Diagnostic and therapeutic guidelines for gastrointestinal neuroendocrine tumors (recommended by the Polish Network of Neuroendocrine Tumors)

We have recently observed an increased interest in gastro-entero-pancreatic neuroendocrine tumors (GEP NET). They are rare cancer types and therefore collaborative effort of specialists in various disciplines of medicine is necessary to work out the diagnostic and therapeutic guidelines. In this publication we present general guidelines of the Polish Network of Neuroendocrine Tumors for the management of patients with GEP NET, developed at the Round Table Conference which took place in Kliczków near Wroc?aw in November 2007. In the subsequent parts of this publication, we present the rules of diagnostic and therapeutic management of: - endocrine tumors of the stomach and duodenum (including gastrinoma); - pancreatic endocrine tumors; - neuroendocrine tumors of the small intestine and the appendix; - neuroendocrine tumors of the colon. We hope that the proposed guidelines by Polish and foreign experts representing various disciplines of medicine, including endocrinology, gastroenterology, surgery, oncology, nuclear medicine and pathomorphology, will become a useful tool in the diagnostics and treatment of these patients.     

Neuroendocrine tumors of the colon - management guidelines (recommended by The Polish Network of Neuroendocrine Tumors)

The neuroendocrine tumors (NET) of the colon are rare with a rising incidence due to an increased number of diagnostic examination including screening colonoscopy. According to distinct prognosis and treatment these tumors are classified as colonic or rectal NET. This paper provides the consensus guidelines for management of patients with these neoplasms recommended by the Polish Neuroendocrine Tumor Network Group. Furthermore the epidemiology and clinical presentation are described.     

Novel therapeutic agents for the treatment of gastroenteropancreatic neuroendocrine tumors

Neuroendocrine tumors (NET) are frequently diagnosed late and not amenable to curative surgery due to metastatic disease to the liver and lymph nodes. The disease is complex and heterogeneous given the various functionalities, distinct tumor growth patterns, and tumor spread upon diagnosis. Established therapies include somatostatin analogues, alpha-interferon, systemic chemotherapy, and loco-regional therapies of the liver. The availability of novel agents and expression of targets, such as growth factor receptors, different subtypes of somatostatin receptors, and the mammalian target of rapamycin (mTOR) have led to the exploration of different classes of drugs and offer new treatment opportunities in neuroendocrine tumors. This review provides an overview on novel drugs, focus on the impact of recently approved drugs on the management of NET disease, and outline future perspectives.     

Neuroendocrine neoplasms of the gastroenteropancreatic system: pathology and classification

Neuroendocrine neoplasms (NEN) appear homogeneous in terms of morphology, but constitute a very heterogeneous group of tumors in terms of biological and clinical features. NEN may occur in any organ, but are most commonly observed in the lung and the gastroenteropancreatic system (GEP). The European Neuroendocrine Tumor Society (ENETS) developed guidelines in the last 5 years to standardize and improve the diagnosis and therapy of GEP-NEN. Taking these guidelines into account, the TNM classification of the Union for International Cancer Control (UICC) was introduced in 2009. The new GEP-NEN classification of the World Health Organization (WHO) was presented 1 year later. According to the guidelines of the ENETS, the UICC, and the WHO, the pathology classification of NEN of GEP consists of several basic components: (1) evidence of the neuroendocrine nature of the tumor, (2) histological distinction between well and poorly differentiated tumors, (3) proliferation-based grading. (4) TNM staging (including data about vascular invasion and resection margins), (5) with reference to the clinical question: evidence of hormones and biogenic amines, and (6) optional, especially in cases of initial diagnosis of NEN: expression of the somatostatin receptor type 2A. Based on these criteria, a standardized prognostic stratification of GEP-NEN can be performed in combination with other clinical parameters. The novel classifications constitute the basis for selecting the procedures of molecular and metabolic imaging as well as for tumor-specific treatments and permit comparisons of larger tumor populations. Close interdisciplinary cooperation is a prerequisite.     

