Thomas M. O’Dorisio

Selective Gene Expression and Activation-Dependent Regulation of Vasoactive Intestinal Peptide Receptor Type 1 and Type 2 in Human T Cells

Vasoactive intestinal peptide (VIP) has potent antiproliferative and anti-inflammatory functions in the immune system. Two structurally distinct G-protein-associated receptors, VIP receptor type 1 (VPAC1) and VIP receptor type 2 (VPAC2), mediate the biological effects of VIP. The regulation of VIP receptor gene expression and the distribution of these receptors in different compartments of the human immune systems are unknown. This study reports, for the first time, a quantitative analysis of VPAC1 and VPAC2 mRNA expression in resting and activated T cells as well as in resting monocytes. Purified human peripheral blood CD4+ T cells and CD8+ T cells were stimulated via the TCR/CD3 receptor complex. Using the novel fluorometric-based kinetic (real-time) RT-PCR, we determined that VPAC1 is constitutively expressed in resting T cells and monocytes; the levels of expression were significantly higher in monocytes and CD4+ T cells than in CD8+ T cells. VPAC1 mRNA expression is significantly higher relative to VPAC2 in resting CD4+ T cells and CD8+ T cells. VPAC2 is expressed at very low levels in resting T cells but is not detectable in resting monocytes. In vitro stimulation of Th cells with soluble anti-CD3 plus PMA induced a T cell activation-dependent down-regulation of VPAC1. VPAC1 is down-regulated under conditions of optimal T cell stimulation. Our results suggest that selective VIP effects on T cell function may be mediated via selective expression of VPAC1 and VPAC2 on T cells and monocytes. Furthermore, down-regulation of VPAC1 in CD4+ T cell subpopulations is highly correlated with T cell activation.

Circulating Biomarkers in Neuroendocrine Tumors of the Enteropancreatic Tract: Application to Diagnosis, Monitoring Disease, and as Prognostic Indicators

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

Patient-reported Symptom Experiences in Patients With Carcinoid Syndrome After Participation in a Study of Telotristat Etiprate: A Qualitative Interview Approach

PURPOSE Telotristat etiprate, a tryptophan hydroxylase inhibitor, was previously evaluated in a Phase II randomized, placebo-controlled clinical trial in patients with carcinoid syndrome (CS) and diarrhea not adequately controlled by octreotide. The objective of the current study was to characterize the symptom experiences of patients participating in that trial. METHODS Consenting patients participated in one-on-one, qualitative interviews focused on eliciting symptoms they had experienced in association with their CS diagnosis and recollection of symptom changes they experienced while participating in the Phase II trial. FINDINGS Among the 23 patients who participated in the previous 4-week dose-escalation study, 16 were eligible for interviews and 11 participated in the present study. The median time from study completion to the interview was 31 months; 4 of 11 patients were receiving telotristat etiprate in a follow-up, open-label trial at the time of interview. All of the patients (100%) described diarrhea as a symptom of CS, with effects on the emotional, social, and physical aspects of their lives. Improvement in diarrhea during the study was described by 82% of participants, and was very impactful in several patients. Results led to the design and implementation of a larger interview program in Phase III and helped to establish a definition of clinically meaningful change for the clinical development program. IMPLICATIONS The diarrhea associated with CS can have a large impact on daily lives, and patient interviews can characterize and capture clinically meaningful improvements with treatment. ClinicalTrials.gov Identifier: NCT00853047.

Gastric inhibitory polypeptide receptor (GIPR) is a promising target for imaging and therapy in neuroendocrine tumors

BACKGROUND Ligands binding the somatostatin receptor type 2 (SSTR2) are useful for imaging and treatment of neuroendocrine tumors (NETs), but not all tumors express high levels of these receptors. The aim of this study was to evaluate gene expression of new therapeutic targets in NETs relative to SSTR2. METHODS RNA was extracted from 103 primary small bowel and pancreatic NETs, matched normal tissue, and 123 metastases. Expression of 12 candidate genes was measured by quantitative polymerase chain reaction normalized to internal controls; candidate gene expression was compared with SSTR2. RESULTS Relative to normal tissue, primary NET expression of SSTR2, GPR98, BRS3, GIPR, GRM1, and OPRK1 were increased by 3, 8, 13, 13, 17, and 20-fold, respectively. Similar changes were found in metastases. Although most candidate genes showed lesser absolute expressions than SSTR2, absolute GIPR expression was closest to SSTR2 (mean dCT 3.6 vs. 2.7, P = .01). Absolute OPRK1 and OXTR expression varied greatly by primary tumor type and was close to SSTR2 in small bowel NETs but not pancreatic NETs. CONCLUSION Compared with the current treatment standard SSTR2, GIPR has only somewhat lesser absolute gene expression in tumor tissue but much lesser expression in normal tissue, making it a promising new target for NET imaging and therapy.

Comparison of Transarterial Liver-directed Therapies for Low-grade Metastatic Neuroendocrine Tumors in a Single Institution

Objective 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. Methods 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. Results 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. Conclusions 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.

Endocrine tumors of the gastroenteropancreatic axis

The endocrine tumors of the gastroenteropancreatic (GEP) axis derive from the diffuse neuroendocrine system of the gut and consist of cells capable of Amine Precursor Uptake and Decarboxylation (APUD). The tendency to label tumors of the GEP axis as APUDomas has merit in that histologic features of endocrine cells are recognized, however this practice does not embrace the clinical syndromes that derive therefrom. Although subsequently modified, the original hypothesis held that all APUD cells have a common embryological origin in the neural crest [132]. Recent experimental studies have confirmed that suprarenal chromaffin cells, C cells of the thyroid gland, and chief cells of the carotid body are indeed derivatives of the neural crest [4, 97, 134]. Current evidence suggests that the source of gut and pancreatic endocrine cells is a discrete population of endodermal stem cells different from other epithelial cells [5, 158, 172]. These cells in their primitive form appear to retain the capacity to differentiate into a number of different cell lines and function to secrete peptides normally not contained in the adult pancreas. A clear example is the gastrinoma syndrome in which the most common site of the tumor is the pancreas that, in the adult, is devoid of G cells.

