Bjorn I. Gustafsson

Neuroendocrine Tumor Epidemiology : Contrasting Norway and North America

The National Cancer Institutes Surveillance, Epidemiology, and End Results (SEER) program has proven to be a significant resource in US neuroendocrine tumor (NET) epidemiology. Norway also holds a robust and detailed cancer registry: the Norwegian Registry of Cancer (NRC).

Bronchopulmonary neuroendocrine tumors.

Bronchopulmonary neuroendocrine tumors (BP‐NETs) comprise ≈20% of all lung cancers and represent a spectrum of tumors arising from neuroendocrine cells of the BP‐epithelium. Although they share structural, morphological, immunohistochemical, and ultrastructural features, they are separated into 4 subgroups: typical carcinoid tumor (TC), atypical carcinoid tumor (AC), large‐cell neuroendocrine carcinoma (LCNEC), and small‐cell lung carcinoma (SCLC), which exhibit considerably different biological characteristics. The clinical presentation includes cough, hemoptysis, and obstructive pneumonia but varies depending on site, size, and growth pattern. Less than 5% of BP‐NETs exhibit hormonally related symptoms such as carcinoid syndrome, Cushing, acromegaly, and SIADH. SCLC is the most common BP‐NET, while LCNEC is rare, ≈10% and ≤1%, respectively, of all lung cancers. Both SCLC and LCNEC progress rapidly, are aggressively metastatic, and exhibit a poor prognosis. The incidence of BP‐carcinoids (TC and AC) in the US was 1.57 of 100,000 in 2003 (an unexplained and substantial increase over the last 30 years, ≈6% per year). No curative treatment except for radical surgery (almost never feasible) exists. The slow‐growing TC exhibit a fairly good prognosis (≈88%, 5‐year survival), whereas AC demonstrate a 5‐year survival of ≈50%, and the highly malignant LCNEC and SCLC5‐year survival of 15% to 57% and <5%, respectively. This review provides a broad overview on BP‐NETs and focuses on the evolution of the disease, general features, and current diagnostic and therapeutic options. Cancer 2008.

Chromogranin A—Biological Function and Clinical Utility in Neuro Endocrine Tumor Disease

BackgroundNeuroendocrine tumors (NETs) are a form of cancer that differ from other neoplasia in that they synthesize, store, and secrete peptides, e.g., chromogranin A (CgA) and amines. A critical issue is late diagnosis due to failure to identify symptoms or to establish the biochemical diagnosis. We review here the utility of CgA measurement in NETs and describe its biological role and the clinical value of its measurement.MethodsLiterature review and analysis of the utility of plasma/serum CgA measurements in NETs and other diseases.ResultsCgA is a member of the chromogranin family; its transcription and peptide processing are well characterized, but its precise function remains unknown. Levels are detectable in the circulation but vary substantially (~25%) depending on which assay is used. Serum and plasma measurements are concordant. CgA is elevated in ~90% of gut NETs and correlates with tumor burden and recurrence. Highest values are noted in ileal NETs and gastrointestinal NETs associated with multiple endocrine neoplasia type 1. Both functioning and nonfunctioning pancreatic NETs have elevated values. CgA is more frequently elevated in well-differentiated tumors compared to poorly differentiated NETs. Effective treatment is often associated with decrease in CgA levels. Proton pump inhibitors falsely increase CgA, but levels normalize with therapy cessation.ConclusionsCgA is currently the best available biomarker for the diagnosis of NETs. It is critical to establish diagnosis and has some utility in predicting disease recurrence, outcome, and efficacy of therapy. Measurement of plasma CgA is mandatory for the effective diagnosis and management of NET disease.

Carcinoid heart disease

The carcinoid syndrome is usually evident when enterochromaffin (EC) cell-derived neuroendocrine tumors (carcinoids) metastasize to the liver. In addition to carcinoid symptomatology, about 40% of patients exhibit carcinoid heart disease (CHD) with fibrotic endocardial plaques and associated heart valve dysfunction. The mechanism behind CHD development is not fully understood, but serotonin (5-HT) is considered to be a major initiator of the fibrotic process. Most patients present with right-sided heart valve dysfunction since pulmonary and tricuspid valves lesions are the most common (>95%) cardiac pathology. Left-sided valvular involvement, and angina associated with coronary vasospasm occur in ~10% of subjects with CHD. Pathognomonic echocardiograpic features include immobility of valve leaflets and thickening and retraction of the cusps most commonly resulting in tricuspid valve regurgitation and pulmonary stenosis. Therapeutic options include cardioactive pharmacotherapy for heart failure and, in selected individuals, cardiac valve replacement. Previously valve replacement was reserved for advanced disease due to a perioperative mortality of >20% however in the last decade, technical advances as well as an earlier diagnosis have decreased surgical mortality to <10% and valve replacements are undertaken more frequently. A recent analysis of 200 cases demonstrated an increase in median survival from 1.5 years to 4.4 years in the last two decades. Although the improved prognosis might also reflect the increased use of surgical cytoreduction, hepatic metastatic ablative therapies and somatostatin analogs a robust correlation between diminution of circulating tumor products and an increased long-term survival in CHD has not been rigorously demonstrated.

