The association of a panel of biomarkers with the presence and severity of carcinoid heart disease: a cross-sectional study.

PURPOSE: Metastatic neuroendocrine tumors secrete serotonin and other vasoactive substances that are responsible for carcinoid syndrome and carcinoid heart disease. We sought to evaluate the discriminatory utility of diagnostic biomarkers in determining the presence and severity of carcinoid heart disease in patients with metastatic neuroendocrine tumors. PATIENTS AND METHODS: A cross-sectional study of patients with neuroendocrine tumors with documented liver metastases and/or carcinoid syndrome between April 2009-October 2012 in 5 tertiary referral centers. Serum was analyzed for Chromogranin A, Chromogranin B and N-terminal pro Brain Natriuretic Peptide (NT-proBNP). Plasma was analyzed for Neurokinin A and 5-Hydroxyindoleacetic acid (5HIAA). Echocardiography was used to determine the presence and severity of carcinoid heart disease. Non-parametric receiver operating characteristic curves were constructed for biomarkers, and the area under the curve determined. The severity of cardiac involvement was correlated with the concentration of each biomarker. RESULTS: A total of 187 patients were identified of whom 37 (20%) had carcinoid heart disease. Significantly higher median values of all biomarkers were found in the patients with cardiac involvement. NT-proBNP and plasma 5HIAA had the highest areas under the curve for the prediction of carcinoid heart disease [NT-proBNP 0.82 (95% confidence interval 0.74-0.90, p<0.0001) and 5HIAA 0.85 (95% confidence interval 0.78-0.92, p<0.0001]. NT-proBNP was moderately correlated (r = 0.48, p<0.001) whereas plasma 5HIAA was only weakly correlated (r = 0.34, p<0.001) with the echocardiographic severity score. CONCLUSION: NT-proBNP and plasma 5HIAA are both sensitive and specific biomarkers for the presence of carcinoid heart disease whereas only NT-proBNP is moderately correlated with disease severity.

Validation of neurokinin a assays in the United States and Europe.

OBJECTIVES: International cooperative group trials require specific, sensitive biomarker assays that are validated between continents. Neurokinin A (NKA) has been shown to be a powerful independent predictor of a poor prognosis in well-differentiated midgut neuroendocrine tumors. We hypothesized that NKA concentrations of clinical specimens evaluated in NKA assays in the United States and the United Kingdom would be equivalent, even though assay techniques were significantly different. METHODS: Frozen clinical specimen aliquots were shipped from the United States to the United Kingdom (n = 67), and from United Kingdom to the United States (n = 50). In addition, spiked plasma standards and medium-spiked standards were exchanged. Samples from the United States were directly assayed in a radioimmunoassay, whereas the UK specimens were extracted, and the reconstituted specimens assayed in the radioimmunoassay. Neurokinin A values from the 2 studies were analyzed by regression analysis. RESULTS: The NKA values from the US and UK laboratories were essentially identical (United States to United Kingdom, r = 0.88, P < 0.0001; and United Kingdom to United States, r = 0.96, P < 0.0001). CONCLUSIONS: Validation of biomarker assays across continents will ensure that laboratory observations made by researchers are equivalent and that prediction of clinical outcomes based on these assays is also reliable.

Circulating biomarkers in neuroendocrine tumors of the enteropancreatic tract: application to diagnosis, monitoring disease, and as prognostic indicators.

Neuroendocrine tumors (NETs) are difficult to diagnose. Their symptoms may be vague or intermittent, and are frequently associated with much more common diseases; many of the tumors may be asymptomatic. Therefore, diagnosis can be delayed for some years. Because most NETs are secretory, the measurement of circulating biomarkers is helpful not only for diagnosis but also for assessing tumor response to treatment, monitoring disease progression, and use as prognostic indicators.

Circulating markers for endocrine tumours of the gastroenteropancreatic tract.

The diffuse endocrine system (DES) includes a wide range of secretory cells that may be the source of tumours. Gastroenteropancreatic endocrine (GEP) tumours arising within the DES secrete a variety of peptides and amines that are found in the circulation and are responsible for the syndromes associated with these tumours. In this review, the most common tumours of the GEP tract are outlined and the circulating products of these tumours identified. Where differential diagnosis is difficult these points are addressed. The peptides most commonly secreted by GEP neuroendocrine tumours are identified and described and their biological activities are discussed. Current methods available for measurement of these peptides are described. Attention is drawn towards molecular specificity where appropriate, as many pancreatic and gut peptides fall within families which show considerable homology, such as the tachykinin family or the glucagon family. Other peptides such as gastrin circulate in multiple molecular forms. This homology and diversity may cause difficulty in the interpretation of peptide measurements in the clinical situation if assays are not specific.

