Pancreastatin Levels Research Articles

The association of plasma pancreastatin levels with insulin resistance in patients with gestational diabetes mellitus

Introduction Gestational diabetes mellitus (GDM) occurs on the background of increased insulin resistance. We aimed to investigate the levels of plasma pancreastatin (PST) levels and its association with metabolic, demographic, and anthropometric parameters in gestational diabetic and normal glucose-tolerant pregnant women. Materials and methods A total of 165 pregnant women in the 24th–28th week of pregnancy were enrolled in this cross-sectional study. PST levels were measured using ELISA method. Results Median PST levels were similar between GDM (n = 62, 37.6%) and normal glucose-tolerant control group (n = 103, 62.4%). In the GDM group, PST level showed a significant positive correlation with fasting insulin and the homeostasis model assessment of insulin resistance (HOMA-IR). In binary logistic regression analysis, PST levels did not predict the presence of GDM significantly. Conclusion Positive correlation of PST with fasting insulin and HOMA-IR suggests that PST could be associated with insulin resistance. Further studies are needed as regards to the role of PST in GDM pathogenesis.

Role of chromogranin A-derived fragments in the assessment of surgical efficacy after resection of non-functioning pancreatic neuroendocrine tumors

Purpose: No reliable biomarkers are currently available for pancreatic neuroendocrine tumors (PanNETs). Vasostatin-1 (VS-1), the N-terminal fragment of Chromogranin A (CgA), seems to a more reliable biomarker compared to its precursor. Primary aim of this study was to investigate the ability of VS-1, compared to total-CgA, to assess the effectiveness of surgical resection performed for NF-PanNETs. Secondary aim was to evaluate two additional CgA-derived fragments, pancreastatin (PST) and vasostatin-2 (VS-2) as possible biomarkers for NF-PanNETs. Method: Consecutive patients who underwent surgery for sporadic NF-PanNETs between May 2018 and October 2019 were included. Plasma levels of CgA and CgA-derived fragments were measured by Enzyme-Linked ImmunoSorbent Assay (ELISA), preoperatively and on postoperative day 5 (POD5). Results: Preoperative VS-1 was significantly higher compared to VS-1 measured on POD5 (pre: 0.338 nM versus POD5: 0.147 nM, P<0.001), whereas total-CgA plasma levels significantly increased after surgery (pre: 1.123 nM versus POD5: 1.949 nM, P=0.006). The proportion of patients with VS-1 plasma levels greater than a previously defined cut-off (0.390 nM) significantly decreased from preoperative time (15/35, 43%) to POD5 (2/35, 6%) (P<0.001). No statistically significant differences in terms of PST (P=0.870) and VS-2 (P=0.909) plasma levels were observed between preoperative and postoperative time. Conclusion: VS-1 seems able to provide an early assessment of surgical efficacy in patients submitted to surgery for NF-PanNETs, whereas total-CgA, PST and VS-2 have no clinical utility in this setting.

Pancreastatin inhibitor PSTi8 attenuates hyperinsulinemia induced obesity and inflammation mediated insulin resistance via MAPK/NOX3-JNK pathway

Pancreastatin (PST), a chromogranin A derived peptide has anti-insulin effects and plays a significant role in obesity-induced insulin resistance. In obesity and type 2 diabetes mellitus, both insulin and PST level are elevated, but it is not clearly understood how anti-insulin effect of PST get regulated in hyperinsulinemic state. Simultaneously we have explored pancreastatin inhibitor PSTi8 against the native PST in the same hyperinsulinemic state. In in-vitro studies, we found that PST treatment increases lipid droplets and reactive oxygen species production in 3T3L1 adipocyte cells and theses effects of PST was found synergistic with chronic-insulin treatment. Treatment of PSTi8 in 3T3L1 adipocytes attenuates PST effect on lipid droplet formation and reactive oxygen species production. We further validated these findings in epididymal white adipose tissue of C57BL/6 mice, implanted with mini-osmotic insulin pump with and without PSTi8 for 4 weeks. We found that chronic hyperinsulinemia enhanced PST levels in circulation which in turn induces expression of various pro-inflammatory cytokines and oxidative stress. In addition, it also stimulated the expression of lipogenic genes, fat mass and body weight gain through the regulation of circulating adiponectin level. The change in PST mediated inflammatory and lipogenic parameters were attenuated by PSTi8 treatment, leading to enhanced insulin sensitivity and improved glucose homeostasis. PSTi8 rescue from PST mediated insulin resistance in adipose via inhibition of MAPK and NOX3-JNK stress signalling pathway which stimulates GLUT4 expression through activation of AKT-AS160 pathway. Thus PSTi8 may be a novel therapeutic agent for the treatment of hyperinsulinemia induced obesity and inflammation mediated insulin resistance.

