An expression signature of the angiogenic response in gastrointestinal neuroendocrine tumours: correlation with tumour phenotype and survival outcomes.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) are heterogeneous with respect to biological behaviour and prognosis. As angiogenesis is a renowned pathogenic hallmark as well as a therapeutic target, we aimed to investigate the prognostic and clinico-pathological role of tissue markers of hypoxia and angiogenesis in GEP-NETs. METHODS: Tissue microarray (TMA) blocks were constructed with 86 tumours diagnosed from 1988 to 2010. Tissue microarray sections were immunostained for hypoxia inducible factor 1α (Hif-1α), vascular endothelial growth factor-A (VEGF-A), carbonic anhydrase IX (Ca-IX) and somatostatin receptors (SSTR) 1-5, Ki-67 and CD31. Biomarker expression was correlated with clinico-pathological variables and tested for survival prediction using Kaplan-Meier and Cox regression methods. RESULTS: Eighty-six consecutive cases were included: 51% male, median age 51 (range 16-82), 68% presenting with a pancreatic primary, 95% well differentiated, 51% metastatic. Higher grading (P=0.03), advanced stage (P<0.001), high Hif-1α and low SSTR-2 expression (P=0.03) predicted for shorter overall survival (OS) on univariate analyses. Stage, SSTR-2 and Hif-1α expression were confirmed as multivariate predictors of OS. Median OS for patients with SSTR-2+/Hif-1α-tumours was not reached after median follow up of 8.8 years, whereas SSTR-2-/Hif-1α+ GEP-NETs had a median survival of only 4.2 years (P=0.006). CONCLUSION: We have identified a coherent expression signature by immunohistochemistry that can be used for patient stratification and to optimise treatment decisions in GEP-NETs independently from stage and grading. Tumours with preserved SSTR-2 and low Hif-1α expression have an indolent phenotype and may be offered less aggressive management and less stringent follow up.

Do flow volume loops alter surgical management in patients with a goitre?

INTRODUCTION: Flow volume loops (FVLs) are considered part of the workup of patients with thyroid enlargement presenting to the endocrinology clinic. They are used to detect upper airway obstruction (UAO) secondary to tracheal compression (TC) from a goitre. Surgical assessment in contrast tends to focus on clinical evaluation supplemented when required by imaging. The aim of this study was to investigate whether FVLs influence the decision to operate in patients with a goitre. METHODS: We identified patients with a goitre referred by the department of endocrinology for FVLs between 2006 and 2011. The results of the FVL were collated, and their impact on patient management was assessed. RESULTS: Ninety-six patients were referred for FVL. In 38 patients, the indication was specifically to evaluate the effects of a goitre. Of these, 33 were reported as normal. Five FVLs were reported as abnormal (3 suggesting lung pathology and 2 TC). Both patients with TC on FVL presented no CT evidence of TC and underwent surgery due to abnormal cytology. Of the 33 normal FVLs, 7 underwent surgery: 2 for local compression, 4 for abnormal cytology and 1 for Graves' disease. None of the FVLs influenced the decision to operate. CONCLUSION: FVLs may detect subradiological TC, but rarely influence management in patients with a goitre. In view of this and the cost of £235 per investigation, FVL should be reserved for goitre patients with suspected primary lung pathology, where the distinction between large and small airway compression is likely to influence management.

Immunohistochemical markers of the hypoxic response can identify malignancy in phaeochromocytomas and paragangliomas and optimize the detection of tumours with VHL germline mutations.

BACKGROUND: There are no reliable markers of malignancy in phaeochromocytomas (PCC) and paragangliomas (PGL). We investigated the relevance of the mammalian target of rapamycin (mTOR)/AKT and hypoxic pathways as novel immunohistochemical markers of malignancy. METHODS: Tissue microarray blocks were constructed with a total of 100 tumours (10 metastatic) and 20 normal adrenomedullary samples. Sections were immunostained for hypoxia-inducible factor 1α (Hif-1α), vascular endothelial growth factor A (VEGF-A), mTOR, carbonic anhydrase IX (CaIX) and AKT. The predictive performance of these markers was studied using univariate, multivariate and receiver operating characteristic analyses. RESULTS: In all, 100 consecutive patients, 64% PCC, 29% familial with a median tumour size of 4.7 cm (range 1-14) were included. Univariate analyses showed Hif-1α overexpression, tumour necrosis, size >5 cm, capsular and vascular invasion to be predictors of metastasis. In multivariate analysis, Hif-1α, necrosis and vascular invasion remained as independent predictors of metastasis. Hif-1α was the most discriminatory biomarker for the presence of metastatic diffusion. Strong membranous CaIX expression was seen in von Hippel-Lindau (VHL) PCC as opposed to other subtypes. CONCLUSION: Lack of vascular invasion, tumour necrosis and low Hif-1α expression identify tumours with lower risk of malignancy. We propose membranous CaIX expression as a potential marker for VHL disease in patients presenting with PCC.

