Plasma Chromogranin A Levels Research Articles

ProSAAS peptide of the granin protein family in biochemical diagnostics of pheochromocytoma.

Pheochromocytoma is a hormonally active tumour originating from neuroendocrine cells of the adrenal medulla. Chromogranin A (CgA) and peptide proSAAS belong to the family of granins and are present in neuroendocrine cells of adrenal medulla, from where they are released to circulation, along with catecholamines. The aim of this study was to assess the usability of proSAAS peptide assay in patients with adrenal pheochromocytoma. 23 patients (13 females and 10 males) with adrenal pheochromocytoma (benign in 18 patients and malignant in 5) confirmed by histopathology examination, and 35 blood donors as a control group. Plasma free metanephrines, CgA, and proSAAS peptide levels were measured in all participants. CgA and proSAAS levels in the group of pheochromocytoma patients vs. the control were: 209 ng/mL and 0.8 ng/mL vs. 59 ng/mL and 0.3 ng/mL (p < 0.001), respectively. The following sensitivity and specificity indexes were obtained from ROC curves for CgA: 83% and 92%, respectively, and for the proSAAS peptide: 39% and 88%, respectively. The combination of 2 parameters: normetanephrine and proSAAS (96% and 100%) had a high diagnostic value, and the value of all determined parameters together (metanephrine, normetanephrine, CgA, and proSAAS) was 100%. A single determination of the proSAAS peptide level is associated with a rather low diagnostic value. But collective determination of CgA and proSAAS may be an additional, valuable tool in biochemical diagnostics of pheochromocytoma.

Associations between chronic work stress and plasma chromogranin A/catestatin among healthy workers.

ObjectivesPlasma chromogranin A (CgA) may play a critical role on linking work stress to health outcomes. The aim of our study was to investigate the associations between work stress and plasma CgA levels in healthy workers without chronic diseases.MethodsThe study included 260 healthy workers from EHOP study. Work stressors were assessed by the Chinese version of the 23‐item ERI‐Q questionnaire. Plasma CgA and catestatin levels were measured by ELISA kits. The demographic characteristics were collected from medical records.ResultsAmong the final 260 subjects including 173 males (66.5%) and 87 females (33.5%), the average age was 37.6 ± 10.6 years old. Effort, overcommitment, and ERI were positively associated with plasma CgA level, respectively (r = 0.267, 0.319, and 0.304, all p < .001), while reward was negatively associated with CgA level (r = −0.237, p < .001). The workers with high effort, overcommitment, or ERI had significantly higher plasma CgA levels, while the workers with high rewards had significantly lower plasma CgA levels. The workers with both high overcommitment and high ERI had highest plasma CgA levels. In the linear regression analysis, after adjustment for confounders, effort, overcommitment, and ERI were respectively positively related to plasma CgA, while reward negatively related to plasma CgA. The associations between work stress and plasma catestatin was not significant. The ratio of CgA and catestatin was associated with work stress.ConclusionsWork stress is associated with plasma CgA which may be play a crucial role on the pathway from chronic work stress to cardiovascular diseases.

Plasma chromogranin A levels are associated with acute ischemic stroke with anterior circulation large vessel occlusion

Background and aimsTo investigate the relationship between chromogranin A (CgA) levels and acute ischemic stroke (AIS), especially anterior circulation large vessel occlusion (LVO). Methods and results587 subjects were included in this study, including 205 AIS patients with anterior circulation LVO and 205 nonocclusive patients, as well as 177 healthy controls. On admission, plasma CgA levels were measured and neurological deficits were assessed by the NIH Stroke Scale. Outcomes were assessed by the modified Rankin Scale at 3 months. The predictive properties of CgA were evaluated by receiver operating characteristic (ROC) curve analysis. Binary logistic analysis assessed the association of CgA levels and AIS or anterior circulation LVO.AIS patients had lower CgA levels than health controls (p < 0.001). Anterior circulation LVO patients had lower CgA levels than nonocclusive patients (p < 0.001). The area under the ROC curve of plasma CgA levels in predicting anterior circulation LVO from AIS was 0.744 and the optimal cutoff value was 15.49 ng/mL with a Youden value of 0.332. Logistic analysis showed that CgA ≤15.49 ng/mL remained an independent risk factor for anterior circulation LVO after adjusting for related factors (OR = 6.519, 95% CI: 3.790–11.214, p < 0.001). CgA was an independent protective factor for mild stroke and good prognosis (p = 0.009, p = 0.005); however, the association disappeared after adjusting for occlusion (p = 0.768, p = 0.335). ConclusionCgA levels were lower in AIS patients, especially in anterior circulation LVO patients. Lower CgA levels are potential biomarker for anterior circulation LVO, and they may indicate good prognosis at 3 months in AIS.