Plasma Pancreastatin Predicts the Outcome of Surgical Cytoreduction in Neuroendocrine Tumors of the Small Bowel.

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.

Prognostic Impact of Serum Pancreastatin Following Chemoembolization for Neuroendocrine Tumors.

The objective of this study was to investigate the prognostic impact of the biomarker serum pancreastatin in patients with metastatic neuroendocrine tumors (NETs) treated with transarterial chemoembolization (TACE). Patients with metastatic NET treated with TACE at a single institution from 2000 to 2013 were analyzed. Patient demographics, response to therapy, and long-term survival were compared with baseline pancreastatin level and changes in pancreastatin levels after TACE. A total of 188 patients underwent TACE during the study period. An initial pancreastatin level greater than 5000pg/mL correlated with worse overall survival (OS) from time of first TACE (median OS, 58.5 vs. 22.1months, p < 0.001). A decrease in pancreastatin level by 50% or more after TACE treatment correlated with improved OS (median OS 53.8 vs. 29.9months, p = 0.032). Patients with carcinoid syndrome were more likely to have a subsequent increase in pancreastatin after initial drop post-TACE (78.1 vs. 55.2%, p = 0.002). Patients with an increase in pancreastatin levels after initial drop post-TACE were more likely to have liver progression on imaging (70.7 vs. 40.7%, p = 0.005) and more likely to need repeat TACE (21.1 vs. 6.7%, p = 0.009). For patients with liver metastases from NET treated with TACE, pancreastatin measurement may be a useful prognostic indicator. Extreme high levels before TACE can predict poor outcomes, whereas significant drops in pancreastatin after TACE correlate with improved survival. An increase in levels after initial decrease may predict progressive liver disease requiring repeat TACE. As such, pancreastatin levels should be measured throughout the TACE treatment period.

Peptide Receptor Radionuclide Therapy Outcomes in a North American Cohort With Metastatic Well-Differentiated Neuroendocrine Tumors

The objective of this study was to describe the outcomes of patients in the University of Iowa Neuroendocrine Tumor (NET) Database treated with peptide receptor radionuclide therapy (PRRT). One hundred thirty-five patients from the University of Iowa NET Database who received PRRT were analyzed, their characteristics were described, and survival was calculated. The median age at diagnosis was 51 years, and 64% were men. The primary tumor was located in the small bowel (SBNET) in 37.8%, in the pancreas (PNET) in 26.0%, in the lung in 13.3%, in unknown primary in 9.6%, and in other sites in 13.3%. A radiographic response of any magnitude was observed in 65.8%, 11.1% had a mixed response, and 15.4% showed progression. The overall survival (OS) from the first PRRT was 40 months, and the median time to progression was 23.9 months. Higher pretreatment chromogranin A and pancreastatin levels predicted inferior OS. Peptide receptor radionuclide therapy resulted in a relatively long OS and time to progression in heavily pretreated North American patients with advanced NETs. Elevated pretreatment chromogranin A and pancreastatin predicted shorter OS after therapy. Peptide receptor radionuclide therapy is a valuable treatment option in patients with advanced NETs, especially SBNETS.