Increased tachykinin levels in induced sputum from asthmatic and cough patients with acid reflux.

BACKGROUND: Acid reflux may aggravate airway disease including asthma and chronic cough. One postulated mechanism concerns a vagally-mediated oesophageal-tracheobronchial reflex with airway sensory nerve activation and tachykinin release. AIM: To test the hypothesis that patients with airways disease and reflux have higher airway tachykinin levels than those without reflux. METHODS: Thirty-two patients with airways disease (16 with mild asthma and 16 non-asthmatic subjects with chronic cough) underwent 24 h oesophageal pH monitoring. Acid reflux was defined as increased total oesophageal acid exposure (% total time pH<4 of >4.9% at the distal probe). All subjects underwent sputum induction. Differential cell counts and concentrations of substance P (SP), neurokinin A (NKA), albumin and alpha2-macroglobulin were determined. RESULTS: SP and NKA levels were significantly higher in patients with reflux than in those without (SP: 1434 (680) pg/ml vs 906 (593) pg/ml, p=0.026; NKA: 81 (33) pg/ml vs 52 (36) pg/ml, p=0.03). Significantly higher tachykinin levels were also found in asthmatic patients with reflux than in asthmatic patients without reflux (SP: 1508 (781) pg/ml vs 737 (512) pg/ml, p=0.035; NKA: median (interquartile range 108 (85-120) pg/ml vs 75 (2-98) pg/ml, p=0.02). In patients with asthma there was a significant positive correlation between distal oesophageal acid exposure and SP levels (r=0.59, p=0.01) and NKA levels (r=0.56, p=0.02). Non-significant increases in SP and NKA were measured in patients with cough with reflux (SP: 1534.71 (711) pg/ml vs 1089 (606) pg/ml, p=0.20; NKA: 56 (43) pg/ml vs 49 (17) pg/ml, p=0.71). No significant difference in differential cell counts or any other biochemical parameter was noted between study groups. CONCLUSION: This study demonstrates increased airway tachykinin levels in patients with asthma and cough patients with coexistent acid reflux. This suggests airway sensory nerve activation in this population.

Plasma concentrations of glucagon-like peptide-2 in adult patients with treated and untreated coeliac disease.

BACKGROUND: Coeliac disease is a common chronic inflammatory enteropathy characterized by villous atrophy and crypt hyperplasia in the small intestine. The mechanism of the intestinal damage in coeliac disease remains unclear. Glucagon-like peptide (GLP)-2 is an enterotrophic peptide that causes crypt hyperplasia and intestinal cell proliferation. We postulate that GLP-2 may be involved in the mucosal changes found in coeliac disease. OBJECTIVES: To study plasma concentrations of GLP-2 in untreated patients with coeliac disease and determine the response to a gluten-free diet (GFD). METHODS: A 440 kcal gluten-free test meal was given to seven controls and 12 coeliac patients at three time intervals: (1) before commencing a GFD; (2) 3 months after a GFD; and (3) 9 months after a GFD. Serial blood sampling was performed over a 2-h period. Each sample was analysed using radioimmunoassay for GLP-2, GLP-1, N-terminal glucagon (N-glucagon) and C-terminal glucagon (C-glucagon). RESULTS: Untreated coeliac patients had significantly higher basal and peak GLP-2 and N-glucagon plasma concentrations compared with controls. After 3 months on a GFD, there was a significant decrease in basal GLP-2 plasma concentrations. There was no significant difference between GLP-1 or C-glucagon in untreated coeliac patients compared with controls. CONCLUSION: This is the first reported study of GLP-2 in coeliac disease. After a GFD there is recovery of the intestine and a reduction in the GLP-2 trophic response. Our findings support the theory that GLP-2 may be part of the mucosal healing and maintenance mechanisms in coeliac disease.

Endobronchial adenosine monophosphate challenge causes tachykinin release in the human airway.