The Emerging Roles of Chromogranins and Derived Polypeptides in Atherosclerosis, Diabetes, and Coronary Heart Disease.

Chromogranin A (CgA), B (CgB), and C (CgC), the family members of the granin glycoproteins, are associated with diabetes. These proteins are abundantly expressed in neurons, endocrine, and neuroendocrine cells. They are also present in other areas of the body. Patients with diabetic retinopathy have higher levels of CgA, CgB, and CgC in the vitreous humor. In addition, type 1 diabetic patients have high CgA and low CgB levels in the circulating blood. Plasma CgA levels are increased in patients with hypertension, coronary heart disease, and heart failure. CgA is the precursor to several functional peptides, including catestatin, vasostatin-1, vasostatin-2, pancreastatin, chromofungin, and many others. Catestatin, vasostain-1, and vasostatin-2 suppress the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in human vascular endothelial cells. Catestatin and vasostatin-1 suppress oxidized low-density lipoprotein-induced foam cell formation in human macrophages. Catestatin and vasostatin-2, but not vasostatin-1, suppress the proliferation and these three peptides suppress the migration in human vascular smooth muscles. Chronic infusion of catestatin, vasostatin-1, or vasostatin-2 suppresses the development of atherosclerosis of the aorta in apolipoprotein E-deficient mice. Catestatin, vasostatin-1, vasostatin-2, and chromofungin protect ischemia/reperfusion-induced myocardial dysfunction in rats. Since pancreastatin inhibits insulin secretion from pancreatic β-cells, and regulates glucose metabolism in liver and adipose tissues, pancreastatin inhibitor peptide-8 (PSTi8) improves insulin resistance and glucose homeostasis. Catestatin stimulates therapeutic angiogenesis in the mouse hind limb ischemia model. Gene therapy with secretoneurin, a CgC-derived peptide, stimulates postischemic neovascularization in apolipoprotein E-deficient mice and streptozotocin-induced diabetic mice, and improves diabetic neuropathy in db/db mice. Therefore, CgA is a biomarker for atherosclerosis, diabetes, hypertension, and coronary heart disease. CgA- and CgC--derived polypeptides provide the therapeutic target for atherosclerosis and ischemia-induced tissue damages. PSTi8 is useful in the treatment of diabetes.

The associations between anxiety/depression and plasma chromogranin A among healthy workers: Results from EHOP study.

ObjectivesChromogranin A (CgA) is regarded as an indicator of sympathetic tone and adrenomedullary system activity. Catestatin is one of CgA‐derived fragments through proteolytic processing. Many studies have confirmed the correlation between anxiety/depression and the salivary CgA level. The study was to investigate the associations between anxiety/depression and plasma CgA/catestatin levels in healthy workers without cardiovascular disease.MethodsThe study included 263 healthy workers (175 men and 88 women). The symptoms of anxiety and depression were measured with the Hospital Anxiety and Depression Scale (HADS). Plasma CgA and catestatin levels were measured by ELISA kits.ResultsIn bivariate correlation analysis, anxiety and depression were positively associated with plasma CgA level, respectively (r = 0.298, P < .001; r = 0.304, P < .001), but not significantly associated with plasma catestatin level.The anxiety group had significantly higher plasma CgA level than that in the no‐anxiety group (median 158.60 vs 70.90, P < .001). The similar results were found for depression scales. The depression group had significantly higher plasma CgA level (median 145.60 vs 82.40, P < .001).In the multiple linear regression model, after adjusting for age, gender, and BMI, anxiety was positively correlated with plasma CgA level (β = 0.359, P < .001), while anxiety was negatively correlated with plasma catestatin level (β = −0.128, P = .044), depression was also positively correlated with plasma CgA level (β = 0.343, P < .001).ConclusionsPlasma CgA was associated with anxiety and depression in healthy workers. It can be considered as the blood indicator for the evaluation of anxiety and depression.