Conventional versus Drug-Eluting Bead Transarterial Chemoembolization for Neuroendocrine Tumor Liver Metastases

PurposeTo compare outcomes of conventional transarterial chemoembolization with drug-eluting bead (DEB) chemoembolization for treatment of neuroendocrine tumor liver metastases. Materials and MethodsThis single-center, retrospective study evaluated 177 transarterial chemoembolization treatments (78 conventional chemoembolization treatments using ethiodized oil–based cisplatin, mitomycin C, and doxorubicin and 99 DEB chemoembolization treatments using doxorubicin-loaded 100–300 μm DEBs) from 2012 to 2015. Hepatic disease distribution was 93% bilobar for both groups with largest lesion size 5.0 cm ± 2.7. No difference was noted in regard to lesion size or distribution, carcinoid syndrome, or pancreastatin production. Clinical outcomes including complications; liver function tests (LFTs); and radiologic (modified Response Evaluation Criteria in Solid Tumors), biochemical (pancreastatin levels), and symptomatic responses were evaluated at 1-month follow-up. ResultsHigher symptomatic response (complete and partial) was identified with conventional transarterial chemoembolization compared with DEB chemoembolization (47% vs 30%; P < .05). Patients receiving DEB transarterial chemoembolization experienced lower elevation of LFTs (aspartate aminotransferase, 39 U/L vs 122 U/L; alanine aminotransferase, 20 U/L vs 93 U/L; bilirubin, 0.001 mg/dL vs 0.123 mg/dL; P < .05) and less postembolization syndrome (50% vs 67%; P < .05). Patients undergoing first-time DEB transarterial chemoembolization had lower periprocedural octreotide maximum rate requirements (58 μg/h vs 66 μg/h; P < .05). No difference was observed in biochemical (P = .60) or radiologic (P < .20) responses. ConclusionsConventional transarterial chemoembolization yields better symptomatic response and may be preferred for patients experiencing carcinoid symptoms. DEB transarterial chemoembolization, with lower LFT elevations and postembolization syndrome incidence, may be preferred for patients with poor liver function.

Elevated Serum Pancreastatin Is an Indicator of Hepatic Metastasis in Patients With Small Bowel Neuroendocrine Tumors.

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.

Elevated Plasma Pancreastatin, but Not Chromogranin A, Predicts Survival in Neuroendocrine Tumors of the Duodenum

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.

Comparison of Transarterial Liver-Directed Therapies for Low-Grade Metastatic Neuroendocrine Tumors in a Single Institution

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.

Serum pancreastatin: The next predictive neuroendocrine tumor marker

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.

Study of the Involvement of Pancreastatin in the Physiopathology of Diabetes Mellitus Associated with Nonsecreting Pituitary Adenomas

Pancreastatin, derived from chromogranin A, inhibits insulin and stimulates glucagon secretion in rodents. Immunohistochemistry localised pancreastatin in human pancreatic islet cells and gonadotroph pituitary cells. Nonsecreting pituitary adenomas, frequently associated with diabetes mellitus, arise quasi-constantly from gonadotroph cells. We evaluated the possible involvement of pancreastatin in the physiopathology of diabetes mellitus associated with nonsecreting pituitary adenomas. Plasma pancreastatin levels were measured by radioimmunoassay in 5 groups of subjects: 10 patients with nonsecreting pituitary adenomas associated with diabetes mellitus (group I), 10 patients with nonsecreting pituitary adenomas without diabetes (Group II), 10 patients with ACTH or GH-secreting pituitary adenomas and diabetes mellitus (Group III), 10 diabetic patients without pituitary adenomas (Group IV), and 10 healthy controls (Group V). Kidney and liver functions were normal in all of them and no patient was treated with a proton pump inhibitor. All pituitary adenomas were trans-sphenoidally removed. Immunohistochemistry against pancreastatin was performed in 5 patients of each of the 3 groups of pituitary adenomas. Plasma pancreastatin levels were not different between the different groups: 182±46 pg/ml (Group I), 195±57 pg/ml (Group II), 239±42 pg/ml (Group III), 134±31 pg/ml, (Group IV), and 122±29 pg/ml (Group V). In contrast, they were significantly (p<0.05) higher before (391±65 pg/ml) than after trans-sphenoidal surgery (149±18 pg/ml) without post-surgical change in diabetes. An immunostaining against pancreastatin was found in a majority of pituitary adenomas, associated or not with diabetes mellitus. These results argue against a role of pancreastatin in the pathogenesis of diabetes mellitus associated with nonsecreting pituitary adenomas.