Polypeptide growth factors in gastroenteropancreatic neuroendocrine tumours

Polypeptide growth factors form a potent class of extracellular signal molecules in the regulation of cellular differentiation and proliferation. Disturbances in the expression of growth factors influence the normal pathway of differentiation and lead to cellular transformation and tumour progression. Contemporary medical studies report that various growth factors such as those for platelet-derived growth factor, vascular endothelial growth factor, epidermal growth factor, hepatocyte growth factor and insulin-like growth factor are expressed in gastroenteropancreatic neuroendocrine tumours (GEP/NET). Polypeptide growth factors have great significance in the growth, progression and development of metastases by various tumours. We describe the role of growth factors in GEP/NET on the basis of the available reports of medical research.     

Clinical and prognostic implications of the genetic diagnosis of hereditary NET syndromes in asymptomatic patients

Neuroendocrine tumors (NETs) can be sporadic or they can arise in complex hereditary syndromes. Patients with hereditary NETs can be identified before the development of tumors by performing genetic screenings. The aim of the study was to evaluate the clinical and prognostic impact of a preclinical genetic screening in subjects with hereditary NET syndromes. 46 subjects referred for hereditary NET syndrome [22 MEN1, 12 MEN2, 12 Familial Paragangliomatosis (FPGL)] were enrolled and divided in 2 groups (group A, 20 subjects with clinical appearance of NET before the genetic diagnosis; group B, 26 subjects with genetic diagnosis of hereditary NET syndromes before the clinical appearance of NETs). The main outcome measures were severity of disease, prognosis, and survival. The rate of surgery for MEN1-, MEN2-, FPGL4-related tumors was 90% in group A and 35% in group B (p<0.01). Both symptoms related to tumors and symptoms related to therapies were significantly less frequent in group B than in group A (p<0.05). Tumor stage was locally advanced or metastatic in 50% of group A and in no one of group B (p<0.01). The mortality rate was 25% in group A and 0% in group B (p<0.05). An early genetic screening for hereditary NET syndromes results in an improvement in clinical presentation and morbidity. A potential impact of the genetic screening on the mortality rate of these subjects is suggested and needs to be investigated in further and more appropriate studies.     

Médicaments radiopharmaceutiques : du diagnostic au théranostique des tumeurs neuroendocrines

Neuroendocrine tumors (NET) are a heterogeneous group originating from endocrine cells, which have the ability to develop themselves on various organs. Most of NET are well differentiated and have the capacity to produce different hormones and biogenic amines. NETs usually appear sporadically and can also be associated with different syndromes (multiple endocrine neoplasia). For the majority of NETs, surgical resection is the treatment of choice requiring the precise location of the tumor before surgery as well as the determination of the stage, followed by monitoring the progression of the disease. In the diagnostic process, nuclear medicine with molecular imaging plays a fundamental role. The secretory functions of these tumors enable the use of molecular imaging by targeting specific metabolic pathways or receptors. In addition, nuclear medicine also plays an important role in the field of therapy by replacing in one radiopharmaceutical drugs, the imaging suited radionuclide by replacing with a radionuclide emitting radiation suitable for therapy, also called vectorized internal radiotherapy. The activity of nuclear medicine, which enables diagnosis and treatment to be carried out using the same structures specific to the molecular targets of neuroendocrine tumors, is fully integrated into the new theragnostic approach, and constitutes one of its main pillars. The objective of this work is to describe the molecular targets expressed by NETs and corresponding radiopharmaceuticals, validated for human use (diagnosis and therapy).     

A Highly Efficient Gene Expression Programming (GEP) Model for Auxiliary Diagnosis of Small Cell Lung Cancer

Background

Lung cancer is an important and common cancer that constitutes a major public health problem, but early detection of small cell lung cancer can significantly improve the survival rate of cancer patients. A number of serum biomarkers have been used in the diagnosis of lung cancers; however, they exhibit low sensitivity and specificity.

Methods

We used biochemical methods to measure blood levels of lactate dehydrogenase (LDH), C-reactive protein (CRP), Na⁺, Cl^-, carcino-embryonic antigen (CEA), and neuron specific enolase (NSE) in 145 small cell lung cancer (SCLC) patients and 155 non-small cell lung cancer and 155 normal controls. A gene expression programming (GEP) model and Receiver Operating Characteristic (ROC) curves incorporating these biomarkers was developed for the auxiliary diagnosis of SCLC.