BACKGROUND: Adenosine 5 monophosphate (AMP) has been shown to cause bronchoconstriction and a sensation of chest tightness when inhaled by asthmatic subjects. This response is attenuated after repeated inhalation of bradykinin, suggesting that AMP may act in part by the release of neuropeptides. OBJECTIVE: This study examined neuropeptide release in the human airway after endobronchial AMP challenge. METHODS: Endobronchial AMP challenge was performed in 20 subjects and tachykinin levels were measured after endobronchial AMP challenge and after placebo endobronchial challenge with saline. RESULTS: All subjects coughed immediately after adenosine challenge. There was a significant increase in neurokinin A and substance P levels (P < .01, P < .01 respectively) when post-saline and post-AMP levels were compared. There was, however, no significant change in calcitonin gene related peptide levels (P = .37). CONCLUSION: This study demonstrates that endobronchial AMP challenge causes tachykinin release in the human airway in vivo.

Soluble vascular endothelial growth factor receptor-1 (sFlt-1) is increased throughout gestation in patients who have preeclampsia develop.

OBJECTIVE: This study was undertaken to analyze prospectively circulating vascular endothelial growth factor (VEGF) and its soluble receptor, (s) Flt-1, throughout normotensive and preeclamptic pregnancies and to assess the importance of these proteins in the development of preeclampsia. STUDY DESIGN: In this longitudinal cohort study, serum samples were collected from recruited subjects throughout pregnancy at 12, 20, 30, and 37 weeks and in the 24 hours before and after delivery. Subjects were divided retrospectively into normotensive and preeclamptic groups. Circulating VEGF and sFlt-1 concentrations were analyzed by radioimmunoassay and enzyme-linked immunosorbent assay, respectively. RESULTS: Circulating sFlt-1 and VEGF significantly increased as gestation progressed and both were further elevated in preeclampsia compared with normotensive pregnancy. Soluble Flt-1 concentrations were elevated early in gestation and were significantly increased at 30 weeks' gestation in those who subsequently developed preeclampsia. CONCLUSION: These results indicate a definite association between elevated sFlt-1 concentrations and the onset of preeclampsia suggesting that sFlt-1 is linked with disease pathogenesis.

Gastrin: an analytical review.

The gastric hormone gastrin is produced in multiple forms that vary in their biological properties. In this analytical review, the strategies available for the assay of different gastrins in plasma are considered. Except for research purposes, it is seldom necessary or even desirable to employ assays that are specific for an individual molecular form of gastrin. Instead, routine clinical assays of plasma gastrin should ideally react equally with the sulphated and unsulphated forms of the COOH-terminally amidated peptides, the most important of which are peptides of 17 and 34 amino acid residues (i.e. G17 and G34), and should not react with the related hormone cholecystokinin. Methods appropriate for the use of such assays are reviewed. These assays are important in the diagnosis of gastrinoma. Although it is recognized that circulating concentrations of gastrin are elevated in other conditions, including chronic atrophic gastritis, Helicobacter pylori infection and long-term administration of proton pump inhibitors, it is not clear whether gastrin radioimmunoassay is important for the clinical management in these conditions.

A safe and noninvasive test for vagal integrity revisited.

HYPOTHESIS: Measurement of pancreatic polypeptide (PP) response to sham feeding and pharmacological stimulation is a safe, noninvasive, and sensitive test for vagal integrity. DESIGN: Interventional study with control arms. SETTING: Tertiary center for esophageal surgery. PATIENTS: Thirty healthy volunteers and 25 patients who underwent total esophagectomy formed the control group with intact vagi and known vagotomy, respectively. INTERVENTION: Blood samples were obtained 15 minutes before and immediately before sham feeding to determine basal PP levels. Samples were also obtained 15, 30, 45, and 60 minutes after the sham feeding and 10 and 20 minutes after administration of 5 mg of intravenous edrophonium hydrochloride. MAIN OUTCOME MEASURE: Pancreatic polypeptide response to sham feeding and edrophonium administration were compared in both groups and the optimal percentage of rise from basal levels with maximal sensitivity and specificity was determined. RESULTS: Basal levels were similar in both groups (50 vs 45 ng/L). The maximum percentage of rise within 30 minutes after sham feeding was significantly higher in healthy subjects than in patients who underwent vagotomy (P<.001). A rise of 50% was seen in 24 (83%) of the 29 healthy subjects vs 2 (8%) of the 25 patients who underwent vagotomy (P<.001). This rise in PP level had a sensitivity of 83%, specificity of 92%, and a positive predictive value of 92% for identifying an intact vagus. The administration of endrophonium did not improve these results. CONCLUSIONS: A rise of more than 50% in the PP level within 30 minutes of sham feeding is a strong indicator of vagal integrity. This test has the potential to investigate vagal injury after gastroesophageal surgery.