The outcome of peptide receptor radionuclide therapy (PRRT) in North American patients with advanced well-differentiated neuroendocrine tumors (WD-NETs).

e14600 Background: PRRT is frequently used in Europe for patients with advanced WD-NETs, but it is not yet readily available in the USA. We analyzed data on 135 North American patients seen at our institution who underwent PRRT. Methods: Cases were identified by searching the University of Iowa Neuroendocrine Tumors Database. Groups were compared using a Wilcoxon rank-sum test, and survival was calculated with the Kaplan-Meier method. Results: Men were 64%, women 36%; median age at diagnosis was 51 years (18 – 78). The primary tumor originated in the small bowel (SBNET) in 37.8%, pancreas (PNET) 26.0%, lung 13.3%, unknown primary 9.6%, other sites 13.3%. PRRT was performed at the University of Basel, Switzerland in 68.8%, University of Iowa in 25.2%, and elsewhere in 6%. 90Y was used in 83.2% and 177Lu in 15.3% for the first PRRT. Median dose of radiation was 180 mCi (range 7.6 – 360). 116 patients received two treatments with median time between the treatments 2.1 months (range 0.4 – 110). Survival is shown in the table. Radiographic responses (any) at 1-6 months after PRRT were observed in 65.8%, 11.1% had a mixed response, and 15.4% progressed. A biochemical response (&gt;50% reduction in chromogranin A and pancreastatin levels) was seen in 18% and 17.3% respectively but data was frequently missing. Conclusions: North American patients with WD-NETs have a relatively long survival. The OS from 1st PRRT was much less than OS after diagnosis, suggesting that PRRT is used late in the disease course. PRRT appears to be a valuable treatment option for WD-NETs, especially SBNETS, and its role earlier in the disease course warrants investigation. [Table: see text]

A Prospective Evaluation of the Effect of Chronic Proton Pump Inhibitor Use on Plasma Biomarker Levels in Humans

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.

Serum Pancreastatin

Serum Pancreastatin

Development of a Highly Sensitive and Specific Carboxy-Terminal Human Pancreastatin Assay to Monitor Neuroendocrine Tumor Behavior

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.

Hepatic Artery Chemoembolization in 122 Patients with Metastatic Carcinoid Tumor: Lessons Learned

BackgroundHepatic artery chemoembolization (HACE) is a treatment option in the management of metastatic carcinoid. We reviewed our experience to identify potential factors that influence survival. MethodsThe records of 122 patients with metastatic carcinoid tumor undergoing HACE were reviewed. Log-rank analysis and Cox proportional hazards were applied to identify factors predictive of decreased survival. ResultsMedian follow-up after HACE was 21.5 months. Complications occurred in 23% with periprocedural mortality of 5%. Radiographic tumor regression was seen in 82%, with stabilization of disease in 12%. Median duration of CT response was 19 months. Improvement in symptoms occurred in 92% for median duration of 13 months. HACE resulted in complete normalization of serum pancreastatin in 14%, with greater than 20% reduction in another 66%. Median overall survival was 33.3 months after HACE. Only pancreastatin level ≥5,000 pg/ml was associated with decreased survival by multivariate analysis. ConclusionHACE offers symptom palliation and long-term survival in patients with incurable carcinoid metastases. Although safe, it should be approached cautiously in patients with significant tumor burden as evidenced by pancreastatin levels ≥5,000 pg/ml. We do not recommend whole-liver embolization in these patients but prefer a staged approach to each lobe of the liver.

Studies of the dysglycemic peptide, pancreastatin, using a human forearm model.