IL1β‐ and LPS‐induced serotonin secretion is increased in EC cells derived from Crohn’s disease

Abstract  Gut mucosal enterochromaffin (EC) cells are regarded as key regulators of intestinal motility and fluid secretion via secretion of serotonin (5HT), are increased in numbers in mucosal inflammation and located in close proximity to immune cells. We examined whether interleukin (IL)1β and Escherichia coli lipopolysaccharide (LPS) induced EC cell 5HT release through Toll‐like/IL‐1 (TIL) receptor activation, nuclear factor kappa B (NFκB) and mitogen‐activated protein kinase (MAPK) phosphorylation and evaluated whether somatostatin could inhibit this phenomenon. Pure (>98%) human intestinal EC cells were isolated by fluorescent activated cell sorting from preparations of normal (n = 5) and Crohn’s colitis (n = 6) mucosa. 5HT release was measured (ELISA), and NFκB and ERK phosphorylation quantitated (ELISA) in response to IL1β and LPS. 5HT secretion was increased by both E. coli LPS (EC50 = 5 ng mL−1) and IL1β (EC50 = 0.05 pmol L−1) >2‐fold (P < 0.05) in Crohn’s EC cells compared with normal EC cells. Secretion was reversible by the TLR4 antagonist, E. coli K12 LPS (IC50 = 12 ng mL−1) and the IL1β receptor antagonist (ILRA; IC50 = 3.4 ng mL−1). IL1β caused significant (P < 0.05) NFκB and MAPK phosphorylation (40–55%). The somatostatin analogue, lanreotide inhibited IL1β‐stimulated secretion in Crohn’s (IC50 = 0.61 nmol L−1) and normal EC cells (IC50 = 1.8 nmol L−1). Interleukins (IL1β) and bacterial products (E. coli LPS) stimulated 5HT secretion from Crohn’s EC cells via TIL receptor activation (TLR4 and IL1β). Immune‐mediated alterations in EC cell secretion of 5HT may represent a component of the pathogenesis of abnormal bowel function in Crohn’s disease. Inhibition of EC cell‐mediated 5HT secretion may be an alternative therapeutic strategy in the amelioration of inflammatory bowel disease symptomatology.

Different skeletal effects of the peroxisome proliferator activated receptor (PPAR)α agonist fenofibrate and the PPARγ agonist pioglitazone

BackgroundAll the peroxisome proliferator activated receptors (PPARs) are found to be expressed in bone cells. The PPARγ agonist rosiglitazone has been shown to decrease bone mass in mice and thiazolidinediones (TZDs) have recently been found to increase bone loss and fracture risk in humans treated for type 2 diabetes mellitus. The aim of the study was to examine the effect of the PPARα agonist fenofibrate (FENO) and the PPARγ agonist pioglitazone (PIO) on bone in intact female rats.MethodsRats were given methylcellulose (vehicle), fenofibrate or pioglitazone (35 mg/kg body weight/day) by gavage for 4 months. BMC, BMD, and body composition were measured by DXA. Histomorphometry and biomechanical testing of excised femurs were performed. Effects of the compounds on bone cells were studied.ResultsThe FENO group had higher femoral BMD and smaller medullary area at the distal femur; while trabecular bone volume was similar to controls. Whole body BMD, BMC, and trabecular bone volume were lower, while medullary area was increased in PIO rats compared to controls. Ultimate bending moment and energy absorption of the femoral shafts were reduced in the PIO group, while similar to controls in the FENO group. Plasma osteocalcin was higher in the FENO group than in the other groups. FENO stimulated proliferation and differentiation of, and OPG release from, the preosteoblast cell line MC3T3-E1.ConclusionWe show opposite skeletal effects of PPARα and γ agonists in intact female rats. FENO resulted in significantly higher femoral BMD and lower medullary area, while PIO induced bone loss and impairment of the mechanical strength. This represents a novel effect of PPARα activation.

A Nomogram to Assess Small-Intestinal Neuroendocrine Tumor ('Carcinoid') Survival

