pancreastatin and Liver-Neoplasms

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) have a propensity to metastasize to the liver, often resulting in massive tumor burden and hepatic dysfunction. While transarterial chemoembolization (TACE) is effective in treating patients with NET metastatic to the liver, there are limited data on its utility and benefit in patients with large hepatic involvement. The aim of our study was to determine the clinical benefit and complication rate of TACE in patients with massive hepatic tumor burden.. Medical records were reviewed in patients with grade 1 or 2 NETs with hepatic metastasis at our institution from January 2000 to September 2014 who underwent TACE. Of 201 total patients, 68 had massive hepatic tumor burden involving >75 % of liver parenchyma.. Carcinoid syndrome was present in 40 (59 %) patients, and 57 (84 %) of the 68 patients were symptomatic from their disease. Complications beyond post-TACE syndrome occurred in 21.7 % of patients, with the most common complication being cardiac arrhythmias. The 30-day mortality rate was 7 %. Biochemical response was observed in 78 % of patients, while symptomatic relief and radiographic response was achieved in 85 and 82 % of patients, respectively. Median overall survival following TACE was 28 months, with 1-, 2-, and 5-year overall survival of 76, 54, and 26 %, respectively.. In spite of massive tumor burden, clinical and biochemical improvements were seen in the majority of patients. Morbidity was acceptable and reversible but with a fairly high mortality rate of 7 %. TACE should still be considered in selective patients with massive hepatic tumor burden from metastatic NET for symptom control and palliation.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Arrhythmias, Cardiac; Chemoembolization, Therapeutic; Chromogranin A; Female; Humans; Length of Stay; Liver Neoplasms; Male; Malignant Carcinoid Syndrome; Middle Aged; Patient Selection; Retrospective Studies; Risk Assessment; Survival Rate; Symptom Assessment; Treatment Outcome; Tumor Burden; Young Adult

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

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

Pancreastatin, a chromogranin A-derived peptide, has a counter-regulatory effect on insulin action. We have previously characterized pancreastatin receptor and signalling in rat liver and HTC hepatoma cells. A G alpha(q/11)-PLC-beta pathway leads to an increase in [Ca2+]i, PKC and mitogen activated protein kinase (MAPK) activation. These data suggested that pancreastatin might have a role in growth and proliferation, similar to other calcium-mobilizing hormones.. DNA and protein synthesis were measured as [3H]-thymidine and [3H]-leucine incorporation. Nitric oxide (NO) was determined by the Griess method and cGMP production was quantified by enzyme-linked immunoassay.. Contrary to the expected results, we have found that pancreastatin inhibits protein and DNA synthesis in HTC hepatoma cells. On the other hand, when the activity of NO synthase was inhibited by N-monomethyl-L-arginine (NMLA), the inhibitory effect of pancreastatin on DNA and protein synthesis was not only reverted, but a dose-dependent stimulatory effect was observed, probably due to MAPK activation, since it was prevented by PD98059. These data strongly suggested the role of NO in the inhibitory effect of pancreastatin on protein and DNA synthesis, which is overcoming the effect on MAPK activation. Moreover, pancreastatin dose-dependently increased NO production in parallel to cyclic guanosine monophosphate (cGMP). Both effects were prevented by NMLA. Finally, an indirect effect of pancreastatin through the induction of apoptosis was ruled out.. Therefore, the NO and the cGMP produced by the NO-activated guanylate cyclase may mediate the dose-dependent inhibitory effect of pancreastatin on growth and proliferation in HTC hepatoma cells.

Topics: Animals; Carcinoma, Hepatocellular; Cell Division; Chromogranin A; Chromogranins; Cyclic GMP; DNA; Dose-Response Relationship, Drug; Enzyme Inhibitors; Liver Neoplasms; Nitric Oxide; omega-N-Methylarginine; Pancreatic Hormones; Protein Synthesis Inhibitors; Rats; Tumor Cells, Cultured

