pancreastatin and Neuroendocrine-Tumors

Gastroenteropancreatic neuroendocrine neoplam (GEP-NEN) is a rare group of tumors with its incidence rising significantly in recent decades. Because of the late presentation of the disease and limitations in conventional biomarkers, about 50% of GEP-NEN patients manifests advanced disease when diagnosed. Therefore, it is vital to identify circulating biomarkers which can not only be used for early diagnosis but also accurately evaluating the biological behavior of GEP-NEN. This review summarizes the advances of circulating biomarkers in diagnosing and evaluating efficacy of treatment in GEP-NEN. Well-known circulating biomarkers include chromogranin A (CgA), pancreastatin (PST), chromogranin B (CgB), neuron-specific enolase (NSE) and pancreatic peptide(PP). Novel biomarkers including circulating tumor cell(CTC), microRNA and NETest are promising biomarkers with potential clinical benefit, but further researches are needed before their clinical applications.

Topics: Biomarkers, Tumor; Chromogranin A; Chromogranin B; Gastrointestinal Neoplasms; Humans; MicroRNAs; Neoplastic Cells, Circulating; Neuroendocrine Tumors; Pancreatic Neoplasms; Pancreatic Polypeptide; Phosphopyruvate Hydratase

In this review, we focus on the use of biochemical markers for the diagnosis of neuroendocrine tumors and exclusion of conditions that masquerade as neuroendocrine tumors. In addition, we outline the use of biochemical markers for follow-up, response to intervention, and determination of prognosis. Previous publications have focused only on markers specific to certain tumor types, but the uniqueness of this chapter is that it presents a new approach ranging from biochemical markers that relate to symptoms to the use of markers that facilitate decision making with regard to optimizing the choices of therapy from the complex arrays of intervention, The sequence of presentation in this chapter is first to provide the usual view, that is, biochemical markers of each tumor type and thereafter the diagnosis of the underlying condition or exclusion thereof and finally the algorithm for their use from the clinical presentation to the suspected diagnosis and the biochemical markers to monitor progression and therapeutic choice. There is also a specific description of the properties of the most important biochemical markers and 2 complications, bone metastasis and carcinoid heart disease, from the biochemical point of view.

Topics: Biomarkers, Tumor; Chromogranin A; Disease Progression; Humans; Neuroendocrine Tumors; Neurokinin A; Pancreatic Hormones; Predictive Value of Tests; Prognosis

Chromogranin A (CgA) belongs to the granin family of uniquely acidic secretory proteins co-stored and co-secreted with other hormones and peptides in elements of the diffuse neuroendocrine system. The granins arise from different genes and are characterized by numerous sites for post-translational cleavage into shorter peptides with postulated regulatory properties. This review is directed towards endocrine aspects of CgA and its biologically active peptides. There is ample evidence from in vitro studies of distinct effects and targets for three CgA-derived peptides, vasostatin-I, pancreastatin and catestatin. Endocrine regulations are indicated from in vivo studies, consistent with the postulated prohormone function of CgA for peptides with regulatory properties. Most of the effects fit into patterns of direct or indirect, inhibitory modulations of major functions, implicating CgA peptides in regulation of calcium and glucose metabolism, cardiovascular functions, gastrointestinal motility and nociception, tissue repair, inflammatory responses and as host defense peptides in the first phase of microbial invasions.

Topics: Animals; Calcium; Carbohydrate Metabolism; Cardiovascular Physiological Phenomena; Chromogranin A; Endocrine Glands; Humans; Immunity, Innate; Inflammation; Models, Biological; Models, Molecular; Neoplasms; Neuroendocrine Tumors; Neurosecretory Systems; Pancreatic Hormones; Peptide Fragments; Structure-Activity Relationship