A comparison of the performance of 68Ga-DOTATATE PET/CT and ¹²³I-MIBG SPECT in the diagnosis and follow-up of phaeochromocytoma and paraganglioma.

PURPOSE: To compare the sensitivity of (123)I-metaiodobenzylguanidine (MIBG) SPECT and (68)Ga-DOTATATE PET/CT in detecting phaeochromocytomas (PCC) and paragangliomas (PGL) in the initial diagnosis and follow-up of patients with PCC and PGL disease. METHODS: Retrospective analysis of 15 patients with PCC/PGL who had contemporaneous (123)I-MIBG and (68)Ga-DOTATATE imaging. RESULTS: Of the 15 patients in the series, 8 were concordant with both modalities picking up clinically significant lesions. There were no patients in whom both modalities failed to pick up clinically significant lesions. There was discordance in seven patients: 5 had positive (68)Ga-DOTATATE and negative (123)I-MIBG, and 2 (12 and 14) had negative (68)Ga-DOTATATE and positive (123)I-MIBG. Utilizing (123)I-MIBG as the gold standard, (68)Ga-DOTATATE had a sensitivity of 80 % and a positive predictive value of 62 %. The greatest discordance was in head and neck lesions, with the lesions in 4 patients being picked up by (68)Ga-DOTATATE and missed by (123)I-MIBG. On a per-lesion analysis, cross-sectional (CT and MRI) and (68)Ga-DOTATATE was superior to (123)I-MIBG in detecting lesions in all anatomical locations, and particularly bony lesions. CONCLUSION: First, (68)Ga-DOTATATE should be considered as a first-line investigation in patients at high risk of PGL and metastatic disease, such as in the screening of carriers for mutations associated with familial PGL syndromes. Second, if (123)I-MIBG does not detect lesions in patients with a high pretest probability of PCC or PGL, (68)Ga-DOTATATE should be considered as the next investigation. Third, (68)Ga-DOTATATE hould be considered in preference to (123)I-MIBG in patients in whom metastatic spread, particularly to the bone, is suspected.

The effects of long-term growth hormone and insulin-like growth factor-1 exposure on the development of cardiovascular, cerebrovascular and metabolic co-morbidities in treated patients with acromegaly.

BACKGROUND: Acromegaly is characterized by the hypersecretion of growth hormone (GH) and insulin-like growth factor-1 (IGF-1). This leads to an increased cardiovascular, cerebrovascular and metabolic morbidity resulting in excess mortality. There is controversy over which biomarker, GH or IGF-1, better predicts this increased morbidity and mortality. The relationship between the cumulative exposure to GH and IGF-1 with co-morbidities in acromegaly has not previously been reported. OBJECTIVE: To investigate the relationship between the cumulative exposure to GH and IGF-1 with cardiovascular, cerebrovascular and metabolic co-morbidities. METHODS: Records of 116 acromegalic patients were retrospectively examined. Cardiovascular and cerebrovascular histories, serum GH and IGF-1, fasting glucose and oral glucose tolerance test results, were reviewed for the duration of follow-up. IGF-1 index was calculated by dividing each serum IGF-1 value by the upper limit of reference range for IGF-1. GH and IGF-1 burdens were calculated for each patient by multiplying known disease duration (in years) by mean level of basal GH or IGF-1 index recorded during the patients' entire follow-up. RESULTS: Patients with abnormal glucose tolerance had a significantly higher mean GH burden compared with euglycaemic patients (P = 0·005). Ischaemic heart disease was also associated with a higher GH burden (P = 0·009) whereas cerebrovascular disease and cardiomyopathy were associated with a significantly higher mean IGF-1 burden (P = 0·018, P = 0·011 respectively). CONCLUSION: This study identifies associations of raised GH and IGF-1 burden with cardiovascular, cerebrovascular and metabolic complications of acromegaly. Results from this study therefore suggest that consideration of the overall level of GH and IGF-1 exposure may provide important information for the management and surveillance of patients with treated acromegaly.