Primary hepatic carcinoid and neuroendocrine carcinoma (NEC) are rare tumors. We experienced three carcinoids and two NEC originating in the liver during the past 25 years and attempted to elucidate the clinicopathological and immunohistochemical features of these tumors. The patients had no endocrine symptoms despite two of them having elevated plasma serotonin. Three of the five patients died of the tumor after operation with an average survival time of 20.6 months. All tumors were large (up to 26 cm in diameter), four of them solitary and one multinodular, and were not associated with liver cirrhosis. The carcinoid tumors showed insular, trabecular or glandular arrangement of argyrophilic cells, whereas in the NEC this histological pattern was distorted. Immunohistochemically the tumors showed expression of chromogranin A (all cases), chromogranin B (three cases), pancreastatin and chromostatin (four cases, respectively), prohormone convertase PC3 (three cases), carcinoembryonic antigen (CEA) and CA19-9 (two cases), cytokeratin 56 kDa (three cases), 160 kDa neurofilament (two cases) and neuron-specific enolase (two cases). Serotonin and glucagon were sporadically detected in two tumors. The most useful marker to confirm the diagnosis was chromogranin A, which was cleaved to pancreastatin and chromostatin in the tumor tissue, and was more reliable than other markers of neuroendocrine differentiation.

Topics: Adult; Aged; Aspartic Acid Endopeptidases; Biomarkers, Tumor; Carcinoid Tumor; Carcinoma, Neuroendocrine; Chromogranin A; Chromogranins; Fatal Outcome; Female; Humans; Immunohistochemistry; Liver Neoplasms; Male; Middle Aged; Pancreatic Hormones; Peptide Fragments; Proprotein Convertases

Pancreastatin-like immunoreactivity has been demonstrated in human carcinoid tumors by immunohistochemistry and radioimmunoassay, employing antisera raised to a synthetic C-terminal fragment of porcine pancreastatin. Immunohistochemistry revealed intense immunoreactivity in all tumors. By radioimmunoassay, high concentrations of pancreastatin-like immunoreactivity were measured in carcinoid tumors arising from the fore-gut (mean +/- S.D. and range: 369 +/- 955 and 9.4-3670 pmol g-1, respectively, n = 14), mid-gut (mean +/- S.D. and range: 1354 +/- 1538 and 337-3978 pmol g-1, respectively, n = 5) and in metastases associated with mid-gut tumors (mean +/- S.D. and range: 684 +/- 739 and 31-2255 pmol g-1, respectively, n = 7), compared to corresponding normal tissues (less than 1.4 pmol g-1). Individuals with hepatic metastases and carcinoid syndrome had elevated circulating levels of pancreastatin-like immunoreactivity (mean +/- S.D. and range: 770 +/- 1249 and 42-4120 pmol l-1; n = 12), significantly above the normal, fasting range (mean +/- S.D. and range: 14.9 +/- 7.5 and 4-37.5 pmol l-1, respectively, n = 42). However, patients with non-metastatic carcinoid tumors (n = 4), who had been clinically cured after primary tumor resection, had plasma levels within the normal range. Chromatographic analysis of extracts of primary lung and ileal tumors, hepatic metastases from ileal tumors and plasma from individuals with carcinoid syndrome revealed molecular heterogeneity of pancreastatin-like immunoreactivity.

Topics: Adult; Aged; Amino Acid Sequence; Blotting, Western; Carcinoid Tumor; Chromatography, Gel; Chromatography, High Pressure Liquid; Chromogranin A; Female; Humans; Intestinal Neoplasms; Liver Neoplasms; Male; Malignant Carcinoid Syndrome; Middle Aged; Molecular Sequence Data; Pancreatic Hormones; Radioimmunoassay

A protein with pancreastatin-like immunoreactivity has been isolated and purified from liver metastasis of a patient with insulinoma. NH2-terminal residue analysis, in conjunction with the use of antibodies that are specific for the C-terminal amide peptide of porcine pancreastatin, identified this protein as a 186-amino-acid protein corresponding to human chromogranin A-116-301 (the fragment corresponding to the positions from 116 to 301 of human chromogranin A). Digestion of this protein with trypsin yielded a 48-amino-acid peptide with the retention of full pancreastatin activity. Serum from patient with insulinoma contains a peptide specie(s) that comigrates with the 48-amino-acid pancreastatin, suggesting that this peptide might be a physiologically important circulation form of pancreastatin in humans. A sensitive radioimmunoassay was established using antibody developed against a synthetic 29-amino-acid peptide amide of pancreastatin. Immunocytochemical staining revealed that a major population of human pancreatic islet cells were immunoreactive to the antiserum but with varying intensity of staining. Pancreastatin-like immunoreactivity was not observed in exocrine acinar cells.