Plasma Chromogranin A as a Prognostic Marker in Pancreatic Ductal Adenocarcinoma.

Neuroendocrine differentiation in pancreatic ductal adenocarcinoma (PDAC) is known, but its clinical significance still remains uncertain. The clinical role of chromogranin A (CgA), a marker of neuroendocrine tumor, was evaluated in patients with PDAC. We retrospectively analyzed 350 patients with PDAC. All patients had plasma CgA levels at diagnosis. Patients were classified as normal and high CgA groups according to the upper limit of plasma CgA. There were 202 patients (57.7%) in the normal CgA group and 148 patients (42.3%) in the high CgA group. High CgA group presented higher rate of metastatic disease (61.5% vs 45.0%; P = 0.002) and shorter median overall survival (OS) (8.2 vs 11.6 months; P = 0.015). Upon grouping patients based on clinical stages, OS was significantly different between the CgA groups only in metastatic disease (6.6 vs 7.2 months; P = 0.022). Multivariate analysis showed no association between high CgA and OS (hazard ratio, 1.22; 95% confidence interval, 0.97-1.54; P = 0.090). However, high CgA was associated with poor OS in patients with metastatic disease (hazard ratio, 1.37; 95% confidence interval, 1.01-1.87; P = 0.047). High CgA levels may predict poor prognosis in patients with pancreatic cancer, especially during metastatic stages.

Biochemical Responses in Symptomatic and Asymptomatic Patients with Neuroendocrine Tumors: Pooled Analysis of Two Phase 3 Trials

Neuroendocrine tumors (NETs) are associated with elevated 5-hydroxyindoleacetic acid (5-HIAA) and chromogranin A (CgA) levels. This study aimed to analyze relationships between urinary 5-HIAA and plasma CgA levels and clinical outcomes. Centrally assessed biomarker levels and correlations with progression-free survival (PFS) and carcinoid syndrome (CS) symptom control were evaluated in a pooled analysis of CLARINET (96-week randomized, double-blind, placebo-controlled) and ELECT (16-week randomized, double-blind, placebo-controlled, 32-week initial open label and ≥2 year long-term extension open label) studies of adults with NETs, with (ELECT) or without (CLARINET) CS at 97 institutions. Patients were treated with subcutaneous lanreotide depot 120 mg monthly. Of 319 pooled patients, 86% and 95% had baseline 5-HIAA and CgA data, respectively, with 47% and 74% having levels greater than the upper limit of normal (ULN). PFS was longer among patients who experienced a decrease in biomarker levels at week 12, with statistical significance reached in the CgA cohort (not reached vs. 14.4 months; P<.0001). A large proportion (87%) of patients without symptoms of CS in the CLARINET study had detectable levels of 5-HIAA (48% >ULN). In ELECT, patients with CS who received lanreotide and experienced a biochemical response (≥50% decrease from baseline) achieved greater symptom control. This pooled analysis of two randomized, placebo-controlled trials demonstrated that 5-HIAA and CgA are secreted as biochemical biomarkers in many patients with NETs, regardless of clinical syndromes. Significant biochemical response was associated with improved clinical outcomes, as measured by improved PFS or improved CS symptom control. 5-HIAA = 5-hydroxyindoleacetic acid; CgA = chromogranin A; CI = confidence interval; CLARINET = Controlled Study of Lanreotide Antiproliferative Response in Neuroendocrine Tumors; CS = carcinoid syndrome; ELECT = Evaluation of Lanreotide Depot/Autogel Efficacy and Safety as a Carcinoid Syndrome Treatment; HR = hazard ratio; ITT = intention-to-treat; NET = neuroendocrine tumor; PanNET = pancreatic NET; PFS = progression-free survival; PPI = proton pump inhibitor; SSA = somatostatin analogue; ULN = upper limit of normal.

Low accuracy of chromogranin A for diagnosing early-stage pancreatic neuroendocrine tumors.