Serum phosphate predicts temporary hypocalcaemia following thyroidectomy.

BACKGROUND: Temporary hypocalcaemia occurs in up to 40% of patients following a total thyroidectomy. Serum calcium and parathyroid hormone (PTH) measurements are currently used to predict post-thyroidectomy hypocalcaemia. However, immediate access to PTH measurement is expensive and not widely available. Serum phosphate responds rapidly to changes in circulating PTH levels, and its measurement is readily available in all hospitals. We evaluated the use of serum phosphate to predict temporary hypocalcaemia post-thyroidectomy. METHODS: We retrospectively assessed 111 consecutive patients who had total or completion thyroidectomy. Patients had serum calcium and phosphate measured preoperatively, on the evening of surgery (day 0), on the morning of day 1 and over the following week as clinically indicated. Serum PTH was measured on the morning of day 1. Vitamin D levels were measured preoperatively. RESULTS: Seventy-six patients did not develop treatment-demanding hypocalcaemia. In these patients, the mean serum phosphate concentration was lower on the morning of day 1 compared to that on the evening of surgery. Seventeen patients with a vitamin D>25 nmol/l developed hypocalcaemia requiring treatment from day 1 onwards. All had an overnight rise in serum phosphate to >1.44 mmol/l (100% sensitivity and specificity for predicting hypocalcaemia). Twelve patients who had a vitamin D<25 nmol/l also developed hypocalcaemia but had an attenuated rise in serum phosphate. CONCLUSION: Serum phosphate is a reliable biochemical predictor of post-thyroidectomy hypocalcaemia in patients without vitamin D deficiency. The use of serum phosphate may facilitate safe day 1 discharge of patients undergoing thyroidectomy.

The role of arterial stimulation and simultaneous venous sampling in addition to cross-sectional imaging for localisation of biochemically proven insulinoma.

Insulinomas, although rare, cause considerable morbidity but are frequently amenable to surgical cure. Laparoscopic surgery can now be considered if the tumour is localised pre-operatively, but the optimal imaging approach has not been determined. The objective of this study was to evaluate the ability of different imaging investigations, including CT, MRI, endoscopic ultrasound, octreotide scintigraphy and arterial stimulation with simultaneous venous sampling (ASVS), to localise insulinomas. All patients with biochemically proven insulinoma at our institution underwent ASVS along with other imaging investigations as part of their routine investigation. The results of these investigations were compared with histological findings. Twenty-eight patients with biochemically proven insulinoma confirmed by histology were identified. Ultimately ASVS localised a lesion in all patients. Seventeen patients (61%) had laparoscopic surgery. Tumor-detection rates for other imaging investigations included 43.5% of cases using CT, 71% using MRI, 86% using endoscopic ultrasound and 33% using octreotide scintigraphy. In four patients, the ASVS was the only test to correctly localise the lesion. ASVS should be considered routinely before surgery to ensure accurate localisation of insulinomas.

Adrenal incidentaloma in familial adenomatous polyposis: a long-term follow-up study and schema for management.

PURPOSE: Adrenal incidentaloma is often diagnosed in patients with familial adenomatous polyposis, because they frequently undergo abdominal imaging and have a raised incidence of adrenal incidentaloma. This study investigates the natural history of adrenal incidentaloma in familial adenomatous polyposis, and suggests a schema for management. METHODS: An original cohort of 14 familial adenomatous polyposis patients with adrenal incidentaloma, identified prospectively 12 years ago, was followed up clinically and radiologically. A further group of 16 patients was also identified. All had lesions >1 cm. For both cohorts, characteristics of patients (genotype, age at diagnosis, concomitant diagnoses) and incidentaloma (size, laterality, rate of growth, outcome) are described. RESULTS: Overall, 3 of 30 patients underwent adrenalectomy; one patient had pheochromocytoma and another had an adenoma of borderline malignancy. A further three lesions were radiologically suspicious for malignancy at the time of diagnosis; one was in a patient who was unfit for surgery but died of nonadrenal causes after nine years. None of the lesions radiologically benign at diagnosis showed an aggressive course, but one patient required referral for surgery after 12 years because of a slow increase in size of the lesion. There were no associations with genotype. CONCLUSIONS: Familial adenomatous polyposis-associated adrenal incidentaloma may warrant long-term follow-up. Although the natural history is similar to lesions occurring sporadically, these patients have concomitant familial adenomatous polyposis-associated manifestations under radiologic surveillance. In this rare condition, development of a robust protocol will require evidence from worldwide patient cohorts. However, a tailored schema is suggested as a consistent basis for future modification.