Repeatability of gallium-68 DOTATOC positron emission tomographic imaging in neuroendocrine tumors.

Objective To evaluate the repeatability of gallium-68 1,4,7,10-tetraazacyclododecane-N,N′,N′′,N′′′-tetraacetic (DOTA)-D-Phe1-Try3-octreotide (68Ga-DOTATOC) positron emission tomography (PET) in neuroendocrine tumors. Methods Five patients with neuroendocrine tumors were imaged with 68Ga-DOTATOC PET twice within 5 days. Maximum and mean standardized uptake values (SUVmax and SUVmean) and kinetic parameters (K-Patlak and K-influx) of target lesions were measured. The repeatability of these measurements was investigated. Results Forty-seven target lesions were identified on whole-body PET and 21 lesions on dynamic images. There was excellent repeatability with intraclass correlation coefficient of 0.99 for SUVmax, SUVmean, and K-Patlak, and 0.85 for K-influx. The median absolute percent differences and the interquartile ranges (IQR) between 2 scans for SUVmax and SUVmean were 7.4% (IQR, 14.1%) and 9.3% (IQR, 10.6%), respectively. The median absolute percent differences for K-Patlak and K-influx were 12.5% (IQR, 12.6%) and 29.9% (IQR, 22.4%), respectively. The SUVmax of target lesions did not differ by more than 25% between the 2 scans. Conclusions 68Ga-DOTATOC PET imaging of neuroendocrine tumors is highly reproducible. A difference of more than 25% in SUVmax represents a change that is larger than the measurement error observed on repeated studies and should reflect a significant change in the biological character of the tumor.

Biochemical Diagnosis and Preoperative Imaging of Gastroenteropancreatic Neuroendocrine Tumors.

Neuroendocrine tumors are a group of neoplasms that can arise in a variety of locations throughout the body and often metastasize early. A patients only chance for cure is surgical removal of the primary tumor and all associated metastases, although even when surgical cure is unlikely, patients can benefit from surgical debulking. A thorough preoperative workup will often require multiple clinical tests and imaging studies to locate the primary tumor, delineate the extent of the disease, and assess tumor functionality. This review discusses the biomarkers important for the diagnosis of these tumors and the imaging modalities needed.

Elevated pancreatic polypeptide levels in pancreatic neuroendocrine tumors and diabetes mellitus: causation or association?

Pancreatic neuroendocrine tumors (PNETs) that secrete primarily pancreatic polypeptide (PP) are rare and usually nonfunctional. There are approximately 2 dozen reports of PP-secreting PNETs, 3 of which have been associated with diabetes mellitus (DM). None suggest a mechanism for the association between PP-secreting PNETs and DM. We describe 5 patients with PP-producing tumors who were diagnosed with DM at the same time as their PNETs, review the literature on PP, and consider its role in the pathophysiology of DM. The cases discussed were extracted from our surgical neuroendocrine tumor database. We examined all patients with PP-predominant PNETs--both with DM (n = 5) and without (n = 8). The 5 patients with DM at the time of PNET diagnosis demonstrated improvement or resolution of their DM postoperatively. In the patients with PP-secreting PNETs but no diagnosis of DM preoperatively, 1 became hypoglycemic postoperatively, and 2 others developed postoperative DM. The 5 cases discussed in detail raise the question of whether the hypersecretion of PP in PNETs might be an important event leading to the development of DM. Although the literature does not provide a mechanism for this association, it may be related to the role of PP in hepatic glucose regulation.

Overexpression of Membrane Proteins in Primary and Metastatic Gastrointestinal Neuroendocrine Tumors

BackgroundSmall bowel and pancreatic neuroendocrine tumors (SBNETs and PNETs) are rare tumors whose incidence is increasing. Drugs targeting the somatostatin receptor are beneficial in these tumors. To identify additional cell-surface targets, we recently found receptors and membrane proteins with gene expression significantly different from adjacent normal tissues in a small number of primary SBNETs and PNETs. We set out to validate these expression differences in a large group of primary neuroendocrine tumors and to determine whether they are present in corresponding liver and lymph node metastases.MethodsPrimary SBNETs and PNETs, normal tissue, nodal, and liver metastases were collected and mRNA expression of six target genes was determined by quantitative PCR. Expression was normalized to GAPDH and POLR2A internal controls, and differences as compared to normal tissue were assessed by Welch’s t test.ResultsGene expression was determined in 45 primary PNETs with 20 nodal and 17 liver metastases, and 51 SBNETs with 50 nodal and 29 liver metastases. Compared to normal tissue, the oxytocin receptor (OXTR) showed significant overexpression in both primary and metastatic SBNETs and PNETs. Significant overexpression was observed for MUC13 and MEP1B in PNET primary tumors, and for GPR113 in primary SBNETs and their metastases. SCTR and ADORA1 were significantly underexpressed in PNETs and their metastases. OXTR protein expression was confirmed by immunohistochemistry.ConclusionsOXTR is significantly overexpressed relative to normal tissue in primary SBNETs and PNETs, and this overexpression is present in their liver and lymph node metastases, making OXTR a promising target for imaging and therapeutic interventions.