Proton pump inhibitors (PPIs) are used primarily to treat gastroesophageal reflux disease. Proton pump inhibitor-induced achlorhydria increases circulating gastrin and chromogranin A (CGA). Chromogranin is a widely used biomarker for the diagnosis and follow-up for gut-based neuroendocrine tumors (NETs). Proton pump inhibitor-induced increases in CGA or gastrin may falsely suggest the presence of a NET when none exists. Pancreastatin, a fragment of CGA, is also commonly used to diagnose and follow NETs. We hypothesized that chronic PPI use would increase circulating plasma gastrin, CGA, and pancreastatin levels.. Thirty patients who used PPIs for 6 months or more (mean ± SD duration, 3.1 ± 2.5 years) and a separate control group of 30 patients who never used antacid medications were prospectively evaluated with plasma gastrin, CGA, and pancreastatin determinations.. Chronic PPI use resulted in significant increases in CGA (15.1 ± 11 vs 131 ± 207 ng/mL; P = 0.005) and significant increases in gastrin (34.8 ± 22.3 vs 167.8 ± 136.2 pg/mL; P = 0.001) compared to controls. In contrast, pancreastatin level in nonusers and chronic PPI users were identical (81.6 ± 36.4 vs 89.4 ± 43.4 pg/mL; P = 0.46).. Pancreastatin levels do not change with chronic PPI use and normal pancreastatin levels may be used to distinguish between drug-induced changes in biomarkers and tumor-related increases in circulating biomarkers.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Chromogranin A; Female; Gastrins; Gastroesophageal Reflux; Humans; Male; Middle Aged; Neuroendocrine Tumors; Pancreas; Pancreatic Hormones; Pancreatic Neoplasms; Prospective Studies; Proton Pump Inhibitors

Topics: Adult; Biomarkers, Tumor; Chromogranin A; False Positive Reactions; Female; Humans; Laboratories; Male; Neuroendocrine Tumors; Pancreatic Neoplasms

Elevated pancreastatin (PST) levels have been shown to be associated with poor prognosis in small bowel neuroendocrine tumors (NETs). We hypothesized that plasma PST levels that remain elevated following surgical cytoreduction portend a poor prognosis in well-differentiated small bowel NETs.. Patients diagnosed with small bowel NETs who underwent surgical cytoreduction at our institution were identified. Demographics, histopathologic characteristics, and biochemical data were collected. Only patients who had serial preoperative PST (PreopPST) and postoperative PST (PostopPST) levels were included in this study. Patients were sorted into groups by PST level to assess their response to surgical cytoreduction (group 1, PreopPST/PostopPST normal; group 2, PreopPST elevated/PostopPST normal; group 3, PreopPST/PostopPST elevated). Survival rates were calculated from the date of surgery.. PreopPST and PostopPST levels were collected from 300 patients. Patients in groups 1 (n = 74) and 2 (n = 81) had a significant survival advantage compared with patients in group 3 (n = 145) (P < 0.0001). Kaplan-Meier 5- and 10-year survival rates were as follows: group 1: 93% and 82%; group 2: 91% and 65%; and group 3: 58% and 34%, respectively.. Serial monitoring of plasma PST is useful in predicting long-term survival following surgical cytoreduction and can be helpful to identify patients who have a poor prognosis.

Topics: Adult; Aged; Biomarkers, Tumor; Chromogranin A; Cytoreduction Surgical Procedures; Female; Humans; Intestine, Small; Kaplan-Meier Estimate; Male; Middle Aged; Neuroendocrine Tumors; Prognosis; Treatment Outcome; Young Adult

Serum pancreastatin is a sensitive and specific diagnostic biomarker in neuroendocrine tumors (NETs). Elevated pancreastatin levels are associated with worse progression-free survival and overall survival in small bowel and pancreatic NETs. In this study, we investigated the clinical significance of elevated serum pancreastatin in identifying metastatic disease to the liver.. Retrospective chart review of patients with NET managed at a single institution was performed. The site of primary tumor, laboratory data, and presence of metastatic disease were reviewed. The sensitivity, specificity, and positive and negative predictive values for pancreastatin as indicator of liver metastasis were ascertained.. Data were abstracted from 77 patient records. Small bowel was the primary tumor site in 44 patients (57%), and 49 patients had metastasis to the liver (64%). Sensitivity and specificity of serum pancreastatin was 85.7% and 66.7%, respectively, which compared with 61.5% and 43.8% for chromogranin A, in identifying liver metastasis in patients with primary tumors of the small bowel.. Elevated serum pancreastatin is a sensitive and specific assay for detecting the incidence of liver metastasis in patients with small-bowel NET. Routine measurement of pancreastatin in patients with NET, especially in patients with small bowel primaries, is supported.