Results

After appropriate modification of the parameters, the GEP model was initially set up based on a training set of 115 SCLC patients and 125 normal controls for GEP model generation. Then the GEP was applied to the remaining 60 subjects (the test set) for model validation. GEP successfully discriminated 281 out of 300 cases, showing a correct classification rate for lung cancer patients of 93.75% (225/240) and 93.33% (56/60) for the training and test sets, respectively. Another GEP model incorporating four biomarkers, including CEA, NSE, LDH, and CRP, exhibited slightly lower detection sensitivity than the GEP model, including six biomarkers. We repeat the models on artificial neural network (ANN), and our results showed that the accuracy of GEP models were higher than that in ANN. GEP model incorporating six serum biomarkers performed by NSCLC patients and normal controls showed low accuracy than SCLC patients and was enough to prove that the GEP model is suitable for the SCLC patients.

Conclusion

We have developed a GEP model with high sensitivity and specificity for the auxiliary diagnosis of SCLC. This GEP model has the potential for the wide use for detection of SCLC in less developed regions.     

Neuroendocrine tumor in gastric adenoma: a diagnostic pitfall mimicking invasive adenocarcinoma

ABSTRACT: Neuroendocrine tumor (NET) in adenoma of the gastrointestinal tract is a rare mixed glandular-endocrine neoplasm and has uncommonly been described mostly in the colon. Histologically, this tumor is composed of a predominant proportion of benign adenomatous component and a small portion of well-differentiated NE component. Only three cases of NET in gastric adenoma have been reported in the literature. We present 4 cases of NET in gastric adenoma mimicking invasive adenocarcinoma. The NETs were 0.62 mm to 4.1 mm in size and located at the basal lamina propria, muscularis mucosa and submucosa. Histologically, NETs consisted of nests, cords, tubules, and clusters of cells that predominantly interposed between the foveolar base without disturbing the overall polyp architecture. The lesions were completely removed by endoscopic submucosal dissection in three cases and in one case, subtotal gastrectomy was performed because endoscopic biopsy was invasive adenocarcinoma. The patients' clinical course was uneventful without an evidence of recurrence or metastasis. The recognition of NET in gastric adenoma will help avoid potential diagnostic pitfalls masquerading as invasvie adenocarcinomas posed by their infiltrative pattern into submucosa.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1688552293761001.     

Oncogene Panel Sequencing Analysis Identifies Candidate Actionable Genes in Advanced Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors

Objective: To report the rate of candidate actionable somatic mutations in patients with locally advanced and metastatic gastro-enteropancreatic (GEP) neuroendocrine tumors (NET) and of other genetic alterations that may be associated with tumorigenesis.Methods: A phase II mutation targeted therapy trial was conducted in patients with advanced well-differentiated G1/G2 GEP-NET. Mutations found in the mTOR pathway-associated genes led to treatment with the mTOR inhibitor everolimus, and were defined as actionable. Tumor deoxyribonucleic acid (DNA) from GEP-NET were sequenced and compared with germline DNA, using the OncoVAR-NET assay, designed for hybrid capture sequencing of 500 tumor suppressor genes and oncogenes. Somatic variants were called and copy-number (CN) variant analysis was performed.Results: Thirty patients (14 small-intestine, 8 pancreatic, 3 unknown primary NET, and 5 of other primary sites) harbored 37 lesions (4 patients had DNA of multiple lesions sequenced). Only 2 patients with sporadic NET (n = 26) had an actionable mutation leading to treatment with everolimus. Driver somatic mutations were detected in 18 of 30 patients (21/37 lesions sequenced). In the remaining samples without a driver mutation, CN alterations were found in 11/16 tumors (10/12 patients), including CN loss of chromosome (Chr) 18 (P<.05), CN gain of Chr 5, and loss of Chr 13. CN losses in Chr 18 were more common in patients without driver mutations detected. Pronounced genetic heterogeneity was detected in patients with multiple lesions sequenced.Conclusion: Genome-wide DNA sequencing may identify candidate actionable genes and lead to the identification of novel target genes for advanced well-differentiated GEP-NET.Abbreviations: Chr = chromosome; CN = copy number; DNA = deoxyribonucleic acid; FDA = Food and Drug Administration; GEP = gastro-enteropancreatic; MEN-1 = multiple endocrine neoplasia syndrome type 1; mTOR = mammalian target of rapamycin; NET = neuroendocrine tumor; PFS = progression-free survival; PNET = pancreatic neuroendocrine tumors; SINET = small-intestine neuroendocrine tumor     