Neuroendocrine tumors (NETs) are a heterogeneous group of cancers of which the commonest site is the small intestine (SI). Most information available to determine tumor behavior reflects univariate assessment of factors or is anecdotal or experience based. There currently exists no objective multivariate analysis of indices that defines SI NET prognosis. A key unmet need is the lack of a rigorous mathematical-based tool – a nomogram – for the assessment of parameters that define progress, determine prognosis and can guide therapy. Since prediction of NET behavior is a critical criterion in determining clinical strategy, we constructed a NET nomogram (Modlin Score) for prognosis prediction, patient group comparisons and a guide for stratification of treatment and surveillance. We used hazard ratio (HR), Cox analysis and Kaplan-Meier analysis of published data and the current Surveillance, Epidemiology and End Results (SEER) database (approx. 20,000 patients) to develop a nomogram from 15 variables demonstrated to provide significant multivariate HRs. These included age, gender, ethnicity, symptoms, urinary 5-hydroxyindoleacetic acid, plasma chromogranin A, liver function tests, tumor size, invasion, metastasis, histology, Ki-67 index, carcinoid heart disease and therapy (surgery or long-acting somatostatin analogs). Internal validation was assessed using 33 SI NET patients. A NET nomoscore (Modlin Score) was developed by HR weighting and stratification into low (<75), medium (75–95) and high risk (>95). This identified significant differences (p <0.03, Kaplan-Meier) in survival (15.5 ± 4.3, 9.7 ± 2.5 and 6.4 ± 1.1 years, respectively). The Modlin Score was significantly elevated (p <0.01) in deceased compared to alive patients. This nomogram represents an optimized construct based upon currently analyzable data, and application will facilitate accurate stratification for comparison in clinical trials. External validation and amplification by identification of additional indices, e.g. molecular biomarkers, are necessary. The development of a mathematically validated nomogram provides a platform for objective assessment of SI NET disease, a finite basis for precise prognostication and a tool to guide management strategy.

Predicting neuroendocrine tumor (carcinoid) neoplasia using gene expression profiling and supervised machine learning

A more accurate taxonomy of small intestinal (SI) neuroendocrine tumors (NETs) is necessary to accurately predict tumor behavior and prognosis and to define therapeutic strategy. In this study, the authors identified a panel of such markers that have been implicated in tumorigenicity, metastasis, and hormone production and hypothesized that transcript levels of the genes melanoma antigen family D2 (MAGE‐D2), metastasis‐associated 1 (MTA1), nucleosome assembly protein 1‐like (NAP1L1), Ki‐67 (a marker of proliferation), survivin, frizzled homolog 7 (FZD7), the Kiss1 metastasis suppressor (Kiss1), neuropilin 2 (NRP2), and chromogranin A (CgA) could be used to define primary SI NETs and to predict the development of metastases.

The 5-HT2B Receptor Plays a Key Regulatory Role in Both Neuroendocrine Tumor Cell Proliferation and the Modulation of the Fibroblast Component of the Neoplastic Microenvironment

Fibrosis is a cardinal feature of small intestinal neuroendocrine tumors (SI‐NETs) both in local peritumoral tissue and systemic sites (cardiac). 5‐HT, a commonly secreted NET amine, is a known inducer of fibrosis, although the mechanistic basis for it and growth factors regulating fibrosis and proliferation in the tumor microenvironment are unclear. We hypothesized that targeting 5‐HT2B receptors on tumor cells would inhibit SI‐NET 5‐HT release and, thereby, fibroblast activation in the tumor microenvironment.

The CCK2 receptor antagonist, YF476, inhibits Mastomys ECL cell hyperplasia and gastric carcinoid tumor development

YF476 is a potent and highly selective cholecystokin 2 (CCK(2)) receptor antagonist of the benzodiazepine class. It inhibits gastric neuroendocrine enterochromaffin-like (ECL) cell secretion, proliferation and spontaneous formation of gastric neuroendocrine tumors (carcinoids) in cotton rats. The Mastomys rodent species exhibits a genetic predisposition to gastric ECL neuroendocrine tumor formation which can be accelerated by acid suppression and induction of hypergastrinemia. In this respect, it mimics the human condition of atrophic gastritis, hypergastrinemia and gastric carcinoid development. We investigated whether YF476 could inhibit acid suppression-induced ECL cell hyperplasia and neoplasia in this model. In addition, we examined whether YF476 could reverse established ECL cell hyperplasia and neoplasia. Targeting the CCK(2) receptor during Loxtidine-induced hypergastrinemia resulted in a reduction in ECL cell secretion (plasma and mucosal histamine, and histidine decarboxylase (HDC) transcripts, p<0.05) and proliferation (numbers of HDC-positive cells, connective tissue growth factor (CTGF) and cyclin D1 transcription). This was associated with a decrease in ECL cell hyperplasia and a 60% reduction in gastric ECL cell microcarcinoid (tumors <0.3mm in size) formation. YF476 inhibited ECL cell neoplasia (gastric carcinoid) in animals with hyperplasia, inhibited the formation of ECL cell tumors when co-administered with Loxtidine and reversed the growth and developement of gastric ECL cell carcinoids in long-term acid suppressed Mastomys. Variable importance analysis using a logistic multinomial regression model indicated the effects of YF476 were specific to the ECL cell and alterations in ECL cell function reflected inhibition of transcripts for HDC, Chromogranin A (CgA), CCK(2) and the autocrine growth factor, CTGF. We conclude that specifically targeting the CCK(2) receptor inhibits gastrin-mediated ECL cell secretion and ECL cell proliferation and tumor development in vivo.