Topics: Biomarkers, Tumor; Chromogranin A; Female; Humans; Intestinal Neoplasms; Intestine, Small; Liver Neoplasms; Male; Middle Aged; Neuroendocrine Tumors; Prognosis; Radioimmunoassay; Retrospective Studies; Sensitivity and Specificity

Neuroendocrine tumors (NETs) of the duodenum are rare, heterogeneous, and often indolent neoplasms. We hypothesized that elevated pancreastatin levels are an indicator of a poor prognosis in well-differentiated duodenal NETs.. Data from patients diagnosed with a primary duodenal NET were analyzed. Patients that underwent esophogogastroduodenoscopy, endoscopic ultrasound, or exploratory surgery to localize their neoplasm and whose tumors were confirmed histologically were included.. Eighty-four patients were diagnosed with duodenal NETs from January 1991 to January 2014. Seventy-five percent and 21% of patients had their tumor localized by esophogogastroduodenoscopy and endoscopic ultrasound, respectively. The remaining 4% were localized during exploratory surgery. The 5-year Kaplan-Meier survival rate for the entire cohort (N = 84) was 80%. Survival sorted by normal vs abnormal pancreastatin level was statistically significant (p < 0.0001). Five-year survival rates were 94% and 37% for normal and abnormal pancreastatin, respectively. In contrast, survival sorted by normal vs abnormal plasma chromogranin A level was not statistically significant (p = 0.24).. Patients with primary duodenal NETs have high 5-year survival rates. Serial monitoring of plasma pancreastatin levels can identify patients who have a poor prognosis.

Topics: Aged; Chromogranin A; Duodenal Neoplasms; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neuroendocrine Tumors; Pancreatic Hormones; Predictive Value of Tests; Prognosis; Retrospective Studies; Survival Rate

We compared the clinical outcomes of patients with metastatic neuroendocrine tumors treated with hepatic artery embolization (HAE), chemoembolization (HACE), and selective internal radiation therapy (SIRT) at our institution over the last 10 years.. The medical records of 42 patients with metastatic neuroendocrine tumors with hepatic metastases treated with HAE, HACE, or SIRT at the University of Iowa from 2001 to 2011 were analyzed.. A total of 13 patients had HAE, 17 patients had HACE, and 12 patients had SIRT as their initial procedure. Time to progression (TTP) was similar between SIRT (15.1 months) and HACE/HAE groups (19.6 months; P = 0.968). There was a trend toward increased TTP in patients receiving HACE (33.4 months) compared with HAE (12.1 months) or SIRT (15.1 months), although not statistically significant (P = 0.512). The overall survival for all patients from the first intervention was 41.9 months. There was no difference between HACE/HAE and SIRT in posttherapy change of chromogranin A (P = 0.233) and pancreastatin (P = 0.158) levels. Time to progression did not correlate with the change in the posttherapy chromogranin A (P = 0.299) or pancreastatin (P = 0.208) levels.. There was no significant difference in TTP in patients treated with SIRT compared with patients treated with HAE or HACE. Baseline and posttherapy marker changes were not predictive of TTP.