Pancreatic endocrine tumors - management guidelines (recommended by the Polish Network of Neuroendocrine Tumors)

Pancreatic endocrine tumors (PETs) are rare neoplasms of this organ. The majority of PETs are tumors without hormonal activity. In this publication, we present the diagnostic and therapeutic guidelines for the management of these tumors proposed by the Polish Network of Neuroendocrine Tumors. These guidelines refer to biochemical and location diagnostics, including scintygraphy of somatostatin receptors, endoscopic ultrasonography and other anatomical and functional imaging methods. High importance is attached to correct histopathological diagnosis which determines further management of patients with PETs. Antitumor therapy requires multidirectional procedure, and therefore the rules of surgical treatment, biotherapy, chemotherapy and peptide receptor radionuclide therapy are discussed.     

Whole body diffusion for metastatic disease assessment in neuroendocrine carcinomas: comparison with OctreoScan(R) in two cases

ABSTRACT: Neuroendocrine tumor (NET) patients must be adequately staged in order to improve a multidisciplinary approach and optimal management for metastatic disease. Currently available imaging studies include somatostatin receptor scintigraphy, like OctreoScan(R), computed tomography (CT), scans and magnetic resonance imaging (MRI), which analyze vascular concentration and intravenous contrast enhancement for anatomic tumor localization. However, these techniques require high degree of expertise for interpretation and are limited by their availability, cost, reproducibility, and follow-up imaging comparisons. NETs significantly reduce water diffusion as compared to normal tissue. Diffusion-weighted imaging (DWI) in MRI has an advantageous contrast difference: the tumor is represented with high signal over a black normal surrounding background. The whole-body diffusion (WBD) technique has been suggested to be a useful test for detecting metastasis from various anatomic sites. In this article we report the use of DWI in MRI and WBD in two cases of metastatic pulmonary NET staging in comparison with OctreoScan(R) in order to illustrate the potential advantage of DWI and WBD in staging NETs.     

降雨因素对生态系统生产总值核算结果的影响

目前生态系统生产总值(GEP)核算工作已在全国多地开展,并在不少地方已将其纳入政绩考核指标,但GEP核算中相关生态系统服务多基于实际降雨数据和多年平均降雨数据,导致在进行年际间GEP变化分析时,结果难以反应实际的生态系统质量和数量的变化,从而影响GEP管理应用的效果。本文以深圳为研究案例,提出了更能代表本地降雨一般化特征的可比降雨条件,以及基于主成分分析的确定方法,并且在可比降雨条件和实际降雨条件下核算了可比降雨年和临近年共3种情景下的生态系统生产总值(GEP),分析了不同情景下的GEP构成以及降雨因素对年际间GEP变化的影响能力。研究发现：(1)2019年为深圳可比降雨年,且符合2008—2020年间各年《深圳市气候公报》对降雨情况的阐述;(2)可比降雨条件下,与降雨相关的4项生态系统服务价值(减少泥沙淤积、减少面源污染、涵养水源、削减洪涝)呈年际间增长趋势,实际降雨条件下,减少泥沙淤积、减少面源污染价值增长,涵养水源、削减洪涝价值下降;(3)降雨因素显著影响GEP年际变化,不同降雨条件下,深圳2019—2020年GEP变化差异高达24.78亿元,而可比降雨条件可以有效减少非人为因素...     