The physiologic effects of the chromogranin A peptide fragment, pancreastatin, were studied in six healthy Caucasian men, ages 25-46 years. Synthetic pancreastatin (human chromogranin A(273-301)-amide) was infused into the brachial artery of each subject to achieve a local concentration of approximately 200 nM over 15 minutes. Forearm blood flow was measured by strain-gauge plethysmography while (A-V)(glucose) was monitored by arterial and venous sampling. Pancreastatin infusion significantly reduced forearm glucose uptake (mean reduction +/- 1 SEM, 54 +/- 15%; P = 0.028) but did not alter forearm blood flow-indicating a metabolic, rather than hemodynamic, effect. Simultaneous infusion of pancreastatin with insulin (0.1 mU/kg/min) did not diminish insulin-induced forearm glucose uptake, suggesting pancreastatin is not simply a negative insulin modulator. The results of this study suggest that pancreastatin may contribute to the dysglycemia associated with type 2 diabetes and essential hypertension, two common human disease states in which plasma pancreastatin levels are elevated.

Indium-111-pentetreotide prolongs survival in gastroenteropancreatic malignancies

Somatostatin and its analogues bind to somatostatin receptors (sst) 1 through 5 that are overexpressed in neuroendocrine neoplasms such as gastroenteropancreatic (GEP) malignancies. After ligand-receptor binding, a fraction of the ligand-receptor complexes internalize. This internalization process is an effective means of delivering cytotoxic radiolabeled somatostatin analogues, especially those emitting short-range decay particles such as Auger electrons, to the neoplastic cell nucleus. Indium-111-pentetreotide, an sst 2 preferring somatostatin analogue with gamma and Auger electron decay characteristics, is commonly used for the scintigraphic evaluation and management of neuroendocrine cancer patients. This clinical trial was performed to determine the effectiveness and tolerability of therapeutic doses of (111)In-pentetreotide in patients with GEP tumors. GEP tumor patients who had failed all forms of conventional therapy, with worsening of tumor-related signs and symptoms and/or radiographically documented progressive disease, an expected survival less than 6 months, and sst positivity as determined by the uptake on a 6.0 mCi (111)In-pentetreotide scan (OctreoScan; Mallinckrodt Medical, Inc, St. Louis, MO), were treated with at least 2 monthly 180-mCi intravenous injections of (111)In-pentetreotide. Baseline clinical assessments, serum chemistries, and plasma pancreastatin levels were measured and repeated before each (111)In-pentetreotide treatment. From February 1997 to February 1998, 27 GEP (24 carcinoid neoplasms with carcinoid syndrome and 3 pancreatic islet cells) patients were accrued, with 26 patients evaluable for clinical and radiographic responses, 21 patients evaluable for biochemical assessments, and 27 patients evaluable for survival analysis and safety. Toxicity was evaluated by using standard National Cancer Institute (NCI) Common Toxicity Criteria guidelines. Clinical benefit occurred in 16 (62%) patients. Pancreastatin levels decreased by 50% or more in 81% of the patients. Objective partial radiographic responses occurred in 2 (8%) patients, and significant tumor necrosis (defined by 20 Hounsfield units or greater decrease from baseline) developed in 7 (27%) patients. The following transient Grades 3/4 NCI Common Toxicity Criteria side effects were observed, respectively: leukocyte: 1/1; platelets: 0/2; hemoglobin: 3/0; bilirubin: 1/3; creatinine: 1/0; neurologic: 1/0. Myeloproliferative disease and/or myelodysplastic syndrome have not been observed in the 6 patients followed-up for 48+ months. The median survival was 18 months (range, 3-54+ mo). Two doses (180 mCi) of (111)In-pentetreotide are safe, well-tolerated, and improve symptoms in 62% of patients, decrease hormonal markers in 81% of patients, decrease Hounsfield units on computed tomography (CT) scans in 27% of patients, with 8% partial radiographic responses and increased expected survival in GEP cancer patients with somatostatin receptor-expressing tumors. The maximal tolerated dose of (111)In-pentetreotide and the optimal dosing schedules remain under investigation.

Serum pancreastatin levels predict response to hepatic artery chemoembolization and somatostatin analogue therapy in metastatic neuroendocrine tumors

Introduction: 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. Methods: Chemoembolization was performed using 30 mg of adriamycin, 50 mg of mitomycin, 12 ml of hexabrix, 10 ml of ethiodol, and 360–500-μm particles. Pancreastatin, a split product of chromogranin A, was measured pre-HACE and post-HACE in all patients. Results: 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. Conclusion: 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.