Topics: Abdominal Pain; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Chemoembolization, Therapeutic; Chromogranin A; Disease Progression; Embolization, Therapeutic; Female; Fever; Hepatic Artery; Humans; Kaplan-Meier Estimate; Liver Neoplasms; Male; Middle Aged; Nausea; Neuroendocrine Tumors; Outcome Assessment, Health Care; Pancreatic Hormones; Proportional Hazards Models; Radiotherapy; Time Factors; Vomiting

Pancreastatin is a derived peptide of chromogranin A (CgA). Pancreastatin has the potential to be a diagnostic and predictive tumor marker in detecting NETs.. Radioimmunoassay tests of pancreastatin and CgA were performed on 103 patient specimens collected at Mount Sinai Medical Center between 1/2010 and 7/2012. Patient demographics, diagnostic tests, surgical procedures, pathologic findings, adjuvant treatments, and survival were retrospectively reviewed. Statistical analysis utilized SPSS v20 software.. Mean pancreastatin levels were significantly higher in the 92 NETs patients than in the 11 non-NETs patients (227.261 vs. 59.727, P < 0.05). Twenty-seven of the 92 patients with elevated pancreastatin levels (mean = 240.67), had normal CgA levels (mean = 4.65). Pancreastatin had sensitivity and specificity of 64% (59/92), and 100% (11/11). CgA had lower sensitivity and specificity of 43% (40/92), and 64% (7/11). In all 27 instances the pancreastatin concentration was found to be sole indicator of NET disease. When controlling for the level of CgA for the entire sample, a statistically significant difference was not found in the mean pancreastatin levels between both patient groups (P = 0.139, R = 0.484).. Pancreastatin has greater sensitivity and specificity in diagnosing NETs than CgA. Further investigation of pancreastatin's diagnostic and predictive value is warranted.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Chromogranin A; Female; Humans; Male; Middle Aged; Neuroendocrine Tumors; Pancreatic Hormones; Prognosis; Radioimmunoassay; Retrospective Studies; Sensitivity and Specificity; Survival Analysis

5-Hydroxyindoleacetic acid (5-HIAA) is used for the evaluation of neuroendocrine tumors (NETs) but currently requires a 24-hour urine collection.. We developed a gas chromatography mass spectroscopy-based plasma 5-HIAA assay. We compared 24-hour urine 5-HIAA values against plasma 5-HIAA values in 115 mixed-variety patients with NETs and in a subset of 72 patients with only small bowel NETs. We also compared the information gained from urinary and plasma 5-HIAA values with other biomarkers of midgut NET activity to determine the plasma assay's clinical implications.. In a group of 115 patients with all types of NETS, in a subset of patients with midgut NET and in a subgroup of midgut NETS with liver metastasis, the correlation between the urine and fasting plasma 5-HIAA values were statistically significant (P ≤ 0.0001). Comparison of the proportion of normal or abnormal urinary and plasma 5-HIAA values to the proportion of chromogranin, serotonin, neurokinin, or pancreastatin values that were in the normal or abnormal range yielded essentially identical information.. Plasma fasting 5-HIAA values are proportional to urinary 5-HIAA values and yielded identical clinical correlation with other biomarkers.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Chromogranin A; Disease Progression; Fasting; Female; Gas Chromatography-Mass Spectrometry; Humans; Hydroxyindoleacetic Acid; Intestinal Neoplasms; Liver Neoplasms; Male; Middle Aged; Neuroendocrine Tumors; Neurokinin A; Pancreatic Hormones; Prognosis; Reference Values; Sensitivity and Specificity; Serotonin

Pancreastatin is a fragment of the chromogranin A (CgA) molecule. Existing pancreastatin assays, which depend on antibodies that cross-react in varying percents with the larger prohormone, may lack sensitivity and specificity to detect small changes in neuroendocrine tumor volume.. We developed a highly specific, sensitive pancreastatin assay. The antibody used recognizes the carboxyl terminal of the peptide hormone and was raised against a 17-amino acid porcine pancreastatin fragment with high homology with the carboxy-terminal amino acids 286-301 of the human CgA.. Our assay measures more than 95% of circulating pancreastatin levels; has little or no cross-reactivity with CgA, even at plasma concentrations of 1000 ng/mL; and can detect pancreastatin levels of 17 pg/mL. Interassay reproducibility for the pancreastatin radioimmunoassay was determined from results of 3 quality control pools in 15 consecutive assays. Coefficients of variation for low, medium, and high pancreastatin levels were less than 20%. The sensitivity of serial pancreastatin assays to detect early liver tumor activity was demonstrated in 2 patients with slowly progressive neuroendocrine tumors and in patients undergoing surgical cytoreduction.. This highly specific, sensitive pancreastatin assay can detect small changes in liver tumor progression and is up to 100-fold more sensitive and specific than CgA assays in the United States.