The aim of the present study was to evaluate the clinical utility of plasma chromogranin A (CgA) in patients diagnosed with early-stage pancreatic neuroendocrine tumors (PNETs) in terms of diagnostic value and treatment response. A total of 35 patients with PNETs were prospectively enrolled from August 2010 to April 2014. Demographic and clinicopathological data were collected, and serial plasma CgA levels were measured. Tumor responses were defined by the Response Evaluation Criteria In Solid Tumors criteria. Pearson's χ2 test was used for the analysis of the association between the plasma CgA level and various factors. Plasma CgA level was significantly associated with the size (P=0.03), metastasis (P=0.02) and tumor stage (P=0.03) of the PNETs. Using 126 U/l as the optimal cutoff value, the sensitivity and specificity were 87.5 and 81.5%, respectively. For localized tumors, the sensitivity of CgA for diagnosing PNETs was relatively low, even following a lowering of the cutoff values (29.6–51.9%). Plasma CgA level was correlated with therapeutic response in those patients with high baseline CgA levels (P=0.025), but not in the patients with low baseline CgA levels (P=0.587). In conclusion, plasma CgA level was associated with tumor size, metastasis and tumor stage in patients with PNET. For early-stage PNETs, CgA exhibited a limited role in diagnosis and treatment response evaluation in the population of the present study.

Quantitative 18F-DOPA PET/CT in pheochromocytoma: the relationship between tumor secretion and its biochemical phenotype.

18F-FDOPA illustrates the properties of uptake and storage of catecholamines in pheochromocytomas (PHEOs). Until now, the relationship between 18F-FDOPA quantitative parameters and a PHEO secretory profile has not been specifically evaluated. Fifty-six patients (56% females, median age: 47.5yrs) with non-metastatic PHEO, evaluated by 18F-FDOPA PET/CT, were included in this retrospective study. Forty-five patients had negative genetic testing (80.4%); five patients (8.9%) had RET, two patients (3.6%) had SDHB, two had SDHD (3.6%), one patient (1.8%) had NF1, and one patient had a VHL (1.8%) mutation. Correlation between 18F-FDOPA metabolic parameters (tumor SUVmax, tumor SUVmean, tumor SUVmax/liver SUVmax, MTV 42%, total lesion uptake), urinary metanephrines (MNs), and plasma chromogranin A (CgA) were evaluated. All patients had positive 18F-FDOPA PET/CT. On univariate analysis, there was a strong correlation between all metabolic parameters and urinary MNs and plasma chromogranin A (CgA). The highest correlations were observed between total lesion (TL) uptake and the value of urinary MNs regardless of their nature (p=8.10-15 and r=0.80) and between MTV 42% and plasma CgA levels (p=2.10-9, r=0.74). On multivariate analysis, the correlation of uptake parameters and CgA levels did not persist further due to the relation of CgA and tumor diameter. A correlation between TL uptake and the normetanephrine/metanephrine ratio (NMN/MN) was also found, a finding that was in accordance with in vitro studies, which were found to have a higher catecholamine content in epinephrine producing PHEOs. This retrospective study shows a correlation between 18F-FDOPA uptake, especially using TL uptake, urinary MNs, and a PHEO biochemical phenotype. This illustrates that beyond its localization value, 18F-FDOPA PET further enables PHEO characterization at a specific metabolic level.

The Monocyte-to-Lymphocyte Ratio Correlates with Psycho-Neuro-Inflammatory Factors in Patients with Stable Coronary Artery Disease

Background: Psychosocial stress and depression have been recognized as major risk factors of coronary artery disease (CAD). Although monocytes are known to be key players in atherosclerosis, monocyte-based associations with psychoneuroendocrino-immuno-inflammatory (PNI) markers have not been widely investigated in stable CAD. Objective: We examined associations between the monocyte-to-lymphocyte ratio (MLR) and key PNI markers in stable CAD. Methods: We studied 23 patients with stable CAD who completed the Beck Depression Inventory (BDI) and Rahe's Brief Stress and Coping Inventory. A white blood cell differential was performed, and levels of cortisol, chromogranin A (CgA), LL-37, interleukin-6 (IL-6) and C-reactive protein (CRP) were assayed in plasma. Results: Monocyte fraction, MLR and plasma CgA levels exceeded reference values, the social support score was low, and 7 patients had elevated BDI scores. In the multivariate-adjusted analysis, a higher MLR was associated with greater depressive symptom severity (r = 0.624, p < 0.01) as well as with higher concentrations of CgA (r = 0.660, p < 0.01), LL-37 (r = 0.643, p < 0.01), IL-6 (r = 0.532, p < 0.05) and CRP (r = 0.470, p < 0.05). BDI scores associated with CgA concentration (r = 0.618, p < 0.01) and CgA level correlated negatively with the social support score (r = -0.511, p < 0.05). Conclusions: Our findings suggest that, in patients with stable CAD, elevated MLR may be associated with depressive symptoms, with increased neuroendocrine-sympathetic activity (marked by CgA) and inflammatory markers that are pertinent to atherosclerosis initiation and progression. The increased neuroendocrine-sympathetic activity correlated with low social support and depressive symptom severity. The MLR might serve as an easy-to-obtain and inexpensive proxy measure of an activated PNI network in stable CAD.