Measurement of basal growth hormone (GH) is a useful test of disease activity in treated acromegalic patients.

BACKGROUND: Nadir GH during oral glucose tolerance test (OGTT) is the gold-standard test of GH secretion in treated acromegaly. However, it was recently reported that variability in GH is reduced postradiotherapy, making basal GH a potential surrogate marker for nadir GH in such patients. OBJECTIVE: We aimed to investigate how predictive basal GH is of nadir GH and IGF-I, and whether radiotherapy influenced these relationships. DESIGN: A total of 226 pairs of basal and nadir GH values from 76 treated acromegalic patients were analysed. Basal GH was defined as the fasting serum GH immediately prior to OGTT. RESULTS: A highly positive linear correlation (Pearson correlation = 0.955, P < 0.01) between basal and nadir GH was found. Negative predictive value for basal GH < 1 microg/l with respect to nadir GH > 1 microg/l was 100% (53/53 in radiotherapy group, 15/15 in nonradiotherapy group). Positive predictive values for basal GH > 2 microg/l with respect to nadir GH > 1 microg/l for patients treated and not treated with radiotherapy were 96.7% (88/91) and 95.2% (20/21), respectively. No significant difference between concordance of basal and nadir GH with IGF-I in assessment of disease activity was found. Discordance between IGF-I and nadir or basal GH < 1 microg/l was lower in the radiotherapy group than nonradiotherapy group, but this was nonsignificant. CONCLUSIONS: Basal GH < 1 microg/l and > 2 microg/l are highly predictive of nadir GH < 1 microg/l and > 1 microg/l, respectively, regardless of previous radiotherapy. Basal GH is as good as nadir GH in concordance with IGF-I. We therefore suggest basal GH is a useful test of disease activity in treated acromegaly, and can reliably replace OGTT unless basal GH is between 1 microg/l and 2 microg/l.

Using kisspeptin to assess GnRH function in an unusual case of primary amenorrhoea.

SUMMARY: Primary amenorrhoea is defined as the failure to commence menstruation by the age of 15 years, in the presence of normal secondary sexual development. The potential causes of primary amenorrhoea extend from structural to chromosomal abnormalities. Polycystic ovarian syndrome (PCOS) is a common cause of secondary amenorrhoea but an uncommon cause of primary amenorrhoea. An early and prompt diagnosis of PCOS is important, as up to 30% of these women are predisposed to glucose intolerance and obesity, with the subgroup of women presenting with primary amenorrhoea and PCOS displaying a higher incidence of metabolic dysfunction. We describe a case of an 18-year-old female presenting with primary amenorrhoea of unknown aetiology. Although initial investigations did not demonstrate clinical or biochemical hyperandrogenism or any radiological evidence of polycystic ovaries, a raised luteinising hormone (LH) suggested a diagnosis of PCOS. If PCOS was the correct diagnosis, then one would expect intact hypothalamic GnRH and pituitary gonadotropin release. We used the novel hormone kisspeptin to confirm intact hypothalamic GnRH release and a GnRH stimulation test to confirm intact pituitary gonadotroph function. This case highlights that kisspeptin is a potential unique tool to test GnRH function in patients presenting with reproductive disorders. LEARNING POINTS: Polycystic ovarian syndrome (PCOS) can present with primary amenorrhoea, and therefore, should be considered in the differential diagnosis.PCOS is a heterogeneous condition that may present in lean women with few or absent signs of hyperandrogenism.GnRH stimulation tests are useful in evaluating pituitary function; however, to date, we do not have a viable test of GnRH function. Kisspeptin has the potential to form a novel diagnostic tool for assessing hypothalamic GnRH function by monitoring gonadotropin response as a surrogate marker of GnRH release.Confirmation of intact GnRH function helps consolidate a diagnosis in primary amenorrhoea and gives an indication of future fertility.