面向生态效益评估的生态系统生产总值GEP核算研究——以青海省为例

开展生态效益评估,对于推动生态效益纳入经济社会评价体系、推进生态文明建设具有重要意义。生态效益是指自然界的生态系统对人类的生产、生活条件和环境条件产生的有益影响和有利效果。GEP(Gross Ecosystem Product)是生态系统生产总值,指一定区域在一定时间内,生态系统为人类提供最终产品与服务的经济价值总和,是一定区域生态系统为人类福祉贡献的总货币价值,可以反映一个地区的生态效益。本研究提出面向生态效益评估的GEP核算框架,建立核算指标体系和技术方法,基于遥感数据和统计数据以青海省为例开展面向生态效益评估的GEP核算研究,并对相关利益者进行分析。研究结果表明,2015年青海省生态系统生产总值GEP为464.16亿元,对生态资产产生的生态效益进行相关利益者分析,80%以上生态效益的受益者是青海省以外的区域。以可比价计算,自2000年以来青海省GEP增加32.6%。根据现有的数据体系和方法核算的GEP是有现实意义的,可以作为生态效益评估的指标,可以作为GDP的重要补充对政策效益和生态保护成效开展评估,还可以作为市场化、多元化生态补偿机制建立和“绿水青山”向“金山银山”转化的依据和参考,为决策者提供重要的信息。     

生态系统生产总值的内涵、核算框架与实施条件——统计视角下的设计与论证

基于已有研究和中国当前实践,对GEP的内涵和核算框架进行理论论证,以期为GEP的后续应用开发提供基本规范。(1)辨析当前GEP已有定义,提出了经过优化的GEP定义:特定时期内一区域生态系统为经济生产和人类其他活动提供的最终产出价值,具体包括生态供应品、生态调节服务和生态文化服务三个组成部分。(2)确定GEP在以下两个方面的应用价值:辅助GDP评价区域发展业绩;为区域生态补偿提供标准。(3)参照国内生产总值(GDP)核算原理,设计出一套生态系统供应品和服务供给表和使用表,在此基础上生成了规范的GEP核算表和核算方法。(4)将框架设计落实到GEP核算实施层面,提出了后续需要考虑的相关分类体系、关键节点、实物和价值核算方法设计等重要问题及解决思路。     

Performance assessment of kernel density clustering for gene expression profile data

Kernel density smoothing techniques have been used in classification or supervised learning of gene expression profile (GEP) data, but their applications to clustering or unsupervised learning of those data have not been explored and assessed. Here we report a kernel density clustering method for analysing GEP data and compare its performance with the three most widely-used clustering methods: hierarchical clustering, K-means clustering, and multivariate mixture model-based clustering. Using several methods to measure agreement, between-cluster isolation, and withincluster coherence, such as the Adjusted Rand Index, the Pseudo F test, the r(2) test, and the profile plot, we have assessed the effectiveness of kernel density clustering for recovering clusters, and its robustness against noise on clustering both simulated and real GEP data. Our results show that the kernel density clustering method has excellent performance in recovering clusters from simulated data and in grouping large real expression profile data sets into compact and well-isolated clusters, and that it is the most robust clustering method for analysing noisy expression profile data compared to the other three methods assessed.     

Improving general flexibility with a mind-body approach: a randomized, controlled trial using neuro emotional Technique®

General flexibility is a key component of health, well-being, and general physical conditioning. Reduced flexibility has both physical and mental/emotional etiologies and can lead to musculoskeletal injuries and athletic underperformance. Few studies have tested the effectiveness of a mind-body therapy on general flexibility. The aim of this study was to investigate if Neuro Emotional Technique? (NET), a mind-body technique shown to be effective in reducing stress, can also improve general flexibility. The sit-and-reach test (SR) score was used as a measure of general flexibility. Forty-five healthy participants were recruited from the general population and assessed for their initial SR score before being randomly allocated to receive (a) two 20-minute sessions of NET (experimental group); (b) two 20-minute sessions of stretching instruction (active control group); or (c) no intervention or instruction (passive control group). After intervention, the participants were reassessed in a similar manner by the same blind assessor. The participants also answered questions about demographics, usual water and caffeine consumption, and activity level, and they completed an anxiety/mood psychometric preintervention and postintervention. The mean (SD) change in the SR score was +3.1 cm (2.5) in the NET group, +1.2 cm (2.3) in the active control group and +1.0 cm (2.6) in the passive control group. Although all the 3 groups showed some improvement, the improvement in the NET group was statistically significant when compared with that of either the passive controls (p = 0.015) or the active controls (p = 0.021). This study suggests that NET could provide an effective treatment in improving general flexibility. A larger study is required to confirm these findings and also to assess longer term effectiveness of this therapy on general flexibility.