CLINICAL VALUE OF CHROMOGRANIN A IN GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS

Background: Neuroendocrine tumors (NET) is a heterogeneous group of neoplasms characterized by hypersecretion of biologically active sub- stances that manifests by specific syndromes and determines the clinical course of the disease. The most common NET types are those of gastrointestinal tract. The obligatory biochemical marker used in the examination of NET patients is chromogranin A (CgA). Aim: Evaluation of the CgA value for diagnostics and monitoring of gastrointestinal NETs. Materials and methods: A comparative study of plasma CgA levels was performed in 146 patients with gastroenteropancreatic neuroendocrine tu- mors and 66 healthy individuals using the enzyme immunoassay “Chromogranin A ELISA kit” (Dako A/S, Denmark). Results: CgA levels were significantly higher in patients with NETs of all localizations, such as pancreas, stomach, gut, small and large bowel, than in the healthy subjects (р < 0.000001). In NET patients, CgA secretion was highly variable, with the highest value in the group of patients with gastric NETs (102000 U/l). The highest CgA medians were detected in patients with small intestinal (183.9 U/l), colon (148.4 U/l) and pancreatic (135.9 U/l) NETs. There was an association between CgA secretion and extension or activity of NETs, with the highest median values in patients with hepatic metastases (395 U/l) and those with carcinoid syndrome (352 U/l). The clinical significance of CgA as a NET marker was assessed using the cut-off value of 33 U/l, calculated according to the results in the control group. Overall diagnostic sensitivity of CgA in NET patients was high (85.8%) with a specificity of 98.5%. Conclusion: The results obtained confirm a high sensitivity of CgA as a NET marker whose determination helps to improve accuracy of diagnostics and to assess NET prevalence.

Chromogranin A: As A Tumor Marker for Neuroendocrine Tumors Diagnosis, Follow-up &amp; Its Correlation with Response to Somatostatin Analogues

Background: Chromogranin A is a useful tumor marker for neuroendocrine tumors (NETs) diagnosis &amp; follow-up, Octreotide (somatostatin-long acting repeatable (SAS-LAR)) is an established treatment for NETs. Studies regarding the relation between response to SAS-LAR &amp; the change in Chromogranin A (CgA) plasma level are still lacking.Objectives: To determine the association between the using of Octreotide (SAS-LAR) and CgA level on time sequence &amp; clinical status.Patients &amp; methods: a prospective observational study included 38 neuroendocrine patients in The Oncology Teaching Hospital/medical city complex/Baghdad, started at September 2013 till May 2016; assessing their circulating chromogranin A (CgA) plasma levels on multiple occasions(0,2 and 4 months) by ELISA technique and its correlation with response to somatostatin analogues (SAS-LAR) in those patients.Results: the study recruited 38 neuroendocrine patients. 21 (55%) of them were males, 23 (60%) patients were older than 50 years old &amp; 17 (44%) had metastasis to different sites. Somatostatin analogues (octreotide 30mg) was administered to 20 out of 38 (52.6%) studied patients. Serial CgA tests were performed in (17 out of 20) patients used SAS-LAR, with a change in mean value from (225.3 U/L) pre-using the agent to (17.5 U/L) two months after its use &amp; to (8.7 U/L) four months after its use (p=0.009, p=0.002 respectively) while the change in mean of CgA level was from (205.9 U/L) to (200.9 U/L) in 10 patients who did not use Octreotide (p=0.2).Also results showed that no statistically significant difference in mean value of CgA pre &amp; two months after using Octreotide with regard to grade of the tumor.Conclusions: Plasma CgA is a reliable marker for NETs (regarding diagnosis, prognosis and response to treatment including somatostatin analogues).All patients with NETs should undergo a baseline plasma CgA level at diagnosis. Serial assessment of circulating CgA could be done for NET patients when there is baseline elevation of CgA level in circulation

Assessment of serum chromogranin-A as prognostic factor in high-risk prostate cancer.