Comparison of the dexamethasone-suppressed corticotropin-releasing hormone test and low-dose dexamethasone suppression test in the diagnosis of Cushing's syndrome.

CONTEXT: The low-dose dexamethasone suppression test (LDDST) is widely used in confirming a diagnosis of Cushing's syndrome. CRH administration at the end of an LDDST has been reported to improve the diagnostic accuracy of this test. OBJECTIVE: Our objective was to assess whether CRH administration after a standard LDDST (LDDST-CRH test) improves diagnostic accuracy in Cushing's syndrome. DESIGN, SETTING, AND PARTICIPANTS: Thirty-six individuals with a clinical suspicion of Cushing's syndrome each completed a standard LDDST and an LDDST-CRH test at Hammersmith Hospitals NHS Trust, London. The LDDST involved administration of 0.5 mg oral dexamethasone given 6-hourly for 48 h. Serum cortisol was measured 6 h after the last dose of dexamethasone, with a value of 50 nmol/liter or below excluding Cushing's syndrome. Immediately after this, the LDDST-CRH test commenced with administration of a ninth dose of 0.5 mg dexamethasone. Exactly 2 h later, 100 mug human-sequence CRH was administered. Serum cortisol was measured 15 min after the CRH injection, with a value of less than 38 nmol/liter also excluding Cushing's syndrome. MAIN OUTCOME MEASURE: Diagnosis or exclusion of Cushing's syndrome was the main outcome measure. RESULTS: Twelve subjects were diagnosed with Cushing's syndrome (eight Cushing's disease and four primary adrenal). The sensitivity of the LDDST in diagnosing Cushing's syndrome was 100%, with a specificity of 88%. In contrast, although the sensitivity of the LDDST-CRH test was also 100%, specificity was reduced at 67%. These results give a positive predictive value of 80% for the LDDST and 60% for the LDDST-CRH test. CONCLUSION: This small study suggests that the addition of CRH to the LDDST does not improve the diagnostic accuracy of the standard LDDST in Cushing's syndrome.

Microinjection of galanin-like peptide into the medial preoptic area stimulates food intake in adult male rats.

Galanin-like peptide (GALP) is a neuropeptide implicated in the regulation of feeding behaviour, metabolism and reproduction. GALP is an endogenous ligand of the galanin receptors, which are widely expressed in the hypothalamus. GALP is predominantly expressed in arcuate nucleus (ARC) neurones, which project to the paraventricular nucleus (PVN) and medial preoptic area (mPOA). Intracerebroventricular or intraparaventricular (iPVN) injection of GALP acutely increases food intake in rats. The effect of GALP injection into the mPOA on feeding behaviour has not previously been studied. In the present study, intra-mPOA (imPOA) injection of GALP potently increased 0-1-h food intake in rats. The dose-response effect of imPOA GALP administration on food intake was similar to that previously observed following iPVN administration. The effects of GALP (1 nmol) or galanin (1 nmol) on food intake were then compared following injection into the PVN, mPOA, ARC, dorsal medial nucleus (DMN), lateral hypothalamus and rostral preoptic area (rPOA). GALP (1 nmol) increased food intake to a similar degree when injected into the imPOA or iPVN, but produced no significant effect when injected into the ARC, DMN, lateral hypothalamus or rPOA. Similarly, galanin (1 nmol) significantly increased food intake following injection imPOA and iPVN. However, the effect was significantly smaller than that following administration of GALP (1 nmol). Galanin also had no significant effect on food intake when administered into the ARC, DMN, lateral hypothalamus and rPOA. These data suggest that the mPOA and the PVN may have specific roles in mediating the orexigenic effect of GALP and galanin.

The clinical characteristics of headache in patients with pituitary tumours.

