truncating germline DICER1 mutation and a tumor-specific hotspot missense mutation within the sequence encoding the RNase IIIb domain. The in-frame deletion found in this family suggests that the germline absence of p.E1705 and p.D1709, which are crucial for RNase IIIb activity, may be enough to permit DICER1 syndrome to occur.

MANAGEMENT OF ENDOCRINE DISEASE: Long-term outcomes of the treatment of central precocious puberty.

GnRH analogues (GnRHa) are the treatment of choice for central precocious puberty (CPP), with the main objective to recover the height potential compromised by the premature fusion of growth cartilages. The aim of this review was to analyze long-term effects of GnRHa on height, body weight, reproductive function, and bone mineral density (BMD) in patients with CPP, as well as the potential predictors of outcome. Because randomized controlled trials on the effectiveness and long-term outcomes of treatment are not available, only qualified conclusions about the efficacy of interventions can be drawn. GnRHa treatment appears to improve adult height in girls with CPP, especially if diagnosed before the age of 6, whereas a real benefit in terms of adult height is still controversial in patients with the onset of puberty between 6 and 8 years of age. No height benefit was shown in patients treated after 8 years. Gonadal function is promptly restored in girls after cessation of treatment, and reproductive potential appears normal in young adulthood. Data are conflicting on the long-term risk of polycystic ovarian syndrome in both treated and untreated women. Fat mass is increased at the start of treatment but normalizes thereafter, and GnRHa itself does not seem to have any long-term effect on BMI. Similarly, analogue treatment does not appear to have a negative impact on BMD. Owing to the paucity of data available, no conclusions can be drawn on the repercussions of CPP and/or its treatment on the timing of menopause and on the health of the offspring.

Acylated ghrelin as a provocative test for the diagnosis of GH deficiency in adults.

OBJECTIVE: Insulin tolerance test (ITT) is the test of reference for the diagnosis of adult GH deficiency (GHD), although GHRH in combination with arginine (ARG) or GH secretagogues are considered equally reliable tests. Testing with GH secretagogue alone is, anyway, a potent stimulus exploring the integrity of hypothalamic pathways controlling somatotropic function. We therefore aimed to determine the diagnostic reliability of testing with ghrelin, the natural GH secretagogue. METHODS: We studied the GH response (every 15 MIN from 15 TO +120 MIN) to acylated ghrelin (1G/KG I.V. AT 0MIN) IN 78 patients with a history of pituitary disease (49 male, 29 female; age (MEANS.D.): 52.1±18.7 years; BMI: 26.7±5.3 kg/m(2)). The lack of GH response to GHRH+ARG and/or ITT was considered the gold standard for the diagnosis of GHD. The best GH cut-off to ghrelin test, defined as the one with the best sensitivity (SE) and specificity (SP), was identified using the receiver-operating characteristic curve analysis. RESULTS: The best GH cut-off to ghrelin test was 7.3 µg/l in lean subjects (SE 88.2%, SP 90.9%), 2.9 µg/l in overweight subjects (SE 92.6%, SP 100%) and 0.6 µg/l in obese subjects (SE 50%, SP 100%). The diagnostic accuracy was 89.3, 94.1 and 62.5% respectively. CONCLUSIONS: Our data show that testing with acylated ghrelin represents a reliable diagnostic tool for the diagnosis of adult GHD, in lean and overweight subjects, if appropriate cut-off limits are assumed. Obesity strongly reduces GH response to ghrelin, GH weight-related cut-off limit and diagnostic reliability of the test.

Hypopituitarism following brain injury: when does it occur and how best to test?

Aim of this review is to highlight how and when Traumatic Brain Injury (TBI) as well as Subarachnoid Haemorrhage (SAH) and primary Brain Tumours (pBT) of the Central Nervous System (CNS) can induce hypopituitarism, an under-diagnosed clinical problem. Moreover, this review aims to clarify, on the basis of the recent evidences, how these patients have to be tested for pituitary-function. Both retrospective and prospective studies recommended that patients with more severe form of Brain Injuries (BI) and in particular, those with fractures of the base of the skull or early diabetes insipidus, have to be closely monitored for signs and symptoms of endocrine dysfunction. Further studies will be crucial to raise awareness and remind physicians on the prevalence of hypopituitarism in patients with BI and to elucidate any incremental benefits these patients may receive from hormone replacement.