How the diffuse neuroendocrine system shapes health, homeostasis, and cancer.

Morphologic and Other Forms of Heterogeneity in Small Cell Lung Cancer: What Can We Learn from Them?

1993). The initial management of NET comprises surgical excision of the primary tumour (aimed at reducing as much as possible of the tumour mass); additionally, in patients who are not cured by surgery alone, medical therapy is used for the control of symptoms and humoral syndromes with agents such as somatostatin analogues and/or a-interferon. Specific therapy with radiopharmaceuticals using radio-labelled substances such as meta-iodobenzylguanidine (MIBG) or somatostatin analogues appears promising for some tumours which show diagnostic uptake, and is the first-line systemic management for sensitive cases. Hepatic artery ligation and/or chemoembolization is also used in patients with excessive hepatic tumour load and uncontrollable symptoms. The control of tumour growth with chemotherapeutic agents is currently mainly reserved for patients with recurrent and/or progressive disease and where other therapeutic modalities have failed. Chemotherapy may be particularly helpful for selected cases of advanced NET, especially pancreatic or poorly differentiated NET. This review deals with the general role of chemotherapy in the management of malignant NET, its integration with other modes of therapy, and the specific protocols which have been used. Histological classification and differentiation of NET

BackgroundCYYR1 is a recently identified gene located on human chromosome 21 whose product has no similarity to any known protein and is of unknown function. Analysis of expressed sequence tags (ESTs) have revealed high human CYYR1 expression in cells belonging to the diffuse neuroendocrine system (DNES). These cells may be the origin of neuroendocrine (NE) tumors. The aim of this study was to conduct an initial analysis of sequence, splicing and expression of the CYYR1 mRNA in human NE tumors.MethodsThe CYYR1 mRNA coding sequence (CDS) was studied in 32 NE tumors by RT-PCR and sequence analysis. A subtle alternative splicing was identified generating two isoforms of CYYR1 mRNA differing in terms of the absence (CAG- isoform, the first described mRNA for CYYR1 locus) or the presence (CAG+ isoform) of a CAG codon. When present, this specific codon determines the presence of an alanine residue, at the exon 3/exon 4 junction of the CYYR1 mRNA. The two mRNA isoform amounts were determined by quantitative relative RT-PCR in 29 NE tumors, 2 non-neuroendocrine tumors and 10 normal tissues. A bioinformatic analysis was performed to search for the existence of the two CYYR1 isoforms in other species.ResultsThe CYYR1 CDS did not show differences compared to the reference sequence in any of the samples, with the exception of an NE tumor arising in the neck region. Sequence analysis of this tumor identified a change in the CDS 333 position (T instead of C), leading to the amino acid mutation P111S. NE tumor samples showed no significant difference in either CYYR1 CAG- or CAG+ isoform expression compared to control tissues. CYYR1 CAG- isoform was significantly more expressed than CAG+ isoform in NE tumors as well as in control samples investigated. Bioinformatic analysis revealed that only the genomic sequence of Pan troglodytes CYYR1 is consistent with the possible existence of the two described mRNA isoforms.ConclusionA new "subtle" splicing isoform (CAG+) of CYYR1 mRNA, the sequence and the expression of this gene were defined in a large series of NE tumors.

The diffuse neuroendocrine system (DNES) is composed of cells and tumors with secretory granules ranging from 50-400 nm in diameter. Members of the DNES commonly stain for chromogranin and synaptophysin by immunohistochemistry and may express a variety of peptide hormones. Recent studies have shown that the proprotein convertases (proconvertases or PCs) are good broad-spectrum markers for members of the DNES. Gene expression can be readily detecting in neuroendocrine cells and tumors by in situ hybridization (ISH). Newer techniques such as in situ polymerase chain reaction (PCR) can be used to detect gene products that are expressed in low copy numbers in neuroendocrine cells. The concept of multidirectional differentiation is an important notion that helps to explain multiple patterns of phenotypic expression observed in some neuroendocrine tumors.