The clinical characteristics of 84 patients with pituitary tumour who had troublesome headache were investigated. The patients presented with chronic (46%) and episodic (30%) migraine, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT; 5%), cluster headache (4%), hemicrania continua (1%) and primary stabbing headache (27%). It was not possible to classify the headache according to International Headache Society diagnostic criteria in six cases (7%). Cavernous sinus invasion was present in the minority of presentations (21%), but was present in two of three patients with cluster headache. SUNCT-like headache was only seen in patients with acromegaly and prolactinoma. Hypophysectomy improved headache in 49% and exacerbated headache in 15% of cases. Somatostatin analogues improved acromegaly-associated headache in 64% of cases, although rebound headache was described in three patients. Dopamine agonists improved headache in 25% and exacerbated headache in 21% of cases. In certain cases, severe exacerbations in headache were observed with dopamine agonists. Headache appears to be a significant problem in pituitary disease and is associated with a range of headache phenotypes. The presenting phenotype is likely to be governed by a combination of factors, including tumour activity, relationship to the cavernous sinus and patient predisposition to headache. A proposed modification of the current classification of pituitary-associated headache is given.

Plasma gastrin measurement cannot be used to diagnose a gastrinoma in patients on either proton pump inhibitors or histamine type-2 receptor antagonists.

BACKGROUND: Patients with a gastrinoma are treated with proton pump inhibitors (PPI) and histamine type-2 receptor antagonists (H2). In order to diagnose a gastrinoma these drugs must be discontinued, but this increases the risk of gastrointestinal perforation. We aimed to determine if a gastrinoma could be diagnosed without cessation of PPI/H2 therapy. METHODS: In all, 90 patients (controls and patients diagnosed with a gastrinoma both on and off PPI/H2 therapy) were recruited, and plasma gastrin measured. RESULTS: Patients with a gastrinoma on PPI/H2 medication had a significantly higher fasting plasma gastrin concentration than control patients on PPI/H2 medication (298+/-33 versus 204+/-30 pmol/L, P = 0.01). However, there was substantial overlap between gastrin levels in these two groups. CONCLUSION: This study confirms that a gastrinoma cannot be diagnosed on the basis of a fasting plasma gastrin assay while patients remain on PPI/H2 therapy.

Agouti related protein (AgRP) is upregulated in Cushing's syndrome.

Alpha melanocyte-stimulating hormone (alpha-MSH) is an agonist at the melanocortin 3 (MC3-R) and melanocortin 4 (MC4-R) receptors. Alpha-MSH stimulates corticosterone release from rat and human adrenal cells. Patients with Cushing's syndrome have elevated levels of serum alpha-MSH. Agouti related protein (AgRP) is an endogenous antagonist at the MC3-R and MC4-R and is expressed in the rat adrenal cortex. AgRP antagonises alpha-MSH-induced corticosterone release from rat and bovine adrenal cells. This suggests that AgRP may have an inhibitory paracrine role in the adrenal gland. We measured adrenal AgRP mRNA expression and circulating AgRP in 2 patients with Cushing's syndrome and controls. Adrenal AgRP mRNA expression and plasma AgRP were higher in the patients with Cushing's syndrome compared to controls. Plasma AgRP in the patients with Cushing's syndrome following bilateral adrenalectomy and hydrocortisone replacement were similar to the levels seen in controls. Our results suggest that AgRP may have a novel inhibitory paracrine role in the human adrenal gland.

A case of excess growth hormone levels.

Patients with anorexia nervosa are known to have elevated basal growth hormone levels, which fail to suppress normally during glucose tolerance testing. We describe a case of probable anorexia nervosa initially diagnosed as acromegaly despite a low insulin-like growth factor-1 level and treated with transsphenoidal surgery based on a pituitary microadenoma on magnetic resonance imaging and a lack of suppression of growth hormone levels during glucose tolerance testing. This case highlights, firstly, that pituitary magnetic resonance imaging will suggest a pituitary adenoma in up to 10% of normal individuals. Secondly, that a diagnosis of acromegaly should be made on clinical features as well as growth hormone measurements.

Comparison of the utility of Cocaine- and Amphetamine-Regulated Transcript (CART), chromogranin A, and chromogranin B in neuroendocrine tumor diagnosis and assessment of disease progression.