The presence of neuroendocrine differentiation may play a key role in androgen-independent tumor progression. The prognostic significance of plasma chromogranin-A (CgA) was assessed in a series of consecutive patients with high-risk prostate cancer (PCa). Twenty-three patients presenting high-risk PCa and 8 healthy individuals, as control group, had their blood samples collected to evaluate CgA, free and total prostate specific antigen, and free and total testosterone in a pilot study. The correlations of serum CgA levels with PSA, testosterone, Gleason score, number of foci of hypercaptation in bone scan, age, and outcomes were evaluated at baseline and after 12 months. Patients with PCa had significantly higher levels of plasma CgA (mean, 8.7; range, 1.9-73) than healthy patients (mean, 3.45; range, 0.6-5.6), P = 0.02. Analyzing only the patients group through correlation of the ranks, it was observed that CgA has low, insignificant correlations with PSA (P = 0.07) and with metastatic extension (P = 0.09). No association was found between the plasma CgA levels and the Gleason score (P = 0.20), age (P = 0.15), or disease progression (P = 0.27). The serum levels of CgA were significantly increased in the group with PCa compared with the healthy group. However, there were low correlations between serum CgA and known prognostic factors (such as total and free PSA, age, Gleason score, and bone metastases) or clinical deterioration. Although future studies are needed with larger samples and longer follow-up, the presented data envisage a limited role to serum CgA as high-risk PCa prognostic factor.

Increased plasma CgA levels associated with nonalcoholic fatty liver disease.

Chromogranin A (CgA), a major soluble protein released by the neuroendocrine system, functions as a prohormone by giving rise to several biologically active peptides. Our study aimed to evaluate the relationship between CgA levels and nonalcoholic fatty liver disease (NAFLD). In total, 111 NAFLD patients and 120 healthy controls were enrolled in the trial. The levels of plasma CgA were quantified by an available enzyme-linked immunosorbent assay kit. Pearson's correlation analysis was conducted to detect whether CgA levels correlated with oxidative stress, insulin resistance, and inflammation profile. A multiple stepwise regression model was used to explore independent determinants for plasma CgA levels. Multivariate logistic regression analysis was conducted to assess whether CgA levels were independent predictors of NAFLD. The levels of plasma CgA between the case and control groups were significantly different (70.9±8.1 μg/L vs 47.6±11.3 μg/L). The levels of plasma CgA positively correlated with high-sensitivity C-reactive protein (hs-CRP; p=0.000), fasting blood glucose (FBG; p=0.025), homeostasis model assessment of insulin resistance index (HOMA-IR; p=0.012), and malondialdehyde (MDA; p=0.037) levels, but negatively associated with superoxide dismutase (SOD; p=0.041) levels. The multiple stepwise regression model indicated that hs-CRP, MDA, and HOMA-IR were independent determinants for plasma CgA levels. The logistic regression analysis showed that plasma levels of CgA were independent predictors of NAFLD. Increased plasma CgA levels were associated with NAFLD.

Chromogranin A as a predictor of radiological disease progression in neuroendocrine tumours.

Chromogranin A (CgA) is the best established neuroendocrine biomarker. This study was aimed at investigating the prognostic value of CgA as a predictor of radiological disease progression in neuroendocrine tumour (NET) patients. Patients with metastatic NETs and evidence of radiological progression (RP) according to RECIST 1.1 were identified from a NET database. Plasma CgA levels were measured 6 and 12 months before RP and at the event of RP. CgA was measured with the Supra-regional-Assay-Service radioimmunoassay (Hammersmith Hospital). A total of 152 patients were evaluated including 91 midgut NETs and 61 pancreatic NETs (PNETs). Of these, 56 were G1 NETs, 65 G2, 10 G3, 21 of unknown histology. For all NETs, there was a positive trend in terms of increase of CgA values 6 months prior to RP compared to 12 months before RP. Subgroup analysis at first episode of RP showed that for PNETs there was evidence of a difference in the median CgA levels. CgA 6 months before RP was 100 pmol/L [interquartile 1 (Q1) =53 and Q3 =286.25 pmol/L) and 12 months before was 52 pmol/L (Q1 =36.25 and Q3 =128 pmol/L), W=52, P=0.48. This observation was not confirmed in midgut NETs, where median CgA 6 months before RP was 389.5 pmol/L (Q1 =131.5 and Q3 =791.5 pmol/L) and 12 months before was 319 pmol/L (Q1 =158 and Q3 =753 pmol/L), W=191, P=0.39]. Low grade tumours (G1) had a median CgA value at 6 months significantly higher than at 12 months [181 (Q1 =56.25, Q3 =624) vs. 149.5 (Q1 =44, Q3 =247.25) pmol/L, W=70, P=0.48]. CgA seems to have predictive value 6 months prior to RP for PNETs and G1 tumours. Further prospective analyses are needed to enable more definitive conclusions.