Neuroendocrine neoplasms(NENs) are relatively rare tumors originating from the diffuse neuroendocrine system, and gastrointestinal tract is one of the most common location of the tumors. Currently, the European Neuroendocrine Neoplasm Society (ENETS) and the National Comprehensive Cancer Network (NCCN) have released the international guidelines for NENs management. And also, experts from Chinese Society of Clinical Oncology (CSCO) have proposed "The Consensus on Gastroenteropancreatic Neuroendocrine Neoplasm in China" in 2016, which is also one of the most important reference standard for the diagnosis and treatment of gastroenteropancreatic(GEP) NENs in China. Here we will interpret these three guidelines or consensus. There are few controversies about endoscopic management principle for GEP-NEN of different locations and sizes among these three guidelines or consensus, but for small NENs without involving intrinsic muscularis, endoscopic resection is recommended and considered. We hope that this interpretation may help clinicians for clinical decision making.

Neuroendocrine tumors (NETs) are a group of biologically and clinically heterogeneous neoplasms arising from the diffuse neuroendocrine system. In the last few years, advances in our understanding of the biology of these tumors have translated into an expansion of treatment options for patients with NETs. Current treatment modalities include somatostatin analogs (SSAs), radiolabeled SSAs, targeted agents, cytotoxic drugs and liver-directed therapies for the management of metastatic disease. Recent studies have expanded the role of SSAs in gastroenteropancreatic (GEP)-NETs, and everolimus has shown robust antitumor activity across a broad range of NETs of the lung and GEP tract. The radiolobeled SSA Lu-DOTATATE has been investigated in a randomized phase III trial, and has demonstrated exceptional efficacy and tolerability in patients with progressive midgut NETs. The new serotonin inhibitor telotristat etiprate has shown significant activity in the palliation of symptoms of carcinoid syndrome, and its approval by regulatory authorities is expected soon. The field of NETs has been transformed from one dominated by limited treatment options to one characterized by an increasing number of therapeutic agents and active clinical trials. Navigating the current therapeutic algorithm may be challenging, and requires an understanding both of the heterogeneity of NETs and of characteristics that are shared by NETs across tumor subtypes.

Gastrointestinal Neuroendocrine Tumors: Pancreatic Endocrine Tumors

T1 rectal NET resection: Does size really matter?

Chromogranin and neuron specific enolase (NSE) are present in most neuroendocrine cells and tumors of the diffuse neuroendocrine system (DNES). Silver stains such as argyrophil and argentaffin stains can be used to determine if a certain cell or tumor belongs to the DNES. However, the use of well characterized polyclonal antisera or monoclonal antibodies for the immunohistochemical study of neuroendocrine cells and tumors offers the advantages of greater specificity, reproducibility, and sensitivity intrinsic to immunohistochemical procedures. The combination of chromogranin and NSE immunostaining in examining cells and tumors for neuroendocrine features has many advantages. Among these are (1) the use of two or more markers in immunohistochemical procedures, which increases the sensitivity of the method and the reliability of a positive result, especially if both markers are positive; (2) (demonstration that the intracytoplasmic target structures of chromogranin and NSE are different, so a cell may express at least one of these two markers, if not both; and (3) evidence of some gastroenteropancreatic (GEP) cells and tumors that are producing peptides and other products, which have not been characterized as yet, so specific antisera are not available to examine these lesions. The use of chromogranin and NSE can be extremely helpful in revealing the neuroendocrine features of such lesions.