CONTEXT: Prognosis in patients with neuroendocrine tumors (NETs) is often poor, frequently reflecting delayed diagnosis. Hence, accurate and practical NET markers are needed. Cocaine- and amphetamine-regulated transcript (CART) peptide is a potential novel NET marker. DESIGN AND PARTICIPANTS: Circulating levels of CART peptide and the established NET markers chromogranin A (CgA) and chromogranin B (CgB) were measured using RIA in 353 patients with NET (normal renal function) and in controls. Clinical data were collected retrospectively. MAIN OUTCOME MEASURE(S): The comparative and combined utility of CART, CgA, and CgB for diagnosis and assessment of disease progression was measured in different NET subtypes. RESULTS: CgA and CgB in combination improved diagnostic accuracy in patients with gut NETs, nongastroenteropancreatic NETs, and NETs with an unknown primary origin compared with each biomarker alone. Measuring CART did not further improve diagnosis in these NET subtypes. For pancreatic NETs, CgB was superior to CgA and CART in detecting stable disease (P < .007), whereas CgA and CART in combination were most effective in identifying progressive disease. In phaeochromocytomas/paragangliomas (PCC/PGL), CART was the most useful biomarker for identifying stable (P < .001) and progressive (P = .001) disease. Consistent with this, plasma CART decreased following PCC/PGL tumor resection, remaining low in all patients in remission, but increasing in those with progressive disease. CONCLUSIONS: CART is a useful marker for identifying progressive pancreatic NETs. CART is superior to CgA and CgB in detecting stable and progressive PCC/PGLs, and may have a role as a surveillance marker for PCC/PGL patients.

Neuroendocrine tumours.

Neuroendocrine tumours are a heterogeneous group including, for example, carcinoid, gastroenteropancreatic neuroendocrine tumours, pituitary tumours, medullary carcinoma of the thyroid and phaeochromocytomas. They have attracted much attention in recent years, both because they are relatively easy to palliate and because they have indicated the chronic effect of the particular hormone elevated. As neuroendocrine phenotypes became better understood, the definition of neuroendocrine cells changed and is now accepted as referring to cells with neurotransmitter, neuromodulator or neuropeptide hormone production, dense-core secretory granules, and the absence of axons and synapses. Neuroendocrine markers, particularly chromogranin A, are invaluable diagnostically. Study of several neuroendocrine tumours has revealed a genetic etiology, and techniques such as genetic screening have allowed risk stratification and prevention of morbidity in patients carrying the particular mutation. Pharmacological therapy for these often slow-growing tumours, e.g. with somatostatin analogues, has dramatically improved symptom control, and radiolabelled somatostatin analogues offer targeted therapy for metastatic or inoperable disease. In this review, the diagnosis and management of patients with carcinoid, gut neuroendocrine tumours, multiple endocrine neoplasia types 1 and 2, and isolated phaeochromocytoma are evaluated.

Adrenomedullin inhibits feeding in the rat by a mechanism involving calcitonin gene-related peptide receptors.

The central effect of adrenomedullin on feeding was investigated in fasted rats. After intracerebroventricular administration, adrenomedullin decreased 2-h food intake in a dose-dependent manner. A dose of 1.7 nmol adrenomedullin decreased 2-h food intake by 57%. Adrenomedullin shares sequence homology with calcitonin gene-related peptide (CGRP), a central anorectic agent, and binding sites for both are present in the hypothalamus. Adrenomedullin competed for [125I]adrenomedullin- and [125I]CGRP-binding sites in hypothalamic membranes. The Kd for the [125I]adrenomedullin-binding site was 0.54 +/- 0.07 nM, with a binding capacity of 214 +/- 27 fmol/mg membrane protein (n = 3). CGRP and the CGRP receptor antagonist CGRP-(8-37) at concentrations up to 1 microM did not compete at these sites. The Kd for the CGRP-binding site was 0.10 +/- 0.02 nM, with a binding capacity of 250 +/- 31 fmol/mg, and the Ki values for adrenomedullin and CGRP-(8-37) were 4.6 +/- 2.1 and 4.0 +/- 1.6 nM, respectively (n = 3). Thus, adrenomedullin showed high affinity binding at both adrenomedullin- and CGRP-binding sites. To establish whether adrenomedullin reduces feeding via CGRP receptors, we coadministered adrenomedullin (1.7 nmol) and CGRP-(8-37) (30 nmol). The reduction in 2-h food intake induced by adrenomedullin was 50% inhibited by CGRP-(8-37). These results show that adrenomedullin decreases food intake in the rat, and this effect is mediated at least in part via CGRP receptors.