Topics: Adenoma, Islet Cell; Amino Acid Sequence; Antibodies; Chromogranin A; Chromogranins; Humans; Immunohistochemistry; Insulinoma; Liver Neoplasms; Molecular Sequence Data; Neoplasm Proteins; Nerve Tissue Proteins; Pancreatic Hormones; Radioimmunoassay; Trypsin

High levels of pancreastatinlike immunoreactivity were detected in the plasma (2.9 pmol/ml, greater than 200-fold the normal level), pancreas (2.9 nmol/g wet wt, greater than 450-fold the normal level), and liver (1.6 nmol/g wet wt) of a patient with pancreatic insulinoma with metastasis to the liver by a sensitive and specific radioimmunoassay for human pancreastatin. Antiserum was produced against the C-terminal fragment of human pancreastatin-(24-52), which was synthesized according to the sequence of human chromogranin A corresponding to that of pancreastatin. With the antiserum, intense immunocytochemical staining was detected in the tumors. Sephadex G-50 gel filtration showed that the tumors and plasma contained two molecular forms of pancreastatinlike immunoreactivity--a molecular form coeluted with synthetic human pancreastatin-52 and a larger molecular form (Mr approximately 12,000-15,000). The smaller form eluted in the same position as synthetic human pancreastatin-52 on reverse-phase high-performance liquid chromatography.

Topics: Adenoma, Islet Cell; Chromatography, High Pressure Liquid; Chromogranin A; Female; Humans; Insulinoma; Liver; Liver Neoplasms; Middle Aged; Pancreas; Pancreatic Hormones; Pancreatic Neoplasms; Radioimmunoassay

A protein with pancreastatin-like immunoreactivity has been isolated and purified from liver metastasis of a patient with insulinoma. NH2-terminal sequence analysis in conjunction with the use of antibodies specific for the C-terminal structure of pancreastatin identified this protein as a 186-amino acid residue protein corresponding to human chromogranin A-116-301. Using a sensitive radioimmunoassay it was found that serum from the patient with insulinoma contains two peptide species; one comigrates with the 186-amino acid residue pancreastatin and the other the 48-residue pancreastatin.

Topics: Amino Acid Sequence; Chromatography, Gel; Chromogranin A; Chromogranins; Humans; Insulinoma; Liver Neoplasms; Nerve Tissue Proteins; Pancreatic Hormones; Peptide Fragments; Radioimmunoassay

Pancreastatin, a novel 49-amino acid peptide isolated from porcine pancreas, shows over 70% sequence homology to the central part of bovine and human chromogranin-A. Using an N-terminal and C-terminal synthetic peptide, we developed two sensitive and specific RIAs for the detection of pancreastatin-like immunoreactivity (PLI) in porcine and human tissue extracts. PLI was present throughout the gastrointestinal tract and in most endocrine and neuronal tissues. Highest concentrations were measured in the pituitary, adrenal gland, and pancreas (1200-4000 pmol/g), similar to the distribution of chromogranin-A. PLI was also detected in human endocrine tumors, with large quantities in some carcinoids (up to 14 nmol/g). HPLC revealed that extracts from porcine pituitary and pancreas contained small pancreastatin-like peptides, whereas in adrenal medulla large chromogranin-A-like molecular forms predominated. Human endocrine tumors showed a different pattern, with intermediate forms distinct from chromogranin-A and pancreastatin. Biochemical analysis was confirmed by immunocytochemistry localizing PLI in pancreatic islets, adrenal medulla, pituitary, duodenum, and human endocrine tumors. Pancreastatin is present in a variety of gastrointestinal, endocrine, and neuronal tissues and may represent a novel peptide of unknown physiological function, derived from chromogranin-A by proteolytic cleavage.

Topics: Amino Acid Sequence; Animals; Carcinoid Tumor; Chromogranin A; Chromogranins; Humans; Immunoenzyme Techniques; Insulinoma; Islets of Langerhans; Liver Neoplasms; Molecular Sequence Data; Organ Specificity; Pancreatic Hormones; Pancreatic Neoplasms; Radioimmunoassay; Species Specificity; Swine