Biomarkers in neuroendocrine tumors.

Neuroendocrine tumors are a heterogeneous group of tumors with cells of neuroendocrine differentiation that arise from diverse anatomic sites with varying morphologic and clinical features. Since the natural history and prognosis varies widely between individual neuroendocrine tumor types, there is a critical need to identify accurate prognostic and predictive biomarkers and markers predictive of therapeutic efficacy. To date, plasma chromogranin-A levels have generally been accepted as the most useful biomarker, despite the fact that there are substantial concerns in sensitivity and discrepancies in measurement techniques. As a consequence, considerable attention has been focused upon the development of novel biomarkers that can be utilized with more clinical efficacy than chromogranin-A. In addition to amplifying the diagnostic/prognostic landscape, the need to calibrate the efficacy of biological targeted therapy has further accelerated the development of molecular biomarkers. At the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting, Chou et al. (Abstract #e15151) presented data that chromogranin A levels can be monitored during treatment to predict clinical outcome. Modlin et al. (Abstract #4137), demonstrated a promising novel biomarker, serum multi-transcript molecular signature. Grande et al. (Abstract #4140), Heetfield et al. (Abstract #e15071) and Casanovas et al. (Abstract #4139) described sVEGFR2, p-mTOR and IGF1R as molecular markers with potential for use in targeted therapy trials. The authors review and summarize these abstracts in this article.

Baseline and dynamic plasma chromogranin A (CgA) level to predict clinical outcome and tumor response in Asian patients with gastroenteropancreatic neuroendocrine tumor (GEP-NET).

e15151 Background: The plasma CgA level is a reliable biomarker in diagnosing neuroendocrine tumors.The objective of this study is to correlate both the baseline value and the dynamic changes of plasma CgA level with disease status in Asian patients with advanced GEP-NET. Methods: Fifty-four patients with advanced GEP-NET were retrospectively evaluated between April 2010 and December 2012 in a single institution. Plasma CgA level and abdominal CT scan were obtained at diagnosis as a baseline and subsequently every 3 to 6 months after starting antitumor therapy.Statistical analysis of plasma CgA level was performed to predict the hazard ratio of clinical outcomes and also to correlate antitumor therapy responses with Response Evaluation Criteria in Solid Tumors Criteria 1.1. Results: Forty-six patients (85%) had elevated baseline CgA level. Twenty-one patients (39%) died at the end of the study with the medial follow-up duration of 292 days (range 12-992 days). Patients with baseline CgA level less than 2-fold of upper normal limit (UNL) had longer overall survival time than those with more than 2-fold of UNL (not reach vs. 272 days, hazard ratio = 0.39, 95% CI 0.15-0.99). Baseline CgA level less than 2-fold of UNL was still a favorable prognostic factor after adjusted for other variables (hazard ratio = 0.30, 95% CI 0.10-0.89). Twenty-eight patients with a total of 81 measurements of serial plasma CgA were available. An increase of plasma CgA level less than 15% predicted favorable antitumor response with a sensitivity of 86% and specificity of 91% (area under curve of receiving operating characteristics curves was 0.94). Conclusions: Baseline plasma CgA level and its dynamic change are useful values to predict clinical outcomes and antitumor responses in patients with GEP-NET.Baseline CgA level and serial measurements during antitumor therapy in patients with GEP-NET should be taken to assess their clinical outcomes.

Chromogranin A: Novel biomarker between periodontal disease and psychosocial stress.