Topics: Biomarkers, Tumor; Chromogranin A; Female; Humans; Liver Neoplasms; Male; Middle Aged; Neuroendocrine Tumors; Pancreatic Hormones; Radioimmunoassay; Reproducibility of Results

Neuroendocrine tumors often metastasize to the liver and present with disabling hormonal symptoms. Hepatic artery chemoembolization (HACE) combined with somatostatin therapy, pre-embolization, peri-embolization and post-embolization, at doses to control symptoms, is an aggressive approach that can relieve hormonal symptoms with minimal morbidity and mortality.. Chemoembolization was performed using 30 mg of adriamycin, 50 mg of mitomycin, 12 ml of hexabrix, 10 ml of ethiodol, and 360-500-microm particles. Pancreastatin, a split product of chromogranin A, was measured pre-HACE and post-HACE in all patients.. Forty-three chemoebolization procedures were performed in 34 symptomatic patients from December 1995 to August 1999. Seventeen patients had intestinal primaries (50%), seven had pancreatic primaries (20%), five had bronchial primaries (15%), and five had unknown primaries (15%). Systemic pancreastatin levels were improved or stable in 31 patients (78%). Symptoms were improved in these 31 patients (78%). Systemic serotonin levels were improved or stable in 24 patients (60%). Radiographic improvement or stability was seen in 18 patients (45%). Procedural related morbidity included pain, fevers, nausea, vomiting, and transient elevations of liver function studies in 75-100% of patients. There was one procedural related mortality (2%). Less than 20% improvement in pancreastatin levels from baseline was associated with death in five of five patients (100%). This was not observed with serotonin levels.. Measurement of serum pancreastatin levels is an easy and useful method to predict success in patients who undergo HACE plus somatostatin therapy for metastatic neuroendocrine tumors to the liver. This therapeutic approach is effective in relieving symptoms in 78% of patients, with minimal major morbidity or mortality.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Chemoembolization, Therapeutic; Chromogranin A; Chromogranins; Contrast Media; Doxorubicin; Ethiodized Oil; Female; Follow-Up Studies; Hepatic Artery; Humans; Ioxaglic Acid; Liver Neoplasms; Male; Middle Aged; Mitomycin; Neuroendocrine Tumors; Pancreatic Hormones; Serotonin; Somatostatin

Distinguishing between neuroendocrine carcinoma and adenocarcinoma may be difficult.. In the current prospective study blood and tumor tissue from patients with gastric carcinoma were collected. The tissue was fixed in different ways to allow examination for neuroendocrine markers by multiple methods such as various histochemical and immunohistochemical methods and electron microscopy. Blood and tumor homogenates were examined by radioimmunoassay for specific hormones and general neuroendocrine markers.. Based on examination of general neuroendocrine markers such as chromogranin A (by immunohistochemistry, Northern blot analysis, and tissue concentration), neuron specific enolase (immunohistochemistry) as well as electron microscopy, it was possible to conclude that approximately 10% of the tumors were actually neuroendocrine malignant tumors. Among these tumors, the enterochromaffin-like (ECL) cell was the most preponderant cell of origin (Sevier-Munger positive and serotonin negative immunoreactive tumor cells with secretory granules resembling those observed in normal ECL-cells). As reported previously, tumors of the diffuse type (according to the classification of Laurén) most often were reclassified as neuroendocrine carcinomas.. The current study shows that neuroendocrine and particularly ECL cell-derived tumors are more common in the stomach than previously recognized.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Chromogranin A; Chromogranins; Enterochromaffin Cells; Female; Gastrins; Histamine; Humans; Immunohistochemistry; Male; Middle Aged; Neuroendocrine Tumors; Pancreatic Hormones; Prospective Studies; RNA, Messenger; Stomach Neoplasms