Neuroendocrine tumors (NETs) are heterogeneous malignancies arising from the diffuse neuroendocrine system. They frequently originate in the gastroenteropancreatic (GEP) tract and the bronchopulmonary tree, and their incidence has steadily increased in the last 3 decades. Fundamental biologic and genomic differences underlie the clinical heterogeneity of NETs, and distinct molecular features characterize NETs of different grades and different primary sites. Although surgery remains the cornerstone of treatment for localized tumors, systemic treatment options for patients with metastatic NETs have expanded considerably. Somatostatin analogs have demonstrated both antisecretory and antitumor efficacy. Peptide receptor radionuclide therapy with lutetium-177 dotatate (177 Lu-DOTATATE) has been approved for advanced GEP-NETs. The antitumor activity of everolimus has been demonstrated across a wide spectrum of NETs, and the antiangiogenic agent sunitinib has been approved for pancreatic NETs (pNETs). Chemotherapy with temozolomide and capecitabine has recently demonstrated an unprecedented prolongation of progression-free survival in a randomized trial of pNETs. Multiple retrospective series have reported the efficacy of liver-directed therapies both for palliating symptoms of hormone excess and for controlling tumor growth. Telotristat, an oral inhibitor of tryptophan hydroxylase, has been shown to reduce diarrhea in patients with carcinoid syndrome. Defining the therapeutic algorithm and identifying biomarkers predictive of response to treatments are among the main priorities for the next decade of research in the NET field.

Update on the Management of Neuroendocrine Hepatic Metastases

Neuroendocrine tumor covers a wide range of neoplasms that originate in the neuroendocrine cells which spread throughout the body. Carcinoid tumor, and neuroendocrine tumor are low-grade malignant tumors, their growth is slow, and mainly in the gastrointestinal epithelium. Esophageal adenocarcinoma tumor is a big problem in esophageal cancer. Combined esophageal adenocarcinoma and carcinoid tumor both as primary tumors is very rare[1]. Neuroendocrine tumors of the esophagus are derived from the diffuse neuroendocrine system in the gastrointestinal tract. Neuroendocrine tumors in the esophagus can be distinguished from other mesenchymal tumors by immunostaining for synaptophysin and chromogranin-A. Both carcinoid of the esophagus and adenocarcinoma of the esophagus are malignant tumors and considered to have a specifi c molecular pathogenesis. This paper presents a rare case diagnosed as carcinoid of the esophagus concomitant with an adenocarcinoma of the esophagus, a review of the literature is also presented here.

Chromogranin A, despite a number of limitations, is still the most valuable marker of neuroendocrine tumors (NETs). Granins belong to the family of acidic proteins that constitute a major component of secretory granules of various endocrine and neuroendocrine cells, which are components of both the classical endocrine glands and the diffuse neuroendocrine system. These cells are a potential source of transformation into neuroendocrine tumors. The awareness of potential causes influencing the false results of its concentrations simplifies diagnosis and treatment. One of the disadvantages of this marker is its non-specificity and the existence of a number of pathological processes leading to an increase in its concentration, which often results in confusion and diagnostic difficulties. The molecular structure is characterized by a number of sites susceptible to the proteolytic activity of enzymes, resulting in the formation of a number of biologically active peptides. Presumably they act as precursors of active proteins. Chromogranin expression correlates with the amount of secretory vesicles in neuroendocrine cells. The peptide chain during biochemical changes becomes a precursor of biologically active proteins with a wide range of activities. There are a number of commercially available kits for the determination of chromogranin A, which differ in methodology. We present the evaluation of chromogranin A as a marker of neuroendocrine tumors in clinical practice and the possible factors that may affect the outcome of its concentration.

18 Vesicle Proteins in Nonendocrine and Nonendocrine Tumors of the Gastrointestinal Tract

The widespread availability and reliability of immunohistochemical techniques in the last three decades have allowed researchers to identify cells with common neuroendocrine markers in virtually every organ. As a whole, these neuroendocrine cells form the so-called diffuse neuroendocrine system. Tumours arising from the cells of the diffuse neuroendocrine system are defined as (neuro)endocrine tumours (NETs). NETs have been increasingly described in recent years. However, despite the increase in the number of published papers focused on NET, we still lack adequate epidemiological data, particularly for non-gastroenteropancreatic (GEP) NETs. Furthermore, the real incidence of neuroendocrine differentiation for most sites is not completely known and is probably underestimated. As a consequence, data on the clinical features of many NET subgroups are not well known or confusing. For all of these reasons, we have attempted to evaluate the epidemiology of non-GEP NETs, reviewing the limited data available in the literature.