Context:The psychosocial stress has long been regarded as a significant pre-disposing factor for periodontal disease. The association between the periodontal disease and the neuroendocrine hormones has been observed. Chromogranin A (CgA) is supposed to link the activity of the neuroendocrine system to local and systemic immune functions and to be related to periodontitis.Aims:The aim of this study was to determine the CgA levels in saliva and plasma in periodontal health and disease and to assess their potential relationship to periodontitis.Settings and Designs:In this case-control study, the association between periodontal disease and stress marker has been assessed.Materials and Methods:Sixty subjects were chosen for this study: With case group comprising of 30 subjects with chronic periodontitis and control group comprising of 30 healthy subjects. Salivary and plasma CgA levels were determined by ELISA technique. Clinical parameters included were plaque index, papillary bleeding index and clinical attachment loss and probing depth. Correlation analysis was calculated by independent sample t-test.Results:Significantly higher CgA levels were found in saliva and plasma of patients with chronic periodontitis compared with healthy individuals (P < 0.05). No significant difference were observed between salivary and plasma CgA levels.Conclusions:The elevated level CgA in the plasma and saliva of subjects with stress induced chronic periodontitis has yielded insights into biological plausible association between the psychosocial stress and chronic periodontitis. Thus, our results suggest that CgA is a useful biomarker for evaluating at least in part the etiopathogenesis of periodontitis.

Clinical Usefulness of Plasma Chromogranin A in Pancreatic Neuroendocrine Neoplasm

Chromogranin A (CgA) is widely used as an immunohistochemical marker of neuroendocrine neoplasms and has been measurable in plasma of patients. We assessed the clinical role of plasma CgA in diagnosing pancreatic neuroendocrine neoplasm (PNEN). CgA was checked in 44 patients with pancreatic mass who underwent surgical resection from 2009 through 2011. The cutoff value for diagnosing PNEN and the relationships between CgA and clinicopathologic variables were analyzed. Twenty-six patients were PNENs and 18 patients were other pancreatic disorders. ROC analysis showed a cutoff of 60.7 ng/mL with 77% sensitivity and 56% specificity, and the area under the curve (AUC) was 0.679. Among PNEN group, the sensitivity and specificity of diagnosing metastasis were 100% and 90% respectively when CgA cutoff was 156.5 ng/mL. The AUC was 0.958. High Ki-67 index (160.8 vs 62.1 ng/mL, P = 0.001) and mitotic count (173.5 vs 74.6 ng/mL, P = 0.044) were significantly correlated with plasma CgA, but the tumor size was not. In conclusion, CgA has a little value in diagnosing PNEN. However, the high level of CgA (more than 156.5 ng/mL) can predict the metastasis. Also, plasma CgA level correlates with Ki-67 index and mitotic count which represents prognosis of PNENs.

Chromogranin-A: A Multifaceted Cardiovascular Role in Health and Disease

Chromogranin A (CgA), a major component of the chromaffin granules, is co-stored and co-released with catecholamines. It is also expressed in extra-adrenal sites, including the heart. In the rat, CgA localizes in atrial myoendocrine cells, associated with Atrial Natriuretic Peptide (ANP), and in the conduction system. In the human heart it is present in the ventricular myocardium, co-localized with B-type NP (BNP). CgA is the precursor of several biologically active peptides generated by proteolytic processing also in the heart. Two of them, vasostatin-1 (VS-1) and catestatin (Cst), inhibit cardiac contraction and relaxation, counter-regulate beta-adrenergic and endothelinergic stimulation, and protect the heart against ischemia/reperfusion damages. Recently, clinical studies have suggested CgA to be involved also in cardiovascular pathologies. High plasma CgA levels were found in hypertension, chronic and acute heart failure, myocardial infarction, decompensated and hypertrophic heart, and acute coronary syndromes. These alterations correlate with those of conventional cardiovascular biomarkers, such as NP and endothelin-1 (ET-1), and have prognostic relevance, being indicative of both severity of the disease and mortality. Accordingly, the current knowledge indicates CgA as a multifaceted peptide in cardiovascular homeostasis. Whether the influence elicited by the protein on both normal and failing heart is beneficial and/or detrimental, as well as its implication in the cardiac neuroendocrine scenario is under intense investigation. This review will focus on: i) the involvement of CgA and its derived peptides in the mechanisms which sustain cardiac function and compensation, ii) CgA clinical relevance, and iii) its putative value as a clinical biomarker.